Type 2 Diabetes Mellitus requires

progressive therapy

Fajar Yuwanto
SMF Penyakit Dalam RSUD Abdul Moeloek
Bandar Lampung
Diabetes: A global emergency, particularly in Asia

IDF Atlas 7th Edition, 2015

 Asian Phenotypes T2DM Patients

Younger Onset
Of Diabetes

Lower Rates Of
Higher Rate Of Type 1 Diabetes
Renal Complications
and Stroke compare to
CV Death &
Major Coronary Event Lower BMI But
High Visceral Fat

Long Disease Low Level of

Duration β-Cell Function

Adapted from Chan JCN, Yeung R, Luk A. Diabetes Voice 2014. March 14, Volume 59
Diabetes in Asia :
Male
Starting at younger age

Female

Yoon KH, Lancet 2006; 368: 1681 - 8

Diabetes in Asia:
More diabetes at Overweight / obesity
lower levels of obesity
/ overweight

Diabetes

Yoon KH, Lancet 2006; 368: 1681 - 8

Interactions by which obesity
and insulin resistance
Hyperglycemia

Hypertension

Insulin Dyslipidemia
resistance
Damage to blood
vessels
Clotting
abnormalities

Inflammation
Atherosclerosis
Zimmet P. Trends Cardiovasc Med 2002; 12:354–362
Schrier RW et al. (2007) Appropriate blood pressure control in hypertensive and normotensive type 2 diabetes mellitus:
a summary of the ABCD trial Nat Clin Pract Nephrol 3: 428–438 doi:10.1038/ncpneph0559
Insulin resistance and -cell dysfunction are core
defects of type 2 DM

Genetic, obesity,
Western lifestyle

 -cell
Insulin
resistance IR dysfunction

Type 2 diabetes
Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.
Criteria for the Diagnosis of Diabetes

A1C ≥6.5%
OR
Fasting plasma glucose (FPG)
≥126 mg/dL (7.0 mmol/L)
OR
2-h plasma glucose ≥200 mg/dL
(11.1 mmol/L) during an OGTT
OR
A random plasma glucose ≥200 mg/dL
(11.1 mmol/L)
ADA, 2015
 AACE Recommendations for A1C Testing
• A1C levels may be misleading in several ethnic
populations (for example, African Americans)
• A1C may be misleading in some clinical settings
– Hemoglobinopathies
– Iron deficiency
– Hemolytic anemias
– Thalassemias
– Spherocytosis
– Severe hepatic or renal disease
• AACE/ACE endorse the use of only standardized,
validated assays for A1C testing

AACE. Endocrine Pract. 2010;16:155-156.

9
 Diabetes is a complex disease that goes beyond elevated
blood glucose levels
• Diabetes is associated with many complications
Stroke
Retinopathy
(caused by microvascular
damage)

Heart disease

Nerve damage Kidney disease

(diabetic neuropathy can cause (caused by microvascular damage)
impotence, problems with digestion
and urination, and pain/loss of
feeling in the extremities)

Pregnancy complications

Foot ulcers and wounds

(caused by diabetic neuropathy and
blood vessel damage, leading to
amputation)

Source: International Diabetes Federation. Diabetes Atlas, 5th Ed. www.diabetesatlas.org (accessed 25 June 2012).
 Diabetes duration (years)
–10 0 10 20
IGT Type 2DM
Microvascular complications

Retinopathy, neuropathy, nephropathy

Macrovascular complications

CAD
Atherosclerosis Advance Amputation
atherosclerosis
STROKE
On-going Blindness
metabolic
CAD derangement
PAD Renal failure
 The Diabetes Numbers

• Every 24 hours:
–New cases 4,100 cases
–Deaths 810 cases
–Amputations 230 cases
–Kidney failure 120 cases
–Blindness 55 cases
Derived from NIDDK, National Diabetes Statistics fact sheet. HHS, NIH, 2005.
 Natural History of type 2 Diabetes
Prediabetes Diagnosed
250 (IFG, IGT) diabetes
Relative Amount

200 Insulin resistance  In early stages, as insulin

resistance rises, there is a
150 compensatory increase in
Incretin effect insulin secretion and
100
Insulin level glucose levels remain
50 normal
β-cell function
0
 As β-cell dysfunction
worsens, insulin secretion
Postmeal glucose falls, IGT and hyperglycemia
350
become apparent, and overt
Glucose (mg/dL)

300 type 2 diabetes develops

250  Glucose levels, both pre- and
Fasting glucose
postprandially, increase
200
steadily as the individual
150 progresses from
100
normoglycemia to IGT and,
finally, type 2 diabetes
50
-15 -10 -5 0 5 10 15 20 25 30 IFG=impaired fasting glucose;
IGT=impaired glucose tolerance.

Diabetes
Years Representative depiction of time course
and function.
Onset

Kendall DM et al. Am J Med. 2009;122(6A):S37-S50

 Decreased
Incretin Effect

Islet -cell

Increased
Impaired Lipolysis
Insulin Secretion

Islet a-cell

Increased Increased Glucose

Glucagon Reabsorption
Secretion

Increased
HGP
Decreased Glucose
Neurotransmitter
Uptake
Dysfunction
DeFronzo RA. Diabetes 2009; 58: 773-795
Type2 Diabetes is progressive, aggressive and needs
polypharmacy
glycemic control …………………..

Normal IGT
GT Type 2 DM
Complications : CVD
CKD, NEUROPATHY
 mortality

Non-pharmacologic
Polypharmacy, High cost

Healthy Life Style

 Need for an early and intensive approach to
type 2 diabetes management

• At diagnosis of type 2 diabetes:

– 50% of patients already have complications1
– up to 50% of -cell function has already been lost2

• Current management:
– two-thirds of patients do not achieve target HbA1c3,4
– majority require polypharmacy to meet glycaemic
goals over time5
 A1C

1%

12% 14% 43% 37% 21%

Sltratlon IM et at. UKPDS35. BMJ 2000..321 (7258) 405-12.

Effect of a multifactorial intervention on mortality in type 2 diabetes
(N Engl J Med 2008; 358; 580-91)
The Problems Therapy in Type 2 DM

1. Delayed in diagnosis and treatment

2. Cannot achieve the target goals

3. Decreased effectivities of OHAs

4. Decreased of beta cell function

5. Delayed to aggressive/combination therapy

6. Reactive treatment paradigm, not think βcell reserve

 Glycemic Recommendation for
Nonpregnant adults with Diabetes
Goals should be individualized based on
 Duration of diabetes
 Age/life expectancy
 Comorbid conditions
 Known CVD or advanced microvascular
complications
 Hypoglycemia unawareness
 Individual patient considerations

ADA, 2015
Approach to the Management of
Hyperglycemia

ADA. Glycemic Targets. Diabetes Care 2015;38(suppl 1):S37.

ADA, 2015
 Glycemic Targets
• Perform the A1C test at least two times a year
in patients :
• Meeting treatment goals
• Stable glycemic control).

• Perform the A1C test quarterly in patients:

• Whose therapy has changed
• Not meeting glycemic goals

ADA,2015
 Many diabetics in Asian population do not achieve
glucose target
• IDPMS (International DM Practice Study)¹
- 5 years survey involving 11,799 pts (9.901 T2DM)

- 36.4% have HbA1c <7%

• JADE (Joint Asia Diabetes Evaluation Program)²

Clinical profile of 3.687 Asian type 2 diabetic patients enrolled in the Joint Asia Diabetes
Eavaluation (JADE) program during comprehensive at baseline
Total Hongkong India Korea Philipines Singapore Taiwan Thailand
(n=3687) (n=832) (n=788) (n=295) (n=1186) (n=256) (n=55) (n=275)
Status of
ABC
targets (%) 35.3 61.8 13.8 40.7 31.3 35.2 25.5 29.8
HbA1c
<7%

.
1 Chan Juliana C.N, et.al. Multifaceted determinants for achieving glycemic control. The International Diabetes
Management Practice Study (IDMPS). Diabetes Care 2009;32: 227-233.
2. SO Wing-Yee, et.al. Comprehensive risk assessments of diabetic patients from seven Asian countries: The Joint Asia Diabetes Evaluation (JADE) program.
Journal of Diabetes 2011;3: 109-118.
Rationale for combination therapy

In the UKPDS, 50% patients at 3 years, and 75%

patients at 9 years needed combination therapy.1

Up-titrating monotherapy to the maximum

recommended dose may not provide benefit.2

Delays often occur between stepping up from

monotherapy to combination therapy.3

1. Turner RC, et al. UKPDS 49. JAMA 1999; 281: 2005–2012.

2. Garber AJ, et al. Am J Med 1997; 103: 491–497.
3. Brown JB, et al. Diab Care 2004; 27: 1535–1540.
 Potential advantages of early combination
therapy

• Earlier achievement of therapeutic goals

• Potential to delay disease progression
• Potential reduction in risk of side effects if you combine drugs
at lower doses versus up-titration of single dose

Opportunity to combine oral antidiabetic

drugs with complementary modes of action
 OTHER CONSIDERATIONS

• Age
• Weight
• Ethnic
• Race
• Genetic
• Comorbidity:
• CKD
• CAD,Heart failure
• Hypoglicemia
• Liver dysfunction

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

GUIDELINES ALGORITHM
RECOMMENDATION

NORMAL GLYCEMIC GOALS

 Targets T2DM Management

Multiple
Lowers HbA1c to Adverse Effects
Defects in Type 2 No Hypoglycemia
normal levels
Diabetes of Therapy

Improves Decreases insulin

Does not cause Type 2 resistance and
Glycemic Hyperglycemia
hepatic glucose
weight gain Diabetes
Control production

Increases or Does not cause

edema or
preserves congestive heart
beta-cell mass failure
 Hypoglycaemia - Why is this important?
• Hypoglycaemia is associated with increased risk of death, especially in patients with
coronary artery disease or acute myocardial infarction1
• Up to 38% of people with type 2 diabetes experience symptomatic hypoglycaemia2
o It is believed that many incidences of hypoglycemia go unreported to
healthcare professionals3
• Hypoglycaemia results in reduced quality of life, treatment satisfaction and therapy
adherence2,4

• Hypoglycaemia is associated with cognitive dysfunction and delayed recovery in

the elderly5

• Hypoglycaemia is associated with increased anxiety6

1. Nordin C. Diabetologia.2010; 53: 1552–61; 2. Alvarez Guisasola F, et al. Diab Obes Metab. 2008; 10 Suppl 1: 25−32
3. Leiter LA, et al. Can J Diab. 2005; 29: 186−92; 4. Jermendy G, et al. Health Qual Life Outcomes. 2008; 6: 88
5. Zammitt N, et al. Diabetes. 2008; 57: 732−6 ; 6. Labad J, et al. Diabetologia. 2010; 53: 467−71
 Risk of hypoglycaemia increases as
therapy intensifies

Wright et al. J Diabetes Complicat 2006;20:395–401 (UKPDS 73)

 Why we have to avoid Hypoglycaemia?
Possible mechanisms1,2 Hypoglycemia as link to
increase ischaemia3
• Haemodynamic changes: *
20 18.5
‒ activation of autonomic nervous system Chest pain

Episodes accompanied by
‒ 10-50 fold increased secretion of

cardiac symptoms (%)

ECG abnormalities
adrenaline & noradrenaline 15
*
11.1
• ECG changes: 10
‒ longer QT interval
‒ hypokalaemia
5
1.7
• Haemorheological changes: 0
‒ platelet activation 0
‒ increased viscosity Hypoglycaemia Hyperglycaemia
Study of 72-h continuous glucose monitoring and
simultaneous cardiac Holter monitoring in patients with
T2DM treated with insulin and history of frequent
hypoglycaemia and coronary artery disease (n=19)
*P <0.01vs episodes during hyperglycaemia and normoglycaemia
54 episodes of hypoglycaemia reported (BGL <70 mg/dl)
1Desouza CV et al. Diabetes Care 2010;33:1389–1394; 59 episodes of hyperglycaemia reported (BGL >200 mg/dl)
2Robert TC et al. Diabetes 2003;52:1469–74;
3Desouza C et al. Diabetes Care 2003; 26:1485–1489
ALGORITHM
ADA–EASD ( 2015)

AACE/ACE (2015)

IDF (2011)

PERKENI (2015)
 Noninsulin Agents Available for T2D
Class Primary Mechanism of Action Agent(s) Available as
a-Glucosidase  Delay carbohydrate absorption from Acarbose Precose or generic
inhibitors intestine Miglitol Glyset
 Decrease glucagon secretion
Amylin analogue  Slow gastric emptying Pramlintide Symlin
 Increase satiety
 Decrease HGP
Biguanide Metformin Glucophage or generic
 Increase glucose uptake in muscle
 Decrease HGP?
Bile acid sequestrant Colesevelam WelChol
 Increase incretin levels?

 Increase glucose-dependent insulin Alogliptin Nesina

Linagliptin Tradjenta
DPP-4 inhibitors secretion
Saxagliptin Onglyza
 Decrease glucagon secretion Sitagliptin Januvia

Dopamine-2 agonist  Activates dopaminergic receptors Bromocriptine Cycloset

Nateglinide Starlix or generic
Glinides  Increase insulin secretion
Repaglinide Prandin

DPP-4 = dipeptidyl peptidase; HGP = hepatic glucose production.

Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.
36
Continued on next slide
 Noninsulin Agents Available for T2D
Class Primary Mechanism of Action Agent(s) Available as
 Increase glucose-dependent insulin Albiglutide Tanzeum
secretion Dulaglutide Trulicity
GLP-1 receptor
 Decrease glucagon secretion Exenatide Byetta
agonists
 Slow gastric emptying Exenatide XR Bydureon
 Increase satiety Liraglutide Victoza

Canagliflozin Invokana
SGLT2 inhibitors  Increase urinary excretion of glucose Dapagliflozin Farxiga
Empagliflozin Jardiance

Glimepiride Amaryl or generic

Glipizide Glucotrol or generic
Sulfonylureas  Increase insulin secretion Glyburide Diaeta, Glynase,
Micronase, or generic

 Increase glucose uptake in muscle and

Pioglitazone Actos
Thiazolidinediones fat
Rosiglitazone Avandia
 Decrease HGP

GLP-1 = glucagon-like peptide; HGP = hepatic glucose production; SGLT2 = sodium glucose cotransporter 2.
Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.
37
Continued from previous slide
ADA, 2015
 Diabetes Care: Management

• People with diabetes should receive medical care from

a team that may include
– Physicians, nurse practitioners, physician’s assistants, nurses,
dietitians, pharmacists, mental health professionals
– In this collaborative and integrated team approach, essential
that individuals with diabetes assume an active role in their
care
• Management plan should recognize diabetes self-
management education (DSME) and on-going diabetes
support

ADA. V. Diabetes Care. Diabetes Care 2013;36(suppl 1):S17.

 Summary of the
Recommendations of ADA/EASD,
AACE/ACE
 Key recommendations (ADA/EASD)
• Metformin is first line
• Metformin should be initiated concurrently
with lifestyle intervention (at diagnosis)
• If goal isnot achieved in 2-3 months, add
another medication
• When adding second/third agents, consider
mechanisms/potential for synergy
 Common Principles in AACE/ACE and ADA/EASD
Type 2 Diabetes Treatment Algorithms
• Individualize glycemic goals based on patient characteristics
• Promptly intensify antihyperglycemic therapy to maintain
blood glucose at individual targets
– Combination therapy necessary for most patients
– Base chose of agent(s) on individual patient medical history,
behaviors and risk factors, ethnocultural background, and
environment
• Insulin eventually necessary for many patients
• SMBG vital for day-to-day management of blood sugar for
- All patients using insulin
- Many patients not using insulin

Inzucchi SE, et al. Diabetes Care, 19 April 2012 [Epub

47
ahead of print]
Rodbard HW, et al. Endocr Pract. 2009;15:540-559
 SUMMARY
• Type 2 Diabetes is a progressive, aggressive and is a
high cost disease especially if it is accompanied by
several complications

• It needs early, intensive and aggressive treatment

• Glycaemic goals algorithm provides steps to be

considered in diabetes aggressive management
 Natural History type 2 DM
Prediabetes Diagnosed
250 (IFG, IGT) diabetes
Relative Amount

200 Insulin resistance  In early stages, as insulin

resistance rises, there is a
150 compensatory increase in
Incretin effect insulin secretion and
100
Insulin level glucose levels remain
50 normal
β-cell function
0
 As β-cell dysfunction
worsens, insulin secretion
Postmeal glucose falls, IGT and hyperglycemia
350
become apparent, and overt
Glucose (mg/dL)

300 type 2 diabetes develops

250  Glucose levels, both pre- and
Fasting glucose
postprandially, increase
200
steadily as the individual
150 progresses from
100
normoglycemia to IGT and,
finally, type 2 diabetes
50
-15 -10 -5 0 5 10 15 20 25 30 IFG=impaired fasting glucose;
IGT=impaired glucose tolerance.

Diabetes
Years Representative depiction of time course
and function.
Onset

Kendall DM et al. Am J Med. 2009;122(6A):S37-S50.

Nature. 2006 Dec 14;444(7121):840-6.
Diabetes. 2009 Apr;58(4):773-95.
Effect of a multifactorial intervention on mortality in type 2 diabetes
(N Engl J Med 2008; 358; 580-91)
 Strategies for Improving Care
• Patient-centered communication style
• Patient-centered approach should include :
• Blood pressure and lipid control
• Smoking prevention and cessation
• Weight management
• Physical activity, and healthy lifestyle choices
• 33–49% of patients still do not meet targets for
glycemic, blood pressure, or cholesterol
control
• Only 14% meet targets for all three measures
and nonsmoking status
• Assess adherence should be addressed as the
first priority.
• If adherence is 80%or above, then treatment
intensification should be considered
• If medication up-titration is not a viable
option, then changing to a different medication
• Intensive glucose control is not advised for the
improvement of poor cognitive function in
hyperglycemic individuals with type 2 diabetes

• Treating depression may improve short-term

glycemic control
Sekresi Insulin pada DM tipe 2

Resistensi Insulin

Produksi
Insulin
Onset Diabetes
 Penurunan sekresi insulin ada hubungannya dengan progresivitas dari Diabetes
Mellitus Tipe 2 itu sendiri
 Awal mula dari diabetes, hanya terjadi setelah fungsi sel beta di pankreas
mengalami penurunan secara bemakna UKPDS
 Pharmacotherapy Tailored for the
Multiple Defects of Type 2 Diabetes

Meglitinides
THIAZOLIDINEDIONES
Increase insulin secretion
1 Increase glucose uptake in
from pancreatic -cells
skeletal muscle and
decrease lipolysis in
adipose tissue

SULFONYLUREAS
Increase insulin secretion
2
from pancreatic -cells BIGUANIDE (METFORMIN)
Decreases hepatic
production and
increases uptake
Insulin
a-Glucosidase inhibitors
DPP - 4 inhibitor Delay intestinal carbohydrate
4
absorption
GLP1 – analoque
Insulin, glucagon
enhancer
Consideration For Selecting Combination
Therapy
Two (or more) oral blood glucose-lowering
medicines that have different mechanisms of
action

Synergy: different of mechanism of action

Secondary Fewer side effects than mono-therapy at higher

effect doses
 Stages of Type 2 Diabetes:
Criteria for Advancing to next stage?
HbA1C Not at target: < 7.0%
100

MonoTherapy
75
Combination
-Cell
50 Therapy
Function
(% )
Type 2 Insulin
25 Diabetes
Phase I Type 2
Diabetes
Phase II Phase III
0
-12 -10 -6 -2 0 2 6 10 14

Years From Diagnosis

Based on data of UKPDS 16: Diabetes. 1995.
 Insulin can be initiated at any time…

• Traditionally, insulin has been reserved as the last line of

therapy…
• …However, considering the benefits of normal glycemic status,
Insulin can be initiated earlier.

Inadequate
+ 1 OAD + 2 OAD + 3 OAD
Lifestyle

INITIATE INSULIN

Adapted from Nathan DM, et al. Diabetes Care 2009; 31:193-203