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Diabetes mellitus type 1

From Wikipedia, the free encyclopedia

Diabetes type 1

A blue circle, the symbol for diabetes.[1]


Classification and external resources
Specialty
Endocrinology
ICD-10
E10
ICD-9-CM
250.01
OMIM
222100
DiseasesDB
3649
MedlinePlus
000305
eMedicine
med/546
MeSH
D003922

Diabetes mellitus type 1 (also known as type 1 diabetes, or T1D; formerly insulin-dependent diabetes or juvenile diabetes) is a form of
diabetes mellitus that results from the autoimmune destruction of the insulin-producing beta cells in the pancreas.[2] The subsequent lack of
insulin leads to increased blood and urine glucose. The classical symptoms are polyuria (frequent urination), polydipsia (increased thirst),
polyphagia (increased hunger) and weight loss.[3]
The cause of diabetes mellitus type 1 is unknown.[4] Type 1 diabetes can be distinguished from type 2 by autoantibody testing. The C-peptide
assay, which measures endogenous insulin production, can also be used.
Administration of insulin is essential for survival. Insulin therapy must be continued indefinitely and typically does not impair normal daily
activities. People are usually trained to independently manage their diabetes; however, for some this can be challenging. Untreated, diabetes can
cause many complications.[4] Acute complications include diabetic ketoacidosis and nonketotic hyperosmolar coma. Serious long-term
complications include heart disease, stroke, kidney failure, foot ulcers and damage to the eyes.[4] Furthermore, complications may arise from low
blood sugar caused by excessive insulin treatment.
Diabetes mellitus type 1 accounts for between 5% and 10% of all diabetes cases.[5][6] Globally, the number of people with DM type 1 is unknown,
[7]
although it is estimated that about 80,000 children develop the disease each year.[7] Within the United States the number of affected persons is
estimated at one to three million.[7][8] The development of new cases vary by country and region; the lowest rates appear to be in Japan and China
with approximately 1 person per 100,000 per year; the highest rates are found in Scandinavia where it is closer to 35 new cases per 100,000 per
year.[9] The United States and other countries in northern Europe fall somewhere in between with 8-17 new cases per 100,000 per year.[9]

Contents

1 Signs and symptoms


2 Cause
o

2.1 Genetics

2.2 Environmental

3 Pathophysiology

4 Diagnosis
o

4.1 Autoantibodies

5 Prevention
o

5.1 Immunosuppressive drugs

5.2 Diet

6 Management
o

6.1 Lifestyle

6.2 Insulin

6.3 Pancreas transplantation

6.4 Islet cell transplantation

7 Complications
o

7.1 Urinary tract infection

7.2 Sexual dysfunction

8 Epidemiology

9 History

10 Society and culture

11 Research

11.1 Stem cells

11.2 Vaccine

12 Labile diabetes

13 References

14 External links

Signs and symptoms

Overview of the most significant symptoms of diabetes


The classical symptoms of type 1 diabetes include: polyuria (excessive urination), polydipsia (increased thirst), xerostomia (dry mouth),
polyphagia (increased hunger), fatigue, and weight loss.[3]

Many type 1 diabetics are diagnosed when they present with diabetic ketoacidosis. The signs and symptoms of diabetic ketoacidosis include
xeroderma (dry skin), rapid deep breathing, drowsiness, abdominal pain, and vomiting.[10]
About 12 percent of people with type 1 diabetes have clinical depression.[11]

Cause
The cause of type 1 diabetes is unknown.[4] A number of explanatory theories have been put forward, and the cause may be one or more of the
following: genetic susceptibility, a diabetogenic trigger, and/or exposure to an antigen.[12]

Genetics
Main article: Genetic causes of diabetes mellitus type 1
Type 1 diabetes is a disease that involves many genes. More than 50 genes are associated to type 1 diabetes.[13] Depending on locus or
combination of loci, they can be dominant, recessive, or somewhere in between. The strongest gene, IDDM1, is located in the MHC Class II
region on chromosome 6, at staining region 6p21. Certain variants of this gene increase the risk for decreased histocompatibility characteristic of
type 1. Such variants include DRB1 0401, DRB1 0402, DRB1 0405, DQA 0301, DQB1 0302 and DQB1 0201, which are common in North
Americans of European ancestry and in Europeans.[14] Some variants also appear to be protective.[14]
The risk of a child developing type 1 diabetes is about 10% if the father has it, about 10% if a sibling has it, about 4% if the mother has type 1
diabetes and was aged 25 or younger when the child was born, and about 1% if the mother was over 25 years old when the child was born.[15]

Environmental
Environmental factors can influence expression of type 1. For identical twins, when one twin has type 1 diabetes, the other twin only has it 30%
50% of the time. Thus for 50%-70% of identical twins where one has the disease, the other will not, despite having exactly the same genome;
this suggests environmental factors, in addition to genetic factors, can influence the disease's prevalence.[16] Other indications of environmental

influence include the presence of a 10-fold difference in occurrence among Caucasians living in different areas of Europe, and that people tend
to acquire the rate of disease of their particular destination country.[12]
Virus
One theory proposes that type 1 diabetes is a virus-triggered autoimmune response in which the immune system attacks virus-infected cells
along with the beta cells in the pancreas.[17] The Coxsackie virus family or rubella is implicated, although the evidence is inconclusive. This
vulnerability is not shared by everyone, for not everyone infected by the suspected virus develops type 1 diabetes. This has suggested presence
of a genetic vulnerability[18] and there is indeed an observed inherited tendency to develop type 1. It has been traced to particular HLA genotypes,
though the connection between them and the triggering of an autoimmune reaction remains poorly understood.
Chemicals and drugs
Some chemicals and drugs selectively destroy pancreatic cells. Pyrinuron (Vacor), a rodenticide introduced in the United States in 1976,
selectively destroys pancreatic beta cells, resulting in type 1 after ingestion. Pyrinuron was withdrawn from the U.S. market in 1979 but is still
used in some countries. Streptozotocin (Zanosar), an antibiotic and antineoplastic agent used in chemotherapy for pancreatic cancer, kills beta
cells, resulting in loss of insulin production.
Other pancreatic problems, including trauma, pancreatitis, or tumors (either malignant or benign) can also lead to loss of insulin production.

Pathophysiology
The pathophysiology in diabetes type 1 is a destruction of beta cells in the pancreas, regardless of which risk factors or causative entities have
been present.
Individual risk factors can have separate pathophysiological processes to, in turn, cause this beta cell destruction. Still, a process that appears to
be common to most risk factors is an autoimmune response towards beta cells, involving an expansion of autoreactive CD4+ T helper cells and
CD8+ T cells, autoantibody-producing B cells and activation of the innate immune system.[14][19]

After starting treatment with insulin a person's own insulin levels may temporarily improve. [20] This is believed to be due to altered immunity and
is known as the "honeymoon phase".[20]

Diagnosis
See also: Glycated hemoglobin and Glucose tolerance test
WHO diabetes diagnostic criteria[21][22] edit
Condition
2 hour glucose
Fasting glucose
HbA1c
Unit
mmol/l(mg/dl)
mmol/l(mg/dl)
mmol/mol DCCT %
Normal
<7.8 (<140)
<6.1 (<110)
<42
<6.0
Impaired fasting glycaemia
<7.8 (<140) 6.1(110) & <7.0(<126) 42-46
6.06.4
Impaired glucose tolerance
7.8 (140)
<7.0 (<126)
42-46
6.06.4
Diabetes mellitus
11.1 (200)
7.0 (126)
48
6.5
Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any one of the following:[23]

Fasting plasma glucose level at or above 7.0 mmol/L (126 mg/dL).


Plasma glucose at or above 11.1 mmol/L (200 mg/dL) two hours after a 75 g oral glucose load as in a glucose tolerance test.

Symptoms of hyperglycemia and casual plasma glucose at or above 11.1 mmol/L (200 mg/dL).

Glycated hemoglobin (hemoglobin A1C) at or above 48 mmol/mol ( 6.5 DCCT %). (This criterion was recommended by the American
Diabetes Association in 2010, although it has yet to be adopted by the WHO.)[24]

About a quarter of people with new type 1 diabetes have developed some degree of diabetic ketoacidosis (a type of metabolic acidosis which is
caused by high concentrations of ketone bodies, formed by the breakdown of fatty acids and the deamination of amino acids) by the time the
diabetes is recognized. The diagnosis of other types of diabetes is usually made in other ways. These include ordinary health screening, detection
of hyperglycemia during other medical investigations, and secondary symptoms such as vision changes or unexplained fatigue. Diabetes is often

detected when a person suffers a problem that may be caused by diabetes, such as a heart attack, stroke, neuropathy, poor wound healing or a
foot ulcer, certain eye problems, certain fungal infections, or delivering a baby with macrosomia or hypoglycemia.
A positive result, in the absence of unequivocal hyperglycemia, should be confirmed by a repeat of any of the above-listed methods on a
different day. Most physicians prefer to measure a fasting glucose level because of the ease of measurement and the considerable time
commitment of formal glucose tolerance testing, which takes two hours to complete and offers no prognostic advantage over the fasting test.[25]
According to the current definition, two fasting glucose measurements above 126 mg/dL (7.0 mmol/L) is considered diagnostic for diabetes
mellitus.
In type 1, pancreatic beta cells in the islets of Langerhans are destroyed, decreasing endogenous insulin production. This distinguishes type 1's
origin from type 2. Type 2 diabetes is characterized by insulin resistance, while type 1 diabetes is characterized by insulin deficiency, generally
without insulin resistance. Another hallmark of type 1 diabetes is islet autoreactivity, which is generally measured by the presence of
autoantibodies directed towards the beta cells.

Autoantibodies
The appearance of diabetes-related autoantibodies has been shown to be able to predict the appearance of diabetes type 1 before any
hyperglycemia arises, the main ones being islet cell autoantibodies, insulin autoantibodies, autoantibodies targeting the 65-kDa isoform of
glutamic acid decarboxylase (GAD), autoantibodies targeting the phosphatase-related IA-2 molecule, and zinc transporter autoantibodies
(ZnT8).[12] By definition, the diagnosis of diabetes type 1 can be made first at the appearance of clinical symptoms and/or signs, but the
emergence of autoantibodies may itself be termed "latent autoimmune diabetes". Not everyone with autoantibodies progresses to diabetes type 1,
but the risk increases with the number of antibody types, with three to four antibody types giving a risk of progressing to diabetes type 1 of
60%100%.[12] The time interval from emergence of autoantibodies to clinically diagnosable diabetes can be a few months in infants and young
children, but in some people it may take years in some cases more than 10 years.[12] Islet cell autoantibodies are detected by conventional
immunofluorescence, while the rest are measured with specific radiobinding assays.[12]

Prevention

Type 1 diabetes is not currently preventable.[26] Some researchers believe it might be prevented at the latent autoimmune stage, before it starts
destroying beta cells.[14]

Immunosuppressive drugs
Cyclosporine A, an immunosuppressive agent, has apparently halted destruction of beta cells (on the basis of reduced insulin usage), but its
kidney toxicity and other side effects make it highly inappropriate for long-term use.[14]
Anti-CD3 antibodies, including teplizumab and otelixizumab, had suggested evidence of preserving insulin production (as evidenced by
sustained C-peptide production) in newly diagnosed type 1 diabetes patients.[14] A probable mechanism of this effect was believed to be
preservation of regulatory T cells that suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance
to self-antigens.[14] The duration of the effect is still unknown, however.[14] In 2011, Phase III studies with otelixizumab and teplizumab both
failed to show clinical efficacy, potentially due to an insufficient dosing schedule.[27][28]
An anti-CD20 antibody, rituximab, inhibits B cells and has been shown to provoke C-peptide responses three months after diagnosis of type 1
diabetes, but long-term effects of this have not been reported.[14]

Diet
Some research has suggested breastfeeding decreases the risk in later life;[29][30] various other nutritional risk factors are being studied, but no firm
evidence has been found.[31] Giving children 2000 IU of Vitamin D during their first year of life is associated with reduced risk of type 1
diabetes, though the causal relationship is obscure.[32]
Children with antibodies to beta cell proteins (i.e. at early stages of an immune reaction to them) but no overt diabetes, and treated with vitamin
B3 the niacinamide version, had less than half the diabetes onset incidence in a seven-year time span than did the general population, and an even
lower incidence relative to those with antibodies as above, but who received no niacinamide.[33]

Management

Further information: Diabetes management

Lifestyle
As psychological stress may have a negative effect on diabetes, a number of measures have been recommended including: exercising, taking up
a new hobby, or joining a charity among others.[34]

Insulin
Main article: Insulin therapy
There are four main types of insulin, rapid acting insulin, short acting insulin, intermediate acting insulin, and long acting insulin. The rapid
acting insulin is used as a bolus dosage. The action onsets in 15 minutes with peak actions in 30 to 90 minutes. Short acting insulin action onsets
within 30 minutes with the peak action around 2 to 4 hours. Intermediate acting insulin action onsets within 1 to 2 hours with peak action of 4 to
10 hours. Long acting insulin is usually given once per day. The action onset is roughly 1 to 2 hours with a sustained action of up to 24 hours.
Because of the insulin deficiency, injections of insulineither via subcutaneous injection or insulin pump is necessary for those living with
type 1 diabetes. It cannot be treated by diet and exercise alone. In addition to insulin therapy dietary management is important. This includes
keeping track of the carbohydrate content of food and careful monitoring of blood glucose levels using glucose meters. Today, the most common
insulins are biosynthetic products produced using genetic recombination techniques; formerly, cattle or pig insulins were used, and even
sometimes insulin from fish.[35] Major global suppliers include Eli Lilly and Company, Novo Nordisk, and Sanofi-Aventis. A more recent trend,
from several suppliers, is insulin analogs which are slightly modified insulins with different onset or duration of action times.
Untreated type 1 diabetes commonly leads to coma, often from diabetic ketoacidosis, which is fatal if untreated. Diabetic ketoacidosis can cause
cerebral edema (accumulation of liquid in the brain). This complication is life-threatening. Children are at an increased risk for cerebral edema,
making ketoacidosis the most common cause of death in pediatric diabetes.[36]
Treatment of diabetes focuses on lowering blood sugar or glucose (BG) to the near normal range, approximately 80140 mg/dl (4.4
7.8 mmol/L).[37] The ultimate goal of normalizing BG is to avoid long-term complications that affect the nervous system (e.g. peripheral

neuropathy leading to pain and/or loss of feeling in the extremities), and the cardiovascular system (e.g. heart attacks, vision loss). This level of
control over a prolonged period of time can be varied by a target HbA1c level of less than 7.5%.[7]
People with type 1 diabetes always need to use insulin, but treatment can lead to low BG (hypoglycemia), i.e. BG less than 70 mg/dl
(3.9 mmol/l). Hypoglycemia is a very common occurrence in people with diabetes, usually the result of a mismatch in the balance among
insulin, food and physical activity. Mild cases are self-treated by eating or drinking something high in sugar. Severe cases can lead to
unconsciousness and are treated with intravenous glucose or injections with glucagon. Continuous glucose monitors can alert patients to the
presence of dangerously high or low blood sugar levels, but technical issues have limited the effect these devices have had on clinical practice.
[citation needed]

Pancreas transplantation
Main article: Pancreas transplantation
In some cases, a pancreas transplant can restore proper glucose regulation. However, the surgery and accompanying immunosuppression
required may be more dangerous than continued insulin replacement therapy, so is generally only used with or some time after a kidney
transplant. One reason for this is that introducing a new kidney requires taking immunosuppressive drugs such as cyclosporine. Nevertheless,
this allows the introduction of a new pancreas to a person with diabetes without any additional immunosuppressive therapy. However, pancreas
transplants alone may be beneficial in people with extremely labile type 1 diabetes mellitus.[38]

Islet cell transplantation


Main article: Islet cell transplantation
Islet cell transplantation may be an option for some people with type 1 diabetes that are not well controlled with insulin.[39] Difficulties include
finding donors that are a compatible, getting the new islets to survive, and the side effects from the medications used to prevent rejection. [39]
Success rates, defined as not needing insulin at 3 years follow the procedure occurred in 44% in on registry from 2010.[39]

Complications

Further information: Complications of diabetes mellitus


Complications of poorly managed type 1 diabetes mellitus may include cardiovascular disease, diabetic neuropathy, and diabetic retinopathy,
among others. However, cardiovascular disease[40] as well as neuropathy[41] may have an autoimmune basis, as well. Women with type 1 DM
have a 40% higher risk of death as compared to men with type 1 DM.[42]

Urinary tract infection


People with diabetes show an increased rate of urinary tract infection.[43] The reason is bladder dysfunction that is more common in diabetics
than in non-diabetics due to diabetic nephropathy. When present, nephropathy can cause a decrease in bladder sensation, which in turn, can cause
increased residual urine, a risk factor for urinary tract infections.[44]

Sexual dysfunction
Sexual dysfunction in diabetics is often a result of physical factors such as nerve damage and/or poor circulation, and psychological factors such
as stress and/or depression caused by the demands of the disease.[45][46]
Males
The most common sexual issues in diabetic males are problems with erections and ejaculation: "With diabetes, blood vessels supplying the
peniss erectile tissue can get hard and narrow, preventing the adequate blood supply needed for a firm erection. The nerve damage caused by
poor blood glucose control can also cause ejaculate to go into the bladder instead of through the penis during ejaculation, called retrograde
ejaculation. When this happens, semen leaves the body in the urine."[45] Another cause for erectile dysfunction are the reactive oxygen species
created as a result of the disease. Antioxidants can be used to help combat this.[47]
Females
While there is less material on the correlation between diabetes and female sexual dysfunction than male sexual dysfunction, studies have shown
there to be a significant prevalence of sexual problems in diabetic women.[46] Common problems include reduced sensation in the genitals,

dryness, difficulty/inability to orgasm, pain during sex, and decreased libido.[45] In some cases diabetes has been shown to decrease oestrogen
levels in females, which can affect vaginal lubrication.[46]
Oral contraceptives can be taken by diabetics. Sometimes, contraceptive pills can cause a blood sugar imbalance, but this usually can be
corrected by a dosage change.[46] As with any medication, side effects should be taken into account and monitored to prevent serious
complications with diabetes.[46]

Epidemiology
Type 1 diabetes causes an estimated 510% of all diabetes cases[48] or 1122 million worldwide.[26] In 2006 it affected 440,000 children under 14
years of age and was the primary cause of diabetes in those less than 10 years of age.[49] The incidence of type 1 diabetes has been increasing by
about 3% per year.[49]
Rates vary widely by country. In Finland, the incidence is a high of 57 per 100,000 per year, in Japan and China a low of 1 to 3 per 100,000 per
year, and in Northern Europe and the U.S., an intermediate of 8 to 17 per 100,000 per year.[9][50]
In the United States, type 1 diabetes affected about 208,000 youths under the age of 20 in 2015. Over 18,000 youths are diagnosed with Type 1
diabetes every year. Compared to non-Hispanic whites, Asian Americans, Hispanic Americans and Hispanic-Black Americans have greater odds
of being diagnosed with diabetes. Every year about 234,051 Americans die due to diabetes or diabetes-related complications, with 69,071 having
it as the primary cause of death.[51]

History
Type 1 diabetes was described as an autoimmune disease in the 1970s, based on observations that autoantibodies against islets were discovered
in diabetics with other autoimmune deficiencies.[52] It was also shown in the 1980s that immunosuppressive therapies could slow disease
progression, further supporting the idea that type 1 diabetes is an autoimmune disorder.[53] The name juvenile diabetes was used earlier as it often
first is diagnosed in childhood.

Society and culture


See also: List of people with diabetes mellitus type 1
The disease was estimated to cause $10.5 billion in annual medical costs ($875 per month per diabetic) and an additional $4.4 billion in indirect
costs ($366 per month per person with diabetes) in the U.S.[54] In the United States $245 billion every year is attributed to diabetes. Individuals
diagnosed with diabetes have 2.3 times the health care costs than individuals who do not have diabetes. 1 in 10 health care dollars are spent on
individuals with diabetes.[51]

Research
Funding for research into type 1 diabetes originates from government, industry (e.g., pharmaceutical companies), and charitable organizations.
Government funding in the United States is distributed via the National Institute of Health, and in the UK via the National Institute for Health
Research or the Medical Research Council. JDRF, originally founded by parents of children with type 1 diabetes, is the world's largest provider
of charity based funding for type 1 diabetes research. Other charities include the American Diabetes Association, Diabetes UK, Diabetes
Research and Wellness Foundation,[55] Diabetes Australia, the Canadian Diabetes Association.

Stem cells
Pluripotent stem cells can be used to generate beta cells but previously these cells did not function as well as normal beta cells.[56] In 2014 more
mature beta cells were produced which released insulin in response to blood sugar when transplanted into mice.[57][58] Before these techniques can
be used in humans more evidence of safety and effectiveness is needed.[56]

Vaccine
Vaccines to treat or prevent Type 1 diabetes are designed to induce immune tolerance to insulin or pancreatic beta cells.[59] While Phase II clinical
trials of a vaccine containing alum and recombinant GAD65, an autoantigen involved in type 1 diabetes, were promising, as of 2014 Phase III

had failed.[59] As of 2014, other approaches, such as a DNA vaccine encoding proinsulin and a peptide fragment of insulin, were in early clinical
development.[59]

Labile diabetes
Insulin-dependent diabetes characterized by dramatic and recurrent swings in glucose levels, often occurring for no apparent reason, is
sometimes known as brittle diabetes, unstable diabetes or labile diabetes, although some experts say the "brittle diabetes" concept "has no
biologic basis and should not be used".[60] The results of such swings can be irregular and unpredictable hyperglycemias, sometimes involving
ketoacidosis, and sometimes serious hypoglycemias. Brittle diabetes occurs no more frequently than in 1% to 2% of diabetics.[61] An insulin
pump may be recommended for brittle diabetes to reduce the number of hypoglycemic episodes and better control the morning rise of blood
sugar due to the dawn phenomenon.[62] In a small study, 10 of 20 brittle diabetic patients aged 1823 years who could be traced had died within
22 years, and the remainder, though suffering high rates of complications, were no longer brittle.[63] These results were similar to those of an
earlier study by the same authors which found a 19% mortality in 26 patients after 10.5 years.[64]
Because labile diabetes is defined as "episodes of hypoglycemia or hyperglycemia that, whatever their cause, constantly disrupt a patient's life",
it can have many causes, some of which include:[65]

errors in diabetes management, which can include too much insulin being given, in ratio, to carbohydrate being consumed
interactions with other medical conditions

psychological problems

biological factors that interfere with how insulin is processed within the body

hypoglycemia and hyperglycemia due to strenuous exercise; however, hypoglycemia is more frequent

insulin exposed to higher temperatures that reduces effectiveness of the insulin hormone in the body

spontaneous production of insulin in the body due to activity in the beta cells during the period shortly after diagnosis of type 1 diabetes

Exercise related hyperglycemia is caused when hormones (such as adrenaline and cortisol) are released during moderate to strenuous exercise.
This happens when the muscles signal the liver to release glucose into the bloodstream by converting stored glycogen into glucose. The cause of
exercise related hypoglycemia, on the other hand, occurs when the muscle group being exercised uses up glucose faster than it can be
replenished by the body.
One of these biological factors is the production of insulin autoantibodies. High antibody titers can cause episodes of hyperglycemia by
neutralizing the insulin, cause clinical insulin resistance requiring doses of over 200 IU/day. However, antibodies may also fail to buffer the
release of the injected insulin into the bloodstream after subcutaneous injection, resulting in episodes of hypoglycemia. In some cases, changing
the type of insulin administered can resolve this problem.[65] There have been a number of reports that insulin autoantibodies can act as a "sink"
for insulin and affect the time to peak, half-life, distribution space, and metabolic clearance, though in most patients these effects are small. [66]

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"Stress". www.diabetes.org. American Diabetes Association. Retrieved 11 November 2014.
Wright JR (2002). "From ugly fish to conquer death: J J R Macleod's fish insulin research, 1922-24". Lancet 359 (9313): 123842.
doi:10.1016/S0140-6736(02)08222-3. PMID 11955558.
Rosenbloom AL, Hanas R (1996). "Diabetic ketoacidosis (DKA): treatment guidelines" (PDF). Clin Pediatr (Phila) 35 (5): 2616.
doi:10.1177/000992289603500506. PMID 8804545.
American Diabetes Association Clinical Guidelines, 2010.
Jennifer L. Larsen. "Pancreas Transplantation: Indications and Consequences". Edrv.endojournals.org. Retrieved 29 November 2011.
Bruni, A; Gala-Lopez, B; Pepper, AR; Abualhassan, NS; Shapiro, AJ (2014). "Islet cell transplantation for the treatment of type 1
diabetes: recent advances and future challenges.". Diabetes, metabolic syndrome and obesity : targets and therapy 7: 21123.
doi:10.2147/DMSO.S50789. PMID 25018643.
Devaraj S, Glaser N, Griffen S, Wang-Polagruto J, Miguelino E, Jialal I (March 2006). "Increased monocytic activity and biomarkers of
inflammation in patients with type 1 diabetes". Diabetes 55 (3): 7749. doi:10.2337/diabetes.55.03.06.db05-1417. PMID 16505242.
Granberg V, Ejskjaer N, Peakman M, Sundkvist G (2005). "Autoantibodies to autonomic nerves associated with cardiac and peripheral
autonomic neuropathy". Diabetes Care 28 (8): 195964. doi:10.2337/diacare.28.8.1959. PMID 16043739.

Huxley, Rachel R; Peters, Sanne A E; Mishra, Gita D; Woodward, Mark (February 2015). "Risk of all-cause mortality and vascular
events in women versus men with type 1 diabetes: a systematic review and meta-analysis". The Lancet Diabetes & Endocrinology.
doi:10.1016/S2213-8587(14)70248-7.
Chen, Hsin-Chui; Su, Li-Ting; Linn, Shin-Zong; Sung, Fung-Chang; Ko, Ming-Chung; Li, Chung-Yi (January 2012). "Increased Risk of
Urinary Tract Calculi Among Patients With Diabetes MellitusA Population-Based Cohort Study". Urology 79 (1): 86.
doi:10.1016/j.urology.2011.07.1431. Retrieved 28 November 2014.
James, R; Hijaz, A (October 2014). "Lower urinary tract symptoms in women with diabetes mellitus: a current review.". Current urology
reports 15 (10): 440. doi:10.1007/s11934-014-0440-3. PMID 25118849.
McCoy, Krisha. "Sexual Issues and Type 1 Diabetes". everyday Health. Everyday Health Media, LLC. Retrieved 28 November 2014.
"Sexual Dysfunction in Women". Diabetes.co.uk. Diabetes Digital Media Ltd. Retrieved 28 November 2014.
Goswami, Sumanta; Vishwanath, Manikanta; Gangadarappa, Suma; Razdan, Rema; Inamdar, Mohammed (JulSep 2014). "Efficacy of
ellagic acid and sildenafil in diabetes-induced sexual dysfunction". Pharmacognosy Magazine 10 (39): 581. doi:10.4103/0973-1296.139790.
Retrieved 30 November 2014.
Daneman D (11 March 2006). "Type 1 diabetes". Lancet 367 (9513): 84758. doi:10.1016/S0140-6736(06)68341-4. PMID 16530579.
Aanstoot HJ, Anderson BJ, Daneman D, Danne T, Donaghue K, Kaufman F, Ra RR, Uchigata Y (October 2007). "The global burden of
youth diabetes: perspectives and potential". Pediatric diabetes. 8. Suppl 8 (s8): 144. doi:10.1111/j.1399-5448.2007.00326.x. PMID 17767619.
Soltesz G, Patterson CC, Dahlquist G (October 2007). "Worldwide childhood type 1 diabetes incidencewhat can we learn from
epidemiology?". Pediatric diabetes. 8. Suppl 6 (s6): 614. doi:10.1111/j.1399-5448.2007.00280.x. PMID 17727380.
"Fast Facts" (PDF). American Diabetes Association.
Bottazzo, GF; Florin-Christensen, A; Doniach, D (Nov 30, 1974). "Islet-cell antibodies in diabetes mellitus with autoimmune
polyendocrine deficiencies.". Lancet 2 (7892): 127983. doi:10.1016/s0140-6736(74)90140-8. PMID 4139522.
Herold, KC; Vignali, DA; Cooke, A; Bluestone, JA (Apr 2013). "Type 1 diabetes: translating mechanistic observations into effective
clinical outcomes.". Nature reviews. Immunology 13 (4): 24356. doi:10.1038/nri3422. PMID 23524461.
Johnson, Linda (18 November 2008). "Study: Cost of diabetes $218B". USA Today. Associated Press.
Diabetes Research and Wellness Foundation
Minami, K; Seino, S (18 March 2013). "Current status of regeneration of pancreatic -cells.". Journal of diabetes investigation 4 (2):
13141. doi:10.1111/jdi.12062. PMID 24843642.
Pagliuca, FW; Millman, JR; Grtler, M; Segel, M; Van Dervort, A; Ryu, JH; Peterson, QP; Greiner, D; Melton, DA (9 October 2014).
"Generation of functional human pancreatic cells in vitro.". Cell 159 (2): 42839. doi:10.1016/j.cell.2014.09.040. PMID 25303535.

Rezania, A; Bruin, JE; Arora, P; Rubin, A; Batushansky, I; Asadi, A; O'Dwyer, S; Quiskamp, N; Mojibian, M; Albrecht, T; Yang, YH;
Johnson, JD; Kieffer, TJ (November 2014). "Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem
cells.". Nature Biotechnology 32 (11): 112133. doi:10.1038/nbt.3033. PMID 25211370.
Lernmark A, Larsson HE. Immune therapy in type 1 diabetes mellitus. Nat Rev Endocrinol. 2013 Feb;9(2):92-103. Review PMID
23296174
"Diabetes Mellitus (DM): Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Merck Manual Professional". Merck.com.
Retrieved 30 July 2010.
Dorner M, Pinget M, Brogard JM (May 1977). "[Essential labile diabetes (author's transl)]". MMW Munch Med Wochenschr 119 (19):
6714. PMID 406527.
Higuchi, Chigusa; Tone, Atsuhito; Iseda, Izumi; Tsukamoto, Keiko; Katayama, Akihiro (2010). "A Pregnant Patient with Brittle Type 1
Diabetes Successfully Managed by CSII Therapy with Insulin Aspart". Journal of Diabetes & Metabolism 01. doi:10.4172/2155-6156.1000104.
Cartwright A, Wallymahmed M, Macfarlane IA, Wallymahmed A, Williams G, Gill GV (2011). "The outcome of brittle type 1 diabetes--a
20 year study". QJM 104 (7): 5759. doi:10.1093/qjmed/hcr010. PMID 21285231.
Kent LA, Gill GV, Williams G (September 1994). "Mortality and outcome of patients with brittle diabetes and recurrent ketoacidosis".
Lancet 344 (8925): 77881. doi:10.1016/S0140-6736(94)92340-X. PMID 7916072.
Davidson MB, Kumar D, Smith W (1991). "Successful treatment of unusual case of brittle diabetes with sulfated beef insulin". Diabetes
Care 14 (11): 110910. doi:10.2337/diacare.14.1.1109b. PMID 1797500.
1.
Fineberg SE, Kawabata TT, Finco-Kent D, Fountaine RJ, Finch GL, Krasner AS (2007). "Immunological Responses to
Exogenous Insulin". Endocrine Reviews 28 (6): 62552. doi:10.1210/er.2007-0002. PMID 17785428.

External links

Diabetes mellitus type 1 at DMOZ


Kids and Teens: Type 1 Diabetes at DMOZ

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Diabetes in America Textbook (PDFs)

IDF Diabetes Atlas

International Diabetes Federation

type 1 Diabetes at the American Diabetes Association

National Diabetes Information Clearinghouse


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1. Basic Pathology - Robbins et al - 9th edition

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Diabetes mellitus type 2


From Wikipedia, the free encyclopedia

Diabetes mellitus type 2

Universal blue circle symbol for diabetes[1]


Classification and external resources
Specialty
Endocrinology
ICD-10
E11
ICD-9-CM
250.00, 250.02
OMIM
125853
DiseasesDB
3661

MedlinePlus
eMedicine
MeSH

000313
article/117853
D003924

Diabetes mellitus type 2 (formerly noninsulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes) is a metabolic disorder that is
characterized by hyperglycemia (high blood sugar) in the context of insulin resistance and relative lack of insulin.[2] This is in contrast to diabetes
mellitus type 1, in which there is an absolute lack of insulin due to breakdown of islet cells in the pancreas.[3] The classic symptoms are excess
thirst, frequent urination, and constant hunger. Type 2 diabetes makes up about 90% of cases of diabetes, with the other 10% due primarily to
diabetes mellitus type 1 and gestational diabetes. Obesity is thought to be the primary cause of type 2 diabetes in people who are genetically
predisposed to the disease (although this is not the case in people of East-Asian ancestry).
Type 2 diabetes is initially managed by increasing exercise and dietary changes. If blood sugar levels are not adequately lowered by these
measures, medications such as metformin or insulin may be needed. In those on insulin, there is typically the requirement to routinely check
blood sugar levels.
Rates of type 2 diabetes have increased markedly since 1960 in parallel with obesity. As of 2010 there were approximately 285 million people
diagnosed with the disease compared to around 30 million in 1985.[4][5] Type 2 diabetes is typically a chronic disease associated with a ten-yearshorter life expectancy.[4] Long-term complications from high blood sugar can include heart disease, strokes, diabetic retinopathy where eyesight
is affected, kidney failure which may require dialysis, and poor blood flow in the limbs leading to amputations. The acute complication of
ketoacidosis, a feature of type 1 diabetes, is uncommon,[6] however hyperosmolar hyperglycemic state may occur.

Contents

1 Signs and symptoms


o 1.1 Complications

2 Cause
o

2.1 Lifestyle

2.2 Genetics

2.3 Medical conditions

3 Pathophysiology

4 Diagnosis

5 Screening

6 Prevention

7 Management
o

7.1 Lifestyle

7.2 Medications

7.3 Surgery

8 Epidemiology

9 History

10 References

11 External links

Signs and symptoms

Overview of the most significant symptoms of diabetes.


The classic symptoms of diabetes are polyuria (frequent urination), polydipsia (increased thirst), polyphagia (increased hunger), and weight loss.
[7]
Other symptoms that are commonly present at diagnosis include a history of blurred vision, itchiness, peripheral neuropathy, recurrent vaginal
infections, and fatigue.[3] Many people, however, have no symptoms during the first few years and are diagnosed on routine testing.[3] People
with type 2 diabetes mellitus may rarely present with hyperosmolar hyperglycemic state (a condition of very high blood sugar associated with a
decreased level of consciousness and low blood pressure).[3]

Complications
Main article: Complications of diabetes mellitus
Type 2 diabetes is typically a chronic disease associated with a ten-year-shorter life expectancy.[4] This is partly due to a number of complications
with which it is associated, including: two to four times the risk of cardiovascular disease, including ischemic heart disease and stroke; a 20-fold
increase in lower limb amputations, and increased rates of hospitalizations.[4] In the developed world, and increasingly elsewhere, type 2 diabetes
is the largest cause of nontraumatic blindness and kidney failure.[8] It has also been associated with an increased risk of cognitive dysfunction and
dementia through disease processes such as Alzheimer's disease and vascular dementia.[9] Other complications include acanthosis nigricans,
sexual dysfunction, and frequent infections.[7]

Cause
The development of type 2 diabetes is caused by a combination of lifestyle and genetic factors.[8][10] While some of these factors are under
personal control, such as diet and obesity, other factors are not, such as increasing age, female gender, and genetics.[4] A lack of sleep has been
linked to type 2 diabetes.[11] This is believed to act through its effect on metabolism.[11] The nutritional status of a mother during fetal
development may also play a role, with one proposed mechanism being that of altered DNA methylation.[12]

Lifestyle
Main article: Lifestyle causes of diabetes mellitus type 2
A number of lifestyle factors are known to be important to the development of type 2 diabetes, including obesity and being overweight (defined
by a body mass index of greater than 25), lack of physical activity, poor diet, stress, and urbanization.[4][13] Excess body fat is associated with
30% of cases in those of Chinese and Japanese descent, 60-80% of cases in those of European and African descent, and 100% of cases in Pima
Indians and Pacific Islanders.[3] Those who are not obese often have a high waisthip ratio.[3] Smoking also appears to increase the risk of type 2
diabetes mellitus.[14]

Dietary factors also influence the risk of developing type 2 diabetes. Consumption of sugar-sweetened drinks in excess is associated with an
increased risk.[15][16] The type of fats in the diet are also important, with saturated fats and trans fatty acids increasing the risk, and
polyunsaturated and monounsaturated fat decreasing the risk.[10] Eating lots of white rice appears to also play a role in increasing risk.[17] A lack
of exercise is believed to cause 7% of cases.[18] Persistent organic pollutants may also play a role.[19]

Genetics
Main article: Genetic causes of diabetes mellitus type 2
Most cases of diabetes involve many genes, with each being a small contributor to an increased probability of becoming a type 2 diabetic.[4] If
one identical twin has diabetes, the chance of the other developing diabetes within his lifetime is greater than 90%, while the rate for
nonidentical siblings is 2550%.[3] As of 2011, more than 36 genes had been found that contribute to the risk of type 2 diabetes.[20] All of these
genes together still only account for 10% of the total heritable component of the disease.[20] The TCF7L2 allele, for example, increases the risk of
developing diabetes by 1.5 times and is the greatest risk of the common genetic variants.[3] Most of the genes linked to diabetes are involved in
beta cell functions.[3]
There are a number of rare cases of diabetes that arise due to an abnormality in a single gene (known as monogenic forms of diabetes or "other
specific types of diabetes").[3][4] These include maturity onset diabetes of the young (MODY), Donohue syndrome, and Rabson-Mendenhall
syndrome, among others.[4] Maturity onset diabetes of the young constitute 15% of all cases of diabetes in young people.[21]

Medical conditions
There are a number of medications and other health problems that can predispose to diabetes.[22] Some of the medications include:
glucocorticoids, thiazides, beta blockers, atypical antipsychotics,[23] and statins.[24] Those who have previously had gestational diabetes are at a
higher risk of developing type 2 diabetes.[7] Other health problems that are associated include: acromegaly, Cushing's syndrome,
hyperthyroidism, pheochromocytoma, and certain cancers such as glucagonomas.[22] Testosterone deficiency is also associated with type 2
diabetes.[25][26]

Pathophysiology

Type 2 diabetes is due to insufficient insulin production from beta cells in the setting of insulin resistance.[3] Insulin resistance, which is the
inability of cells to respond adequately to normal levels of insulin, occurs primarily within the muscles, liver, and fat tissue.[27] In the liver,
insulin normally suppresses glucose release. However, in the setting of insulin resistance, the liver inappropriately releases glucose into the
blood.[4] The proportion of insulin resistance versus beta cell dysfunction differs among individuals, with some having primarily insulin
resistance and only a minor defect in insulin secretion and others with slight insulin resistance and primarily a lack of insulin secretion.[3]
Other potentially important mechanisms associated with type 2 diabetes and insulin resistance include: increased breakdown of lipids within fat
cells, resistance to and lack of incretin, high glucagon levels in the blood, increased retention of salt and water by the kidneys, and inappropriate
regulation of metabolism by the central nervous system.[4] However, not all people with insulin resistance develop diabetes, since an impairment
of insulin secretion by pancreatic beta cells is also required.[3]

Diagnosis
WHO diabetes diagnostic criteria[28][29] edit
Condition
2 hour glucose
Fasting glucose
HbA1c
Unit
mmol/l(mg/dl)
mmol/l(mg/dl)
mmol/mol DCCT %
Normal
<7.8 (<140)
<6.1 (<110)
<42
<6.0
Impaired fasting glycaemia
<7.8 (<140) 6.1(110) & <7.0(<126) 42-46
6.06.4
Impaired glucose tolerance
7.8 (140)
<7.0 (<126)
42-46
6.06.4
Diabetes mellitus
11.1 (200)
7.0 (126)
48
6.5
The World Health Organization definition of diabetes (both type 1 and type 2) is for a single raised glucose reading with symptoms, otherwise
raised values on two occasions, of either:[30]

fasting plasma glucose 7.0 mmol/l (126 mg/dl)

or
with a glucose tolerance test, two hours after the oral dose a plasma glucose 11.1 mmol/l (200 mg/dl)

A random blood sugar of greater than 11.1 mmol/l (200 mg/dL) in association with typical symptoms[7] or a glycated hemoglobin (HbA1c) of
48 mmol/mol ( 6.5 DCCT %) is another method of diagnosing diabetes.[4] In 2009 an International Expert Committee that included
representatives of the American Diabetes Association (ADA), the International Diabetes Federation (IDF), and the European Association for the
Study of Diabetes (EASD) recommended that a threshold of 48 mmol/mol ( 6.5 DCCT %) should be used to diagnose diabetes.[31] This
recommendation was adopted by the American Diabetes Association in 2010.[32] Positive tests should be repeated unless the person presents with
typical symptoms and blood sugars >11.1 mmol/l (>200 mg/dl).[31]
Threshold for diagnosis of diabetes is based on the relationship between results of glucose tolerance tests, fasting glucose or HbA1c and
complications such as retinal problems.[4] A fasting or random blood sugar is preferred over the glucose tolerance test, as they are more
convenient for people.[4] HbA1c has the advantages that fasting is not required and results are more stable but has the disadvantage that the test is
more costly than measurement of blood glucose.[33] It is estimated that 20% of people with diabetes in the United States do not realize that they
have the disease.[4]
Diabetes mellitus type 2 is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency.[2] This is in
contrast to diabetes mellitus type 1 in which there is an absolute insulin deficiency due to destruction of [islet cells in the pancreas and
gestational diabetes mellitus that is a new onset of high blood sugars associated with pregnancy.[3] Type 1 and type 2 diabetes can typically be
distinguished based on the presenting circumstances.[31] If the diagnosis is in doubt antibody testing may be useful to confirm type 1 diabetes and
C-peptide levels may be useful to confirm type 2 diabetes,[34] with C-peptide levels normal or high in type 2 diabetes, but low in type 1 diabetes.
[35]

Screening
No major organization recommends universal screening for diabetes as there is no evidence that such a program improve outcomes.[36][37]
Screening is recommended by the United States Preventive Services Task Force (USPSTF) in adults without symptoms whose blood pressure is
greater than 135/80 mmHg.[38] For those whose blood pressure is less, the evidence is insufficient to recommend for or against screening.[38]
There is no evidence that it changes the risk of death in this group of people.[39] They also recommend screening among those who are
overweight and between the ages of 40 and 70.[40]

The World Health Organization recommends testing those groups at high risk[36] and in 2014 the USPSTF is considering a similar
recommendation.[41] High-risk groups in the United States include: those over 45 years old; those with a first degree relative with diabetes; some
ethnic groups, including Hispanics, African-Americans, and Native-Americans; a history of gestational diabetes; polycystic ovary syndrome;
excess weight; and conditions associated with metabolic syndrome.[7] The American Diabetes Association recommends screening those who
have a BMI over 25 (in people of Asian descent screening is recommending for a BMI over 23.[42]

Prevention
Main article: Prevention of diabetes mellitus type 2
Onset of type 2 diabetes can be delayed or prevented through proper nutrition and regular exercise.[43][44] Intensive lifestyle measures may reduce
the risk by over half.[8][45] The benefit of exercise occurs regardless of the person's initial weight or subsequent weight loss.[46] Evidence for the
benefit of dietary changes alone, however, is limited,[47] with some evidence for a diet high in green leafy vegetables[48] and some for limiting the
intake of sugary drinks.[15] In those with impaired glucose tolerance, diet and exercise either alone or in combination with metformin or acarbose
may decrease the risk of developing diabetes.[8][49] Lifestyle interventions are more effective than metformin.[8] While low vitamin D levels are
associated with an increased risk of diabetes, correcting the levels by supplementing vitamin D3 does not improve that risk.[50]

Management
Further information: Diabetes management
Management of type 2 diabetes focuses on lifestyle interventions, lowering other cardiovascular risk factors, and maintaining blood glucose
levels in the normal range.[8] Self-monitoring of blood glucose for people with newly diagnosed type 2 diabetes may be used in combination with
education,[51] however the benefit of self monitoring in those not using multi-dose insulin is questionable.[8][52] In those who do not want to
measure blood levels, measuring urine levels may be done.[51] Managing other cardiovascular risk factors, such as hypertension, high cholesterol,
and microalbuminuria, improves a person's life expectancy.[8] Decreasing the systolic blood pressure to less than 140 mmHg is associated with a
lower risk of death and better outcomes.[53] Intensive blood pressure management (less than 130/80 mmHg) as opposed to standard blood
pressure management (less than 140/85100 mmHg) results in a slight decrease in stroke risk but no effect on overall risk of death.[54]

Intensive blood sugar lowering (HbA1c<6%) as opposed to standard blood sugar lowering (HbA1c of 77.9%) does not appear to change
mortality.[55][56] The goal of treatment is typically an HbA1c of around 7% or a fasting glucose of less than 7.2 mmol/L (130 mg/dL); however
these goals may be changed after professional clinical consultation, taking into account particular risks of hypoglycemia and life expectancy.[57]
[58]
It is recommended that all people with type 2 diabetes get regular ophthalmology examination.[3] Treating gum disease in those with diabetes
may result in a small improvement in blood sugar levels.[59]

Lifestyle
A proper diet and exercise are the foundations of diabetic care,[7] with a greater amount of exercise yielding better results.[60] Aerobic exercise
leads to a decrease in HbA1c and improved insulin sensitivity.[60] Resistance training is also useful and the combination of both types of exercise
may be most effective.[60] A diabetic diet that promotes weight loss is important.[61] While the best diet type to achieve this is controversial,[61] a
low glycemic index diet or low carbohydrate diet has been found to improve blood sugar control.[62][63] Culturally appropriate education may help
people with type 2 diabetes control their blood sugar levels, for up to six months at least.[64][needs update] If changes in lifestyle in those with mild
diabetes has not resulted in improved blood sugars within six weeks, medications should then be considered.[7] There is not enough evidence to
determine if lifestyle interventions affect mortality in those who already have DM2.[45]

Medications

Metformin 500mg tablets.


There are several classes of anti-diabetic medications available. Metformin is generally recommended as a first line treatment as there is some
evidence that it decreases mortality;[8] however, this conclusion is questioned.[65] Metformin should not be used in those with severe kidney or
liver problems.[7]
A second oral agent of another class or insulin may be added if metformin is not sufficient after three months.[57] Other classes of medications
include: sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and glucagon-like peptide-1 analog.[57] There is
no significant difference between these agents.[57] Rosiglitazone, a thiazolidinedione, has not been found to improve long-term outcomes even
though it improves blood sugar levels.[66] Additionally it is associated with increased rates of heart disease and death.[67] Angiotensin-converting
enzyme inhibitors (ACEIs) prevent kidney disease and improve outcomes in those with diabetes.[68][69] The similar medications angiotensin
receptor blockers (ARBs) do not.[69]
Injections of insulin may either be added to oral medication or used alone.[8] Most people do not initially need insulin.[3] When it is used, a longacting formulation is typically added at night, with oral medications being continued.[7][8] Doses are then increased to effect (blood sugar levels

being well controlled).[8] When nightly insulin is insufficient, twice daily insulin may achieve better control.[7] The long acting insulins glargine
and detemir are equally safe and effective,[70] and do not appear much better than neutral protamine Hagedorn (NPH) insulin, but as they are
significantly more expensive, they are not cost effective as of 2010.[71] In those who are pregnant insulin is generally the treatment of choice.[7]

Surgery
Weight loss surgery in those who are obese is an effective measure to treat diabetes.[72] Many are able to maintain normal blood sugar levels with
little or no medications following surgery[73] and long-term mortality is decreased.[74] There however is some short-term mortality risk of less than
1% from the surgery.[75] The body mass index cutoffs for when surgery is appropriate are not yet clear.[74] It is recommended that this option be
considered in those who are unable to get both their weight and blood sugar under control.[76]

Epidemiology

Prevalence of diabetes worldwide in 2000. World average was 28 per 1000 inhabitants.
no data
4552.5
7.5
52.560
7.515
6067.5
1522.5
67.575
22.530
7582.5
3037.5
82.5
37.545

Globally as of 2010 it was estimated that there were 285 million people with type 2 diabetes making up about 90% of diabetes cases.[4] This is
equivalent to about 6% of the world's adult population.[77] Diabetes is common both in the developed and the developing world.[4] It remains
uncommon, however, in the underdeveloped world.[3]
Women seem to be at a greater risk as do certain ethnic groups,[4][78] such as South Asians, Pacific Islanders, Latinos, and Native Americans.[7]
This may be due to enhanced sensitivity to a Western lifestyle in certain ethnic groups.[79] Traditionally considered a disease of adults, type 2
diabetes is increasingly diagnosed in children in parallel with rising obesity rates.[4] Type 2 diabetes is now diagnosed as frequently as type 1
diabetes in teenagers in the United States.[3]
Rates of diabetes in 1985 were estimated at 30 million, increasing to 135 million in 1995 and 217 million in 2005.[5] This increase is believed to
be primarily due to the global population aging, a decrease in exercise, and increasing rates of obesity.[5] The five countries with the greatest
number of people with diabetes as of 2000 are India having 31.7 million, China 20.8 million, the United States 17.7 million, Indonesia
8.4 million, and Japan 6.8 million.[80] It is recognized as a global epidemic by the World Health Organization.[81]

History
Main article: History of diabetes
Diabetes is one of the first diseases described[82] with an Egyptian manuscript from c. 1500 BCE mentioning "too great emptying of the urine."[83]
The first described cases are believed to be of type 1 diabetes.[83] Indian physicians around the same time identified the disease and classified it as
madhumeha or honey urine noting that the urine would attract ants.[83] The term "diabetes" or "to pass through" was first used in 230 BCE by the
Greek Apollonius Of Memphis.[83] The disease was rare during the time of the Roman empire with Galen commenting that he had only seen two
cases during his career.[83]
Type 1 and type 2 diabetes were identified as separate conditions for the first time by the Indian physicians Sushruta and Charaka in 400-500 AD
with type 1 associated with youth and type 2 with being overweight.[83] The term "mellitus" or "from honey" was added by the Briton John Rolle
in the late 1700s to separate the condition from diabetes insipidus which is also associated with frequent urination.[83] Effective treatment was not
developed until the early part of the 20th century when the Canadians Frederick Banting and Charles Best discovered insulin in 1921 and 1922.
[83]
This was followed by the development of the long acting NPH insulin in the 1940s.[83]

References
1.
"Diabetes Blue Circle Symbol". International Diabetes Federation. 17 March 2006.
Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Cotran, Ramzi S. ; Robbins, Stanley L. (2005). Robbins and Cotran Pathologic Basis of
Disease (7th ed.). Philadelphia, Pa.: Saunders. pp. 11941195. ISBN 0-7216-0187-1.
Shoback, edited by David G. Gardner, Dolores (2011). Greenspan's basic & clinical endocrinology (9th ed.). New York: McGraw-Hill
Medical. pp. Chapter 17. ISBN 0-07-162243-8.
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Open Access
Peer-reviewed
Research Article

Projections of Global Mortality and Burden of Disease from 2002 to


2030

Colin D Mathers ,

Dejan Loncar

Projections of Global Mortality and Burden of Disease from 2002 to


2030

Colin D Mathers,
Dejan Loncar

Published: November 28, 2006


DOI: 10.1371/journal.pmed.0030442

Article

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Abstract

Editors' Summary

Introduction

Methods

Results

Discussion

Supporting Information

Acknowledgments

Author Contributions

References

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Abstract
Background
Global and regional projections of mortality and burden of disease by cause for the years 2000, 2010, and 2030 were published by Murray and
Lopez in 1996 as part of the Global Burden of Disease project. These projections, which are based on 1990 data, continue to be widely quoted,
although they are substantially outdated; in particular, they substantially underestimated the spread of HIV/AIDS. To address the widespread
demand for information on likely future trends in global health, and thereby to support international health policy and priority setting, we have
prepared new projections of mortality and burden of disease to 2030 starting from World Health Organization estimates of mortality and burden
of disease for 2002. This paper describes the methods, assumptions, input data, and results.

Methods and Findings


Relatively simple models were used to project future health trends under three scenariosbaseline, optimistic, and pessimisticbased largely
on projections of economic and social development, and using the historically observed relationships of these with cause-specific mortality rates.
Data inputs have been updated to take account of the greater availability of death registration data and the latest available projections for
HIV/AIDS, income, human capital, tobacco smoking, body mass index, and other inputs. In all three scenarios there is a dramatic shift in the
distribution of deaths from younger to older ages and from communicable, maternal, perinatal, and nutritional causes to noncommunicable
disease causes. The risk of death for children younger than 5 y is projected to fall by nearly 50% in the baseline scenario between 2002 and
2030. The proportion of deaths due to noncommunicable disease is projected to rise from 59% in 2002 to 69% in 2030. Global HIV/AIDS deaths
are projected to rise from 2.8 million in 2002 to 6.5 million in 2030 under the baseline scenario, which assumes coverage with antiretroviral
drugs reaches 80% by 2012. Under the optimistic scenario, which also assumes increased prevention activity, HIV/AIDS deaths are projected to
drop to 3.7 million in 2030. Total tobacco-attributable deaths are projected to rise from 5.4 million in 2005 to 6.4 million in 2015 and 8.3 million
in 2030 under our baseline scenario. Tobacco is projected to kill 50% more people in 2015 than HIV/AIDS, and to be responsible for 10% of all
deaths globally. The three leading causes of burden of disease in 2030 are projected to include HIV/AIDS, unipolar depressive disorders, and
ischaemic heart disease in the baseline and pessimistic scenarios. Road traffic accidents are the fourth leading cause in the baseline scenario, and
the third leading cause ahead of ischaemic heart disease in the optimistic scenario. Under the baseline scenario, HIV/AIDS becomes the leading
cause of burden of disease in middle- and low-income countries by 2015.

Conclusions
These projections represent a set of three visions of the future for population health, based on certain explicit assumptions. Despite the wide
uncertainty ranges around future projections, they enable us to appreciate better the implications for health and health policy of currently
observed trends, and the likely impact of fairly certain future trends, such as the ageing of the population, the continued spread of HIV/AIDS in
many regions, and the continuation of the epidemiological transition in developing countries. The results depend strongly on the assumption that
future mortality trends in poor countries will have a relationship to economic and social development similar to those that have occurred in the
higher-income countries.

Figures

Citation: Mathers CD, Loncar D (2006) Projections of Global Mortality and Burden of Disease from 2002 to 2030. PLoS Med 3(11): e442.
doi:10.1371/journal.pmed.0030442
Academic Editor: Jon Samet, Johns Hopkins School of Public Health, United States of America
Received: January 27, 2006; Accepted: September 5, 2006; Published: November 28, 2006
Copyright: 2006 Mathers and Loncar. This is an open-access article distributed under the terms of the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Financial support for this project was provided by the World Health Organization (WHO) Department of Chronic Diseases and Health
Promotion and the WHO Commission on Intellectual Property Rights, Innovation and Public Health. The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.

Abbreviations: ART, antiretroviral therapy; COPD, chronic obstructive pulmonary disease; CRA, Comparative Risk Assessment; DALY,
disability-adjusted life year; DOTS, directly observed therapy, short-course; GBD, Global Burden of Disease; GDP, gross domestic product;
ICD, International Classification of Diseases; SIR , smoking impact ratio; UNAIDS, Joint United Nations Programme on HIV/AIDS; YLD,
years lived with disability; YLL, years of life lost due to mortality

Editors' Summary
Background.
For most of human history, little has been known about the main causes of illness in different countries and which diseases kill most people. But
public-health officials need to know whether heart disease kills more people than cancer in their country, for example, or whether diabetes causes
more disability than mental illness so that they can use their resources wisely. They also have to have some idea about how patterns of illness
(morbidity) and death (mortality) are likely to change so that they can plan for the future. In the early 1990s, the World Bank sponsored the 1990
Global Burden of Disease study carried out by researchers at Harvard University and the World Health Organization (WHO). This study
provided the first comprehensive, global estimates of death and illness by age, sex, and region. It also provided projections of the global burden
of disease and mortality up to 2020 using models that assumed that health trends are related to a set of independent variables. These variables
were income per person (as people become richer, they, live longer), average number of years of education (as this human capital increases, so
does life expectancy), time (to allow for improved knowledge about various diseases), and tobacco use (a major global cause of illness and
death).

Why Was This Study Done?


These health projections have been widely used by WHO and governments to help them plan their health policies. However, because they are
based on the 1990 estimates of the global burden of disease, the projections now need updating, particularly since they underestimate the spread
of HIV/AIDS and the associated increase in death from tuberculosis. In this study, the researchers used similar methods to those used in the 1990
Global Burden of Disease study to prepare new projections of mortality and burden of disease up to 2030 starting from the 2002 WHO global
estimates of mortality and burden of disease.

What Did the Researchers Do and Find?

As before, the researchers used projections of socio-economic development to model future patterns of mortality and illness for a baseline
scenario, a pessimistic scenario that assumed a slower rate of socio-economic development, and an optimistic scenario that assumed a faster rate
of growth. Their analysis predicts that between 2002 and 2030 for all three scenarios life expectancy will increase around the world, fewer
children younger than 5 years will die, and the proportion of people dying from non-communicable diseases such as heart disease and cancer
will increase. Although deaths from infectious diseases will decrease overall, HIV/AIDS deaths will continue to increase; the exact magnitude of
the increase will depend on how many people have access to antiretroviral drugs and the efficacy of prevention programs. But, even given the
rise in HIV/AIDS deaths, the new projections predict that more people will die of tobacco-related disease than of HIV/AIDS in 2015. The
researchers also predict that by 2030, the three leading causes of illness will be HIV/AIDS, depression, and ischaemic heart disease (problems
caused by a poor blood supply to the heart) in the baseline and pessimistic scenarios; in the optimistic scenario, road-traffic accidents will
replace heart disease as the third leading cause (there will be more traffic accidents with faster economic growth).

What Do These Findings Mean?


The models used by the researchers provide a wealth of information about possible patterns of global death and illness between 2002 and 2030,
but because they include many assumptions, like all models, they can provide only indications of future trends, not absolute figures. For
example, based on global mortality data from 2002, the researchers estimate that global deaths in 2030 will be 64.9 million under the optimistic
scenario. However, the actual figure may be quite a bit bigger or smaller because accurate baseline counts of deaths were not available for every
country in the world. Another limitation of the study is that the models used assume that future increases in prosperity in developing countries
will affect their population's health in the same way as similar increases affected health in the past in countries with death registration data (these
are mostly developed countries). However, even given these and other limitations, the projections reported in this study provide useful insights
into the future health of the world. These can now be used by public-health officials to plan future policy and to monitor the effect of new publichealth initiatives on the global burden of disease and death.

Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030442.

World Health Organization, provides information on the Global Burden of Disease Project and links to other related resources Global
Burden of Disease Project

Harvard School of Public Health, Burden of Disease Unit, offers information on the 1990 Global Burden of Disease study and its
projections Harvard School of Public Health

Introduction
As part of the groundbreaking Global Burden of Disease (GBD) study for 1990, Murray and Lopez [1,2] prepared projections of mortality and
burden of disease by cause to 2000, 2010, and 2020 under three alternative scenarios. These projections have been widely used and continue to
be widely quoted to provide information on likely future trends in global health, for example in the Atlas of Heart Disease and Stroke [3].
However, these projections were based on the GBD 1990 estimates and on projections of HIV/AIDS, smoking, income, and human capital from
1990 to 2020, and are now outdated. The HIV/AIDS projections in particular substantially underestimate the spread of the HIV epidemic and the
level of HIV/AIDS mortality around 2000.
We have thus prepared updated projections of mortality and burden of disease from 2002 to 2030 using methods similar to those of the original
GBD study and new input information. An earlier version of these projections has already been extensively used in the recently released World
Health Organization (WHO) global report Preventing chronic diseases: A vital investment [4].
There is a substantial literature on the projection or forecasting of all-cause mortality rates and mortality rates for specific diseases. The methods
used fall into two broad groups. First are those methods based on time-series analysis of historical trends in mortality rates. These aggregate
models, whether for all-cause mortality or for specific causes, use the previous trend of the variable of interest as the basis for predicting its
future value. By their data requirements, such methods are generally limited to high-income countries with good death registration data (see, for
example, Lee and Carter [5,6]). Second are the structural models, which are based on relationships between mortality and a set of independent
variables, and are necessarily projections of those independent variables. To the extent that the structural model identifies the important
componentsand the relationships among themof the system that determines the variable of interest, they offer the potential for more
robust predictions. When the underlying system is complex and sensitive to one or more of its components, a shift in some of the system
variables can introduce large changes in the outcome that may be missed by extrapolation (such as the discovery of antibiotics and infectious
disease trends or the change in tuberculosis mortality after the HIV epidemic). Aggregate models, in contrast, require considerably less
knowledge of the system components and the relationships among them. These models can therefore provide more reliable estimates when such
information is not available, especially when the system is not very sensitive to its inputs in time intervals that are in the order of the prediction
time.

The GBD projections fall into the structural models class, as do a number of more sophisticated and data-demanding risk factorbased models
for specific causes [710]. Methods also vary as to whether mortality is projected for all age groups simultaneously or separate models are
developed for each agesex group, and as to whether separate cause-specific projections are carried out. To our knowledge, the original GBD
projections represent the only attempt to date to project cause-specific mortality, rather than all-cause mortality, for a complete set of causes at
global and regional levels. The GBD projections use separate structural models for each of a small set of major cause groups and causecompositional models for detailed causes within these groups. The latter are a special case of more general cause-compositional models that
relate the proportional distributions of causes of death to the levels of all-cause mortality [11].
Recently, both types of projection model have been extended to allow incorporation of prior knowledge and enforce coherence in the resulting
mortality estimates across age groups, causes, and regions. Czado et al. [12] extended the Lee-Carter Poisson log-bilinear model into a Bayesian
model, in which the prior data impose smoothness of age and period effects in the projections. Girosi and King [13] developed a forecasting
model that models future values of log-mortality as functions of covariates known to affect risk of death. They also used a Bayesian approach to
allow different countryagegroup cross-sections to borrow strength from each other in order to overcome the serious data limitations faced
for many countries. Their model also constrains the projections to vary smoothly over time and across age groups in accordance with known age
profiles for specific causes of death.
The detailed application of such methods may result in substantially improved forecasts of global mortality and burden of disease trends in the
next few years. In the meantime, these updated projections provide a comprehensive update of the original GBD projections, with some
methodological improvements and extensions.

Methods
The methods used in the present study for the projections of mortality and burden of disease are similar to those used in the original GBD study
[2]. Separate projections models for males and females and for seven age groups (04, 514, 1529, 3044, 4559, 6069, and 70 y and older)
were developed to produce parsimonious equations for ten cause-of-death clusters. Baseline, pessimistic, and optimistic projections of covariates
in the regression equations were developed and used to project mortality rates for the cause clusters. Separate projection models were developed
for HIV/AIDS, tuberculosis, lung cancer, diabetes mellitus, and chronic respiratory diseases. Separate regression equations were developed
relating age- and sex-specific mortality rates for 132 detailed causes to the age- and sex-specific mortality rates from corresponding cause
clusters, based on International Classification of Diseases Ninth Edition (ICD-9) coded vital registration data from 98 countries.

Whereas the original GBD study carried out projections for eight regions of the world, we carried out these projections at country level, but
aggregated the results into regional or income groups for presentation of results. Four income groups were defined based on World Bank
estimates of GDP per capita in 2001 (see Table S1 for definitions of the regional and income groups). Baseline estimates at country level for
2002 were derived from the GBD analyses for 2002 as published in the World Health Report 2004 [14]. Data sources and methods for the 2002
estimates were comprehensively documented by Mathers et al. [15], together with an analysis of uncertainty levels of the results [16]. Mortality
and burden of disease trends from 1990 to 2001 were recently analyzed by Lopez et al. [17].
Projections of burden of disease measured in disability-adjusted life years (DALYs) were then developed for the three scenarios based on
projected mortality rates and alternative assumptions for those causes with little or no mortality. Population projections were developed based on
United Nations Population Division projections of fertility and net migration and our projected mortality rates. We describe the main features of
the methods, assumptions, and input data in this section, with a particular emphasis on revisions and changes to the original methods used by
Murray and Lopez. Protocol S1 and Tables S1S7 provide full details.

Regressions for Major-Cause Clusters


Disease and injury causes of death are classified in the GBD using a tree structure in which the first level comprises three broad cause groups:
Group I (communicable, maternal, perinatal, and nutritional conditions), Group II (noncommunicable diseases), and Group III (injuries) [15]. We
projected age- and sex-specific death rates at country level for ten major-cause clusters: Group I conditions excluding HIV/AIDS
(communicable, maternal, perinatal, and nutritional conditions as defined in Table S2), malignant neoplasms (excluding lung cancer), diabetes
mellitus, cardiovascular diseases, digestive disorders, chronic respiratory conditions, other Group II diseases, road traffic accidents, other
unintentional injuries, and intentional injuries. In contrast to the original GBD projections, diabetes mellitus was treated as a separate cause
category from other Group II diseases, since the available evidence suggests that its dominant risk factor, overweight and obesity, is becoming
more prevalent over time in both developed and developing regions and is projected to continue to rise [18].
Rather than attempt to model the effects of the many separate direct determinants or risk factors for disease from the limited data that are
available, the GBD methodology considered a limited number of socioeconomic variables: (1) average income per capita, measured as gross
domestic product (GDP) per capita; (2) the average number of years of schooling in adults, referred to as human capital; and (3) time, a proxy
measure for the impact of technological change on health status. This latter variable captures the effects of accumulating knowledge and

technological development, allowing the implementation of more cost-effective health interventions, both preventive and curative, at constant
levels of income and human capital [1].
These socioeconomic variables show clear historical relationships with mortality rates, and may be regarded as indirect, or distal, determinants
of health, although it is not necessary for the purposes of projection to know whether these associations are causal. In addition, a fourth variable,
tobacco use, was included in the projections for cancers, cardiovascular diseases, and chronic respiratory diseases, because of its overwhelming
importance in determining trends for these causes. Tobacco use was measured in terms of smoking impactthat component of observed lung
cancer mortality attributable to tobacco smoking [19]. This indirect measure of the accumulated hazards provides a better measure than do
current smoking rates for the overall health impact of tobacco, taking into account lag times as well as important aspects of exposure such as
duration, type, amount, and mode of smoking (see Protocol S1 for more details).
We used a regression equation of the same form as in the original GBD projections:
where Ca,k,i is a constant term, Ma,k,i is the mortality level for age
group a, sex k, and cause i, and Y, HC, and T denote GDP per capita, human capital, and time, respectively. The log of the smoking impact SI is
included in the equation only for malignant neoplasms, cardiovascular diseases, and respiratory diseases. This basic functional relationship
makes no specific assumptions about the relationships between these more distal socioeconomic factors and more proximate determinants of
mortality rates such as environment, lifestyle, and physiological risk factors. Nevertheless, our regression results indicate that a considerable
proportion of the variance in age-, sex-, and cause-specific mortality rates can be explained by this limited set of distal determinants.
Murray and Lopez used a variety of econometric approaches to estimate the equations (Equation 1), including methods that take into account
auto-correlation and heteroscedasticity. Because these methods substantially restricted the subset of panel data that could be used, and in
particular resulted in much loss of information for moderate- to high-mortality populations, they chose to use ordinary least-squares regression
based on the entire dataset for the final set of parameter estimates. We followed the same approach and estimated equations (of the form
illustrated by Equation 1) separately for each agesexcause group.
Death registration data from 106 countries for 19502002 [20] were used to estimate the regression equations. In total, 2,605 country-years were
available, almost double those used for the original projections by Murray and Lopez. Although the dataset is extensive, it does not include many
observations from populations with high rates of mortality. Whereas the original GBD projections applied a single set of models based on all

observed death registration data for projections in all regions, the new projections for low and lower-middle-income countries (income in
international dollars less than $3,000 per capita in 2002) were based on the observed relationships for a dataset consisting of 1,734 country-years
of observation where income per capita was less than $10,000 per year. Additionally, observed regional trends in child mortality from 1990 to
2002 were compared with those predicted by the projection model for low-income countries conditional on the observed time series for the
model covariates for that period. As a result, the regression coefficient for time was set to zero for sub-Saharan Africa, and to 25% of its original
value for other low-income countries.
Final parsimonious regression results are listed in Tables S3 and S4. The low-income regression results give somewhat more conservative
declines for Group II (noncommunicable) diseases in low-income regions. In general, the final regression equations are broadly similar to those
estimated for the original projections. Apart from injuries, they explain a surprising proportion of the variance for many agesexcause
categories. For males and females aged 70 y and above, the R2 for many cause clusters was generally lower than for other age groups, probably
reflecting poorer quality of coding of causes of death or the smaller range of variation in mortality rates between countries at these older ages, as
well as the inherent reductions in the explanatory power of covariates with increasing death rates with age. The lower proportions of variance
explained for injuries may reflect lower levels of temporal variation in these causes as well as more heterogeneous injury causes that may be less
well-correlated with income and human capital.
For cause clusters in agesex groups in which the R2 was less than 10%, we carefully examined the consistency of the projections with other
agesex groups, and made a choice between using the final parsimonious regression equation, an alternative assumption such as stable (constant)
rates, or a separate prediction model based on projections for the major relevant risk factor (diabetes mellitus and chronic respiratory diseases).
Model predictions of age-, sex-, and cause-specific mortality rates in 2002 for each of the ten clusters of causes were compared for each country
with the results of the GBD study for that year. A series of scalars were then derived so that projected values for 2002 were identical to the 2002
GBD results. It was then assumed that these scalars would remain constant over the period 20022030.

Diabetes and Chronic Respiratory Conditions


Initial regression analysis for diabetes mellitus found inconsistent trends between males and females, probably reflecting the large variations
across countries and inaccuracies in recording diabetes as the underlying cause of death in many death registration systems. While overall trends
for diabetes mortality showed no consistent relationship across the sexes or levels of development, the regression analysis found significant betas

for T (year) with death rates increasing with time. Since a substantial proportion of diabetes mortality is attributable to overweight and obesity
[21], a separate projection model for diabetes mortality was developed using WHO projection of trends in body mass index distributions from
2000 to 2010 (see Protocol S1 for more details).
Initial projections for chronic respiratory diseases resulted in substantially increasing rates for high-income countries, although smoking is the
main risk factor and smoking impact has been generally decreasing. It is likely that the initial projections may reflect increasing propensity to
code chronic obstructive pulmonary disease (COPD) as the underlying cause of death with time. Projections of mortality for chronic respiratory
diseases were thus adjusted for projected changes in smoking impact (see Protocol S1 for more details).

Projections of Income, Human Capital, and Smoking Impact


Revised country-level projections for income per capita, human capital, and smoking impact were developed for the baseline, pessimistic, and
optimistic projections. Income per capita was measured using average GDP per capita expressed in international dollars (purchasing power
parity adjusted). Country-specific and regional income growth forecasts by the World Bank were used to project GDP per capita for all WHO
member states. Beyond 2015, projected growth rates for most regions approach 3% per annum under the baseline scenario, with somewhat lower
growth rates in sub-Saharan Africa, the Middle East, and high-income countries (see Protocol S1 for more details).
Revised estimates and projections of human capital for WHO member states were prepared for the period 19502030 drawing on previous
estimates by Barro and Lee for 98 countries [22] and observed relationships between growth in human capital and growth in GDP per capita.
Smoking impact was calculated for the historical mortality countryyear observations by subtracting nonsmoker lung cancer rates from observed
total lung cancer mortality rates in the data. Higher nonsmoker lung cancer mortality rates were used in China and Southeast Asian countries, to
reflect the higher levels of lung cancer in nonsmokers due to indoor air pollution from exposure to smoke from solid fuels [23,24].
Ezzati and Lopez developed projections of smoking intensity for 14 sub-regions of the WHO regions for the Comparative Risk Assessment
(CRA) project, based on an analysis of past and current agesex-specific smoking prevalence calibrated to regional characteristics of the tobacco
epidemic for different sub-regions [23,24]. These regional projections were used to develop country-specific projections drawing also on more
recent World Bank data on trends in adult per capita consumption of cigarettes and recent observed trends in agesex-specific lung cancer

mortality (see Protocol S1 for more details). For four high-income countries, recent projections were used based on an ageperiodcohort model
estimated using historical data on agesex-specific tobacco consumption, average tar content, and adult tobacco consumption per capita [25].

Regression Equations for Detailed Causes


To project death rates for specific causes within the major-cause clusters, we followed the original GBD methodology in estimating the
relationship between trends in agesex-specific mortality for each specific cause with the trend in the agesex-specific mortality for the majorcause cluster to which the specific cause belongs. To avoid biasing the results due to changes in specific cause death rates associated with use of
different versions of ICD, we restricted the analysis to country-years for which deaths were coded using ICD-9. The regression parameters were
estimated on 1,357 country-year observations for 98 countries.
For each individual regression, observations were excluded from analysis if they related to fewer than 50 deaths. Regression results were used
only where the relationship was reasonably strong, as measured by an R2 greater than 0.25 and a p-value less than 0.001 for the regression
coefficient. The resulting coefficients are shown in Table S5.
The major-cause cluster regression equation for intentional injury predicted generally falling death rates in middle- and low-income countries
and rising death rates in high-income countries. For homicide, this is the opposite of the observed trends in the larger high-income countries. For
this reason, homicide death rates were assumed to remain constant under the baseline scenario, with some modifications for country-specific
observed trends. Similarly, war deaths were assumed to remain constant under the baseline scenario.
For countries with good death registration data and populations of 5 million or more, trends in mortality rates were estimated for ischaemic heart
disease, cerebrovascular disease, tuberculosis, suicide, and homicide. These were used to adjust the initial years of relevant country-specific
projections to match the recent observed trends.

Projections for HIV/AIDS and Tuberculosis


We used separate projections for HIV/AIDS mortality under several scenarios derived from existing models. The Joint United Nations
Programme on HIV/AIDS (UNAIDS) and WHO [26] have prepared projections of HIV/AIDS mortality under a range of assumptions about the

future of the HIV epidemics in all regions and with varying treatment scale-up assumptions for both adult and children using a transmission
model previously used to assess the impact of preventive interventions [10,27].
The model includes underlying regional demography, acquisition of HIV and other sexually transmitted infections, and progression from HIV
infection to AIDS and death. For countries with generalized epidemics (mostly in sub-Saharan Africa), the model variables were estimated from
sentinel site prevalence data. For countries with epidemics concentrated in groups with higher-risk behaviour, the size and HIV prevalence was
estimated for each of these groups, and prevalence in low-risk populations was estimated by allowing for transmission from high-risk to low-risk
groups via sexual mixing. Projections of these epidemics were based on assumptions about degree of saturation for each of the high-risk groups,
time to saturation, and spread from high-risk to low-risk populations over time (see Protocol S1 for further information).
Our baseline projections for HIV/AIDS agesex-specific mortality rates were based on the UNAIDS and WHO medium scenario for treatment
scale-up. Under this scenario, antiretroviral therapy (ART) coverage will reach 80% by 2012 in all regions, remaining constant beyond that year.
The treatment scenarios assumed no effect of treatment on transmission and incidence rates, and no additional prevention efforts resulting in
reduction of transmission and incidence rates.
Our pessimistic projections for HIV/AIDS agesex-specific mortality rates were based on the UNAIDS and WHO slow scenario for treatment
scale-up. Under this scenario, ART coverage will reach 60% by 2012 in all regions except Latin America, where it reaches 70% in 2013.
HIV/AIDS mortality rates in high-income countries were assumed to remain constant as in the baseline scenario.
Salomon et al. [28] have modelled scenarios for sub-Saharan Africa combining treatment and additional prevention efforts. In one scenario, ART
coverage is scaled up and optimal assumptions are made about treatment impact on transmissibility and patient behaviour. A second scenario
assumes that an emphasis on treatment leads to less effective implementation of prevention, resulting in only 25% attainment of the maximum
potential impact of prevention efforts. For our optimistic projection of HIV/AIDS mortality, we used a third unpublished scenario prepared by
Salomon et al. that is approximately halfway between their two published mixed treatment-prevention scenarios. For low- and middle-income
countries outside sub-Saharan Africa, we assumed similar proportional reductions in incidence rates for HIV infection due to increased
prevention, as estimated for sub-Saharan Africa (see Protocol S1 for more details).
Because of the powerful interaction between tuberculosis and HIV infections in regions such as sub-Saharan Africa, Murray and Lopez modified
the original projections from 1990 to 2020 for tuberculosis death rates. As part of the Global Plan to Stop TB covering the period 20062015, the
Stop TB Partnership has prepared three projection scenarios for tuberculosis incidence, prevalence, and mortality based on different assumptions

about the pace of scale-up and coverage of interventions to achieve the UN's Millennium Development Goals for tuberculosis [29]. The Global
Plan scenario assumes massive scale-up in tuberculosis control activities, achieving case detection levels of more than 70% and using the WHO
DOTS (directly observed therapy, short-course) treatment strategy to reach cure rates of more than 85%. The Sustained DOTS scenario
assumes that case detection and treatment success rates increase until 2005 and then remain constant to 2015. A third No DOTS scenario
assumes that the DOTS treatment strategy was never introduced in any region, so case detection, treatment, and cure rates would continue as
they were pre-DOTS (see Protocol S1 for more details).
The projected annual regional trends in tuberculosis death rates for HIV-negative cases under these three scenarios were used to project
tuberculosis death rates for countries in each region as follows. Annual projected trends under the Sustained DOTS scenario were used for the
baseline projections, and those under the Global Plan scenario were used for the optimistic projections. For the pessimistic projections, annual
trends in rates were estimated as halfway between those projected under the sustained DOTS scenario and those projected under the No
DOTS scenario from 2006 onwards. For 20162030, annual trends from 2015 to 2030 were assumed to converge on the regional projected
trends for Group I causes excluding HIV/AIDS under the baseline scenario. For the optimistic and pessimistic scenarios, annual regional trends
were assumed to remain constant from 2015 to 2030.

Projections of Tobacco-Caused Deaths


As part of the WHO's CRA project, Ezzati and Lopez [23] estimated the total mortality attributable to tobacco smoking in 2000 for the world and
for WHO sub-regions. Current levels of smoking impact ratio (SIR) were used as an indirect indicator of accumulated smoking risk based on
excess lung cancer mortality. SIR measures the absolute excess lung cancer mortality due to smoking in the study population, relative to the
absolute excess lung cancer mortality in lifelong smokers of the reference population. SIR values were calculated from the projected smoking
impact variables for individual countries for age groups 3044 y and older.
Projected mortality attributable to tobacco was estimated using the CRA methods for lung cancer, upper aerodigestive cancer, all other cancers,
COPD, other respiratory diseases, cardiovascular diseases, tuberculosis, and selected other disease causes.

Projecting the Burden of Disease and Injury

The WHO has undertaken new assessments of the GBD for 20002002, with consecutive revisions and updates published annually in WHO's
World Health Reports. These assessments use a health gap measure, the DALY, developed by Murray and Lopez [30] to quantify the equivalent
years of full health lost due to diseases and injury in WHO member states. The data sources and methods used for the GBD 2002 are
documented elsewhere [1517], and summary results for 14 regions of the world are published in the World Health Report 2004 [14] and
available at http://www.who.int/evidence/bod.
The burden of disease estimates for 2002 were used as a base for projections of burden of disease to 2030. Years of life lost (YLL) were
calculated from the projections of mortality by cause, age, and sex, according to the GBD method. To project DALYs, it is also necessary to
project years lived with disability (YLD). Given the lack of good information on trends in disability and health state distributions, the approach
used here is an elaboration of the methods and assumptions used by Murray and Lopez in the original GBD projections [1].
YLD projections were generally derived from the YLL projections by applying the ratio of YLD to YLL for 2002. For ischaemic heart disease
and stroke, future incidence rates were assumed to decline at 50% of their mortality rate declines reflecting declining case fatality rates as well as
incidence rates. For causes where there is little or no mortality, agesex-specific YLD rates per capita were generally assumed to remain constant
into the future. For certain mental disorders, musculoskeletal conditions, and hearing loss, disability weights were assumed to decline somewhat
with improvements in income per capita reflecting increasing treatment coverage. YLD rates for nonfatal communicable diseases and nutritional
deficiencies were assumed to decline at between 50% and 100% of the mortality rate declines for Group I causes.

Projections of Population and Numbers of Deaths and DALYs


Our projections of mortality rates, together with UN medium variant assumptions for fertility rate projections and projected migration rates [31],
were also used to prepare consistent population projections for all regions. The projected global population in 2015 was 7.1 billion compared to
the UN medium variant projection of 7.2 billion, reflecting somewhat higher adult death rates in our mortality projections.
Projected death and DALY rates for 192 WHO member states for 20032030 were applied to the projected populations to generate projected
numbers of deaths and DALYs for each of the three scenarios. The resulting country projections were added back into regional groups for
presentation of results (see Table S1).The choices and assumptions incorporated in each of the baseline, pessimistic, and optimistic scenarios are
summarized in Table S7.

Results
This section provides an overview of the projections. Detailed results for 2002, 2015, and 2030 are presented in Dataset S1 for deaths and
Dataset S2 for DALYs. These tables include baseline, pessimistic, and optimistic projected totals for each cause category, as well as a sex and
age breakdown for the baseline category.
Figure 1 shows projected life expectancies at birth in 2030 under the three scenarios, for World Bank regions. Life expectancy at birth is
projected to increase in all World Bank regions, with the largest increases in the African region and the South Asian regions. However, under the
baseline scenario, male life expectancy in the African region will still remain less than 55 y. In all regions except the European region, life
expectancy increases are greater for females than for males. Life expectancy for women in the high-income countries may reach 85.0 y by 2030,
compared with 79.7 y for men. The highest projected life expectancy in 2030 is for Japanese women at 88.5 y (with a range of 87.7 to 89.2
across the pessimistic and optimistic scenarios). The femalemale difference in life expectancy at birth is projected to narrrow from 5.9 y in
2002 to 5.3 y in 2030 in the high-income countries, whereas the gap will more than double in low-income countries to 5.2 y in 2030.

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Figure 1. Projected Life Expectancy at Birth in 2030 by World Bank Region and Sex: Baseline, Optimistic, and Pessimistic Scenarios Compared
with 2002 Estimates
doi:10.1371/journal.pmed.0030442.g001
Projected global deaths in 2030 ranged from 64.9 million under the optimistic scenario to 80.7 million under the pessimistic scenario, variations
of 11% to +10% relative to the baseline projection of 73.2 million. Figure 2 shows the projected global numbers of deaths in 2030 by age in the
three scenarios, compared with the numbers of deaths by age in 2002. In all three scenarios there is a dramatic shift in the distribution of deaths
from younger to older ages. The risk of death for children younger than 5 y is projected to fall substantially in the baseline scenario, by almost
25% between 2005 and 2015, and by more than 40% between 2005 and 2030. These rates of decline are similar to those projected between 2000
and 2015 in the original GBD projections. The vertical bars attached to the points for 2030 in Figure 2 represent the range of deaths projected
under the optimistic and pessimistic scenarios.

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Figure 2. Global Numbers of Deaths by Age and Sex: Baseline, Optimistic, and Pessimistic Scenarios for 2030 Compared with 2002 Estimates
doi:10.1371/journal.pmed.0030442.g002

Trends in Cause-Specific Mortality


Table 1 summarizes the projected annual average changes in age-standardized death rates for selected major causes for the baseline projections
for the period 20022020. For all the Group I and Group II cause groups in which the projections were based on the major-cause cluster
regression equations, age-specific and age-standardized death rates are projected to decline over the next 20 years. The average annual rate of
decline is greater (at about 3%) for Group I causes than for Group II causes. The HIV/AIDS projections, discussed in more detail below, have a
substantial projected average annual rate of increase of 3% for males and 2% for females. Other causes with projected increases in agestandardized rates include lung cancer, diabetes, chronic respiratory diseases, road traffic accidents, violence, and war.

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Table 1.
Projected Average Annual Rates of Change in Age-Standardized Death Rates for Selected Causes: World, 20022020
doi:10.1371/journal.pmed.0030442.t001
The Group I causes, excluding HIV/AIDS and tuberculosis, decline with average annual rates of change typically about one-third slower than the
original GBD projections of Murray and Lopez. To some extent, this reflects the more conservative projections for low-income countries, where
the coefficient of the time factor was reduced or set to zero. Average rates of decline for Group II causes (excluding lung cancer and chronic
respiratory conditions) are similar for females to those in the original projections. However, the differential between males and females in the
original projections has disappeared in the current projections, with males having a greater average annual rate of decline for Group II conditions
than previously projected.
Figure 3 summarizes the contributions of major causes to global trends in numbers of deaths for the three major cause groups. Large declines in
mortality between 2002 and 2030 are projected for all of the principal Group I causes, with the exception of HIV/AIDS. Under the baseline
scenario involving scale-up of ART coverage to 80% by 2012, but not additional prevention efforts, HIV/AIDS deaths increase from 2.8 million
in 2002 to 6.5 million in 2030. Total deaths due to other Group I causes decline from 15.5 million in 2002 to 9.0 million in 2030. Unfortunately,
this is substantially offset by the projected rise in HIV/AIDS deaths. Under the optimistic scenario involving additional HIV prevention activity,
3.7 million HIV/AIDS deaths are projected for 2030, so that total deaths due to Group I conditions would decline from 32% of all deaths in 2002
to 14% of all deaths in 2030.

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Figure 3. Baseline Projections of Deaths from Group I, Group II, and Group III Causes, World, 20022030
doi:10.1371/journal.pmed.0030442.g003
Although age-specific death rates for most Group II conditions are projected to decline, ageing of the population will result in significantly
increasing total deaths due to most Group II conditions over the next 30 years (Figure 3). Global cancer deaths are projected to increase from 7.1
million in 2002 to 11.5 million in 2030, and global cardiovascular deaths from 16.7 million in 2002 to 23.3 million in 2030. Overall, Group II
conditions will account for almost 70% of all deaths in 2030 under the baseline scenario.
The projected 40% increase in global deaths due to injury between 2002 and 2030 are predominantly due to the increasing numbers of road
traffic accident deaths, together with increases in population numbers more than offsetting small declines in age-specific death rates for other
causes of injury. Road traffic accident deaths are projected to increase from 1.2 million in 2002 to 2.1 million in 2030, primarily due to increased
motor vehicle fatalities associated with economic growth in low- and middle-income countries.

Projections of HIV/AIDS Mortality and Other Selected Causes

Figure 4 summarizes projected HIV/AIDS deaths by income group for the three scenarios. The declining death rates for 20052010 in the
baseline and pessimistic scenarios, followed by increasing death rates, reflect the effects of the assumed treatment scale-up scenarios. Rapidly
increasing levels of ART coverage result in postponement of deaths for a number of years, but once the ART coverage plateaus at its final level,
numbers of deaths continue to rise, reflecting largely the underlying growth in population. HIV incidence rates essentially remain constant in the
baseline scenario for sub-Saharan Africa, and the global growth in incident cases and in deaths is largely driven by population growth in subSaharan Africa.

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Figure 4. Projections of Total AIDS Deaths (Thousands) by Income Group for Three Scenarios
Scenarios are indicated: baseline (solid lines), optimistic (dotted lines), and pessimistic (dashed lines).
doi:10.1371/journal.pmed.0030442.g004
Under the baseline scenario, the total deaths from HIV/AIDS over the 25-y period 20062030 are projected to be 117 million. Under the
optimistic scenario, in which additional prevention efforts result in a long-term 3% decline in incidence rates, the projected total deaths over
20062030 are 89 million, a saving of 28 million lives.
The ranges defined by the optimistic and pessimistic projections differ substantially by cause (Figure 5). For example, the range for
cardiovascular disease before age 70 y is much wider than that for cancers before age 70 y or for road traffic accidents. Group I deaths
(excluding HIV/AIDS) have a wider range than most other causes, although the total deaths decline substantially in all three scenarios.

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Figure 5. Projections of Global Deaths (Millions) for Selected Causes, for Three Scenarios: Baseline, Optimistic, and Pessimistic, 20022030
doi:10.1371/journal.pmed.0030442.g005

Comparison with GBD 1990 Projections


Figure 6 compares projected global deaths for each of the three major cause groups for 20022030 with the corresponding projections for 1990
2020 from the original GBD study [1]. Projections for Group I causes are substantially different, mainly because of the very large difference in
projected HIV/AIDS mortality. Total global deaths for Group II and Group III causes are projected to increase at a somewhat slower rate than the
original GBD projections, and in addition, the base levels for these causes in 2002 are somewhat lower than the levels projected by the original
GBD study.

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Figure 6. Comparison of Baseline Projections 20022030 with the Original GBD Projections 19902020: Global Deaths for All Causes, and
Major Cause Groups
doi:10.1371/journal.pmed.0030442.g006
Despite these differences for all three major cause groups, and differences in projected global population numbers, the projections of total global
all-cause deaths are almost identical to those in the original GBD study. Global deaths in 2020 under the baseline scenario are 66.5 million,
compared with 68.3 million projected by Murray and Lopez from the 1990 base, and the overall trend is almost identical.
Projected trends for global deaths due to most Group I causes other than HIV/AIDS are broadly similar. The new baseline projections for lung
cancer give lower global numbers and a lower rate of increase. Trends in global respiratory deaths are similar for the two sets of projections, but
the projected rates of increase in global deaths due to cancers, cardiovascular disease, and digestive disorders are all somewhat slower for the
current projections. Increases for road traffic accidents are somewhat slower in the current projections, whereas trends for other unintentional
causes are quite similar. There are some substantial differences in trends for intentional causes, reflecting different assumptions and decisions
concerning use of the regression parameters.

Leading Causes of Death


Table 2 lists the 15 leading causes of death according to the baseline scenario for males, females, and both sexes combined as projected for 2030
globally. Table 3 provides similar lists of the ten leading causes of death according to the baseline scenario for the four income groups of
countries. The four leading causes of death in all scenarios are projected to be ischaemic heart disease, cerebrovascular disease (stroke),
HIV/AIDS, and COPD, although HIV/AIDS moves from third to fourth position in the optimistic scenario.

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Table 2.

Changes in Rankings for 15 Leading Causes of Death, 2002 and 2030 (Baseline Scenario)
doi:10.1371/journal.pmed.0030442.t002

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Table 3.
Ten Leading Causes of Death, by Income Group, 2030 (Baseline Scenario)
doi:10.1371/journal.pmed.0030442.t003
Table 2 also summarises the changes in rank order of deaths between 2002 and 2030 for the 15 leading causes. Lower-respiratory infections,
perinatal conditions, diarrhoeal diseases, malaria, and measles are all projected to decline substantially in importance. On the other hand,
diabetes mellitus, lung cancer, stomach cancer, and liver and colorectal cancer are all projected to move up three or more places in the rankings.

Decomposition
The results discussed so far have described projected changes in mortality in terms of the absolute (and relative) numbers of deaths expected
under the various scenarios. These changes may be due to changes in age-specific disease and injury mortality risks, or due to demographic
change that alters the size and age composition of the population, or both. Because mortality risks are strongly age dependent for most causes,
changes in the age structure of a population may result in substantial changes in the number of deaths, even when the age-specific risks remain
unchanged.
We further analysed the relative impact of demographic and epidemiological change on the projected numbers of deaths by cause by calculating
three hypothetical alternatives. In the first, we calculated the expected number of deaths in 2030 given the 2030 projected age-specific rates
under the baseline scenario and the 2002 population. The difference between this and the 2002 mortality estimates is a measure of the change in
mortality expected solely on the basis of changing age-specific mortality rates, and is labelled epidemiological change in Figure 7.

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Figure 7. Decomposition of Projected Change in Numbers of Deaths into Demographic and Epidemiological Components, by Broad Cause
Group and Income Group, 20022030
doi:10.1371/journal.pmed.0030442.g007
Second, we calculated the expected number of deaths in 2030 by taking the 2002 age-specific death rates and applying them to the 2030
projected population. The difference between this and the 2002 mortality estimates is a measure of the change in mortality expected solely on the
basis of changing demography (including size and age composition of the population). We then repeated this calculation, but applied the 2002
age-specific death rates to projected population numbers for 2030 that matched the total projected male and female population numbers for each
country but retained the 2002 age distribution of the population. The difference between this and the 2002 mortality estimates is a measure of the
change in mortality expected solely on the basis of population growth excluding changes in age composition. The difference between the total
change in mortality due to demography and this latter estimate gives a measure of the effect of the change in age composition of the population
alone. These two components of demographic change are labelled population growth and population ageing in Figure 7. The total projected
change in numbers of deaths between 2002 and 2030 is the sum of the population growth, population ageing, and epidemiological change
components.
In almost all cases, demographic and epidemiological factors are operating in opposing directions in determining mortality in 2030. The major
exception is HIV/AIDS, where demographic and epidemiological change are acting in the same direction to increase total HIV/AIDS deaths to
6.5 million deaths in 2030 under the baseline scenario. Demographic change dominates, as the majority of HIV/AIDS deaths are in sub-Saharan
Africa, where population growth is highest and where HIV/AIDS incidence rates are assumed to remain largely constant under the baseline
scenario.

For Group I conditions other than HIV/AIDS for which substantial declines in mortality rates are projected, the effect of these declines will be
attenuated in most regions by demographic change leading to an increase in the child population most at risk for these conditions. Population
growth and population ageing act in opposite directions for Group I mortality excluding HIV/AIDS in low-income countries, but not in other
income groups. If future fertility rates are higher than projected, then the higher child population numbers will further offset the projected
reductions in death rates for Group I conditions.
For Group II (noncommunicable diseases), demographic changes in all regions will tend to increase deaths substantially, with offsetting
reductions in projected death rates in all regions. Population growth and population ageing both act to increase Group II deaths in all regions,
although the impact of population ageing is generally much more important than population growth. Population growth has the largest relative
impact for low-income countries, and the smallest for lower-middle-income countries. The latter group includes Eastern European populations
such as Russia that will experience negative population growth.
For Group III (injuries), demographic change similarly dominates the epidemiological change. The latter is small at group level in most regions,
because the projected increase in road traffic fatalities is offset by projected decreases in death rates for other unintentional injuries.

Tobacco-Attributable Deaths
Figure 8 summarises the projected number of tobacco-attributable deaths for the world, and for high-income and low- and middle-income
countries. Under the baseline scenario, total tobacco-attributable deaths will rise from 5.4 million in 2005 to 6.4 million in 2015 and 8.3 million
in 2030. Projected deaths for 2030 range from 7.4 million in the optimistic scenario to 9.7 million in the pessimistic scenario. Tobaccoattributable deaths are projected to decline by 9% between 2002 and 2030 in high-income countries, but to double from 3.4 million to 6.8 million
in low- and middle-income countries.

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Figure 8. Projected Numbers of Tobacco-Caused Deaths for the World and for High-Income and Middle- plus Low-Income Countries, Three
Scenarios, 20022030
doi:10.1371/journal.pmed.0030442.g008
Table 4 divides the projected 2015 global mortality due to smoking into leading causes: cancers are responsible for one-third of the deaths,
followed by cardiovascular diseases and chronic respiratory diseases, each responsible for 30% of the deaths. According to our baseline
projection, smoking will kill 50% more people in 2015 than HIV/AIDS, and will be responsible for 10% of all deaths globally.

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Table 4.
Projected Global Tobacco-Caused Deaths, by Cause, 2015 Baseline Scenario
doi:10.1371/journal.pmed.0030442.t004

Burden of Disease
Global DALYs lost are projected to increase from 1.48 billion in 2002 to 1.54 billion in 2030, an overall increase of only 3%. Since the
population increase is projected to be 27% during the same period, there is actually a decrease in the global per capita burden. Unlike deaths,
where the overall global death rate is projected to increase by 1%, the DALY rate decreases because the increasing number of deaths is offset by
the shift in age at death to older ages, associated with fewer lost years of life. Even with the assumption that the age-specific burden for most
nonfatal causes remains constant into the future, and hence that the overall burden for these conditions increases with the ageing of the
population, there is still an overall projected decrease in the global burden of disease per capita of 19% from 2002 to 2030.
The proportional contribution of the three major cause groups to the total disease burden is projected to change substantially, however. Group I
causes are projected to account for 30% of total DALYs lost in 2030, compared with more than 40% in 2002. In low-income countries, the
decline is even greater, from 56% in 2002 to 41% in 2030, even including the doubling of the HIV/AIDS burden. The noncommunicable disease
(Group II) burden is projected to increase to 57% in 2030, and to represent a greater burden of disease than Group I conditions in all income
groups, including low-income countries.
Table 5 lists the 15 leading causes of DALYs globally in 2002 and in 2030 according to the baseline scenario, and Table 6 provides similar lists
of the ten leading causes of burden of disease for high-, middle-, and low-income country groups. The three leading causes of DALYs in the
baseline and pessimistic scenarios are projected to be HIV/AIDS, unipolar depressive disorders, and ischaemic heart disease. Road traffic
accidents become the third leading cause under the optimistic scenario, ahead of ischaemic heart disease and cerebrovascular disease. Perinatal
conditions are the fourth leading cause under the pessimistic scenario and the fifth leading cause under the baseline scenario, after road traffic
accidents. HIV/AIDS becomes the leading cause of burden of disease in middle-income countries, as well as low-income countries, by 2015.

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Table 5.
Changes in Rankings for 15 Leading Causes of DALYs, 2002 and 2030 (Baseline Scenario)
doi:10.1371/journal.pmed.0030442.t005

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Table 6.

Ten Leading Causes of DALYs, by Income Group and Sex, 2030 (Baseline Scenario)
doi:10.1371/journal.pmed.0030442.t006
Table 5 also illustrates the changes in rank order of DALYs between 2002 and 2030 for the 15 leading causes globally. Lower-respiratory
infections, perinatal conditions, diarrhoeal diseases, malaria, measles, tuberculosis, and congenital anomalies are all projected to decline
substantially in importance. On the other hand, ischaemic heart disease, diabetes mellitus, road traffic accidents, self-inflicted injuries, COPD,
hearing loss, and cataracts are all projected to move up three or more places in the rankings. Hearing loss is projected to be among the top ten
causes of burden of disease in high- and middle-income countries, and Alzheimer disease and other dementias and alcohol-use disorders among
the top four causes in high-income countries in 2030. In low-income countries in 2030, Group I conditions continue to account for five of the ten
leading causes of burden of disease. These are HIV/AIDS, perinatal conditions, diarrhoeal diseases, malaria, and acute lower-respiratory
infections.

Discussion
We have addressed the need for updated projections of mortality and burden of disease using methods similar to those of the original GBD study.
Our intent was not to undertake major new methodological developments, but rather to provide updated projections for the first 30 years of the
21st century, using as much relevant new information as is available. We project that life expectancy will increase around the world for all three
scenarios, fewer children younger than 5 y will die (a 50% decline under the baseline scenario), and the proportion of people dying from noncommunicable diseases will increase (from 59% in 2002 to 69% in 2030 under the baseline scenario). Although deaths from infectious diseases
will decrease overall, HIV/AIDS deaths will continue to increase; the exact magnitude of the increase will depend to a limited extent on how
many people have access to antiretroviral drugs and much more on whether there are increased prevention efforts. Although a projected 6.5
million people will die from HIV/AIDS under the 2030 baseline projection, an even larger number will die from disease attributable to tobacco
smoking (8.3 million). By 2030, the three leading causes of burden of disease will be HIV/AIDS, depression, and ischaemic heart disease in the
baseline and pessimistic scenarios. Road traffic accidents are the fourth leading cause in the baseline scenario, and the third leading cause ahead
of ischaemic heart disease in the optimistic scenario.
These updated projections of mortality and burden of disease have been prepared using a similar methodology to that of the original GBD study,
but with some changes described above and with updated inputs and an updated base set of estimates for 2002. We have incorporated a number

of methodological improvements and changes. These include carrying out the projections at country rather than regional level, use of separate
regression equations for low-income countries, incorporation of information from death registration datasets on recent observed trends for
selected causes, and calibration of the regression equations through a comparison of back-projections with observed child mortality trends from
1990 to 2002. Additionally, separate risk factorbased projection models were developed for diabetes mellitus and chronic respiratory diseases.
Population projections also included UN projections for net migration rates.
Baseline estimates of deaths, disability, and DALYs lost in 2002 have been projected into the future based on an explicit set of assumptions and
methods, and the results are nothing more than the numerical consequences of the assumptions and methods employed. In this paper and the
accompanying Protocol S1 and Tables S1S7, we have tried to explicitly describe and summarize all inputs and assumptions for the three
scenarios to enable replication of these projections for different scenarios. Additional information and detailed datasets are available from the
authors on request.
We do not claim that the scenarios presented here necessarily represent the best predictions of future global and regional health trends, and it is
possible that more sophisticated causal models incorporating projections of important determinants may provide better predictions for specific
diseases. However, we do believe that these projections, as with the previous GBD projections of Murray and Lopez, represent the most
comprehensive and consistent set of health status projections available today.

Comparisons with Other Projections


We are not aware of any projections of global and regional mortality, apart from the previous GBD projections, that have included a
comprehensive set of causes of death. A review of other published studies containing global and regional projections for specific single causes
identified relatively few studies that did not either apply base estimates of agesex-specific death rates (assumed not to change in the future) to
UN population projections, or were based on the previous GBD projections, or were earlier versions of the projections by WHO and/or UNAIDS
for HIV/AIDS and tuberculosis used here.
Our projected global population in 2015 under the baseline scenario was 7.1 billion, compared with the UN medium variant projection of 7.2
billion [32], a difference of only 1.6% (see Protocol S1 for details of projection methods). By 2030, the difference between WHO and UN
baseline projections of population grew to 3.5%, and the range from pessimistic to optimistic scenarios to 7.75 billion to 8.07 billion. The

largest difference in the population growth projections is for the European region, where we project the total population to decline at a faster rate
than the UN projections.
Projected global deaths in 2030 ranged from 64.9 million under the optimistic scenario to 80.7 million under the pessimistic scenario, with a
baseline projection of 73.2 million. Projected global deaths in 2030 under the UN medium variant projections were 1% higher, at 74.0 million
[32]. Our global projections for all-cause mortality are remarkably close to the UN projections, given that our projections are the sum of
independent projections for 13 separate cause groups, whereas the UN projections are based on estimated trends in all-cause mortality, with
adjustments for projected HIV/AIDS mortality.
Our baseline global projection for all-cause mortality in 2020 (66.5 million deaths) is also remarkably similar to the original GBD baseline
projection for 2020 of 68.3 million deaths, although the projected numbers of deaths for each of the three major cause groups differ quite
significantly, as do projections for HIV/AIDS and tuberculosis. The congruence in numbers and trends in rates for all-cause mortality is almost
certainly a coincidence, since the global total death projections are derived from summing separate projections across 13 cause groups, and
almost all of the inputs to those projections have changed significantly from those used in the original projections.
Under our baseline projection, mortality of children younger than 5 y will decline globally by 29% from 2002 to 2015 (range 44% to 14% under
the optimistic and pessimistic scenarios). For sub-Saharan Africa the decline is projected to be 25%. In contrast, child mortality declined by only
12% globally and 7% in sub-Saharan Africa between 1990 and 2001 [17]. The more-than doubling of the decline in child mortality for subSaharan Africa projected for the next decade is largely determined by the relatively high projected economic growth for this region according to
the World Bank (about 2% annual increase in income per capita). Income per capita growth averaged only 0.5% in sub-Saharan Africa during the
period 19902002. Despite this, our back-projections to 1990 predicted a larger decline in child mortality than observed. The major regression
coefficients were adjusted for low-income countries, and in particular for sub-Saharan Africa, to match observed trends (see Protocol S1 for
details). Even with this adjustment, we are predicting more than double the decline in child mortality in the next decade compared to that
observed in the 1990s. This reflects the higher levels of economic growth projected for the next decade in sub-Saharan Africa.
Trends in tuberculosis death rates projected by the Stop TB Partnership for deaths of HIV-negative persons were used here, as the GBD classifies
deaths of HIV-positive persons as due to HIV/AIDS. The GBD base estimates of tuberculosis deaths for 2002 are higher than the Stop TB
Partnership 2002 estimates for deaths in sub-Saharan Africa and substantially lower in Southeast Asia (see Protocol S1). As a result of these
differences in base estimates, our baseline projection gives 960,000 tuberculosis deaths in 2015, compared to the 888,000 projected by the Stop

TB Partnership under the Sustained DOTS scenario. Both these estimates are substantially lower than the approximately 2.2 million
tuberculosis deaths projected for 2015 by Murray and Lopez in the original GBD study [1,2].
Bray and Mller have published global projections for cancer incidence in 2020 [33]. They projected that total cancer incidence would rise from
11 million new cases in 2002 to 16.5 million in 2020, assuming that 2002 agesex-specific incidence rates remained unchanged. Taking into
account projected changes in agesexsite-specific incidence rates, we project global incidence for all types of cancer to be 15.5 million cases in
2020, 6% lower than Bray and Mller's estimate. They also estimated global incidence in 2010 of 1.5 million new breast cancer cases and 1
million new prostate cancer cases, taking into account current trends in incidence rates. These are higher than our projections of 1.3 million and
0.85 million, respectively, mainly reflecting differences in the base incidence estimates for 2002.
Wilde et al. [34] estimated that the global diabetes prevalence would rise from 171 million in 2000 to 366 million in 2030, assuming that age
sex-specific diabetes prevalence rates remain unchanged within urban and rural populations in each region, but taking into account projected
increases in urbanization to 2030. Their estimate is somewhat higher than our projection of 328 million diabetes cases in 2030. Our projections
took into account projected trends for overweight and obesity, which may capture some of the impact of urbanization but did not explicitly
account for trends in urbanization. Projections based on prevalence trends have been made for diabetes in Canada and the US [35,36]. These
studies estimated that diabetes prevalence would reach 2.4 million for Canada in 2016, and 19.9 million for the US in 2025. Our projections of
diabetes prevalence for the same years are one-third higher for Canada (3.2 million) and slightly higher for the US (20.9 million).
Projected tobacco-attributable deaths in 2030 under the baseline scenario are lower than the 10 million predicted by Peto et al. [37] to occur
sometime in the 2020s or early 2030s. This earlier prediction is fairly consistent with our projection of 9.7 million tobacco-attributable deaths
under the pessimistic scenario. Murray and Lopez projected 8.4 million tobacco-attributable deaths in 2020, also somewhat higher than our
baseline projection of 7.0 million. Our lower projection reflects our downward adjustment of projected lung cancer mortality to reflect recent
trends in tobacco consumption. It must be emphasized that there is very substantial uncertainty in the tobacco-attributable mortality projections,
as the trends in apparent consumption of tobacco do not necessarily account for changes in duration, type, per capita amount, and mode of
smoking.
A recent World Bank report projected deaths due to road traffic accidents from 1990 to 2020 using an economic model that related death rates to
changes in fatalities per motor vehicle and motor vehicle ownership per person due to economic growth [38]. An overall growth of 66% was
projected for road traffic fatalities from 2000 to 2020, somewhat higher than our projection of a 51% increase in global deaths due to road traffic
accidents from 2002 to 2020 (Figure 9). Projected regional increases were generally similar, although the World Bank projected a substantially

greater increase in South Asia than we did, and a small growth for Europe and Central Asia, rather than a decline. In terms of absolute numbers
of deaths, the projections are quite different, reflecting large differences in base estimates. The World Bank study estimated global road fatalities
in 2000 as 723,000, compared with our estimate for 2002 of 1.2 million. The World Bank base estimates were derived from police statistics,
unadjusted for under-reporting. Police statistics are known to generally substantially underestimate deaths due to road traffic accidents. For
example, the World Bank estimate of 32,000 deaths for Europe and Central Asia in 2000 is 60% lower than the GBD estimate of 82,000 for
2002, based on reasonably complete death registration data.

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Figure 9. Projected Growth in Road Traffic Fatalities, 20022020: A Comparison of World Bank Projections with GBD Projections
doi:10.1371/journal.pmed.0030442.g009

Uncertainties and Limitations


There have been substantial improvements in the data and methods available for the assessment of global and regional mortality by cause. The
GBD 2002 estimates of deaths by cause, age, and sex were carried out separately for 226 countries and territories, drawing on a total of 770
country-years of death registration data, as well as 535 additional sources of information on levels of child and adult mortality, and in excess of
2,600 datasets providing information on specific causes of death in regions not well covered by death registration systems [15].
There remain, however, a large number of methodological and empirical challenges to more reliably estimating global, regional, and national
disease burden. For regions with limited death registration data, such as the Eastern Mediterranean region, sub-Saharan Africa, and parts of Asia
and the Pacific, there is considerable uncertainty in estimates of deaths by cause. Uncertainty ranges for all-cause deaths in 2001 were estimated
by Mathers et al. [16] to increase from around 1% for high-income countries to around 20% for sub-Saharan Africa. For most specific causes,
uncertainty ranges are greater than those of the all-cause mortality estimates, since there is additional uncertainty associated with cause
attribution. For example, the relative uncertainty ranges for ischaemic heart disease in 2001 were estimated to range from about 12% for highincome countries to around 30% for sub-Saharan Africa. The uncertainty range for HIV/AIDS deaths in sub-Saharan Africa was narrower at
15%, reflecting the substantial data base for these estimates.
The projections of burden are not intended as forecasts of what will happen in the future but as projections of current and past trends, based on
certain explicit assumptions. The methods used base the disease burden projections largely on broad mortality projections driven by World Bank
projections of future growth in income and WHO projections of increases in human capital in different regions of the world, together with a
model relating these to cause-specific mortality trends based on the historical observations in countries with death registration data from the past
50 years. The results depend strongly on the assumption that future mortality trends in developing countries will have a similar relationship to

economic and social development as has occurred in the more developed countries. If this assumption is not correct, then the projections for lowincome countries will be over-optimistic in the rate of decline of communicable diseases and the speed of the epidemiological transition.
The predictions of the projections model were compared with historical trends in child mortality from 1990 to 2002, and as a result, certain
regression coefficients were modified for low-income countries. As a result, our revised projections assume that projected rates of change for
cause-specific mortality rates over time, given levels of constant income and human capital, will be slower than those observed in the mainly
high- and middle-income countries with death registration data from the past 50 years. This has reduced the projected rates of decline in Group I
conditions for low-income countries compared to the original GBD projections, and it is entirely possible that this adjustment may be too
conservative. On the other hand, the many problems facing low-income countries in improving and sustaining access to effective health
interventions, and in scaling up health systems to cost-effectively address these challenges, may mean that the low-income countries do not
experience the temporal pace of health improvement at constant levels of income and human capital that have been seen in the high-income
countries in the past 50 years.
The projections have also not taken explicit account of trends in major risk factors apart from tobacco smoking, and, to a limited extent,
overweight and obesity. If broad trends in risk factors are for worsening of risk exposures with development, rather than the improvements
observed in recent decades in many high-income countries, then again the projections for low- and middle-income countries presented here will
be too optimistic. There is a need to develop much more comprehensive projection models that take explicit account of available information on
trends in a wide range of risk factors. The HIV/AIDS baseline projections in particular assume that transmission probabilities will remain largely
unchanged in the future and there will not be substantial reductions in risk factors for HIV.
A projections exercise such as this by its nature involves substantial assumptions about the similarity of future trends to past trends, and about
the future trends in broad drivers of health improvement. There are thus wide uncertainty ranges around future projections. Nevertheless, there
are some aspects of the projections that clearly involve more uncertainty than others. For example, the projections of HIV/AIDS mortality are
strongly affected by the assumptions made about the levels of additional prevention effort that occur over the next two decades. Additionally,
there are substantial uncertainties about the future trends in chronic respiratory disease mortality for non-smokers, and diabetes mortality for
persons not overweight. Also, the evidence on the associations of injury mortality with income and human capital was weaker than for Group I
and Group II conditions, and stronger assumptions were thus required for injury projections for some external causes. In the absence of any
realistic approach to forecasting future war deaths, rates for these were assumed to remain constant over time in the baseline scenario. This may
be too conservative, given the substantial decrease in the number of wars and civil conflicts in the past decade or two.

Finally, as did Murray and Lopez, we recognize that the approach taken to projecting YLD is extremely crude, and that the projections of
DALYs are likely to be even more uncertain than the projections of deaths. It may be the case that case fatality rates for many diseases decline
during the next 30 years, so that YLD become an increasing proportion of the total DALYs for these causes. On the other hand, improvements in
risk factors and/or health interventions may lead to decreases in burden for some nonfatal conditions. Substantial research remains to develop
robust and unbiased methods for measuring trends in case fatality rates, survival times, and disability due to specific causes, let alone collecting
such data across all regions of the world.

Conclusions
Despite these uncertainties, projections provide a useful perspective on population health trends and health policies, provided that they are
interpreted with a degree of caution. Projections enable us to appreciate better the implications for health and health policy of currently observed
trends, and the likely impact of fairly certain future trends, such as the ageing of the population, and the continuation of the epidemiological
transition in developing countries. These projections represent a set of three visions of the future for population health, under an explicit set of
assumptions and for specific projections of income, human capital, and of future trends in tobacco smoking, HIV/AIDS transmission and
survival, and overweight and obesity. If the future is not like the pastfor example, through sustained and additional efforts to address the
Millennium Development Goals, or through major scientific breakthroughsthen the world may well achieve faster progress than projected
here, even under the optimistic scenario. On the other hand, if economic growth in low-income countries is lower than the forecasts used here,
then the world may achieve slower progress and widening of health inequalities.

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Alternative Language Text S1. Translation of the Article into French


doi:10.1371/journal.pmed.0030442.sd001
(37 KB DOC)

Dataset S1. Deaths by Cause, Scenario, Sex, and Age for 2002, 2015, and 2030
doi:10.1371/journal.pmed.0030442.sd002
(1 MB XLS)

Dataset S2. DALYs by Cause, Scenario, Sex, and Age for 2002, 2015, and 2030
doi:10.1371/journal.pmed.0030442.sd003
(1 MB XLS)

Protocol S1. Technical Appendix


doi:10.1371/journal.pmed.0030442.sd004
(200 KB PDF)

Table S1. Country Classifications Used for Reporting Results: World Bank Regional Groups and World Bank Income
Groups
doi:10.1371/journal.pmed.0030442.st001
(69 KB DOC)

Table S2. GBD Cause Categories and ICD Codes


doi:10.1371/journal.pmed.0030442.st002
(184 KB DOC)

Table S3. Parsimonious Regression Equations for Nine Major Cause Clusters Based on the Full Country Panel Dataset,
19502002
doi:10.1371/journal.pmed.0030442.st003
(334 KB DOC)

Table S4. Parsimonious Regression Equations for Nine Major Cause Clusters Based on the Low-Income Country Panel
Dataset, 19502002
doi:10.1371/journal.pmed.0030442.st004
(335 KB DOC)

Table S5. Results of Regressions of AgeSex-Specific Mortality for Detailed Causes on the Respective Cause Cluster
Based on the Full Country Panel Dataset, 19502002
doi:10.1371/journal.pmed.0030442.st005
(765 KB DOC)

Table S6. Results of Log-Linear Poisson Regressions for Deaths Due to Selected Causes, by Age and Sex, for Countries
with Complete Death Registration Data and Population of More Than 5 Million
doi:10.1371/journal.pmed.0030442.st006
(1.2 MB DOC)

Table S7. Summary of Assumptions and Inputs for Baseline, Optimistic, and Pessimistic Projection Scenarios
doi:10.1371/journal.pmed.0030442.st007
(67 KB DOC)

Acknowledgments
We gratefully acknowledge the assistance of Hongyi Xu, Niels Tomijima, Doris Ma Fat, and Mie Inoue in the preparation of inputs for the
projections calculations. We thank Ajay Tandon for providing WHO projections of income and human capital. We thank Karen Stanecki,
Elizabeth Zaniewski, and Peter Ghys, all from UNAIDS, for assistance in obtaining detailed HIV projections and documentation prepared by the
WHO and UNAIDS Working Party. Josh Salomon provided further unpublished results for projections of HIV mortality for scenarios with
additional prevention efforts. We thank Chris Dye and Catherine Watt for providing Stop TB Partnership projections for tuberculosis in HIV-

negative persons. Kate Strong and Tomoko Ono provided projections of body mass index distributions. Marie-Claude von Rulach-Duvernay
provided secretarial and translation assistance.

Author Contributions
CDM designed the study. CDM and DL analyzed the data. CDM and DL contributed to writing the paper. CDM led the design of the study and
was primarily responsible for the burden of disease and population projections and the interpretation of the results. DL was primarily responsible
for the preparation and analysis of the input mortality data (data from the WHO mortality database). Both authors participated in the
development of the mortality projections under the three scenarios.

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Open Access
Peer-reviewed
Research Article

Projections of Global Mortality and Burden of Disease from 2002 to


2030

Colin D Mathers ,
Dejan Loncar

Projections of Global Mortality and Burden of Disease from 2002 to


2030

Colin D Mathers,
Dejan Loncar

Published: November 28, 2006


DOI: 10.1371/journal.pmed.0030442

Article

About the Authors

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Abstract

Editors' Summary

Introduction

Methods

Results

Discussion

Supporting Information

Acknowledgments

Author Contributions

References

Reader Comments (0)

Media Coverage (1)

Figures

Abstract
Background
Global and regional projections of mortality and burden of disease by cause for the years 2000, 2010, and 2030 were published by Murray and
Lopez in 1996 as part of the Global Burden of Disease project. These projections, which are based on 1990 data, continue to be widely quoted,
although they are substantially outdated; in particular, they substantially underestimated the spread of HIV/AIDS. To address the widespread
demand for information on likely future trends in global health, and thereby to support international health policy and priority setting, we have
prepared new projections of mortality and burden of disease to 2030 starting from World Health Organization estimates of mortality and burden
of disease for 2002. This paper describes the methods, assumptions, input data, and results.

Methods and Findings

Relatively simple models were used to project future health trends under three scenariosbaseline, optimistic, and pessimisticbased largely
on projections of economic and social development, and using the historically observed relationships of these with cause-specific mortality rates.
Data inputs have been updated to take account of the greater availability of death registration data and the latest available projections for
HIV/AIDS, income, human capital, tobacco smoking, body mass index, and other inputs. In all three scenarios there is a dramatic shift in the
distribution of deaths from younger to older ages and from communicable, maternal, perinatal, and nutritional causes to noncommunicable
disease causes. The risk of death for children younger than 5 y is projected to fall by nearly 50% in the baseline scenario between 2002 and
2030. The proportion of deaths due to noncommunicable disease is projected to rise from 59% in 2002 to 69% in 2030. Global HIV/AIDS deaths
are projected to rise from 2.8 million in 2002 to 6.5 million in 2030 under the baseline scenario, which assumes coverage with antiretroviral
drugs reaches 80% by 2012. Under the optimistic scenario, which also assumes increased prevention activity, HIV/AIDS deaths are projected to
drop to 3.7 million in 2030. Total tobacco-attributable deaths are projected to rise from 5.4 million in 2005 to 6.4 million in 2015 and 8.3 million
in 2030 under our baseline scenario. Tobacco is projected to kill 50% more people in 2015 than HIV/AIDS, and to be responsible for 10% of all
deaths globally. The three leading causes of burden of disease in 2030 are projected to include HIV/AIDS, unipolar depressive disorders, and
ischaemic heart disease in the baseline and pessimistic scenarios. Road traffic accidents are the fourth leading cause in the baseline scenario, and
the third leading cause ahead of ischaemic heart disease in the optimistic scenario. Under the baseline scenario, HIV/AIDS becomes the leading
cause of burden of disease in middle- and low-income countries by 2015.

Conclusions
These projections represent a set of three visions of the future for population health, based on certain explicit assumptions. Despite the wide
uncertainty ranges around future projections, they enable us to appreciate better the implications for health and health policy of currently
observed trends, and the likely impact of fairly certain future trends, such as the ageing of the population, the continued spread of HIV/AIDS in
many regions, and the continuation of the epidemiological transition in developing countries. The results depend strongly on the assumption that
future mortality trends in poor countries will have a relationship to economic and social development similar to those that have occurred in the
higher-income countries.

Figures

Citation: Mathers CD, Loncar D (2006) Projections of Global Mortality and Burden of Disease from 2002 to 2030. PLoS Med 3(11): e442.
doi:10.1371/journal.pmed.0030442
Academic Editor: Jon Samet, Johns Hopkins School of Public Health, United States of America
Received: January 27, 2006; Accepted: September 5, 2006; Published: November 28, 2006
Copyright: 2006 Mathers and Loncar. This is an open-access article distributed under the terms of the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Financial support for this project was provided by the World Health Organization (WHO) Department of Chronic Diseases and Health
Promotion and the WHO Commission on Intellectual Property Rights, Innovation and Public Health. The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.

Abbreviations: ART, antiretroviral therapy; COPD, chronic obstructive pulmonary disease; CRA, Comparative Risk Assessment; DALY,
disability-adjusted life year; DOTS, directly observed therapy, short-course; GBD, Global Burden of Disease; GDP, gross domestic product;
ICD, International Classification of Diseases; SIR , smoking impact ratio; UNAIDS, Joint United Nations Programme on HIV/AIDS; YLD,
years lived with disability; YLL, years of life lost due to mortality

Editors' Summary
Background.
For most of human history, little has been known about the main causes of illness in different countries and which diseases kill most people. But
public-health officials need to know whether heart disease kills more people than cancer in their country, for example, or whether diabetes causes
more disability than mental illness so that they can use their resources wisely. They also have to have some idea about how patterns of illness
(morbidity) and death (mortality) are likely to change so that they can plan for the future. In the early 1990s, the World Bank sponsored the 1990
Global Burden of Disease study carried out by researchers at Harvard University and the World Health Organization (WHO). This study
provided the first comprehensive, global estimates of death and illness by age, sex, and region. It also provided projections of the global burden
of disease and mortality up to 2020 using models that assumed that health trends are related to a set of independent variables. These variables
were income per person (as people become richer, they, live longer), average number of years of education (as this human capital increases, so
does life expectancy), time (to allow for improved knowledge about various diseases), and tobacco use (a major global cause of illness and
death).

Why Was This Study Done?


These health projections have been widely used by WHO and governments to help them plan their health policies. However, because they are
based on the 1990 estimates of the global burden of disease, the projections now need updating, particularly since they underestimate the spread
of HIV/AIDS and the associated increase in death from tuberculosis. In this study, the researchers used similar methods to those used in the 1990
Global Burden of Disease study to prepare new projections of mortality and burden of disease up to 2030 starting from the 2002 WHO global
estimates of mortality and burden of disease.

What Did the Researchers Do and Find?

As before, the researchers used projections of socio-economic development to model future patterns of mortality and illness for a baseline
scenario, a pessimistic scenario that assumed a slower rate of socio-economic development, and an optimistic scenario that assumed a faster rate
of growth. Their analysis predicts that between 2002 and 2030 for all three scenarios life expectancy will increase around the world, fewer
children younger than 5 years will die, and the proportion of people dying from non-communicable diseases such as heart disease and cancer
will increase. Although deaths from infectious diseases will decrease overall, HIV/AIDS deaths will continue to increase; the exact magnitude of
the increase will depend on how many people have access to antiretroviral drugs and the efficacy of prevention programs. But, even given the
rise in HIV/AIDS deaths, the new projections predict that more people will die of tobacco-related disease than of HIV/AIDS in 2015. The
researchers also predict that by 2030, the three leading causes of illness will be HIV/AIDS, depression, and ischaemic heart disease (problems
caused by a poor blood supply to the heart) in the baseline and pessimistic scenarios; in the optimistic scenario, road-traffic accidents will
replace heart disease as the third leading cause (there will be more traffic accidents with faster economic growth).

What Do These Findings Mean?


The models used by the researchers provide a wealth of information about possible patterns of global death and illness between 2002 and 2030,
but because they include many assumptions, like all models, they can provide only indications of future trends, not absolute figures. For
example, based on global mortality data from 2002, the researchers estimate that global deaths in 2030 will be 64.9 million under the optimistic
scenario. However, the actual figure may be quite a bit bigger or smaller because accurate baseline counts of deaths were not available for every
country in the world. Another limitation of the study is that the models used assume that future increases in prosperity in developing countries
will affect their population's health in the same way as similar increases affected health in the past in countries with death registration data (these
are mostly developed countries). However, even given these and other limitations, the projections reported in this study provide useful insights
into the future health of the world. These can now be used by public-health officials to plan future policy and to monitor the effect of new publichealth initiatives on the global burden of disease and death.

Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030442.

World Health Organization, provides information on the Global Burden of Disease Project and links to other related resources Global
Burden of Disease Project

Harvard School of Public Health, Burden of Disease Unit, offers information on the 1990 Global Burden of Disease study and its
projections Harvard School of Public Health

Introduction
As part of the groundbreaking Global Burden of Disease (GBD) study for 1990, Murray and Lopez [1,2] prepared projections of mortality and
burden of disease by cause to 2000, 2010, and 2020 under three alternative scenarios. These projections have been widely used and continue to
be widely quoted to provide information on likely future trends in global health, for example in the Atlas of Heart Disease and Stroke [3].
However, these projections were based on the GBD 1990 estimates and on projections of HIV/AIDS, smoking, income, and human capital from
1990 to 2020, and are now outdated. The HIV/AIDS projections in particular substantially underestimate the spread of the HIV epidemic and the
level of HIV/AIDS mortality around 2000.
We have thus prepared updated projections of mortality and burden of disease from 2002 to 2030 using methods similar to those of the original
GBD study and new input information. An earlier version of these projections has already been extensively used in the recently released World
Health Organization (WHO) global report Preventing chronic diseases: A vital investment [4].
There is a substantial literature on the projection or forecasting of all-cause mortality rates and mortality rates for specific diseases. The methods
used fall into two broad groups. First are those methods based on time-series analysis of historical trends in mortality rates. These aggregate
models, whether for all-cause mortality or for specific causes, use the previous trend of the variable of interest as the basis for predicting its
future value. By their data requirements, such methods are generally limited to high-income countries with good death registration data (see, for
example, Lee and Carter [5,6]). Second are the structural models, which are based on relationships between mortality and a set of independent
variables, and are necessarily projections of those independent variables. To the extent that the structural model identifies the important
componentsand the relationships among themof the system that determines the variable of interest, they offer the potential for more
robust predictions. When the underlying system is complex and sensitive to one or more of its components, a shift in some of the system
variables can introduce large changes in the outcome that may be missed by extrapolation (such as the discovery of antibiotics and infectious
disease trends or the change in tuberculosis mortality after the HIV epidemic). Aggregate models, in contrast, require considerably less
knowledge of the system components and the relationships among them. These models can therefore provide more reliable estimates when such
information is not available, especially when the system is not very sensitive to its inputs in time intervals that are in the order of the prediction
time.

The GBD projections fall into the structural models class, as do a number of more sophisticated and data-demanding risk factorbased models
for specific causes [710]. Methods also vary as to whether mortality is projected for all age groups simultaneously or separate models are
developed for each agesex group, and as to whether separate cause-specific projections are carried out. To our knowledge, the original GBD
projections represent the only attempt to date to project cause-specific mortality, rather than all-cause mortality, for a complete set of causes at
global and regional levels. The GBD projections use separate structural models for each of a small set of major cause groups and causecompositional models for detailed causes within these groups. The latter are a special case of more general cause-compositional models that
relate the proportional distributions of causes of death to the levels of all-cause mortality [11].
Recently, both types of projection model have been extended to allow incorporation of prior knowledge and enforce coherence in the resulting
mortality estimates across age groups, causes, and regions. Czado et al. [12] extended the Lee-Carter Poisson log-bilinear model into a Bayesian
model, in which the prior data impose smoothness of age and period effects in the projections. Girosi and King [13] developed a forecasting
model that models future values of log-mortality as functions of covariates known to affect risk of death. They also used a Bayesian approach to
allow different countryagegroup cross-sections to borrow strength from each other in order to overcome the serious data limitations faced
for many countries. Their model also constrains the projections to vary smoothly over time and across age groups in accordance with known age
profiles for specific causes of death.
The detailed application of such methods may result in substantially improved forecasts of global mortality and burden of disease trends in the
next few years. In the meantime, these updated projections provide a comprehensive update of the original GBD projections, with some
methodological improvements and extensions.

Methods
The methods used in the present study for the projections of mortality and burden of disease are similar to those used in the original GBD study
[2]. Separate projections models for males and females and for seven age groups (04, 514, 1529, 3044, 4559, 6069, and 70 y and older)
were developed to produce parsimonious equations for ten cause-of-death clusters. Baseline, pessimistic, and optimistic projections of covariates
in the regression equations were developed and used to project mortality rates for the cause clusters. Separate projection models were developed
for HIV/AIDS, tuberculosis, lung cancer, diabetes mellitus, and chronic respiratory diseases. Separate regression equations were developed
relating age- and sex-specific mortality rates for 132 detailed causes to the age- and sex-specific mortality rates from corresponding cause
clusters, based on International Classification of Diseases Ninth Edition (ICD-9) coded vital registration data from 98 countries.

Whereas the original GBD study carried out projections for eight regions of the world, we carried out these projections at country level, but
aggregated the results into regional or income groups for presentation of results. Four income groups were defined based on World Bank
estimates of GDP per capita in 2001 (see Table S1 for definitions of the regional and income groups). Baseline estimates at country level for
2002 were derived from the GBD analyses for 2002 as published in the World Health Report 2004 [14]. Data sources and methods for the 2002
estimates were comprehensively documented by Mathers et al. [15], together with an analysis of uncertainty levels of the results [16]. Mortality
and burden of disease trends from 1990 to 2001 were recently analyzed by Lopez et al. [17].
Projections of burden of disease measured in disability-adjusted life years (DALYs) were then developed for the three scenarios based on
projected mortality rates and alternative assumptions for those causes with little or no mortality. Population projections were developed based on
United Nations Population Division projections of fertility and net migration and our projected mortality rates. We describe the main features of
the methods, assumptions, and input data in this section, with a particular emphasis on revisions and changes to the original methods used by
Murray and Lopez. Protocol S1 and Tables S1S7 provide full details.

Regressions for Major-Cause Clusters


Disease and injury causes of death are classified in the GBD using a tree structure in which the first level comprises three broad cause groups:
Group I (communicable, maternal, perinatal, and nutritional conditions), Group II (noncommunicable diseases), and Group III (injuries) [15]. We
projected age- and sex-specific death rates at country level for ten major-cause clusters: Group I conditions excluding HIV/AIDS
(communicable, maternal, perinatal, and nutritional conditions as defined in Table S2), malignant neoplasms (excluding lung cancer), diabetes
mellitus, cardiovascular diseases, digestive disorders, chronic respiratory conditions, other Group II diseases, road traffic accidents, other
unintentional injuries, and intentional injuries. In contrast to the original GBD projections, diabetes mellitus was treated as a separate cause
category from other Group II diseases, since the available evidence suggests that its dominant risk factor, overweight and obesity, is becoming
more prevalent over time in both developed and developing regions and is projected to continue to rise [18].
Rather than attempt to model the effects of the many separate direct determinants or risk factors for disease from the limited data that are
available, the GBD methodology considered a limited number of socioeconomic variables: (1) average income per capita, measured as gross
domestic product (GDP) per capita; (2) the average number of years of schooling in adults, referred to as human capital; and (3) time, a proxy
measure for the impact of technological change on health status. This latter variable captures the effects of accumulating knowledge and

technological development, allowing the implementation of more cost-effective health interventions, both preventive and curative, at constant
levels of income and human capital [1].
These socioeconomic variables show clear historical relationships with mortality rates, and may be regarded as indirect, or distal, determinants
of health, although it is not necessary for the purposes of projection to know whether these associations are causal. In addition, a fourth variable,
tobacco use, was included in the projections for cancers, cardiovascular diseases, and chronic respiratory diseases, because of its overwhelming
importance in determining trends for these causes. Tobacco use was measured in terms of smoking impactthat component of observed lung
cancer mortality attributable to tobacco smoking [19]. This indirect measure of the accumulated hazards provides a better measure than do
current smoking rates for the overall health impact of tobacco, taking into account lag times as well as important aspects of exposure such as
duration, type, amount, and mode of smoking (see Protocol S1 for more details).
We used a regression equation of the same form as in the original GBD projections:
where Ca,k,i is a constant term, Ma,k,i is the mortality level for age
group a, sex k, and cause i, and Y, HC, and T denote GDP per capita, human capital, and time, respectively. The log of the smoking impact SI is
included in the equation only for malignant neoplasms, cardiovascular diseases, and respiratory diseases. This basic functional relationship
makes no specific assumptions about the relationships between these more distal socioeconomic factors and more proximate determinants of
mortality rates such as environment, lifestyle, and physiological risk factors. Nevertheless, our regression results indicate that a considerable
proportion of the variance in age-, sex-, and cause-specific mortality rates can be explained by this limited set of distal determinants.
Murray and Lopez used a variety of econometric approaches to estimate the equations (Equation 1), including methods that take into account
auto-correlation and heteroscedasticity. Because these methods substantially restricted the subset of panel data that could be used, and in
particular resulted in much loss of information for moderate- to high-mortality populations, they chose to use ordinary least-squares regression
based on the entire dataset for the final set of parameter estimates. We followed the same approach and estimated equations (of the form
illustrated by Equation 1) separately for each agesexcause group.
Death registration data from 106 countries for 19502002 [20] were used to estimate the regression equations. In total, 2,605 country-years were
available, almost double those used for the original projections by Murray and Lopez. Although the dataset is extensive, it does not include many
observations from populations with high rates of mortality. Whereas the original GBD projections applied a single set of models based on all

observed death registration data for projections in all regions, the new projections for low and lower-middle-income countries (income in
international dollars less than $3,000 per capita in 2002) were based on the observed relationships for a dataset consisting of 1,734 country-years
of observation where income per capita was less than $10,000 per year. Additionally, observed regional trends in child mortality from 1990 to
2002 were compared with those predicted by the projection model for low-income countries conditional on the observed time series for the
model covariates for that period. As a result, the regression coefficient for time was set to zero for sub-Saharan Africa, and to 25% of its original
value for other low-income countries.
Final parsimonious regression results are listed in Tables S3 and S4. The low-income regression results give somewhat more conservative
declines for Group II (noncommunicable) diseases in low-income regions. In general, the final regression equations are broadly similar to those
estimated for the original projections. Apart from injuries, they explain a surprising proportion of the variance for many agesexcause
categories. For males and females aged 70 y and above, the R2 for many cause clusters was generally lower than for other age groups, probably
reflecting poorer quality of coding of causes of death or the smaller range of variation in mortality rates between countries at these older ages, as
well as the inherent reductions in the explanatory power of covariates with increasing death rates with age. The lower proportions of variance
explained for injuries may reflect lower levels of temporal variation in these causes as well as more heterogeneous injury causes that may be less
well-correlated with income and human capital.
For cause clusters in agesex groups in which the R2 was less than 10%, we carefully examined the consistency of the projections with other
agesex groups, and made a choice between using the final parsimonious regression equation, an alternative assumption such as stable (constant)
rates, or a separate prediction model based on projections for the major relevant risk factor (diabetes mellitus and chronic respiratory diseases).
Model predictions of age-, sex-, and cause-specific mortality rates in 2002 for each of the ten clusters of causes were compared for each country
with the results of the GBD study for that year. A series of scalars were then derived so that projected values for 2002 were identical to the 2002
GBD results. It was then assumed that these scalars would remain constant over the period 20022030.

Diabetes and Chronic Respiratory Conditions


Initial regression analysis for diabetes mellitus found inconsistent trends between males and females, probably reflecting the large variations
across countries and inaccuracies in recording diabetes as the underlying cause of death in many death registration systems. While overall trends
for diabetes mortality showed no consistent relationship across the sexes or levels of development, the regression analysis found significant betas

for T (year) with death rates increasing with time. Since a substantial proportion of diabetes mortality is attributable to overweight and obesity
[21], a separate projection model for diabetes mortality was developed using WHO projection of trends in body mass index distributions from
2000 to 2010 (see Protocol S1 for more details).
Initial projections for chronic respiratory diseases resulted in substantially increasing rates for high-income countries, although smoking is the
main risk factor and smoking impact has been generally decreasing. It is likely that the initial projections may reflect increasing propensity to
code chronic obstructive pulmonary disease (COPD) as the underlying cause of death with time. Projections of mortality for chronic respiratory
diseases were thus adjusted for projected changes in smoking impact (see Protocol S1 for more details).

Projections of Income, Human Capital, and Smoking Impact


Revised country-level projections for income per capita, human capital, and smoking impact were developed for the baseline, pessimistic, and
optimistic projections. Income per capita was measured using average GDP per capita expressed in international dollars (purchasing power
parity adjusted). Country-specific and regional income growth forecasts by the World Bank were used to project GDP per capita for all WHO
member states. Beyond 2015, projected growth rates for most regions approach 3% per annum under the baseline scenario, with somewhat lower
growth rates in sub-Saharan Africa, the Middle East, and high-income countries (see Protocol S1 for more details).
Revised estimates and projections of human capital for WHO member states were prepared for the period 19502030 drawing on previous
estimates by Barro and Lee for 98 countries [22] and observed relationships between growth in human capital and growth in GDP per capita.
Smoking impact was calculated for the historical mortality countryyear observations by subtracting nonsmoker lung cancer rates from observed
total lung cancer mortality rates in the data. Higher nonsmoker lung cancer mortality rates were used in China and Southeast Asian countries, to
reflect the higher levels of lung cancer in nonsmokers due to indoor air pollution from exposure to smoke from solid fuels [23,24].
Ezzati and Lopez developed projections of smoking intensity for 14 sub-regions of the WHO regions for the Comparative Risk Assessment
(CRA) project, based on an analysis of past and current agesex-specific smoking prevalence calibrated to regional characteristics of the tobacco
epidemic for different sub-regions [23,24]. These regional projections were used to develop country-specific projections drawing also on more
recent World Bank data on trends in adult per capita consumption of cigarettes and recent observed trends in agesex-specific lung cancer

mortality (see Protocol S1 for more details). For four high-income countries, recent projections were used based on an ageperiodcohort model
estimated using historical data on agesex-specific tobacco consumption, average tar content, and adult tobacco consumption per capita [25].

Regression Equations for Detailed Causes


To project death rates for specific causes within the major-cause clusters, we followed the original GBD methodology in estimating the
relationship between trends in agesex-specific mortality for each specific cause with the trend in the agesex-specific mortality for the majorcause cluster to which the specific cause belongs. To avoid biasing the results due to changes in specific cause death rates associated with use of
different versions of ICD, we restricted the analysis to country-years for which deaths were coded using ICD-9. The regression parameters were
estimated on 1,357 country-year observations for 98 countries.
For each individual regression, observations were excluded from analysis if they related to fewer than 50 deaths. Regression results were used
only where the relationship was reasonably strong, as measured by an R2 greater than 0.25 and a p-value less than 0.001 for the regression
coefficient. The resulting coefficients are shown in Table S5.
The major-cause cluster regression equation for intentional injury predicted generally falling death rates in middle- and low-income countries
and rising death rates in high-income countries. For homicide, this is the opposite of the observed trends in the larger high-income countries. For
this reason, homicide death rates were assumed to remain constant under the baseline scenario, with some modifications for country-specific
observed trends. Similarly, war deaths were assumed to remain constant under the baseline scenario.
For countries with good death registration data and populations of 5 million or more, trends in mortality rates were estimated for ischaemic heart
disease, cerebrovascular disease, tuberculosis, suicide, and homicide. These were used to adjust the initial years of relevant country-specific
projections to match the recent observed trends.

Projections for HIV/AIDS and Tuberculosis


We used separate projections for HIV/AIDS mortality under several scenarios derived from existing models. The Joint United Nations
Programme on HIV/AIDS (UNAIDS) and WHO [26] have prepared projections of HIV/AIDS mortality under a range of assumptions about the

future of the HIV epidemics in all regions and with varying treatment scale-up assumptions for both adult and children using a transmission
model previously used to assess the impact of preventive interventions [10,27].
The model includes underlying regional demography, acquisition of HIV and other sexually transmitted infections, and progression from HIV
infection to AIDS and death. For countries with generalized epidemics (mostly in sub-Saharan Africa), the model variables were estimated from
sentinel site prevalence data. For countries with epidemics concentrated in groups with higher-risk behaviour, the size and HIV prevalence was
estimated for each of these groups, and prevalence in low-risk populations was estimated by allowing for transmission from high-risk to low-risk
groups via sexual mixing. Projections of these epidemics were based on assumptions about degree of saturation for each of the high-risk groups,
time to saturation, and spread from high-risk to low-risk populations over time (see Protocol S1 for further information).
Our baseline projections for HIV/AIDS agesex-specific mortality rates were based on the UNAIDS and WHO medium scenario for treatment
scale-up. Under this scenario, antiretroviral therapy (ART) coverage will reach 80% by 2012 in all regions, remaining constant beyond that year.
The treatment scenarios assumed no effect of treatment on transmission and incidence rates, and no additional prevention efforts resulting in
reduction of transmission and incidence rates.
Our pessimistic projections for HIV/AIDS agesex-specific mortality rates were based on the UNAIDS and WHO slow scenario for treatment
scale-up. Under this scenario, ART coverage will reach 60% by 2012 in all regions except Latin America, where it reaches 70% in 2013.
HIV/AIDS mortality rates in high-income countries were assumed to remain constant as in the baseline scenario.
Salomon et al. [28] have modelled scenarios for sub-Saharan Africa combining treatment and additional prevention efforts. In one scenario, ART
coverage is scaled up and optimal assumptions are made about treatment impact on transmissibility and patient behaviour. A second scenario
assumes that an emphasis on treatment leads to less effective implementation of prevention, resulting in only 25% attainment of the maximum
potential impact of prevention efforts. For our optimistic projection of HIV/AIDS mortality, we used a third unpublished scenario prepared by
Salomon et al. that is approximately halfway between their two published mixed treatment-prevention scenarios. For low- and middle-income
countries outside sub-Saharan Africa, we assumed similar proportional reductions in incidence rates for HIV infection due to increased
prevention, as estimated for sub-Saharan Africa (see Protocol S1 for more details).
Because of the powerful interaction between tuberculosis and HIV infections in regions such as sub-Saharan Africa, Murray and Lopez modified
the original projections from 1990 to 2020 for tuberculosis death rates. As part of the Global Plan to Stop TB covering the period 20062015, the
Stop TB Partnership has prepared three projection scenarios for tuberculosis incidence, prevalence, and mortality based on different assumptions

about the pace of scale-up and coverage of interventions to achieve the UN's Millennium Development Goals for tuberculosis [29]. The Global
Plan scenario assumes massive scale-up in tuberculosis control activities, achieving case detection levels of more than 70% and using the WHO
DOTS (directly observed therapy, short-course) treatment strategy to reach cure rates of more than 85%. The Sustained DOTS scenario
assumes that case detection and treatment success rates increase until 2005 and then remain constant to 2015. A third No DOTS scenario
assumes that the DOTS treatment strategy was never introduced in any region, so case detection, treatment, and cure rates would continue as
they were pre-DOTS (see Protocol S1 for more details).
The projected annual regional trends in tuberculosis death rates for HIV-negative cases under these three scenarios were used to project
tuberculosis death rates for countries in each region as follows. Annual projected trends under the Sustained DOTS scenario were used for the
baseline projections, and those under the Global Plan scenario were used for the optimistic projections. For the pessimistic projections, annual
trends in rates were estimated as halfway between those projected under the sustained DOTS scenario and those projected under the No
DOTS scenario from 2006 onwards. For 20162030, annual trends from 2015 to 2030 were assumed to converge on the regional projected
trends for Group I causes excluding HIV/AIDS under the baseline scenario. For the optimistic and pessimistic scenarios, annual regional trends
were assumed to remain constant from 2015 to 2030.

Projections of Tobacco-Caused Deaths


As part of the WHO's CRA project, Ezzati and Lopez [23] estimated the total mortality attributable to tobacco smoking in 2000 for the world and
for WHO sub-regions. Current levels of smoking impact ratio (SIR) were used as an indirect indicator of accumulated smoking risk based on
excess lung cancer mortality. SIR measures the absolute excess lung cancer mortality due to smoking in the study population, relative to the
absolute excess lung cancer mortality in lifelong smokers of the reference population. SIR values were calculated from the projected smoking
impact variables for individual countries for age groups 3044 y and older.
Projected mortality attributable to tobacco was estimated using the CRA methods for lung cancer, upper aerodigestive cancer, all other cancers,
COPD, other respiratory diseases, cardiovascular diseases, tuberculosis, and selected other disease causes.

Projecting the Burden of Disease and Injury

The WHO has undertaken new assessments of the GBD for 20002002, with consecutive revisions and updates published annually in WHO's
World Health Reports. These assessments use a health gap measure, the DALY, developed by Murray and Lopez [30] to quantify the equivalent
years of full health lost due to diseases and injury in WHO member states. The data sources and methods used for the GBD 2002 are
documented elsewhere [1517], and summary results for 14 regions of the world are published in the World Health Report 2004 [14] and
available at http://www.who.int/evidence/bod.
The burden of disease estimates for 2002 were used as a base for projections of burden of disease to 2030. Years of life lost (YLL) were
calculated from the projections of mortality by cause, age, and sex, according to the GBD method. To project DALYs, it is also necessary to
project years lived with disability (YLD). Given the lack of good information on trends in disability and health state distributions, the approach
used here is an elaboration of the methods and assumptions used by Murray and Lopez in the original GBD projections [1].
YLD projections were generally derived from the YLL projections by applying the ratio of YLD to YLL for 2002. For ischaemic heart disease
and stroke, future incidence rates were assumed to decline at 50% of their mortality rate declines reflecting declining case fatality rates as well as
incidence rates. For causes where there is little or no mortality, agesex-specific YLD rates per capita were generally assumed to remain constant
into the future. For certain mental disorders, musculoskeletal conditions, and hearing loss, disability weights were assumed to decline somewhat
with improvements in income per capita reflecting increasing treatment coverage. YLD rates for nonfatal communicable diseases and nutritional
deficiencies were assumed to decline at between 50% and 100% of the mortality rate declines for Group I causes.

Projections of Population and Numbers of Deaths and DALYs


Our projections of mortality rates, together with UN medium variant assumptions for fertility rate projections and projected migration rates [31],
were also used to prepare consistent population projections for all regions. The projected global population in 2015 was 7.1 billion compared to
the UN medium variant projection of 7.2 billion, reflecting somewhat higher adult death rates in our mortality projections.
Projected death and DALY rates for 192 WHO member states for 20032030 were applied to the projected populations to generate projected
numbers of deaths and DALYs for each of the three scenarios. The resulting country projections were added back into regional groups for
presentation of results (see Table S1).The choices and assumptions incorporated in each of the baseline, pessimistic, and optimistic scenarios are
summarized in Table S7.

Results
This section provides an overview of the projections. Detailed results for 2002, 2015, and 2030 are presented in Dataset S1 for deaths and
Dataset S2 for DALYs. These tables include baseline, pessimistic, and optimistic projected totals for each cause category, as well as a sex and
age breakdown for the baseline category.
Figure 1 shows projected life expectancies at birth in 2030 under the three scenarios, for World Bank regions. Life expectancy at birth is
projected to increase in all World Bank regions, with the largest increases in the African region and the South Asian regions. However, under the
baseline scenario, male life expectancy in the African region will still remain less than 55 y. In all regions except the European region, life
expectancy increases are greater for females than for males. Life expectancy for women in the high-income countries may reach 85.0 y by 2030,
compared with 79.7 y for men. The highest projected life expectancy in 2030 is for Japanese women at 88.5 y (with a range of 87.7 to 89.2
across the pessimistic and optimistic scenarios). The femalemale difference in life expectancy at birth is projected to narrrow from 5.9 y in
2002 to 5.3 y in 2030 in the high-income countries, whereas the gap will more than double in low-income countries to 5.2 y in 2030.

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Figure 1. Projected Life Expectancy at Birth in 2030 by World Bank Region and Sex: Baseline, Optimistic, and Pessimistic Scenarios Compared
with 2002 Estimates
doi:10.1371/journal.pmed.0030442.g001
Projected global deaths in 2030 ranged from 64.9 million under the optimistic scenario to 80.7 million under the pessimistic scenario, variations
of 11% to +10% relative to the baseline projection of 73.2 million. Figure 2 shows the projected global numbers of deaths in 2030 by age in the
three scenarios, compared with the numbers of deaths by age in 2002. In all three scenarios there is a dramatic shift in the distribution of deaths
from younger to older ages. The risk of death for children younger than 5 y is projected to fall substantially in the baseline scenario, by almost
25% between 2005 and 2015, and by more than 40% between 2005 and 2030. These rates of decline are similar to those projected between 2000
and 2015 in the original GBD projections. The vertical bars attached to the points for 2030 in Figure 2 represent the range of deaths projected
under the optimistic and pessimistic scenarios.

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Figure 2. Global Numbers of Deaths by Age and Sex: Baseline, Optimistic, and Pessimistic Scenarios for 2030 Compared with 2002 Estimates
doi:10.1371/journal.pmed.0030442.g002

Trends in Cause-Specific Mortality


Table 1 summarizes the projected annual average changes in age-standardized death rates for selected major causes for the baseline projections
for the period 20022020. For all the Group I and Group II cause groups in which the projections were based on the major-cause cluster
regression equations, age-specific and age-standardized death rates are projected to decline over the next 20 years. The average annual rate of
decline is greater (at about 3%) for Group I causes than for Group II causes. The HIV/AIDS projections, discussed in more detail below, have a
substantial projected average annual rate of increase of 3% for males and 2% for females. Other causes with projected increases in agestandardized rates include lung cancer, diabetes, chronic respiratory diseases, road traffic accidents, violence, and war.

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Table 1.
Projected Average Annual Rates of Change in Age-Standardized Death Rates for Selected Causes: World, 20022020
doi:10.1371/journal.pmed.0030442.t001
The Group I causes, excluding HIV/AIDS and tuberculosis, decline with average annual rates of change typically about one-third slower than the
original GBD projections of Murray and Lopez. To some extent, this reflects the more conservative projections for low-income countries, where
the coefficient of the time factor was reduced or set to zero. Average rates of decline for Group II causes (excluding lung cancer and chronic
respiratory conditions) are similar for females to those in the original projections. However, the differential between males and females in the
original projections has disappeared in the current projections, with males having a greater average annual rate of decline for Group II conditions
than previously projected.
Figure 3 summarizes the contributions of major causes to global trends in numbers of deaths for the three major cause groups. Large declines in
mortality between 2002 and 2030 are projected for all of the principal Group I causes, with the exception of HIV/AIDS. Under the baseline
scenario involving scale-up of ART coverage to 80% by 2012, but not additional prevention efforts, HIV/AIDS deaths increase from 2.8 million
in 2002 to 6.5 million in 2030. Total deaths due to other Group I causes decline from 15.5 million in 2002 to 9.0 million in 2030. Unfortunately,
this is substantially offset by the projected rise in HIV/AIDS deaths. Under the optimistic scenario involving additional HIV prevention activity,
3.7 million HIV/AIDS deaths are projected for 2030, so that total deaths due to Group I conditions would decline from 32% of all deaths in 2002
to 14% of all deaths in 2030.

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Figure 3. Baseline Projections of Deaths from Group I, Group II, and Group III Causes, World, 20022030
doi:10.1371/journal.pmed.0030442.g003
Although age-specific death rates for most Group II conditions are projected to decline, ageing of the population will result in significantly
increasing total deaths due to most Group II conditions over the next 30 years (Figure 3). Global cancer deaths are projected to increase from 7.1
million in 2002 to 11.5 million in 2030, and global cardiovascular deaths from 16.7 million in 2002 to 23.3 million in 2030. Overall, Group II
conditions will account for almost 70% of all deaths in 2030 under the baseline scenario.
The projected 40% increase in global deaths due to injury between 2002 and 2030 are predominantly due to the increasing numbers of road
traffic accident deaths, together with increases in population numbers more than offsetting small declines in age-specific death rates for other
causes of injury. Road traffic accident deaths are projected to increase from 1.2 million in 2002 to 2.1 million in 2030, primarily due to increased
motor vehicle fatalities associated with economic growth in low- and middle-income countries.

Projections of HIV/AIDS Mortality and Other Selected Causes

Figure 4 summarizes projected HIV/AIDS deaths by income group for the three scenarios. The declining death rates for 20052010 in the
baseline and pessimistic scenarios, followed by increasing death rates, reflect the effects of the assumed treatment scale-up scenarios. Rapidly
increasing levels of ART coverage result in postponement of deaths for a number of years, but once the ART coverage plateaus at its final level,
numbers of deaths continue to rise, reflecting largely the underlying growth in population. HIV incidence rates essentially remain constant in the
baseline scenario for sub-Saharan Africa, and the global growth in incident cases and in deaths is largely driven by population growth in subSaharan Africa.

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Figure 4. Projections of Total AIDS Deaths (Thousands) by Income Group for Three Scenarios
Scenarios are indicated: baseline (solid lines), optimistic (dotted lines), and pessimistic (dashed lines).
doi:10.1371/journal.pmed.0030442.g004
Under the baseline scenario, the total deaths from HIV/AIDS over the 25-y period 20062030 are projected to be 117 million. Under the
optimistic scenario, in which additional prevention efforts result in a long-term 3% decline in incidence rates, the projected total deaths over
20062030 are 89 million, a saving of 28 million lives.
The ranges defined by the optimistic and pessimistic projections differ substantially by cause (Figure 5). For example, the range for
cardiovascular disease before age 70 y is much wider than that for cancers before age 70 y or for road traffic accidents. Group I deaths
(excluding HIV/AIDS) have a wider range than most other causes, although the total deaths decline substantially in all three scenarios.

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Figure 5. Projections of Global Deaths (Millions) for Selected Causes, for Three Scenarios: Baseline, Optimistic, and Pessimistic, 20022030
doi:10.1371/journal.pmed.0030442.g005

Comparison with GBD 1990 Projections


Figure 6 compares projected global deaths for each of the three major cause groups for 20022030 with the corresponding projections for 1990
2020 from the original GBD study [1]. Projections for Group I causes are substantially different, mainly because of the very large difference in
projected HIV/AIDS mortality. Total global deaths for Group II and Group III causes are projected to increase at a somewhat slower rate than the
original GBD projections, and in addition, the base levels for these causes in 2002 are somewhat lower than the levels projected by the original
GBD study.

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Figure 6. Comparison of Baseline Projections 20022030 with the Original GBD Projections 19902020: Global Deaths for All Causes, and
Major Cause Groups
doi:10.1371/journal.pmed.0030442.g006
Despite these differences for all three major cause groups, and differences in projected global population numbers, the projections of total global
all-cause deaths are almost identical to those in the original GBD study. Global deaths in 2020 under the baseline scenario are 66.5 million,
compared with 68.3 million projected by Murray and Lopez from the 1990 base, and the overall trend is almost identical.
Projected trends for global deaths due to most Group I causes other than HIV/AIDS are broadly similar. The new baseline projections for lung
cancer give lower global numbers and a lower rate of increase. Trends in global respiratory deaths are similar for the two sets of projections, but
the projected rates of increase in global deaths due to cancers, cardiovascular disease, and digestive disorders are all somewhat slower for the
current projections. Increases for road traffic accidents are somewhat slower in the current projections, whereas trends for other unintentional
causes are quite similar. There are some substantial differences in trends for intentional causes, reflecting different assumptions and decisions
concerning use of the regression parameters.

Leading Causes of Death


Table 2 lists the 15 leading causes of death according to the baseline scenario for males, females, and both sexes combined as projected for 2030
globally. Table 3 provides similar lists of the ten leading causes of death according to the baseline scenario for the four income groups of
countries. The four leading causes of death in all scenarios are projected to be ischaemic heart disease, cerebrovascular disease (stroke),
HIV/AIDS, and COPD, although HIV/AIDS moves from third to fourth position in the optimistic scenario.

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Table 2.

Changes in Rankings for 15 Leading Causes of Death, 2002 and 2030 (Baseline Scenario)
doi:10.1371/journal.pmed.0030442.t002

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Table 3.
Ten Leading Causes of Death, by Income Group, 2030 (Baseline Scenario)
doi:10.1371/journal.pmed.0030442.t003
Table 2 also summarises the changes in rank order of deaths between 2002 and 2030 for the 15 leading causes. Lower-respiratory infections,
perinatal conditions, diarrhoeal diseases, malaria, and measles are all projected to decline substantially in importance. On the other hand,
diabetes mellitus, lung cancer, stomach cancer, and liver and colorectal cancer are all projected to move up three or more places in the rankings.

Decomposition
The results discussed so far have described projected changes in mortality in terms of the absolute (and relative) numbers of deaths expected
under the various scenarios. These changes may be due to changes in age-specific disease and injury mortality risks, or due to demographic
change that alters the size and age composition of the population, or both. Because mortality risks are strongly age dependent for most causes,
changes in the age structure of a population may result in substantial changes in the number of deaths, even when the age-specific risks remain
unchanged.
We further analysed the relative impact of demographic and epidemiological change on the projected numbers of deaths by cause by calculating
three hypothetical alternatives. In the first, we calculated the expected number of deaths in 2030 given the 2030 projected age-specific rates
under the baseline scenario and the 2002 population. The difference between this and the 2002 mortality estimates is a measure of the change in
mortality expected solely on the basis of changing age-specific mortality rates, and is labelled epidemiological change in Figure 7.

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Figure 7. Decomposition of Projected Change in Numbers of Deaths into Demographic and Epidemiological Components, by Broad Cause
Group and Income Group, 20022030
doi:10.1371/journal.pmed.0030442.g007
Second, we calculated the expected number of deaths in 2030 by taking the 2002 age-specific death rates and applying them to the 2030
projected population. The difference between this and the 2002 mortality estimates is a measure of the change in mortality expected solely on the
basis of changing demography (including size and age composition of the population). We then repeated this calculation, but applied the 2002
age-specific death rates to projected population numbers for 2030 that matched the total projected male and female population numbers for each
country but retained the 2002 age distribution of the population. The difference between this and the 2002 mortality estimates is a measure of the
change in mortality expected solely on the basis of population growth excluding changes in age composition. The difference between the total
change in mortality due to demography and this latter estimate gives a measure of the effect of the change in age composition of the population
alone. These two components of demographic change are labelled population growth and population ageing in Figure 7. The total projected
change in numbers of deaths between 2002 and 2030 is the sum of the population growth, population ageing, and epidemiological change
components.
In almost all cases, demographic and epidemiological factors are operating in opposing directions in determining mortality in 2030. The major
exception is HIV/AIDS, where demographic and epidemiological change are acting in the same direction to increase total HIV/AIDS deaths to
6.5 million deaths in 2030 under the baseline scenario. Demographic change dominates, as the majority of HIV/AIDS deaths are in sub-Saharan
Africa, where population growth is highest and where HIV/AIDS incidence rates are assumed to remain largely constant under the baseline
scenario.

For Group I conditions other than HIV/AIDS for which substantial declines in mortality rates are projected, the effect of these declines will be
attenuated in most regions by demographic change leading to an increase in the child population most at risk for these conditions. Population
growth and population ageing act in opposite directions for Group I mortality excluding HIV/AIDS in low-income countries, but not in other
income groups. If future fertility rates are higher than projected, then the higher child population numbers will further offset the projected
reductions in death rates for Group I conditions.
For Group II (noncommunicable diseases), demographic changes in all regions will tend to increase deaths substantially, with offsetting
reductions in projected death rates in all regions. Population growth and population ageing both act to increase Group II deaths in all regions,
although the impact of population ageing is generally much more important than population growth. Population growth has the largest relative
impact for low-income countries, and the smallest for lower-middle-income countries. The latter group includes Eastern European populations
such as Russia that will experience negative population growth.
For Group III (injuries), demographic change similarly dominates the epidemiological change. The latter is small at group level in most regions,
because the projected increase in road traffic fatalities is offset by projected decreases in death rates for other unintentional injuries.

Tobacco-Attributable Deaths
Figure 8 summarises the projected number of tobacco-attributable deaths for the world, and for high-income and low- and middle-income
countries. Under the baseline scenario, total tobacco-attributable deaths will rise from 5.4 million in 2005 to 6.4 million in 2015 and 8.3 million
in 2030. Projected deaths for 2030 range from 7.4 million in the optimistic scenario to 9.7 million in the pessimistic scenario. Tobaccoattributable deaths are projected to decline by 9% between 2002 and 2030 in high-income countries, but to double from 3.4 million to 6.8 million
in low- and middle-income countries.

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Figure 8. Projected Numbers of Tobacco-Caused Deaths for the World and for High-Income and Middle- plus Low-Income Countries, Three
Scenarios, 20022030
doi:10.1371/journal.pmed.0030442.g008
Table 4 divides the projected 2015 global mortality due to smoking into leading causes: cancers are responsible for one-third of the deaths,
followed by cardiovascular diseases and chronic respiratory diseases, each responsible for 30% of the deaths. According to our baseline
projection, smoking will kill 50% more people in 2015 than HIV/AIDS, and will be responsible for 10% of all deaths globally.

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Table 4.
Projected Global Tobacco-Caused Deaths, by Cause, 2015 Baseline Scenario
doi:10.1371/journal.pmed.0030442.t004

Burden of Disease
Global DALYs lost are projected to increase from 1.48 billion in 2002 to 1.54 billion in 2030, an overall increase of only 3%. Since the
population increase is projected to be 27% during the same period, there is actually a decrease in the global per capita burden. Unlike deaths,
where the overall global death rate is projected to increase by 1%, the DALY rate decreases because the increasing number of deaths is offset by
the shift in age at death to older ages, associated with fewer lost years of life. Even with the assumption that the age-specific burden for most
nonfatal causes remains constant into the future, and hence that the overall burden for these conditions increases with the ageing of the
population, there is still an overall projected decrease in the global burden of disease per capita of 19% from 2002 to 2030.
The proportional contribution of the three major cause groups to the total disease burden is projected to change substantially, however. Group I
causes are projected to account for 30% of total DALYs lost in 2030, compared with more than 40% in 2002. In low-income countries, the
decline is even greater, from 56% in 2002 to 41% in 2030, even including the doubling of the HIV/AIDS burden. The noncommunicable disease
(Group II) burden is projected to increase to 57% in 2030, and to represent a greater burden of disease than Group I conditions in all income
groups, including low-income countries.
Table 5 lists the 15 leading causes of DALYs globally in 2002 and in 2030 according to the baseline scenario, and Table 6 provides similar lists
of the ten leading causes of burden of disease for high-, middle-, and low-income country groups. The three leading causes of DALYs in the
baseline and pessimistic scenarios are projected to be HIV/AIDS, unipolar depressive disorders, and ischaemic heart disease. Road traffic
accidents become the third leading cause under the optimistic scenario, ahead of ischaemic heart disease and cerebrovascular disease. Perinatal
conditions are the fourth leading cause under the pessimistic scenario and the fifth leading cause under the baseline scenario, after road traffic
accidents. HIV/AIDS becomes the leading cause of burden of disease in middle-income countries, as well as low-income countries, by 2015.

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Table 5.
Changes in Rankings for 15 Leading Causes of DALYs, 2002 and 2030 (Baseline Scenario)
doi:10.1371/journal.pmed.0030442.t005

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Table 6.

Ten Leading Causes of DALYs, by Income Group and Sex, 2030 (Baseline Scenario)
doi:10.1371/journal.pmed.0030442.t006
Table 5 also illustrates the changes in rank order of DALYs between 2002 and 2030 for the 15 leading causes globally. Lower-respiratory
infections, perinatal conditions, diarrhoeal diseases, malaria, measles, tuberculosis, and congenital anomalies are all projected to decline
substantially in importance. On the other hand, ischaemic heart disease, diabetes mellitus, road traffic accidents, self-inflicted injuries, COPD,
hearing loss, and cataracts are all projected to move up three or more places in the rankings. Hearing loss is projected to be among the top ten
causes of burden of disease in high- and middle-income countries, and Alzheimer disease and other dementias and alcohol-use disorders among
the top four causes in high-income countries in 2030. In low-income countries in 2030, Group I conditions continue to account for five of the ten
leading causes of burden of disease. These are HIV/AIDS, perinatal conditions, diarrhoeal diseases, malaria, and acute lower-respiratory
infections.

Discussion
We have addressed the need for updated projections of mortality and burden of disease using methods similar to those of the original GBD study.
Our intent was not to undertake major new methodological developments, but rather to provide updated projections for the first 30 years of the
21st century, using as much relevant new information as is available. We project that life expectancy will increase around the world for all three
scenarios, fewer children younger than 5 y will die (a 50% decline under the baseline scenario), and the proportion of people dying from noncommunicable diseases will increase (from 59% in 2002 to 69% in 2030 under the baseline scenario). Although deaths from infectious diseases
will decrease overall, HIV/AIDS deaths will continue to increase; the exact magnitude of the increase will depend to a limited extent on how
many people have access to antiretroviral drugs and much more on whether there are increased prevention efforts. Although a projected 6.5
million people will die from HIV/AIDS under the 2030 baseline projection, an even larger number will die from disease attributable to tobacco
smoking (8.3 million). By 2030, the three leading causes of burden of disease will be HIV/AIDS, depression, and ischaemic heart disease in the
baseline and pessimistic scenarios. Road traffic accidents are the fourth leading cause in the baseline scenario, and the third leading cause ahead
of ischaemic heart disease in the optimistic scenario.
These updated projections of mortality and burden of disease have been prepared using a similar methodology to that of the original GBD study,
but with some changes described above and with updated inputs and an updated base set of estimates for 2002. We have incorporated a number

of methodological improvements and changes. These include carrying out the projections at country rather than regional level, use of separate
regression equations for low-income countries, incorporation of information from death registration datasets on recent observed trends for
selected causes, and calibration of the regression equations through a comparison of back-projections with observed child mortality trends from
1990 to 2002. Additionally, separate risk factorbased projection models were developed for diabetes mellitus and chronic respiratory diseases.
Population projections also included UN projections for net migration rates.
Baseline estimates of deaths, disability, and DALYs lost in 2002 have been projected into the future based on an explicit set of assumptions and
methods, and the results are nothing more than the numerical consequences of the assumptions and methods employed. In this paper and the
accompanying Protocol S1 and Tables S1S7, we have tried to explicitly describe and summarize all inputs and assumptions for the three
scenarios to enable replication of these projections for different scenarios. Additional information and detailed datasets are available from the
authors on request.
We do not claim that the scenarios presented here necessarily represent the best predictions of future global and regional health trends, and it is
possible that more sophisticated causal models incorporating projections of important determinants may provide better predictions for specific
diseases. However, we do believe that these projections, as with the previous GBD projections of Murray and Lopez, represent the most
comprehensive and consistent set of health status projections available today.

Comparisons with Other Projections


We are not aware of any projections of global and regional mortality, apart from the previous GBD projections, that have included a
comprehensive set of causes of death. A review of other published studies containing global and regional projections for specific single causes
identified relatively few studies that did not either apply base estimates of agesex-specific death rates (assumed not to change in the future) to
UN population projections, or were based on the previous GBD projections, or were earlier versions of the projections by WHO and/or UNAIDS
for HIV/AIDS and tuberculosis used here.
Our projected global population in 2015 under the baseline scenario was 7.1 billion, compared with the UN medium variant projection of 7.2
billion [32], a difference of only 1.6% (see Protocol S1 for details of projection methods). By 2030, the difference between WHO and UN
baseline projections of population grew to 3.5%, and the range from pessimistic to optimistic scenarios to 7.75 billion to 8.07 billion. The

largest difference in the population growth projections is for the European region, where we project the total population to decline at a faster rate
than the UN projections.
Projected global deaths in 2030 ranged from 64.9 million under the optimistic scenario to 80.7 million under the pessimistic scenario, with a
baseline projection of 73.2 million. Projected global deaths in 2030 under the UN medium variant projections were 1% higher, at 74.0 million
[32]. Our global projections for all-cause mortality are remarkably close to the UN projections, given that our projections are the sum of
independent projections for 13 separate cause groups, whereas the UN projections are based on estimated trends in all-cause mortality, with
adjustments for projected HIV/AIDS mortality.
Our baseline global projection for all-cause mortality in 2020 (66.5 million deaths) is also remarkably similar to the original GBD baseline
projection for 2020 of 68.3 million deaths, although the projected numbers of deaths for each of the three major cause groups differ quite
significantly, as do projections for HIV/AIDS and tuberculosis. The congruence in numbers and trends in rates for all-cause mortality is almost
certainly a coincidence, since the global total death projections are derived from summing separate projections across 13 cause groups, and
almost all of the inputs to those projections have changed significantly from those used in the original projections.
Under our baseline projection, mortality of children younger than 5 y will decline globally by 29% from 2002 to 2015 (range 44% to 14% under
the optimistic and pessimistic scenarios). For sub-Saharan Africa the decline is projected to be 25%. In contrast, child mortality declined by only
12% globally and 7% in sub-Saharan Africa between 1990 and 2001 [17]. The more-than doubling of the decline in child mortality for subSaharan Africa projected for the next decade is largely determined by the relatively high projected economic growth for this region according to
the World Bank (about 2% annual increase in income per capita). Income per capita growth averaged only 0.5% in sub-Saharan Africa during the
period 19902002. Despite this, our back-projections to 1990 predicted a larger decline in child mortality than observed. The major regression
coefficients were adjusted for low-income countries, and in particular for sub-Saharan Africa, to match observed trends (see Protocol S1 for
details). Even with this adjustment, we are predicting more than double the decline in child mortality in the next decade compared to that
observed in the 1990s. This reflects the higher levels of economic growth projected for the next decade in sub-Saharan Africa.
Trends in tuberculosis death rates projected by the Stop TB Partnership for deaths of HIV-negative persons were used here, as the GBD classifies
deaths of HIV-positive persons as due to HIV/AIDS. The GBD base estimates of tuberculosis deaths for 2002 are higher than the Stop TB
Partnership 2002 estimates for deaths in sub-Saharan Africa and substantially lower in Southeast Asia (see Protocol S1). As a result of these
differences in base estimates, our baseline projection gives 960,000 tuberculosis deaths in 2015, compared to the 888,000 projected by the Stop

TB Partnership under the Sustained DOTS scenario. Both these estimates are substantially lower than the approximately 2.2 million
tuberculosis deaths projected for 2015 by Murray and Lopez in the original GBD study [1,2].
Bray and Mller have published global projections for cancer incidence in 2020 [33]. They projected that total cancer incidence would rise from
11 million new cases in 2002 to 16.5 million in 2020, assuming that 2002 agesex-specific incidence rates remained unchanged. Taking into
account projected changes in agesexsite-specific incidence rates, we project global incidence for all types of cancer to be 15.5 million cases in
2020, 6% lower than Bray and Mller's estimate. They also estimated global incidence in 2010 of 1.5 million new breast cancer cases and 1
million new prostate cancer cases, taking into account current trends in incidence rates. These are higher than our projections of 1.3 million and
0.85 million, respectively, mainly reflecting differences in the base incidence estimates for 2002.
Wilde et al. [34] estimated that the global diabetes prevalence would rise from 171 million in 2000 to 366 million in 2030, assuming that age
sex-specific diabetes prevalence rates remain unchanged within urban and rural populations in each region, but taking into account projected
increases in urbanization to 2030. Their estimate is somewhat higher than our projection of 328 million diabetes cases in 2030. Our projections
took into account projected trends for overweight and obesity, which may capture some of the impact of urbanization but did not explicitly
account for trends in urbanization. Projections based on prevalence trends have been made for diabetes in Canada and the US [35,36]. These
studies estimated that diabetes prevalence would reach 2.4 million for Canada in 2016, and 19.9 million for the US in 2025. Our projections of
diabetes prevalence for the same years are one-third higher for Canada (3.2 million) and slightly higher for the US (20.9 million).
Projected tobacco-attributable deaths in 2030 under the baseline scenario are lower than the 10 million predicted by Peto et al. [37] to occur
sometime in the 2020s or early 2030s. This earlier prediction is fairly consistent with our projection of 9.7 million tobacco-attributable deaths
under the pessimistic scenario. Murray and Lopez projected 8.4 million tobacco-attributable deaths in 2020, also somewhat higher than our
baseline projection of 7.0 million. Our lower projection reflects our downward adjustment of projected lung cancer mortality to reflect recent
trends in tobacco consumption. It must be emphasized that there is very substantial uncertainty in the tobacco-attributable mortality projections,
as the trends in apparent consumption of tobacco do not necessarily account for changes in duration, type, per capita amount, and mode of
smoking.
A recent World Bank report projected deaths due to road traffic accidents from 1990 to 2020 using an economic model that related death rates to
changes in fatalities per motor vehicle and motor vehicle ownership per person due to economic growth [38]. An overall growth of 66% was
projected for road traffic fatalities from 2000 to 2020, somewhat higher than our projection of a 51% increase in global deaths due to road traffic
accidents from 2002 to 2020 (Figure 9). Projected regional increases were generally similar, although the World Bank projected a substantially

greater increase in South Asia than we did, and a small growth for Europe and Central Asia, rather than a decline. In terms of absolute numbers
of deaths, the projections are quite different, reflecting large differences in base estimates. The World Bank study estimated global road fatalities
in 2000 as 723,000, compared with our estimate for 2002 of 1.2 million. The World Bank base estimates were derived from police statistics,
unadjusted for under-reporting. Police statistics are known to generally substantially underestimate deaths due to road traffic accidents. For
example, the World Bank estimate of 32,000 deaths for Europe and Central Asia in 2000 is 60% lower than the GBD estimate of 82,000 for
2002, based on reasonably complete death registration data.

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Figure 9. Projected Growth in Road Traffic Fatalities, 20022020: A Comparison of World Bank Projections with GBD Projections
doi:10.1371/journal.pmed.0030442.g009

Uncertainties and Limitations


There have been substantial improvements in the data and methods available for the assessment of global and regional mortality by cause. The
GBD 2002 estimates of deaths by cause, age, and sex were carried out separately for 226 countries and territories, drawing on a total of 770
country-years of death registration data, as well as 535 additional sources of information on levels of child and adult mortality, and in excess of
2,600 datasets providing information on specific causes of death in regions not well covered by death registration systems [15].
There remain, however, a large number of methodological and empirical challenges to more reliably estimating global, regional, and national
disease burden. For regions with limited death registration data, such as the Eastern Mediterranean region, sub-Saharan Africa, and parts of Asia
and the Pacific, there is considerable uncertainty in estimates of deaths by cause. Uncertainty ranges for all-cause deaths in 2001 were estimated
by Mathers et al. [16] to increase from around 1% for high-income countries to around 20% for sub-Saharan Africa. For most specific causes,
uncertainty ranges are greater than those of the all-cause mortality estimates, since there is additional uncertainty associated with cause
attribution. For example, the relative uncertainty ranges for ischaemic heart disease in 2001 were estimated to range from about 12% for highincome countries to around 30% for sub-Saharan Africa. The uncertainty range for HIV/AIDS deaths in sub-Saharan Africa was narrower at
15%, reflecting the substantial data base for these estimates.
The projections of burden are not intended as forecasts of what will happen in the future but as projections of current and past trends, based on
certain explicit assumptions. The methods used base the disease burden projections largely on broad mortality projections driven by World Bank
projections of future growth in income and WHO projections of increases in human capital in different regions of the world, together with a
model relating these to cause-specific mortality trends based on the historical observations in countries with death registration data from the past
50 years. The results depend strongly on the assumption that future mortality trends in developing countries will have a similar relationship to

economic and social development as has occurred in the more developed countries. If this assumption is not correct, then the projections for lowincome countries will be over-optimistic in the rate of decline of communicable diseases and the speed of the epidemiological transition.
The predictions of the projections model were compared with historical trends in child mortality from 1990 to 2002, and as a result, certain
regression coefficients were modified for low-income countries. As a result, our revised projections assume that projected rates of change for
cause-specific mortality rates over time, given levels of constant income and human capital, will be slower than those observed in the mainly
high- and middle-income countries with death registration data from the past 50 years. This has reduced the projected rates of decline in Group I
conditions for low-income countries compared to the original GBD projections, and it is entirely possible that this adjustment may be too
conservative. On the other hand, the many problems facing low-income countries in improving and sustaining access to effective health
interventions, and in scaling up health systems to cost-effectively address these challenges, may mean that the low-income countries do not
experience the temporal pace of health improvement at constant levels of income and human capital that have been seen in the high-income
countries in the past 50 years.
The projections have also not taken explicit account of trends in major risk factors apart from tobacco smoking, and, to a limited extent,
overweight and obesity. If broad trends in risk factors are for worsening of risk exposures with development, rather than the improvements
observed in recent decades in many high-income countries, then again the projections for low- and middle-income countries presented here will
be too optimistic. There is a need to develop much more comprehensive projection models that take explicit account of available information on
trends in a wide range of risk factors. The HIV/AIDS baseline projections in particular assume that transmission probabilities will remain largely
unchanged in the future and there will not be substantial reductions in risk factors for HIV.
A projections exercise such as this by its nature involves substantial assumptions about the similarity of future trends to past trends, and about
the future trends in broad drivers of health improvement. There are thus wide uncertainty ranges around future projections. Nevertheless, there
are some aspects of the projections that clearly involve more uncertainty than others. For example, the projections of HIV/AIDS mortality are
strongly affected by the assumptions made about the levels of additional prevention effort that occur over the next two decades. Additionally,
there are substantial uncertainties about the future trends in chronic respiratory disease mortality for non-smokers, and diabetes mortality for
persons not overweight. Also, the evidence on the associations of injury mortality with income and human capital was weaker than for Group I
and Group II conditions, and stronger assumptions were thus required for injury projections for some external causes. In the absence of any
realistic approach to forecasting future war deaths, rates for these were assumed to remain constant over time in the baseline scenario. This may
be too conservative, given the substantial decrease in the number of wars and civil conflicts in the past decade or two.

Finally, as did Murray and Lopez, we recognize that the approach taken to projecting YLD is extremely crude, and that the projections of
DALYs are likely to be even more uncertain than the projections of deaths. It may be the case that case fatality rates for many diseases decline
during the next 30 years, so that YLD become an increasing proportion of the total DALYs for these causes. On the other hand, improvements in
risk factors and/or health interventions may lead to decreases in burden for some nonfatal conditions. Substantial research remains to develop
robust and unbiased methods for measuring trends in case fatality rates, survival times, and disability due to specific causes, let alone collecting
such data across all regions of the world.

Conclusions
Despite these uncertainties, projections provide a useful perspective on population health trends and health policies, provided that they are
interpreted with a degree of caution. Projections enable us to appreciate better the implications for health and health policy of currently observed
trends, and the likely impact of fairly certain future trends, such as the ageing of the population, and the continuation of the epidemiological
transition in developing countries. These projections represent a set of three visions of the future for population health, under an explicit set of
assumptions and for specific projections of income, human capital, and of future trends in tobacco smoking, HIV/AIDS transmission and
survival, and overweight and obesity. If the future is not like the pastfor example, through sustained and additional efforts to address the
Millennium Development Goals, or through major scientific breakthroughsthen the world may well achieve faster progress than projected
here, even under the optimistic scenario. On the other hand, if economic growth in low-income countries is lower than the forecasts used here,
then the world may achieve slower progress and widening of health inequalities.

Supporting Information
Alternative_Language_Text_S1.doc
1 / 11

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Alternative Language Text S1. Translation of the Article into French


doi:10.1371/journal.pmed.0030442.sd001
(37 KB DOC)

Dataset S1. Deaths by Cause, Scenario, Sex, and Age for 2002, 2015, and 2030
doi:10.1371/journal.pmed.0030442.sd002
(1 MB XLS)

Dataset S2. DALYs by Cause, Scenario, Sex, and Age for 2002, 2015, and 2030
doi:10.1371/journal.pmed.0030442.sd003
(1 MB XLS)

Protocol S1. Technical Appendix


doi:10.1371/journal.pmed.0030442.sd004
(200 KB PDF)

Table S1. Country Classifications Used for Reporting Results: World Bank Regional Groups and World Bank Income
Groups
doi:10.1371/journal.pmed.0030442.st001
(69 KB DOC)

Table S2. GBD Cause Categories and ICD Codes


doi:10.1371/journal.pmed.0030442.st002
(184 KB DOC)

Table S3. Parsimonious Regression Equations for Nine Major Cause Clusters Based on the Full Country Panel Dataset,
19502002
doi:10.1371/journal.pmed.0030442.st003
(334 KB DOC)

Table S4. Parsimonious Regression Equations for Nine Major Cause Clusters Based on the Low-Income Country Panel
Dataset, 19502002
doi:10.1371/journal.pmed.0030442.st004
(335 KB DOC)

Table S5. Results of Regressions of AgeSex-Specific Mortality for Detailed Causes on the Respective Cause Cluster
Based on the Full Country Panel Dataset, 19502002
doi:10.1371/journal.pmed.0030442.st005
(765 KB DOC)

Table S6. Results of Log-Linear Poisson Regressions for Deaths Due to Selected Causes, by Age and Sex, for Countries
with Complete Death Registration Data and Population of More Than 5 Million
doi:10.1371/journal.pmed.0030442.st006
(1.2 MB DOC)

Table S7. Summary of Assumptions and Inputs for Baseline, Optimistic, and Pessimistic Projection Scenarios
doi:10.1371/journal.pmed.0030442.st007
(67 KB DOC)

Acknowledgments
We gratefully acknowledge the assistance of Hongyi Xu, Niels Tomijima, Doris Ma Fat, and Mie Inoue in the preparation of inputs for the
projections calculations. We thank Ajay Tandon for providing WHO projections of income and human capital. We thank Karen Stanecki,
Elizabeth Zaniewski, and Peter Ghys, all from UNAIDS, for assistance in obtaining detailed HIV projections and documentation prepared by the
WHO and UNAIDS Working Party. Josh Salomon provided further unpublished results for projections of HIV mortality for scenarios with
additional prevention efforts. We thank Chris Dye and Catherine Watt for providing Stop TB Partnership projections for tuberculosis in HIV-

negative persons. Kate Strong and Tomoko Ono provided projections of body mass index distributions. Marie-Claude von Rulach-Duvernay
provided secretarial and translation assistance.

Author Contributions
CDM designed the study. CDM and DL analyzed the data. CDM and DL contributed to writing the paper. CDM led the design of the study and
was primarily responsible for the burden of disease and population projections and the interpretation of the results. DL was primarily responsible
for the preparation and analysis of the input mortality data (data from the WHO mortality database). Both authors participated in the
development of the mortality projections under the three scenarios.

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Diabetes
Fact sheet N312
Updated January 2015

Key facts

In 2014 the global prevalence of diabetes * was estimated to be 9% among adults aged 18+ years (1).

In 2012, an estimated 1.5 million deaths were directly caused by diabetes (2).

More than 80% of diabetes deaths occur in low- and middle-income countries (2).

WHO projects that diabetes will be the 7th leading cause of death in 2030 (3).

Healthy diet, regular physical activity, maintaining a normal body weight and avoiding tobacco use can prevent or delay the onset of type
2 diabetes (4).

What is diabetes?
Diabetes is a chronic disease that occurs either when the pancreas does not produce enough insulin or when the body cannot effectively use the
insulin it produces. Insulin is a hormone that regulates blood sugar (5). Hyperglycaemia, or raised blood sugar, is a common effect of
uncontrolled diabetes and over time leads to serious damage to many of the body's systems, especially the nerves and blood vessels.
In 2014, 9% of adults 18 years and older had diabetes. In 2012 diabetes was the direct cause of 1.5 million deaths. More than 80% of diabetes
deaths occur in low- and middle-income countries.
Type 1 diabetes
Type 1 diabetes (previously known as insulin-dependent, juvenile or childhood-onset) is characterized by deficient insulin production and
requires daily administration of insulin. The cause of type 1 diabetes is not known and it is not preventable with current knowledge.
Symptoms include excessive excretion of urine (polyuria), thirst (polydipsia), constant hunger, weight loss, vision changes and fatigue. These
symptoms may occur suddenly.
Type 2 diabetes

Type 2 diabetes (formerly called non-insulin-dependent or adult-onset) results from the bodys ineffective use of insulin. Type 2 diabetes
comprises 90% of people with diabetes around the world (5), and is largely the result of excess body weight and physical inactivity.
Symptoms may be similar to those of Type 1 diabetes, but are often less marked. As a result, the disease may be diagnosed several years after
onset, once complications have already arisen.
Until recently, this type of diabetes was seen only in adults but it is now also occurring in children.
Gestational diabetes
Gestational diabetes is hyperglycaemia with blood glucose values above normal but below those diagnostic of diabetes, occurring during
pregnancy. Women with gestational diabetes are at an increased risk of complications during pregnancy and at delivery. They are also at
increased risk of type 2 diabetes in the future.
Gestational diabetes is diagnosed through prenatal screening, rather than reported symptoms.
Impaired glucose tolerance (IGT) and impaired fasting glycaemia (IFG)
Impaired glucose tolerance (IGT) and impaired fasting glycaemia (IFG) are intermediate conditions in the transition between normality and
diabetes. People with IGT or IFG are at high risk of progressing to type 2 diabetes, although this is not inevitable.

What are common consequences of diabetes?


Over time, diabetes can damage the heart, blood vessels, eyes, kidneys, and nerves.

Diabetes increases the risk of heart disease and stroke. In a multinational study, 50% of people with diabetes die of cardiovascular disease
(primarily heart disease and stroke) (6).
Combined with reduced blood flow, neuropathy (nerve damage) in the feet increases the chance of foot ulcers, infection and eventual
need for limb amputation.

Diabetic retinopathy is an important cause of blindness, and occurs as a result of long-term accumulated damage to the small blood
vessels in the retina. One percent of global blindness can be attributed to diabetes (7).

Diabetes is among the leading causes of kidney failure (4).

The overall risk of dying among people with diabetes is at least double the risk of their peers without diabetes (8).

How can the burden of diabetes be reduced?


Prevention
Simple lifestyle measures have been shown to be effective in preventing or delaying the onset of type 2 diabetes. To help prevent type 2 diabetes
and its complications, people should:

achieve and maintain healthy body weight;


be physically active at least 30 minutes of regular, moderate-intensity activity on most days. More activity is required for weight
control;

eat a healthy diet of between 3 and 5 servings of fruit and vegetables a day and reduce sugar and saturated fats intake;

avoid tobacco use smoking increases the risk of cardiovascular diseases.

Diagnosis and treatment


Early diagnosis can be accomplished through relatively inexpensive blood testing.
Treatment of diabetes involves lowering blood glucose and the levels of other known risk factors that damage blood vessels. Tobacco use
cessation is also important to avoid complications.
Interventions that are both cost saving and feasible in developing countries include:

moderate blood glucose control. People with type 1 diabetes require insulin; people with type 2 diabetes can be treated with oral
medication, but may also require insulin;
blood pressure control;

foot care.

Other cost saving interventions include:

screening and treatment for retinopathy (which causes blindness);


blood lipid control (to regulate cholesterol levels);

screening for early signs of diabetes-related kidney disease.

These measures should be supported by a healthy diet, regular physical activity, maintaining a normal body weight and avoiding tobacco use.

WHO response
WHO aims to stimulate and support the adoption of effective measures for the surveillance, prevention and control of diabetes and its
complications, particularly in low and middle-income countries. To this end, WHO:

provides scientific guidelines for diabetes prevention;


develops norms and standards for diabetes diagnosis and care;

builds awareness on the global epidemic of diabetes; celebration of World Diabetes Day (14 November);

conducts surveillance of diabetes and its risk factors.

The WHO Global strategy on diet, physical activity and health complements WHO's diabetes work by focusing on population-wide approaches
to promote healthy diet and regular physical activity, thereby reducing the growing global problem of overweight and obesity.

Defined as fasting blood glucose >= 7 mmol/l or on medication for raised blood glucose or with a history of diagnosis of diabetes.

References
(1) Global status report on noncommunicable diseases 2014. Geneva, World Health Organization, 2012.
(2) World Health Organization. Global Health Estimates: Deaths by Cause, Age, Sex and Country, 2000-2012. Geneva, WHO, 2014.
(3) Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med, 2006, 3(11):e442.
(4) Global status report on noncommunicable diseases 2010. Geneva, World Health Organization, 2011.
(5) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus.
Geneva, World Health Organization, 1999 (WHO/NCD/NCS/99.2).
(6) Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in
Diabetes. Diabetologia 2001, 44 Suppl 2:S14S21.
(7) Global data on visual impairments 2010. Geneva, World Health Organization, 2012.
(8) Roglic G, Unwin N, Bennett PH, Mathers C, Tuomilehto J, Nag S et al. The burden of mortality attributable to diabetes: realistic estimates
for the year 2000. Diabetes Care, 2005, 28(9):21302135.

Diabetes Care
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Type 1 Diabetes Through the Life Span: A Position Statement of the


American Diabetes Association
1. Jane L. Chiang1,
2. M. Sue Kirkman2,
3. Lori M.B. Laffel3 and
4. Anne L. Peters4
5. on behalf of the Type 1 Diabetes Sourcebook Authors*
1

American Diabetes Association, Alexandria, VA


Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC
3
Pediatric, Adolescent and Young Adult Section, Joslin Diabetes Center; Department of Pediatrics, Harvard Medical School, Boston, MA
4
Division of Endocrinology, Keck School of Medicine of the University of Southern California, Los Angeles, CA
1. Corresponding author: Jane L. Chiang, jchiang{at}diabetes.org.
1.
2.
3.
4.

Type 1 diabetes is characterized by an immune-mediated depletion of -cells that results in lifelong dependence on exogenous insulin. While
both type 1 and type 2 diabetes result in hyperglycemia, the pathophysiology and etiology of the diseases are distinct and require us to consider
each type of diabetes independently. As such, this position statement summarizes available data specific to the comprehensive care of individuals
with type 1 diabetes. The goal is to enhance our ability to recognize and manage type 1 diabetes, to prevent its associated complications, and to
eventually cure and prevent this disease.

Next Section

Incidence and Prevalence of Type 1 Diabetes


The exact number of individuals with type 1 diabetes around the world is not known, but in the U.S., there are estimated to be up to 3 million
(1). Although it has long been called juvenile diabetes due to the more frequent and relatively straightforward diagnosis in children, the
majority of individuals with type 1 diabetes are adults.
Most children are referred and treated in tertiary centers, where clinical data are more readily captured. The SEARCH for Diabetes in Youth
study estimated that, in 2009, 18,436 U.S. youth were newly diagnosed with type 1 diabetes (12,945 non-Hispanic white, 3,098 Hispanic, 2,070
non-Hispanic black, 276 Asian-Pacific Islander, and 47 American Indian) (2). Worldwide, 78,000 youth are diagnosed with type 1 diabetes
annually. Incidence varies tremendously among countries: East Asians and American Indians have the lowest incidence rates (0.18 per
100,000/year) as compared with the Finnish who have the highest rates (>64.2 per 100,000/year) (3). In the U.S., the number of youth with type
1 diabetes was estimated to be 166,984 (4).
The precise incidence of new-onset type 1 diabetes in those over 20 years of age is unknown. This may be due to the prolonged phase of onset
and the subtleties in distinguishing the different types of diabetes. In one European study of adults aged 3070 years, 9% tested positive for
GAD antibodies (GADA) within 5 years of a diabetes diagnosis, consistent with other studies (5).
Adults with type 1 diabetes often receive care in primary care settings rather than with an endocrinologist. Unlike the consolidated care seen in
pediatric diabetes management, the lack of consolidated care in adults makes incidence and prevalence rates difficult to characterize, and
therefore they are often underestimated. The number of adults living with type 1 diabetes is increasing due to two factors: 1) the rising number of
new-onset cases of type 1 diabetes in adults, including those diagnosed with latent autoimmune diabetes in adults (LADA), and 2) individuals
with childhood-onset diabetes are living longer (6,7).
Previous SectionNext Section

Classification and Diagnosis

Type 1 diabetes has traditionally been diagnosed based on clinical catabolic symptoms suggestive of insulin deficiency: polyuria, polydipsia,
weight loss, and marked hyperglycemia that is nonresponsive to oral agents. It is classified as an autoimmune disease with progressive -cell
destruction, resulting in a physiological dependence on exogenous insulin. Recent studies have broadened our understanding of the disease, but
have made diagnosis more complex.
There is tremendous variability in the initial presentation of type 1 diabetes in both youth and adults. Children often present acutely, with severe
symptoms of polyuria, polydipsia, and ketonemia. However, in adults, type 1 diabetes presents with a more gradual onset, with a clinical
presentation that may initially appear consistent with type 2 diabetes. Distinguishing between type 1 and type 2 diabetes presents diagnostic
challenges. Traditionally, progressive -cell destruction has been the hallmark of type 1 diabetes, but residual C-peptide (a surrogate marker for
insulin secretion) may be detected over 40 years after initial diagnosis, regardless of whether the initial diagnosis was made in childhood or in
adulthood (8).

Clinical Clues
Much of the diagnosis will depend on clinical clues, but the rising incidence of overweight/obesity has also confounded the diagnosis of type 1
diabetes. A lean individual presenting with clinical symptoms without a first-degree relative with diabetes (but often with a history of distant
relatives with type 1 diabetes or other autoimmune disease) is generally suggestive of type 1 diabetes. An overweight individual (of any age)
with metabolic syndrome and a strong family history of type 2 diabetes may be assessed only for the development of type 2 diabetes, even
though type 1 diabetes is on the differential diagnosis. Obesity does not preclude that autoimmunity and hyperglycemia will occur even amid the
relatively higher levels of endogenous insulin secretion observed in obesity. In young patients aged 1017 years with phenotypic type 2 diabetes,
10% have evidence of islet autoimmunity suggesting that type 1 diabetes was the likely diagnosis (9). Thus, although leaner individuals are more
likely to be diagnosed as having type 1 diabetes, the potential for type 1 diabetes exists in those who phenotypically appear to have type 2
diabetes. If hyperglycemia persists after treatment with noninsulin agents, which is unusual in the treatment of newly diagnosed type 2 diabetes,
then type 1 diabetes should be considered.

Pancreatic Autoantibodies
Pancreatic autoantibodies are characteristic of type 1 diabetes. Highly sensitive laboratory measurements capture 98% of individuals with
autoantibodies at diagnosis (10). Unfortunately, most commercial laboratories do not have reliably sensitive or specific assays that measure all

five autoantibodies: GADA, islet cell antibodies (ICA), insulin autoantibodies (IAA), protein tyrosine phosphatase antibodies (ICA512 or
IA2A), and zinc transporter protein (ZnT8). Thus, it may be inappropriate to report a patient as autoantibody negative. Another cause of falsenegative autoantibodies is testing far out from diagnosis as antibody titers diminish over time (Fig. 1). It appears that there is an increased
incidence of type 1 diabetes in ethnic populations where autoantibody markers may be of variable utility, such as in Asians where autoantibodies
are often negative (1115).

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Figure 1
The percentage of antibody-positive subjects is affected by the duration of type 1 diabetes for GADA (A) and IA2A (B). Given an increase in the
scatter (due to lower numbers of subjects), the x-axis is truncated at a duration of 30 years. Reproduced with permission from Tridgell et al. (16).

Family History
Type 1 diabetes has a genetic predilection and, in some cases, can be predicted in family members. The overall prevalence of type 1 diabetes in
the U.S. is 0.3%, but if a first-degree relative has diabetes, the empiric risk of being affected is 5% (17,18), representing a 15-fold increase
among family members. Studies evaluating children at risk for developing type 1 diabetes have shown that the presence of more than two
autoantibodies was associated with a nearly 70% risk for disease development within 10 years and 84% within 15 years (19). Evaluating at-risk
individuals in the clinical setting is not yet recommended due to limited clinical interventions; however, ongoing research studies are identifying

at-risk individuals through genetic testing in both the lower-risk general population and in the higher-risk population of relatives of people with
type 1 diabetes.

Recommendations
Diagnosis

The American Diabetes Associations (ADAs) diagnostic criteria for type 1 and type 2 diabetes are the same (Table 1). (A)
Consider measurement of pancreatic autoantibodies to confirm the diagnosis of type 1 diabetes. (B)

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Table 1
Criteria for the diagnosis of diabetes

Identification of At-Risk Relatives

Inform type 1 diabetic patients of the opportunity to have their relatives tested for type 1 diabetes risk in the setting of a clinical research
study. (B)

Previous SectionNext Section

Initial Evaluation and Follow-up


General Considerations

All patients with type 1 diabetes need age-appropriate care, with an understanding of their specific needs and limitations. Infants and toddlers are
approached quite differently from adolescents; the needs of young adults may vary from middle-aged or older adults. Regardless of age, the
patients needs are the same: an individualized care plan with ongoing education and support, ongoing assessment for acute and chronic
complications, and access to medical providers with type 1 diabetes expertise. Just as patients change, the therapeutic approach should change
and should be evaluated at each visit and modified as needed.
Type 1 diabetes care must be an iterative process, adapted as the needs of the individual evolve. Clinical assessments for type 1 diabetes in
children and adults should incorporate age-appropriate and complication-focused evaluations, based on the likelihood that an abnormality will be
present. For example, a young adult with low cardiovascular disease (CVD) risk and no complications may need more of an assessment of
lifestyle adjustment as opposed to an older adult with longer duration of the disease who may need more evaluation of vascular and neurological
issues.

Transition of Care From Pediatric to Adult Providers


As youth transition into emerging adulthood, the supportive infrastructure often abruptly disappears and glycemic control tends to deteriorate.
The ADA recognizes that this is a challenging time and recommends a strong, practical transition plan to anticipate the upcoming changes. A
successful transition plan should be initiated early (e.g., early teenage years) and include ongoing dialogue between the family and youth. The
discussion should include finances, insurance, obtainment of supplies, identification of an adult care provider (ideally with communication
between the two providers), psychosocial issues (e.g., depression), and other issues identified by the family/youth. Health care providers, family,
and youth should agree to an achievable diabetes management plan and provide resources for unanticipated issues. We refer the reader to the
ADAs position statement on diabetes care for emerging adults (20).
Table 2 provides the childhood developmental phases and needs. Tables 3, 4, and 5 provide detailed elements of the initial and follow-up
evaluation in individuals with type 1 diabetes.
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Table 2
Major developmental issues and their effect on diabetes in children and adolescents
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Table 3
Medical history
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Table 4
Children and adolescents*
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Table 5
Adults*

Assessing the history of acute complications (e.g., severe hypoglycemia/hyperglycemia and diabetic ketoacidosis [DKA]) is important. Providers
should provide continuing education for the patient/family to prevent ongoing recurrence. For example, it is important to review exercise
management to reduce hypoglycemia risk and discuss sick-day management to reduce DKA risk.
Risk factor (e.g., cardiovascular) evaluation for prevention and screening for early evidence of micro- and macrovascular complications for early
intervention should be implemented starting in adolescence and continue through adulthood. For children, risk factors should be assessed shortly
after diagnosis based on family history and initial screening laboratory test results. Providers should manage risk factors, considering agespecific goals and targets (e.g., blood pressure, lipid, depression, and BMI assessment and management). The frequency of ongoing screening for
complications should be based on age and disease duration.

Coexistent Autoimmunity
Celiac Disease
Celiac disease is an immune-mediated disorder that occurs with increased frequency in patients with type 1 diabetes (116% of individuals
compared with 0.31% in the general population) (21,22). Symptoms of celiac disease include diarrhea, weight loss or poor weight gain,
abdominal pain, bloating, chronic fatigue, malnutrition due to malabsorption, and unexplained hypoglycemia or erratic blood glucose levels.
Screening for celiac disease with serum levels of tissue transglutaminase or antiendomysial antibodies should be considered soon after the
diagnosis of diabetes and/or if symptoms develop. Individuals who test positive should be referred to a gastroenterologist for possible smallbowel biopsy to confirm the diagnosis, although this is not necessary in all cases. Symptomatic children with strongly positive antibodies and
supportive genetic or HLA testing may not require a biopsy, but asymptomatic at-risk children should have a biopsy (23). In symptomatic
individuals with type 1 diabetes and confirmed celiac disease, a gluten-free diet reduces symptoms and decreases rates of hypoglycemia (24).
Thyroid Disease
About one-quarter of children with type 1 diabetes have thyroid autoantibodies (thyroid peroxidase antibodies or antithyroglobulin antibodies) at
the time of diagnosis (25,26). The presence of thyroid autoantibodies is predictive of thyroid dysfunction, generally hypothyroidism and less
commonly hyperthyroidism (27). Thyroid dysfunction is more common in adults with type 1 diabetes, although the exact prevalence is
unknown. Women are more commonly affected than men. Subclinical hypothyroidism, hyperthyroidism, or coexistent Addison disease (adrenal

insufficiency) may also deteriorate metabolic control with increased risk of symptomatic hypoglycemia (28) and may reduce linear growth in
children (29).

Additional Considerations for Pediatrics


All children require some level of adult supervision in managing their diabetes. Assessments of pediatric patients should address issues specific
to infants/preschoolers, school-aged children, adolescents, and emerging adults (Table 2). Health care providers should do a thorough assessment
of the developmental needs of the youth (and caregiver), focusing on physical and emotional development, family issues, and psychosocial
needs. The diabetes treatment plan should be individualized and tailored to the needs of individual patients and their families. Efforts to achieve
target blood glucose and A1C levels should be balanced with preservation of quality of life and protect against excessive hypoglycemia.
Height and weight should be measured at each visit and tracked via appropriate height and weight growth charts. An age-adjusted BMI can be
calculated starting at age 2 years. These tools can be found for children and teens at http://apps.nccd.cdc.gov/dnpabmi. Blood pressure
measurements should be determined correctly, using the appropriate size cuff and with the child seated and relaxed. Hypertension should be
confirmed on at least 3 separate days. Normal blood pressure levels for age, sex, and height and appropriate methods for determinations are
available online at www.nhlbi.nih.gov/health/prof/heart/hbp/hbp_ped.pdf.

Chronic Complications in Children


Retinopathy, nephropathy, and neuropathy rarely have been reported in prepubertal children and children with diabetes duration of only 12
years; however, they may occur after the onset of puberty or after 510 years of diabetes (30). As screening recommendations are based on
recent evidence, these periodically change. Therefore, we refer the reader to the ADA Standards of Care for the current screening
recommendations for children. It is recommended that those with expertise in diabetes management should conduct the assessments. For
example, ophthalmologic exams should be performed by those skilled in diabetic retinopathy management and experienced in counseling
pediatric patients and parents on the importance of early prevention/intervention. Another example, nephrologists with experience with diabetic
nephropathy would be aware that intermittent elevations in urinary albumin excretion are common in pediatric patients, particularly in
association with exercise.

Additional Considerations for Adults

Adults with type 1 diabetes now span a very large age spectrumfrom 18 to 100 years of age and beyond. Unlike the well-characterized
developmental stages of children, the life stages traversed through adulthood are often less well documented and underappreciated. However, an
understanding of each individuals circumstances is vital. This is true for aging in general, but particularly true for those with significant
comorbidities due to long-standing type 1 diabetes. Thus, it is important to assess the clinical needs of the patient, setting specific goals and
expectations that may differ significantly between a healthy 26-year-old and a frail 84-year-old with CVD and retinopathy.

Recommendations
See 2014 ADA Standards of Medical Care for detailed screening information for CVD, nephropathy, retinopathy, neuropathy, and foot care.

Access to health care should include clinicians with expertise in type 1 diabetes management, including (but not limited to) an
endocrinologist (or other health care provider with expertise in type 1 diabetes management), a registered dietitian, a diabetes educator, a
mental health professional, an exercise specialist/physiologist, and specialists required to treat diabetes complications. (E)
Routine follow-up (generally quarterly) should include review of self-monitoring of blood glucose (SMBG), continuous glucose
monitoring (CGM) and pump data (if applicable), A1C measurement, evidence for acute and/or chronic complications of diabetes
(particularly episodes of DKA and mild and/or severe hypoglycemia), measurement of blood pressure and weight (and height in
children), foot exam, inspection of injection/insertion sites, and discussion of psychosocial and educational needs (Tables 4 and 5). (E)

Providers should routinely document the patients age and disease duration. When clinically indicated, laboratory measures such as
lipids, renal function measurements, and antibodies for associated autoimmune disease (thyroid or celiac disease) should be documented.
(E)

Parent/guardian involvement in care is required throughout childhood, with a gradual shift in responsibility of care from the
parent/guardian to the youth. (E)

Health care for adults should be focused on the needs of the individual throughout the various stages of their life, with age-appropriate
evaluation and treatment. (E)

Evaluation and treatment of CVD risk should be individualized. (E)

Immunizations should be given as recommended by the Centers for Disease Control and Prevention (CDC) for children/adults in
general and people with diabetes specifically. (C)

Consider screening for celiac disease by measuring IgA antitissue transglutaminase or antiendomysial antibodies, with documentation
of normal total serum IgA levels, soon after the diagnosis of diabetes and/or if symptoms develop. Refer the patient to a
gastroenterologist if the test is positive. (E)

Consider screening for thyroid peroxidase and thyroglobulin antibodies soon after diagnosis. (E)

Screen for thyroid dysfunction by measuring thyroid-stimulating hormone (TSH) concentrations soon after type 1 diabetes diagnosis (and
after stable metabolic control). If normal, consider rechecking every 12 years or more frequently if the patient develops unusual
glycemic variation or symptoms of thyroid dysfunction or thyromegaly. (E)

Assess for the presence of additional autoimmune conditions at diagnosis and if symptoms develop. (E)

Ongoing nutrition and diabetes self-management education (DSME) and support (DSMS) are needed to address changes in food
preferences, access to food, daily schedules, activity patterns, and potential barriers to self-care, including the risk of an eating disorder.
(E)

Assess psychosocial status annually and more often as needed; treat and/or refer to a mental health professional as indicated. (E)

Previous SectionNext Section

DSME and DSMS


DSME and DSMS are the ongoing processes of facilitating the knowledge, skill, and ability necessary for diabetes self-care. These processes
incorporate the needs, goals, and life experiences of the person with diabetes. The overall objectives of DSME and DSMS are to support
informed decision making, self-care behaviors, problem solving, and active collaboration with the health care team to improve clinical outcomes,
health status, and quality of life in a cost-effective manner (31). Because changes in both treatment and life circumstances occur across the life
span, DSME and DSMS must be a continuous process adapted throughout the life of the person with type 1 diabetes so that self-management
can be sustained.

No matter how sound the medical regimen, it can only be as successful as the ability of the individual and/or family to implement it. Family
involvement remains an important component of optimal diabetes management throughout childhood and adolescence. Health care providers
who care for children and adolescents must, therefore, be capable of evaluating the educational, behavioral, emotional, and psychosocial factors
that impact implementation of a treatment plan and must assist the individual and family to overcome barriers or redefine goals as appropriate
(Table 6). Diabetes education should occur at diagnosis and upon transition to adult diabetes care and should be an ongoing process. The
information needs to be individualized and continually adapted to the patients needs.
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Table 6
DSME content based on life stages

Recommendations

Individuals with type 1 diabetes and parents/caregivers (for individuals aged <19 years) should receive culturally sensitive and
developmentally appropriate individualized DSME and DSMS according to national standards for DSME and DSMS when their diabetes
is diagnosed and routinely thereafter. (B)

Additional Considerations for Pediatrics

Education should be provided to appropriate school personnel as a significant portion of a childs day is spent in school. (E)
The developing teenager must be educated about the transition to adult health care, beginning in early to mid-adolescence, with
increasing efforts to establish self-reliance in diabetes care beginning at least 1 year prior to the transition. Even after the transition to
adult care is made, support and reinforcement are recommended. (E)

Additional Considerations for Adults

Adult learning theory can be used to tailor DSME and DSMS to the age, life stage, culture, literacy/numeracy, knowledge, experience,
and cognitive ability of the patient. (C)

Previous SectionNext Section

Psychosocial: Assessment and Treatment of Psychosocial Issues


Assessment and appropriate management of psychosocial issues are important throughout the life span of individuals with type 1 diabetes. In
pediatrics, health care providers should assess the individual child and the childs family for their ability to function and behave appropriately
regarding safe and responsible diabetes care. For adults, the individual is the focus of care. However, family involvement should be strongly
encouraged when appropriate.
Depression screening and discussion about psychosocial issues are important components of the diabetes visit. Special attention should be paid
to diabetes-related distress, fear of hypoglycemia (and hyperglycemia), eating disorders, insulin omission, subclinical depression, and clinical
depression. These factors are significantly associated with poor diabetes self-management, a lower quality of life, and higher rates of diabetes
complications. As individuals age, health care providers should evaluate issues related to self-care capacity, mobility, and autonomy. Such factors
are to be promptly addressed, as they make the management of type 1 diabetes ever more problematic.

Recommendations

Make age-appropriate screenings for psychosocial issues a component of most diabetes visits. Any concerns should be pursued through
treatment that may include referral to a mental health specialist. (E)

Additional Considerations for Pediatrics

Ensure that there is developmentally appropriate parent/family involvement in the management of the childs/adolescents diabetes care
tasks, avoiding a premature transfer of sole responsibility for diabetes management to the developing child/teenager. (B)

Directly ask about diabetes-related family conflict and stress and negotiate an acceptable resolution with the child/adolescent and
parent(s). However, if family conflict is extremely entrenched and cannot be resolved by the diabetes team, referral should be made to a
mental health specialist who is knowledgeable about type 1 diabetes in youth and family functioning. (C)

Additional Considerations for Adults

Ongoing evaluation of patients general and diabetes-related quality of life, emotional well-being, distress, depression, and resources is
warranted, preferably by a team that includes a mental health specialist if such resources are available. (C)
Health care providers should promptly address issues related to self-care capacity, mobility, and autonomy. (E)

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Nutrition Therapy
Nutrition therapy is an important component of the treatment plan for all individuals with type 1 diabetes. Each patient should have an
individualized food plan based on food preferences, schedule, and physical activity. Nutrition therapy aims to ensure that the patient and family
understand the impact food has on blood glucose, how food interacts with exercise and insulin to prevent hypo- and hyperglycemia and to
achieve glucose goals, and how to implement the food plan in a variety of situations. The food plan takes into consideration the patients
numeracy, literacy, engagement, and ability to adjust insulin.
General diabetes nutrition principles, as defined in the ADA Standards of Care, apply to people with type 1 diabetes, particularly in reference to
normal growth and development in youth and the maintenance of a healthy body weight at all ages. Specifically, with regards to individuals with
type 1 diabetes, topics such as carbohydrate counting and meal composition should be addressed. For selected individuals who have mastered
carbohydrate counting, education on the impact of protein and fat on glycemic excursions should be incorporated into diabetes management
(32). Those who are overweight or obese may benefit from weight reduction counseling.

Recommendations

Individualized medical nutrition therapy is recommended for all people with type 1 diabetes as an effective component of the overall
treatment plan. (A)
Monitoring carbohydrate intake, whether by carbohydrate counting or experience-based estimation, remains a key strategy in achieving
glycemic control. (B)
If adults with type 1 diabetes choose to drink alcohol, they should be advised to do so in moderation (one drink per day or less for adult
women and two drinks per day or less for adult men). Discussion with a health care provider is advised to explore potential interactions
with medications. Adults should be advised that alcohol can lower blood glucose levels and that driving after drinking alcohol is
contraindicated. (E)

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Physical Activity and Exercise


Exercise has many positive health and psychological benefits including physical fitness, weight management, and enhanced insulin sensitivity. It
also provides opportunities for social interactions and builds self-esteem. However, exercise creates challenges for people with type 1 diabetes
due to the increased risk for both hypoglycemia and hyperglycemia. During exercise, multiple hormones (insulin, glucagon, catecholamines,
growth hormone, and cortisol) control fuel metabolism and create a balance between glucose uptake by exercising muscles and hepatic glucose
production (33,34). The equilibrium between insulin secretion and the counterregulatory hormones varies according to the exercise type,
intensity, and duration (35).
Hyperglycemia results from counterregulatory hormone excess with insufficient insulin, leading to excessive hepatic glucose production and
limiting increased glucose uptake into skeletal muscle. Hyperglycemia can occur before, during, and after various types of exercise. If the patient
feels well, with negative or minimal urine and/or blood ketones, and there is a clear reason for the elevated blood glucose level, such as
underdosing insulin at the preceding meal, it is not necessary to postpone exercise based solely on hyperglycemia. However, when people with
type 1 diabetes are deprived of insulin for 1248 h and are ketotic, exercise can worsen hyperglycemia and ketosis. Therefore, vigorous activity
should be avoided in the presence of severe hyperglycemia and ketosis, especially with known insulin omission.

Physical activity increases hypoglycemia risk during and immediately following exercise, and, again, about 711 h postexercise. This delayed
susceptibility to hypoglycemia is referred to as the lag effect of exercise (36,37) and is caused by muscles replenishing glycogen stores
postexercise. Hypoglycemia and fear of hypoglycemia can limit participation in exercise.
Strategies should be developed to prevent and treat hypoglycemia readily. Individualization is necessary, but clinical experience suggests that it
is safest for most patients to have a blood glucose level of 100 mg/dL (5.6 mmol/L) or higher prior to starting exercise. This may be achieved by
reducing the prandial insulin dose for the meal/snack preceding exercise and/or increasing food intake. Some patients can avoid hypoglycemia
by reducing insulin (such as by lowering pump basal rates) (38) or by consuming additional carbohydrates during prolonged physical activity.
One study in children on pumps suggested that a reduction in overnight basal insulin the night following exercise may reduce the risk of delayed
exercise-induced hypoglycemia (39). Frequent SMBG and/or CGM use are key to exercising safely, as is ready access to carbohydrates.
Basic recommendations for physical activity are the same as those for all children and adults, independent of the diagnosis of diabetes: children
should be encouraged to engage in at least 60 min of physical activity daily, and adults should be advised to perform at least 150 min/week of
moderate-intensity aerobic physical activity (5070% of maximum heart rate) or a lesser amount (6075 min/week) of vigorous-intensity
activity (40,41). Exercise should also include resistance and flexibility training.
Individuals, particularly adults, should be assessed for cardiovascular risk and the presence of complications that might limit exercise as
discussed more fully in the ADA Standards of Medical Care in Diabetes (42).

Recommendations

Exercise should be a standard recommendation as it is for individuals without diabetes; however, recommendations may need
modifications due to the presence of macro- and microvascular diabetes complications. (E)
Patients of all ages (or caregivers of children) should be educated about the prevention and management of hypoglycemia that may occur
during or after exercise. (E)
Patients should be advised about safe preexercise blood glucose levels (typically 100 mg/dL or higher depending on the individual and
type of physical activity). (E)

Reducing the prandial insulin dose for the meal/snack preceding exercise and/or increasing food intake can be used to help raise the
preexercise blood glucose level and reduce hypoglycemia. (E)

A reduction in overnight basal insulin the night following exercise may reduce the risk for delayed exercise-induced hypoglycemia. (C)

SMBG should be performed as frequently as needed (before, during, and after exercise) in order to prevent, detect, and treat
hypoglycemia and hyperglycemia. (E)

Source(s) of simple carbohydrate should be readily available before, during, and after exercise to prevent and treat hypoglycemia. (E)

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Treatment Targets
General Considerations
Hyperglycemia defines diabetes and is directly related to the incidence of complications. Therefore, glycemic control is fundamental to diabetes
management. The Diabetes Control and Complications Trial (DCCT) (43) was a prospective randomized controlled study comparing intensive
versus standard glycemic control in patients diagnosed with type 1 diabetes relatively recently. The DCCT demonstrated that achieving an A1C
of <7% reduced the incidence of microvascular complications of type 1 diabetes compared with standard control, which achieved an A1C of
9% during the period of the randomized trial. The Epidemiology of Diabetes Interventions and Complications (EDIC) study (44,45) was a
follow-up of the DCCT cohorts. The EDIC study remarkably demonstrated persistent microvascular and cardiovascular benefits in subjects who
had previously received intensive treatment, even though their glycemic control had deteriorated over time.
While A1C and blood glucose targets are needed, the ADA emphasizes that glycemic targets should be individualized with the goal of
achieving the best possible control while minimizing the risk of severe hyperglycemia and hypoglycemia (Table 7). Goals should be
individualized based on duration of diabetes, age/life expectancy, comorbid conditions, known CVD or advanced microvascular complications,
hypoglycemia unawareness, and individual patient considerations. More or less stringent glycemic goals may be appropriate for individual
patients. Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial glucose goals.

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Table 7
Summary of A1C recommendations for nonpregnant people with diabetes*

Recommendation

Lifestyle, psychosocial, and medical circumstances should be considered when recommending glycemic goals for all age-groups. (E)

Glycemic Control Goals in Pediatrics


As the DCCT only included pediatric patients aged 13 years (195 adolescents aged 1317 years at entry), treatment guidelines for pediatric
patients have been based nearly exclusively on professional, expert advice. Furthermore, despite the overall A1C goal of <7% for adults with
type 1 diabetes, pediatric patients, aged 1319 years, had an A1C target of <7.5%. This slightly higher A1C target for adolescents with type 1
diabetes was based on expert recommendations and the clinical reality that optimizing glycemic control in adolescent patients with type 1
diabetes is especially challenging, given the physiological and behavioral challenges that confront this age-group.
The ADAs blood glucose and A1C goals traditionally have been developmentally or age based in the pediatric population, but it is now time to
alter the traditional goals based on recent data. The traditional recommendations are an A1C goal of <8.5% for youth under the age of 6 years,
<8% for those 612 years old, and <7.5% for those 1319 years old. Lower blood glucose levels and lower A1C targets should be pursued as
long as patients can avoid severe, recurrent hypoglycemia. Thus, the overall recommendation has included the goal to achieve as close to normal
blood glucose and A1C levels as is possible without the occurrence of severe, recurrent hypoglycemia.
Historically, the ADA recommended higher A1C targets for young children. This recommendation arose from a combination of two lines of
unsubstantiated evidence. First, an older body of literature, reflecting therapy in the premodern era, devoid of insulin analogs, easy-to-use blood
glucose monitors, smart pumps, and CGM devices, indicated that severe recurrent hypoglycemia with seizure and/or coma in young children

was associated with neurocognitive compromise (46). The second line of evidence arose from literature that questioned what, if any, impact
blood glucose and A1C levels prior to puberty have on the risk for the development of future long-term complications of diabetes (47,48). With
the combination of these two independent lines of reports, it is not surprising that earlier recommendations regarding glycemic targets focused on
the avoidance of severe hypoglycemia in order to reduce risk of neurocognitive dysfunction, especially in young children and even school-aged
children.
Currently, treatment strategies for children recommend physiological insulin replacement with modern strategies and treatment tools. More
recent investigation and active ongoing research have dispelled concerns regarding hypoglycemia and neurocognitive dysfunction (49,50).
Studies assessing neurocognitive function have failed to identify adverse effects of a past history of hypoglycemia in the young child; however,
as always, further research needs to be conducted.
There are also questions regarding the premise that the years prior to puberty do not impact the future risk of complications (51). Many
investigators and clinicians believe in the importance of controlling blood glucose and A1C levels prior to puberty to reduce risk for both microand macrovascular complications. Additionally, there is burgeoning evidence that elevated blood glucose levels and glycemic variability in the
very young child with diabetes may produce adverse outcomes in the short term on neurocognitive function and the central nervous system
(52,53). These recent articles suggest that hyperglycemia and glycemic variability are associated with changes in the central nervous system
white matter, as observed in MRI scans.
Taking into account the combination of spotty past evidence related to the adverse effects of hypoglycemia on the developing brain and
increasing evidence from more recent investigations focused on the potential risks of hyperglycemia and glucose variability on the central
nervous system, the ADA has decided to alter the recommendations for glycemic targets in pediatric patients with type 1 diabetes and harmonize
with other organizations. The International Society for Pediatric and Adolescent Diabetes (ISPAD) uses a single A1C goal of <7.5% across all
pediatric age-groups. This recommendation is based on clinical studies and expert opinion, as rigorous evidence does not currently exist.
Specifically, the recommendation is derived from a combination of clinical experience and intensive management strategies that provide
opportunities to achieve as near-normal glycemic control as possible without the occurrence of severe hypoglycemia.
In light of the above evidence, the ADA will harmonize its glycemic goals with those of ISPAD (as well as the Pediatric Endocrine Society
and the International Diabetes Federation) by using a single A1C goal of <7.5% across all pediatric age-groups.

However, as mentioned previously, it must be emphasized that the ADA strongly believes that blood glucose and A1C targets should be
individualized with the goal of achieving the best possible control while minimizing the risk of severe hyperglycemia and hypoglycemia and
maintaining normal growth and development.

Recommendation

An A1C goal of <7.5% is recommended across all pediatric age-groups. (E)

Glycemic Control Goals in Adults


Similar to in children, the care of older adults with diabetes is complicated by their clinical and functional heterogeneity. Unlike the large older
adult population with type 2 diabetes, which includes patients with both long-standing and new-onset diabetes, most older adults with type 1
diabetes have long-standing disease. Even so, there is a wide spectrum of health across older individuals. They may have advanced
complications, or they may have lived with diabetes for many years without the development of complications. Some older patients have
multiple comorbid conditions and/or impairments of physical or cognitive functioning, while others have little comorbidity and high functional
status. Life expectancy is highly variable and is defined by comorbidity and functional status more than it is by age.
Health care providers caring for older adults with diabetes must take this heterogeneity into consideration when setting and prioritizing treatment
goals. The benefits of interventions such as stringent glycemic control may not apply to those with advanced complications of diabetes or to
those with a life expectancy of less than the anticipated time frame of benefit. Conversely, the risks of interventions such as tight glycemic
control (hypoglycemia, treatment burden) may be greater in older patients. Although individualization is critical, in general, older patients with
long life expectancy and little comorbidity should have treatment targets similar to those of middle-aged or younger adults. In more frail patients,
treatment targets might reasonably be relaxed, while symptomatic hyperglycemia or the risk of DKA should still be avoided (54).

Recommendations

Lowering A1C to below or around 7% has been shown to reduce microvascular complications of diabetes, and, if achieved soon after the
diagnosis of diabetes, is associated with long-term reduction in macrovascular disease. Therefore, a reasonable A1C goal for many
nonpregnant adults with type 1 diabetes is <7%. (B)

Providers might reasonably suggest more stringent A1C goals (such as <6.5%) for select individual patients, if this can be achieved
without significant hypoglycemia or other adverse effects of treatment. Appropriate patients might include those with a short duration of
diabetes, a long life expectancy, hypoglycemia awareness, and no significant CVD. (C)

Less stringent A1C goals (such as <8.5%) may be appropriate for patients with a history of severe hypoglycemia, hypoglycemia
unawareness, limited life expectancy, advanced microvascular/macrovascular complications, or extensive comorbid conditions. (B)

Glycemic control for those of any age with type 1 diabetes should be assessed based on frequent SMBG levels (and CGM data, if
available) in addition to A1C in order to direct changes in therapy. (B)

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Monitoring
SMBG
The DCCT demonstrated the benefits of intensive glycemic control on diabetes complications with SMBG as part of a multifactorial
intervention, suggesting that SMBG is a crucial component of effective therapy. SMBG allows patients to evaluate their individual response to
therapy and assess whether glycemic targets are being achieved. SMBG results are useful in preventing hypoglycemia, adjusting medications
(particularly prandial insulin doses), and understanding the impact of appropriate nutrition therapy and physical activity. More frequent SMBG is
correlated to lower A1C levels (55,56).
SMBG frequency and timing should be dictated by the patients specific needs and goals. When prescribing SMBG, providers must ensure that
patients receive ongoing instruction and regular evaluation of their SMBG technique and their ability to use SMBG data to adjust therapy
(insulin and/or food). Furthermore, SMBG results should be downloaded and reviewed at each visit.
SMBG is especially important for patients with type 1 diabetes to monitor for and prevent asymptomatic hypoglycemia and hyperglycemia. Type
1 diabetic patients should perform SMBG prior to, and sometimes after, meals and snacks, at bedtime, before and after exercise, when they
suspect low blood glucose, after treating low blood glucose until they are normoglycemic, and prior to critical tasks such as driving. For many

patients, this will require testing 610 times daily, although individual needs may vary. For example, sick children may require up to 10 SMBG
tests per day or more.
A study of children and adolescents with type 1 diabetes showed that, after adjustment for multiple confounders, increased SMBG frequency was
significantly associated with lower A1C. In the range of 05 tests per day, A1C decreased by 0.46% per additional test per day. Increased testing
was associated with significantly less DKA and (probably due to reverse causality) significantly more hypoglycemia (55,56).
SMBG accuracy is dependent on both the instrument and the user (57), so it is important to evaluate each patients monitoring technique, both
initially and at regular intervals thereafter. Optimal use of SMBG requires a proper review and interpretation of the data by both the patient and
the provider.

CGM
Real-time CGM through the measurement of interstitial glucose (which correlates well with plasma glucose) is available. These sensors require
calibration with SMBG, and CGM users still require SMBG for making acute treatment decisions. CGM devices have alarms for hypo- and
hyperglycemic excursions that include absolute level and rate-of-change alerts. A 26-week randomized trial of 322 type 1 diabetic patients
showed that adults aged 25 years using intensive insulin therapy and CGM experienced a 0.5% reduction in A1C (from 7.6% to 7.1%)
compared with usual intensive insulin therapy with SMBG (58). Participants aged <25 years (children, teenagers, and young adults) randomized
to sensor use did not achieve a significant A1C reduction. However, these younger patients did not use CGM consistently. The greatest predictor
of A1C lowering for all age-groups was frequency of sensor use, which was lowest in 15- to 24-year-old subjects. There was no significant
difference in hypoglycemia in any age-group. In a smaller randomized controlled trial of 129 adults and children with baseline A1C <7.0%,
outcomes combining A1C and hypoglycemia favored the group using CGM, suggesting that CGM is beneficial for pediatric patients and adults
with type 1 diabetes who have already achieved excellent control (58).
Overall, meta-analyses suggest that, compared with SMBG, CGM use is associated with A1C lowering by 0.26% (59) without an increase in
hypoglycemia, although existing studies have small sample sizes and are of relatively short duration. The technology may be particularly useful
in those with hypoglycemia unawareness and/or frequent hypoglycemic episodes, although studies have not consistently shown significant
reductions in the occurrence of severe hypoglycemia. A CGM device equipped with an automatic low threshold suspend feature was approved
by the U.S. Food and Drug Administration (FDA) in 2013. The Automation to Simulate Pancreatic Insulin Response (ASPIRE) trial of 247

patients showed that sensor-augmented insulin pump therapy with a low glucose suspend feature significantly reduced nocturnal hypoglycemia
without increasing A1C levels for those >16 years of age (60). These devices may offer the opportunity to reduce severe hypoglycemia for those
with a history of nocturnal hypoglycemia, although more clinical trials are needed.

Recommendations

Patients with type 1 diabetes should perform SMBG prior to meals and snacks, at a minimum, and at other times, including
postprandially to assess insulin-to-carbohydrate ratios; at bedtime; midsleep; prior to, during, and/or after exercise; when they suspect
low blood glucose; after treating low blood glucose until they have restored normoglycemia; when correcting a high blood glucose level;
prior to critical tasks such as driving; and at more frequent intervals during illness or stress. (B)
Individuals with type 1 diabetes need to have unimpeded access to glucose test strips for blood glucose testing. Regardless of age,
individuals may require 10 or more strips daily to monitor for hypoglycemia, assess insulin needs prior to eating, and determine if their
blood glucose level is safe enough for overnight sleeping. (B)
CGM is a useful tool to reduce A1C levels in adults without increasing hypoglycemia and can reduce glycemic excursions in children.
Glycemic improvements are correlated with frequency of CGM use across all ages. (A)

Additional Considerations for Pediatrics

Children should have additional blood glucose checks if the parent/caregiver is concerned that the childs behavior may be due to
low/high blood glucose levels. (E)
School employees and caregivers should be knowledgeable about SMBG and equipped with all necessary supplies. (E)

Capable children should be permitted to self-manage their diabetes at school. (E)

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A1C Testing

A1C reflects average glycemia over 23 months (57) and strongly predicts diabetes complications (43,61). Thus, A1C testing should be
performed routinely in all patients with diabetes at initial assessment and as part of continuing care. A1C is a convenient method to track
diabetes control; however, there are disadvantages. Glycation rates, and thus A1C levels, may vary with patients race/ethnicity. However, this is
controversial. Additionally, anemias, hemoglobinopathies, and situations of abnormal red cell turnover affect A1C (42).
A1C measurements approximately every 3 months determine whether a patients glycemic targets have been reached and maintained. For any
individual patient, the frequency of A1C testing should be dependent on the clinical situation, the treatment regimen used, and the clinicians
judgment. Unstable or highly intensively managed patients (e.g., pregnant type 1 diabetic women) may require more frequent testing than every
3 months (62). In patients with hemoglobinopathies that interfere with the A1C assay or with hemolytic anemia or other conditions that shorten
the red blood cell life span, the A1C may not accurately reflect glycemic control or correlate well with SMBG testing results. In such conditions,
fructosamine may be considered as a substitute measure of long-term (average over 2 weeks) glycemic control.

Recommendations

Perform the A1C test quarterly in most patients with type 1 diabetes and more frequently as clinically indicated (i.e., pregnancy). (A)
Point-of-care A1C testing, using a DCCT standardized assay, may provide an opportunity for more timely treatment changes. (E)

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Insulin Therapy
The DCCT clearly showed that intensive insulin therapy, defined as three or more injections per day of insulin or continuous subcutaneous
insulin infusion (CSII) (or insulin pump therapy), was a key part of improved glycemia and better outcomes (43,63). The study was carried out
with short- and intermediate-acting human insulins. Despite better microvascular outcomes, intensive insulin therapy was associated with a high
rate of severe hypoglycemia (62 episodes per 100 patient-years of therapy). Since the completion of the DCCT, a number of rapid-acting and
long-acting insulin analogs have been developed. These analogs are associated with less hypoglycemia than human insulin while offering the
same amount of A1C lowering in people with type 1 diabetes (64,65).

The Sensor-Augmented Pump Therapy for A1C Reduction (STAR 3) study was a large (n = 485) randomized clinical trial comparing insulin
pump therapy and CGM with insulin injections in youth and adults with type 1 diabetes. The two study groups started with the same baseline
A1C of 8.3%. After 1 year, the group using insulin pump therapy and CGM had lower A1C levels (7.5% vs. 8.1%, P < 0.001) without significant
nocturnal hypoglycemia compared with the insulin injection cohort (66). Recently, a large randomized trial in patients with type 1 diabetes and
nocturnal hypoglycemia reported that the use of sensor-augmented insulin pump therapy with the threshold-suspend feature reduced nocturnal
hypoglycemia without increasing glycated hemoglobin values (60). In general, intensive management using pump therapy/CGM should be
strongly encouraged, with active patient/family participation enhancing successful outcomes (6769).

Recommendations

Most individuals with type 1 diabetes should be treated with multiple daily insulin injections (three or more injections per day of prandial
insulin and one to two injections of basal insulin) or CSII. (A)
Most individuals with type 1 diabetes should be educated in how to match prandial insulin dose to carbohydrate intake, premeal blood
glucose, and anticipated activity. (E)

Most individuals with type 1 diabetes should use insulin analogs to reduce hypoglycemia risk. (A)

All individuals with type 1 diabetes should be taught how to manage blood glucose levels under varying circumstances, such as when ill
or receiving glucocorticoids or for those on pumps, when pump problems arise. (E)

Child caregivers and school personnel should be taught how to administer insulin based on provider orders when a child cannot selfmanage and is out of the care and control of his or her parent/guardian. (E)

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Interdiction
Therapy trials to prevent type 1 diabetes development (prevention), to preserve remaining -cells (preservation), and to replace -cells
(transplantation) are ongoing. Although means are available to screen and predict family members at risk for developing type 1 diabetes, efforts
to delay or prevent disease onset have been largely disappointing. A variety of different immunomodulatory and immune-suppressive agents

have been evaluated in patients with recent-onset type 1 diabetes, and the effects have been modest at best: for the subset of drugs that appear to
have an effect, not all patients respond; for those who do, the effects are generally transient. Many of the agents tested to date are FDA approved
for other indications, but given the observations to date and potential toxicities, the recommendation is that patients should only receive these
drugs after being enrolled in clinical research protocols with appropriate follow-up. Long-term safety and efficacy data are scarce, especially in
children. Investigators continue to evaluate promising new agents and combinations of drugs or cell-based therapies in an effort to safely and
effectively modulate the autoimmune response (70).
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-Cell Replacement Therapy


-Cell replacement may be achieved through pancreas or islet transplantation in select candidates. Pancreas transplants are now accepted as a
proven therapy, while islet transplants, though significantly improving, are still mostly done on an experimental basis.

Pancreas Transplants
Pancreas transplants are most often performed in combination with kidney transplantation, either as a simultaneous pancreas-kidney (SPK)
transplant or as a pancreas-after-kidney (PAK) transplant (71). SPK and PAK transplants may be considered for individuals with late-stage
kidney disease because the transplants can normalize glucose levels, which will prevent hypoglycemia and provide some protection for the
transplanted kidney (72), and provide other benefits, including an improvement in quality of life (71). These recipients will already require
immunosuppression for their renal transplants, which means the major additional risk is the operative procedure. SPK transplants function for an
average of 9 years, compared with 6 years for PAK transplants (71).
There has been debate about pancreas transplant alone (PTA) in the absence of an indication for kidney transplantation because of the risks of
mortality, morbidity, and immunosuppression. Outcomes have gradually improved (73), such that the procedure can be cautiously considered for
individuals without renal failure who have unstable glucose control and hypoglycemia unawareness. Because of the risks of pancreas
transplantation compared with traditional methods for controlling blood glucose levels, all available efforts to use exogenous insulin combined
with technology, education, and glucose follow-up should be exhausted before PTA is performed. The durability of function averages 6 years,
which is much better than islet transplantation but about the same as PAK and not as good as SPK (73).

Islet Transplantation
A major appeal of islet transplantation is that it does not require major surgery. Moreover, outcomes have improved over the past decade such
that normoglycemia without insulin is now maintained for an average of 3 years in specialized protocols (74). Even when insulin treatment is
reinstituted, residual insulin secretion can help recipients maintain good control with less hypoglycemia and a less complicated regimen for
several more years.
At the present time, few islet transplants are being performed and most are experimental. However, they can be considered as a treatment option
for those who are poor candidates for whole-organ transplants. Importantly, their current success has established a proof of principle for cellular
transplantation. Great progress is being made in finding an abundant source of healthy insulin-producing cells and in developing better ways to
protect transplanted cells from immune destruction (75,76). Potential solutions for the shortage of islets include embryonic stem cells, induced
pluripotent stem cells, xenogeneic tissue, and various other potential sourcesall the focus of ongoing research efforts. Another possible way to
replenish the -cell deficiency of diabetes is through regeneration of the endocrine pancreas; this too is being worked on intensively.

Recommendations

Consider solid organ pancreas transplantation simultaneously with kidney transplantation in patients with type 1 diabetes who have an
indication for kidney transplantation and are poorly controlled with large glycemic excursions. (B)
Consider solid organ pancreas transplantation after kidney transplantation in adult patients with type 1 diabetes who have already
received a kidney transplant. (C)

Judiciously consider solid organ pancreas transplantation alone in adults with type 1 diabetes, unstable glucose control, hypoglycemia
unawareness, and an increased risk of diabetes-related mortality, who have attempted all of the more traditional approaches to glycemic
control and have remained unsuccessful, yet are judged responsible enough to manage the antirejection medication regimen, risks, and
follow-up required with an organ transplant. (C)

Consider referral to research centers for protocolized islet cell transplantation in patients with type 1 diabetes and debilitating
complications of diabetes who are interested in research possibilities and fit the criteria for the research protocol. (E)

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Adjunctive Therapies
Pramlintide
Pramlintide, an amylin analog, is an agent that delays gastric emptying, blunts pancreatic secretion of glucagon, and enhances satiety. It is an
FDA-approved therapy for use in type 1 diabetic patients and has been shown to reduce A1C, induce weight loss, and lower insulin dose.
However, it is only indicated for adults. Two 52-week trials of pramlintide (n = 1,131; age >18 years) showed A1C reductions of 0.30.4%
(77,78). In both studies, a greater proportion of participants achieved an A1C target of <7% with the therapy than without the therapy. There are
a few small, short-term studies of pramlintide use in children with type 1 diabetes, with outcomes similar to those in the adult studies. Clearly,
larger, long-term studies are needed in pediatrics.

Incretin-Based Therapies
Injectable glucagon-like peptide-1 (GLP-1) agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors are increasingly being studied in the type
1 diabetic population, but are not approved by the FDA for this indication. GLP-1 agonists delay gastric emptying, suppress the postprandial rise
in glucagon secretion, and may increase satiety. Preliminary studies indicate that these agents may also facilitate weight loss. Further long-term
clinical trials in type 1 diabetic patients are needed.

Sodium-Glucose Cotransporter 2 Inhibitors


Sodium-glucose cotransporter 2 (SGLT2) inhibitors work by inhibiting glucose reabsorption in the kidney and are also being tested in
individuals with type 1 diabetes. These agents provide insulin-independent glucose lowering by blocking glucose reabsorption in the proximal
renal tubule, leading to weight loss and A1C reduction in individuals with type 2 diabetes. However, insufficient data exist to recommend
clinical use of these agents in type 1 diabetes at this time.

Metformin

Metformin is a biguanide that decreases hepatic gluconeogenesis and is used as first-line therapy in type 2 diabetes. It has been shown to have
some benefit in reducing insulin doses and weight in small studies in patients with type 1 diabetes (79) and is now being evaluated more fully for
use in patients with type 1 diabetes. Two randomized controlled trials are currently under way evaluating metformin in type 1 diabetic patients.
The first study is in adults and is using carotid intima-medial thickness as an outcome measure (ClinicalTrials.gov identifier: NCT01483560).
The second study is focusing on overweight or obese youths between the ages of 12 and 19 years who require 0.85 units/kg/day of insulin
(ClinicalTrials.gov identifier: NCT01808690). Results are currently pending.

Recommendations

Pramlintide may be considered for use as adjunctive therapy to prandial insulin in adults with type 1 diabetes failing to achieve glycemic
goals. (B)
Evidence suggests that adding metformin to insulin therapy may reduce insulin requirements and improve metabolic control in
overweight/obese patients and poorly controlled adolescents with type 1 diabetes, but evidence from larger longitudinal studies is
required. (C)
Current type 2 diabetes medications (GLP-1 agonists, DPP-4 inhibitors, and SGLT2 inhibitors) may be potential therapies for type 1
diabetic patients, but require large clinical trials before use in type 1 diabetic patients. (E)

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Hypoglycemia
Hypoglycemia risk is the limiting step in the treatment of type 1 diabetes at any age. Because current methods of blood glucose detection and
insulin replacement are imperfect (though improved from prior eras), hypoglycemia risk is invariably present. Patient education (80), frequent
SMBG, and CGM can help detect hypoglycemia and allow for adjustments in insulin dosing and carbohydrate intake. Severe hypoglycemia rates
increase with antecedent episodes of hypoglycemia, age, and duration of diabetes; thus, this is an issue that must be reassessed frequently (81).
Hypoglycemia unawareness is related to a reduced sympathoadrenal response to hypoglycemia; it can occur in the setting of recurrent
hypoglycemia or autonomic failure and can be reversed by scrupulous avoidance of hypoglycemia. Patients should be screened to determine the

threshold at which hypoglycemia symptoms occur; if the threshold is suggestive of hypoglycemia unawareness, the treatment goals and regimen
should be revisited and counseling regarding appropriate self-monitoring before critical tasks should be reinforced (82).
Oral carbohydrate is the treatment of choice for self-treatment or for the treatment of hypoglycemic adults and children who are alert and able to
eat. Glucagon is used for severe hypoglycemia. In children, small studies have led to the concept of using age-based mini-dose glucagon if the
child is alert but not able to eat (83).

Recommendations

Individuals with type 1 diabetes, or their caregivers, should be asked about symptomatic and asymptomatic hypoglycemia at each
encounter. (E)
Glucose (1520 g) is the preferred treatment for the conscious individual with hypoglycemia, although any form of carbohydrate may be
used. If the SMBG result 15 min after treatment shows continued hypoglycemia, the treatment should be repeated. Once blood glucose
concentration returns to normal, the individual should consume a meal or snack to prevent recurrence of hypoglycemia. (E)

Glucagon should be prescribed for all individuals with type 1 diabetes. Caregivers or family members of these individuals should be
instructed in its administration. (E)

Hypoglycemia unawareness or one or more episodes of severe hypoglycemia should trigger reevaluation of the treatment regimen. (E)

Insulin-treated patients with hypoglycemia unawareness or an episode of severe hypoglycemia should be advised to raise their glycemic
targets to strictly avoid further hypoglycemia for at least several weeks to partially reverse hypoglycemia unawareness and reduce the
risk of future episodes. (B)

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DKA
DKA (see ref. 70 for definition) is an acute complication of diabetes that can be associated with new-onset type 1 diabetes, insulin omission, and
increased levels of counterregulatory hormones/cytokines associated with stress, such as an infection. Mild cases can be safely and effectively

treated in an acute care setting with appropriate resources and may not require hospitalization. Education must be provided to individuals with
type 1 diabetes in order to help prevent DKA, which can have serious sequelae, particularly in children under 5 years of age. Although DKA and
hyperglycemic hyperosmolar state (HHS) may overlap, especially when dehydration is severe, DKA must be distinguished from HHS (serum
glucose >600 mg/dL, serum osmolality >330 mOsm/kg, and no significant ketosis and acidosis) because patients with HHS typically are
severely dehydrated and require more aggressive fluid management. There are multiple guidelines available for the management of DKA (84).

Recommendations

Individuals and caregivers of individuals with type 1 diabetes should be educated and reminded annually how to prevent DKA, including
a review of sick-day rules and the critical importance of always administering insulin and monitoring both glucose and ketone levels. (B)
Insulin omission is the major cause of DKA; therefore, individuals with type 1 diabetes must have access to an uninterrupted supply of
insulin. (E)

Patients with type 1 diabetes and their families should have around-the-clock access to medical advice and support to assist with sick-day
management. (C)

Standard protocols for DKA treatment should be available in emergency departments and hospitals. (E)

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CVD Screening and Treatment


Much of the existing data on the risk of CVD in individuals with diabetes is based on people with type 2 diabetes who often have additional
CVD risk factors, such as metabolic syndrome, hypertension, and dyslipidemia. How much is applicable to people with type 1 diabetes is
unknown. However, people with type 1 diabetes are at increased risk for CVD, particularly those with additional risk factors.
In type 1 diabetes, standard risk factors apply, such as hyperlipidemia, hypertension, age, family history, smoking, weight, and presence of
albuminuria. As such, these should be considered when determining the need for evaluation and treatment for CVD. However, even in the
absence of classic risk factors, there may be high CVD risk. An adult with childhood-onset type 1 diabetes of 20-year duration has a substantially

increased risk of coronary artery disease of 1% per year (83), thus meriting high-intensity statin therapy according to the new joint American
College of Cardiology/American Heart Association guidelines (7.5% 10-year risk) (85). In some cases, measurement of coronary artery
calcification may be a helpful method for determining CVD risk (86). Here, as with all management issues for people with type 1 diabetes,
providers need to individualize assessment and treatment options.
With regard to treatment, statin therapy is the preferred treatment for lipid lowering/CVD risk reduction (85). The Heart Protection Study (HPS)
did include type 1 diabetic participants who appeared to experience the same degree of benefit from statins as others in the study, though the
finding was not statistically significant due to low numbers (87). Unfortunately, there are no blood pressure intervention trials with CVD end
points in type 1 diabetes and only one LDL cholesterollowering trial (85). Statin and aspirin therapy (if not contraindicated) should be
considered and used as is individually indicated.

Recommendations

Therapy for those under age 40 years with less than a 20-year diabetes duration (or over age 75 years) should be considered on an
individual basis, though, depending on overall risk, an LDL cholesterol <100 mg/dL has been suggested as an appropriate goal with statin
intervention for those with LDL cholesterol levels of 130160 mg/dL. (E)
Individuals with type 1 diabetes aged 4075 years may benefit from moderate-to-intensive statin therapy with consideration of diabetes
duration and CVD risk factors. If 10-year risk is estimated to be 7.5%, then intensive statin therapy should be considered. (B)

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Specific Settings and Populations


Pregnancy
Preconception Counseling and Care
To minimize risks associated with pregnancy and type 1 diabetes, preconception counseling and care are critical. Preconception care with tight
glycemic control improves outcomes including lower cesarean rates (88), decreased perinatal mortality (8991), and decreased congenital

malformations (8997). Although there is some evidence that childbearing may be reduced (98100), in general, fertility should be assumed to
be normal, and all young women with type 1 diabetes should receive preconception counseling covering diabetes and general topics, including
use of prenatal vitamin, discontinuation of potentially teratogenic medications, and the importance of glycemic control to reduce the risk of
congenital malformations.
Pregnancy
Type 1 diabetes affects approximately 0.10.2% of all pregnancies (101). During pregnancy, there are substantial changes in maternal insulin
sensitivity that may cause profound changes in insulin requirements. Whereas insulin resistance increases markedly during the second and third
trimesters, a greater proportion of total daily insulin dose must be given prandially and a lower proportion used to cover basal metabolic
requirements (102). Pregnant women with type 1 diabetes require meticulous glycemic management by experts trained in obstetrics,
endocrinology, and maternal-fetal medicine. Women who are planning pregnancy or who are pregnant may need to test blood glucose levels
frequently (often 10 or more times daily) to reach and maintain a near-normal A1C level without excessive hypoglycemia.
Severe hypoglycemia may occur early during pregnancy (102). This is followed by periods of insulin resistance and subsequent hyperglycemia if
the increased insulin needs are not met. Therefore, health care providers must be vigilant and frequently adjust insulin dosing throughout
gestation.
In a pregnancy complicated by diabetes and chronic hypertension, target blood pressure goals of systolic blood pressure 110129 mmHg and
diastolic blood pressure 6579 mmHg are reasonable. Lower blood pressure levels may be associated with impaired fetal growth (Table 8). ACE
inhibitors and angiotensin receptor blockers are contraindicated during pregnancy because they may have adverse effects on the fetus.
Antihypertensive drugs known to be effective and safe in pregnancy include methyldopa, labetalol, diltiazem, clonidine, and prazosin.
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Table 8

ADA Standards of Care optimal targets in pregnancy*


Eye examinations should occur in the first trimester with close follow-up throughout pregnancy and for 1 year postpartum because of the risk of
rapid retinopathy progression during pregnancy. Those with progressive retinopathy should have more frequent screening by an ophthalmologist
experienced in retinopathy management. See the American Diabetes Association/JDRF Type 1 Diabetes Sourcebook (70) for a summary of
pregnancy recommendations. The prevalence of Hashimoto thyroiditis may be as high as 31% in women with type 1 diabetes (105). Therefore,
all pregnant women with type 1 diabetes should be screened for thyroid disease early in pregnancy.

Recommendations

Starting at puberty, preconception counseling should be incorporated into routine diabetes clinic visits for all adolescents and women of
childbearing potential, and appropriate birth control techniques should be discussed with women who do not desire pregnancy. (C)
As most pregnancies are unplanned, consider the potential risks and benefits of medications that are contraindicated in pregnancy in all
adolescents and women of childbearing potential and counsel women using such medications accordingly. (E)

Such medications should be evaluated prior to conception, as drugs commonly used to treat diabetes and its complications may be
contraindicated or not recommended in pregnancy, including statins, ACE inhibitors, angiotensin receptor blockers, and most noninsulin
therapies. (B)

Prenatal vitamins with folate should be started with preconception planning to reduce the risk for birth defects. (B)

All pregnant women with type 1 diabetes should be screened for thyroid disease early in pregnancy. (B)

Women contemplating pregnancy should be evaluated and, if indicated, treated for diabetic retinopathy, nephropathy, neuropathy, and
CVD. (B)

A1C levels should be as close to normal as possible (<7%) before conception is attempted. (B)

Nutritional intake should be optimized and included in preconception planning according to general pregnancy guidelines. (E)

Inpatient Management and Outpatient Procedures

Management of individuals with type 1 diabetes in the hospital and in preparation for scheduled outpatient procedures often differs from that of
individuals with type 2 diabetes. The challenges include difficulties associated with fasting, maintaining a consistent source of carbohydrate, and
facilitating inpatient blood glucose management while modifying scheduled insulin therapy. Outpatient procedures should be performed with the
awareness that individuals with type 1 diabetes may have difficulty fasting for long periods of time (more than 10 h) prior to a procedure.
Patients with type 1 diabetes should be prepared with a treatment plan for insulin dose adjustments and oral glucose intake prior to any
procedure that requires alterations in dietary intake and/or fasting.
It is imperative that the entire health care team, including anesthesiologists and surgeons as well as other specialists who perform procedures,
understands type 1 diabetes and how it factors into the comprehensive delivery of care. From a practical perspective, this means that people with
type 1 diabetes will be at high risk for hypoglycemia during prolonged fasting and are at risk for ketosis if insulin is inappropriately withheld.
Once under anesthesia, individuals with type 1 diabetes must be carefully monitored for hypoglycemia and hyperglycemia.
For some individuals, once the most acute phase of an illness has resolved or improved, patients may be able to self-administer their prior
multiple-dose or CSII insulin regimen under the guidance of hospital personnel who are knowledgeable in glycemic management. Individuals
managed with insulin pumps and/or multiple-dose regimens with carbohydrate counting and correction dosing may be allowed to manage their
own diabetes if this is what they desire, once they are capable of doing so.

Recommendations

All patients admitted to the hospital should have type 1 diabetes clearly identified in the medical record. (E)
SMBG should be ordered to fit the patients usual insulin regimen with modifications as needed based on clinical status. (E)

Goals for blood glucose levels are the same as for people with type 2 diabetes or hospital-related hyperglycemia. (E)

A plan for preventing and treating hypoglycemia should be established for each patient. (E)

Insulin dosing adjustments should be made in the perioperative period and inpatient setting with consideration of changes in oral intake,
recent blood glucose trends, and the need for uninterrupted basal insulin to prevent hyperglycemia and ketoacidosis, with adjustment of
the long-acting insulin or basal insulin requirement to reflect true basal requirements, insofar as they may be anticipated. (B)

Child Care and Schools


Because a large portion of a childs day may be spent in school and/or in the child care setting, close communication with and cooperation of the
school or day care personnel is essential for optimal diabetes management, safety, and maximal academic opportunities. Child care personnel
and school staff should receive training to provide diabetes care in the absence of a school nurse or licensed health care professional. Able and
willing school staff members should be taught the principles of diabetes management and trained to provide needed care for the child according
to the ADAs Safe at School program (see the ADA position statement on diabetes care in the school and day care setting [106] for further
discussion). Young children often lack the motor, cognitive, and communication skills and abilities to manage their diabetes and completely
depend on adult caregivers. The management priority for younger children is the prevention, recognition, and treatment of hypoglycemia and
marked hyperglycemia.
Students with diabetes should receive proper diabetes management in school, with as little disruption to the school and childs routine as
possible. Whenever possible, the student should have the opportunity to self-manage by performing blood glucose monitoring, using CGM (if
utilized), administering insulin, having access to meals/snacks, managing hypoglycemia (with trained personnel prepared to provide glucagon
treatment, if required) and hyperglycemia, and participating fully in all school-sponsored activities (Table 9).
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Table 9
Diabetes care tasks for school personnel

Camps
A diabetes camp is an ideal place for children and youth to have an enjoyable camp experience and receive peer support from other children with
diabetes under close medical oversight. The goals for campers are to learn to cope more effectively with diabetes, learn self-management skills
to gain more independence, and share experiences with other young people with diabetes.

The camp medical director is responsible for the diabetes management of the children. A registered dietitian oversees dietary planning at camp.
Medical directors and staff should have expertise in managing type 1 diabetes and must receive training concerning routine diabetes management
and treatment of diabetes-related emergencies at camp. Staff must follow universal precautions including Occupational Safety and Health
Administration (OSHA) regulations, Clinical Laboratory Improvement Amendments (CLIA) standards, and state regulations (107).

Diabetes in the Workplace


There are practical and legal issues related to diabetes in the workplace. Employers and employees with diabetes should work together to find
solutions and educate themselves about the rights of individuals with diabetes. Individuals with diabetes are responsible for having all necessary
diabetes supplies, eating properly, and being aware of safety issues and regulations at work. The Americans with Disabilities Act states that most
employers must provide reasonable accommodations to allow an individual with diabetes to safely and successfully perform a job, unless
doing so would place an undue burden on the employer. We refer the reader to ADA position statement on diabetes and employment for
additional information (108) and to the relevant section of the American Diabetes Association/JDRF Type 1 Diabetes Sourcebook (70).

Older Adults
Older individuals with type 1 diabetes are unique in that they have lived for many years with a complex disease. Not all older adults are alike:
some may continue a rigorous regimen, with tighter control, while others may require less stringent targets. Along with age-related conditions,
older adults may develop diabetes-related complications, which make managing type 1 diabetes more challenging. Providers should be aware
that insulin dosing errors, meal planning, and physical activities must be properly managed in older adults. Severe hyperglycemia can lead to
symptoms of dehydration and hyperglycemic crises. While chronic hyperglycemia is detrimental, hypoglycemia may be more of a concern in
some older adults. Declining cognition may contribute to hypoglycemia unawareness or the inability to safely manage hypoglycemia when it
occurs. An individualized approach that includes the reassessment of prior targets may be warranted. We refer the reader to the ADA consensus
report Diabetes in Older Adults (54). Even though this report focuses primarily on the type 2 diabetic population, there is significant overlap in
the comorbidities and complications experienced by the older type 1 and type 2 diabetic populations.

Special Population Groups

Although type 1 diabetes is increasing in several ethnic and racial groups, it remains less common in people of non-European descent. A better
understanding of the unique pathophysiology of type 1 diabetes is needed. In addition, multidisciplinary diabetes teams should receive training
to properly address the diverse cultural needs of these populations and to optimize health care delivery, improve glycemic control, and prevent
complications. Additionally, there is a need for approaches to reduce health disparities and improve outcomes in racial/ethnic minorities and in
the underserved population with type 1 diabetes (70).

Developing Countries: The Global Epidemic


Type 1 diabetes is an increasing global public health burden. The demands of daily management, chronicity of the disease, potential
complications, paucity of diabetes specialists, and rising incidence are challenging in the U.S., but these issues, including the considerable cost
of management, are crippling for those in the developing world. International organizations play a major role in improving care for individuals
with type 1 diabetes in the developing world, but implementable, cost-saving, and sustainable strategies are needed to make such programs
successful (70).
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Article Information
Acknowledgments. The authors thank the following contributors to the American Diabetes Association/JDRF Type 1 Diabetes Sourcebook:
Nora Algothani, Pamela Allweiss, Barbara J. Anderson, Florence M. Brown, H. Peter Chase, William L. Clarke, Sheri R. Colberg, Kathleen
Dungan, Steven Edelman, Martha M. Funnell, Stephen E. Gitelman, Ann E. Goebel-Fabbri, Jeffrey S. Gonzalez, Carla J. Greenbaum, Michael J.
Haller, Kara Hawkins, Laurie A. Higgins, Irl B. Hirsch, William C. Hsu, Heba Ismail, Crystal Crismond Jackson, Tamarra James-Todd,
Georgeanna J. Klingensmith, David C. Klonoff, Mary Korytkowski, David Maahs, Hussain Mahmud, Medha N. Munshi, Trevor Orchard, Bruce
A. Perkins, Jeremy Hodson Pettus, Andrew M. Posselt, Michael C. Riddell, Elizabeth R. Seaquist, Janet Silverstein, Linda M. Siminerio, Peter
Stock, William V. Tamborlane, Guillermo E. Umpierrez, Raynard Washington, Joseph I. Wolfsdorf, Howard Wolpert, Jennifer Ann Wyckoff, and
Mary Ziotas Zacharatos. The authors acknowledge Gordon Weir and the Steering Committee members: Belinda Childs, Richard A. Insel,
Margaret A. Powers, Richard Rubin, Desmond Schatz, and Linda M. Siminerio.
The authors also thank Erika Gebel Berg (American Diabetes Association) for her invaluable editorial contribution.

Duality of Interest. M.S.K. received research support from Novo Nordisk (to the University of North Carolina) for a study of an investigational
drug for type 1 diabetes. In 20132014, L.M.B.L. received grant support from Bayer Diabetes Care; served as a consultant/advisory board
member for Bristol-Myers Squibb/AstraZeneca, Sanofi, Novo Nordisk, and Boehringer Ingelheim; and served as a consultant for Johnson &
Johnson, LifeScan/Animas, Lilly, Menarini, and Dexcom. In the past year, A.L.P. consulted with Abbott Diabetes Care, BD, Janssen, Lilly,
Medscape, Medtronic MiniMed, Novo Nordisk, Sanofi, and Takeda; has been on the speakers bureau for Bristol-Myers Squibb/AstraZeneca
and Novo Nordisk; and received grant funding from the Medtronic MiniMed Foundation. No other potential conflicts of interest relevant to this
article were reported.
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Footnotes

The position statement was reviewed and approved by the Professional Practice Committee in April 2014 and approved by the Executive
Committee of the Board of Directors in April 2014.
*A list of authors of the American Diabetes Association/JDRF Type 1 Diabetes Sourcebook can be found in the
ACKNOWLEDGMENTS.
2014 by the American Diabetes Association.

Readers may use the content as long as the work is properly cited and linked to the original source, the use is educational and not for profit, and
the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
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1. Top
2. Incidence and Prevalence of Type 1 Diabetes
3. Classification and Diagnosis
4. Initial Evaluation and Follow-up

5. DSME and DSMS


6. Psychosocial: Assessment and Treatment of Psychosocial Issues
7. Nutrition Therapy
8. Physical Activity and Exercise
9. Treatment Targets
10. Monitoring
11. A1C Testing
12. Insulin Therapy
13. Interdiction
14. -Cell Replacement Therapy
15. Adjunctive Therapies
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17. DKA
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Diabetologia. 2001 Sep;44 Suppl 2:S14-21.

Mortality and causes of death in the WHO Multinational Study of


Vascular Disease in Diabetes.
Morrish NJ1, Wang SL, Stevens LK, Fuller JH, Keen H.

Author information
Abstract
AIMS/HYPOTHESIS:
We aimed to examine the mortality rates, excess mortality and causes of death in diabetic patients from ten centres throughout the world.
METHODS:
A mortality follow-up of 4713 WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD) participants from ten centres was
carried out, causes of death were ascertained and age-adjusted mortality rates were calculated by centre, sex and type of diabetes. Excess
mortality, compared with the background population, was assessed in terms of standardised mortality ratios (SMRs) for each of the 10 cohorts.

RESULTS:
Cardiovascular disease was the most common underlying cause of death, accounting for 44 % of deaths in Type I (insulin-dependent) diabetes
mellitus and 52 % of deaths in Type II (non-insulin-dependent) diabetes mellitus. Renal disease accounted for 21% of deaths in Type I diabetes
and 11% in Type II diabetes. For Type I diabetes, all-cause mortality rates were highest in Berlin men and Warsaw women, and lowest in London
men and Zagreb women. For Type II diabetes, rates were highest in Warsaw men and Oklahoma women and lowest in Tokyo men and women.
Age adjusted mortality rates and SMRs were generally higher in patients with Type I diabetes compared with those with Type II diabetes. Men
and women in the Tokyo cohort had a very low excess mortality when compared with the background population.
CONCLUSION/INTERPRETATION:
This study confirms the importance of cardiovascular disease as the major cause of death in people with both types of diabetes. The low excess
mortality in the Japanese cohort could have implications for the possible reduction of the burden of mortality associated with diabetes in other
parts of the world.

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Diabetes Care. 2005 Sep;28(9):2130-5.

The burden of mortality attributable to diabetes: realistic estimates


for the year 2000.
Roglic G1, Unwin N, Bennett PH, Mathers C, Tuomilehto J, Nag S, Connolly V, King H.

Author information
Abstract
OBJECTIVE:
To estimate the global number of excess deaths due to diabetes in the year 2000.
RESEARCH DESIGN AND METHODS:
We used a computerized generic formal disease model (DisMod II), used by the World Health Organization to assess disease burden through
modeling the relationships between incidence, prevalence, and disease-specific mortality. Baseline input data included population structure, ageand sex-specific estimates of diabetes prevalence, and available published estimates of relative risk of death for people with diabetes compared
with people without diabetes. The results were validated with population-based observations and independent estimates of relative risk of death.
RESULTS:
The excess global mortality attributable to diabetes in the year 2000 was estimated to be 2.9 million deaths, equivalent to 5.2% of all deaths.
Excess mortality attributable to diabetes accounted for 2-3% of deaths in poorest countries and over 8% in the U.S., Canada, and the Middle
East. In people 35-64 years old, 6-27% of deaths were attributable to diabetes.

CONCLUSIONS:
These are the first global estimates of mortality attributable to diabetes. Globally, diabetes is likely to be the fifth leading cause of death.