1. NAME : Dr. D.

Hemanth Rao
2. FATHER’S NAME : D. Rangaiah
3. CORRESPONDENCE ADDRESS: Dr. D. Hemanth Rao
Department of General Medicine
CSI Holdsworth Memorial Hospital
Mysuru – 570021.
Mobile Number: 9591226603
E-mail: hemanthlastcrusade@gmail.com
4. REGISTRATION DETAILS
a) Reg No. : Awaited
b) Date of Registration : Awaited
c) Scheduled date of completion of DNB training : 6th April 2018

5. DETAILS OF DNB TRAINING:

Subject: General medicine
Institute: C.S.I. Holdsworth Memorial Hospital, Mysuru.
State: Karnataka
Correspondence Address of Institute: C.S.I Holdsworth Memorial Hospital
Post Box-38,
Mysore-21
Karnataka.

6. DETAILS OF THESIS PROTOCOL:

Subject: General Medicine
Name of the guide: Dr. Mohan Kumar G.

Title of the thesis : “A prospective interventional study to evaluate weight loss in Type
2 Diabetes Mellitus patients treated with Dapagliflozin (Sodium Glucose Co transporter 2
Inhibitor) .”
 INTRODUCTION

Type 2 Diabetes Mellitus (T2DM) is a systemic, progressive disorder characterized by

hyperglycemia that arises from dysfunction of β cells of the pancreatic Islets and insulin
resistance in peripheral tissues.(1) The prevalence and incidence of the disease are increasing
worldwide. Diabetes Mellitus has become a potential epidemic in India with more than 62
million diabetic individuals currently diagnosed with the disease. .In 2000, India (31.7 million)
topped the world with the highest number of people with Diabetes Mellitus, followed by China
(20.8 million) and the United States (17.7 million) in second and third place respectively.(2)

According to Wild et al. the prevalence of diabetes is predicted to double globally from 171
million in 2000 to 366 million in 2030 with a maximum increase in India. It is predicted that by
2030 Diabetes Mellitus may afflict up to 79.4 million individuals in India, while China (42.3
million) and the United States (30.3 million) will also see significant increases in those affected
by the disease.(3)

The increasing incidence of obesity is undoubtedly the strongest drive to hyperglycemia

through mechanisms including insulin resistance, subclinical inflammation and increased
oxidative stress which adversely affect β cell function and survival.(4) Approximately 85% of
patients with T2DM are overweight or obese and failure to lose even part of the excess weight
and continual weight gain are powerful forces against acceptable glycemic control.(5)

An additional clinical concern is the co-morbidity of obesity, high blood pressure and
dyslipidemia with chronic hyperglycemia causing the micro vascular and macro vascular
complications of long-standing Diabetes Mellitus.
 In overweight and obese individuals with T2DM, even modest amounts of weight loss of
approximately 5% of body weight have been shown to improve glycaemic control. Longitudinal
cohort studies indicate that changes in Body Mass Index among patients with T2DM are
significant predictors of changes in HbA1c and patients who lose weight are more likely to
achieve target HbA1c values than those with stable weight or weight gain.(6)

One of the main challenges is to have a drug that control glycaemia and also inducing weight
loss or preventing further weight gain. Major adverse effects of some of the new agents such as
recurrent hypoglycemia and gastrointestinal discomfort have hampered efforts to optimize
metabolic control.

Inhibition of renal glucose reabsorption is the current pharmacological target which holds
promise in terms of glycaemic as well as weight control. An important effect of Sodium Glucose
Co transporter 2 inhibitions is weight loss. A decrement of 2.5–4.0% of body weight has been
reported in patients with T2DM. Initially, this weight loss is predominantly due to fluid
depletion, but subsequently consists of loss of adipose tissue from both subcutaneous and
visceral depots. This effect is clearly consistent with a persistent caloric loss through the
urine.(7)

There is no prospective study on weight reducing effect of SGLT2 inhibitors in diabetic

patients in India .This proposed study is to evaluate effects of SGLT2 inhibitors on weight ,
HbA1C , FBS and lipid profile in patients with T2DM .
REVIEW OF LITERATURE

Diabetes mellitus (DM) refers to a group of common metabolic disorders

that share the phenotype of hyperglycemia. DM is caused by a complex
interaction of genetics and environmental factors.

Depending on the etiology of the DM, factors contributing to hyperglycemia

include reduced insulin secretion, decreased glucose utilization, and increased
glucose production. The metabolic dysregulation associated with DM causes
secondary pathophysiologic changes in multiple organ systems that impose a
tremendous burden on the individual with diabetes and on the health care system.

DM is the leading cause of end-stage renal disease (ESRD), non traumatic lower
extremity amputations, and adult blindness. It also predisposes to cardiovascular
diseases. With an increasing incidence worldwide, DM will be likely a leading
cause of morbidity and mortality in the future.(8)

According to the International Diabetes Federation (IDF), there are approximately

382 million people with diabetes in 2014, and this number is expected to reach 592
million by 2035. (9)

The regional prevalence of diabetes among adults of South East Asia is estimated
at 8.2% (72 million) in 2013, which is projected to increase to 10.1% (123 million)
in 2035.(10)

Diabetes has emerged as one of the major public health concern in Asian countries
which harbor more than 60% of the world’s diabetic population. It is estimated
that, for every diagnosed case of diabetes in Asia, there is at least one undiagnosed
case of glucose intolerance, suggesting that the actual population at risk would be
much higher than the actual estimates. The epidemic of diabetes in India is at its
worst with as many as 66.85 million diagnosed of which 35.5 million undiagnosed
cases of diabetes in 2014. It is predicted that by 2035 diabetes may afflict up to 109
million, being rightly referred to as “diabetes capital of the world”.(9)
The increased prevalence of diabetes is attributed to rapid cultural and socio-
economic growth such as ageing populations, increasing urbanisation, dietary &
lifestyle changes, reduced physical activity and unhealthy behaviours .
CLASSIFICATION OF DIABETES MELLITUS

Diabetes can be classified into the following general categories:

1. Type 1 diabetes (due to autoimmune b-cell destruction, usually leading to

absolute insulin deficiency).

2. Type 2 diabetes (due to a progressive loss of b-cell insulin secretion frequently

on the background of insulin resistance).

3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third

trimester of pregnancy that was not clearly overt diabetes prior to gestation).

4. Specific types of diabetes due to other causes, e.g., monogenic diabetes

syndromes (such as neonatal diabetes and maturity-onset diabetes of the young
[MODY]), diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or
chemical-induced diabetes (such as with glucocorticoid use, in the treatment of
HIV/AIDS, or after organ transplantation).

Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical
presentation and disease progression may vary considerably. Classification is
important for determining therapy, but some individuals cannot be clearly
classified as having type 1 or type 2 diabetes at the time of diagnosis. The
traditional model of type 2 diabetes occurring only in adults and type 1 diabetes
only in children is no longer accurate, as both diseases occur in both cohorts.(11).
TYPE 2 DIABETES MELLITUS

Type 2 diabetes mellitus (T2DM), previously referred to as “noninsulin-

dependent diabetes” or “adult-onset diabetes,” accounts for 90–95% of all diabetes.
It is often asymptomatic in its early stages and can remain undiagnosed for many
years. During this period the body is exposed to excess blood glucose
(hyperglycemia) resulting in irreversible organ damage.

By the time T2DM is diagnosed, many of the complications of T2DM have

already developed in these patients.
In Asian Indians, T2DM occurs almost a decade earlier than the Caucasians . They
have greater predilection for cardiovascular (CV) complications such as coronary
artery disease (CAD) and atherosclerosis at any age point , and have significant
procoagulant tendencies .(12)

MAJOR RISK FACTORS FOR TYPE 2 DIABETES MELLITUS

• Overweight (BMI ≥25 kg/m2 or ≥23 kg/m2 in Asian Americans)
• Physical inactivity
• First-degree relative with diabetes
• Member of a high-risk ethnic population (e.g., African American,
Latino, Native American, Asian American, Pacific Islander)
• Female with a history of delivering a baby weighing >9 lb or prior
diagnosis of GDM
• Hypertension (≥140/90 mm Hg or on therapy for hypertension)
• HDL cholesterol level <35 mg/dL (0.90 mmol/L) or triglyceride level
>250 mg/dL (2.82 mmol/L) or both
• Female with polycystic ovary syndrome
• Hemoglobin A1c ≥5.7%, impaired glucose tolerance, or impaired
Fasting glucose on previous testing
• Other clinical conditions associated with insulin resistance (e.g.,
severe obesity, acanthosis nigricans)
• History of cardiovascular disease
• Age over 45 years.(13)
PATHOPHYSIOLOGY

The pathogenesis of T2DM is complex and involves the interaction of genetic and
environmental factors. Among environmental factors excessive caloric intake
leading to obesity and a sedentary lifestyle play critical role. The clinical
presentation is heterogeneous, with a wide range in age at onset, severity of
associated hyperglycemia, and degree of obesity.

Individuals with T2DM consistently demonstrate three cardinal abnormalities.

• Resistance to the action of insulin in peripheral tissues,

particularly muscle and fat but also liver
• Defective insulin secretion, particularly in response to a
glucose stimulus
• Increased glucose production by the liver.

The precise way in which genetic, environmental, and pathophysiologic factors

interact to lead to the clinical onset of T2DM is not known, though the
understanding of these processes has increased substantially. With the exception of
specific monogenic forms of the disease that might result from defects largely
confined to the pathways that regulate insulin action in muscle, liver, and fat or
defects in insulin secretory function in the pancreatic beta cell, it is currently
believed that the common forms of T2DM are polygenic in nature and are caused
by a combination of insulin resistance, abnormal insulin secretion, and other
factors.

The inability of the pancreatic beta cell to adapt to the reductions in insulin
sensitivity that occur over a lifetime precipitates the onset of T2DM. The most
common factors that place an increased secretory burden on the beta cell are
puberty, pregnancy, a sedentary lifestyle, and overeating leading to weight gain.
An underlying genetic predisposition appears to be a critical factor in determining
the frequency with which beta cell failure occurs.(1)
TYPE 2 DIABETES MELLITUS AND OBESITY

The association of obesity with T2DM has been recognized for decades and a close
association between obesity and insulin resistance is seen in all ethnic groups
across the full range of body weights, all ages, and in both sexes .(7)

In a meta-analysis of prospective cohort studies from the United States (US) and
Europe, obese men had a sevenfold higher risk of developing T2DM, and obese
women a 12-fold higher risk, compared with individuals in the healthy weight
range . Patients were defined as obese based on the widely used cut-off of body
mass index (BMI) over 30 kg/m2 , but similarly increased risks were observed
using abdominal obesity, defined by waist circumference of at least 88 cm for
women or 102 cm for men . For some ethnic groups, these risks appear to occur at
lower levels of BMI, particularly in people of South Asian origin; however, the
relationship between weight and T2DM remains same (14).

Central (intra-abdominal) adiposity is more strongly linked to insulin resistance

and to a number of important metabolic variables, including plasma glucose,
insulin, total plasma cholesterol and triglyceride concentrations, and decreased
plasma high-density lipoprotein (HDL) cholesterol concentration, than is total
adiposity. The association between abdominal fat and glucose tolerance is
independent of total adiposity. The reason for the relationship between intra-
abdominal fat and abnormal metabolism is not clearly defined.(15)

Although obesity is fundamentally related to an imbalance between

energy intake and energy expenditure, it is estimated that genetic variability
accounts for around 50% of the variation in body mass within a population via
impact on hormone levels, body composition, and energy metabolism . Additional
factors leading to alterations in metabolism are lack of sleep, illness, and choice of
macronutrients . The resultant energy imbalance leads to hypertrophy and
hyperplasia of adipocytes .

Adipose tissues modulate metabolism by releasing non-esterified fatty acids ,

glycerol, hormones ( leptin and adiponectin ) and proinflammatory cytokines such
as interleukin -6, and insulin growth factor -1.(16)
 The expansion of adipose tissue in obese patients is associated with changes in
the release of numerous adipokines from adipocytes, aswell as from macrophages
and other cells that populate adipose tissue. In particular, NEFAs, which are
released from adipocytes, have been shown to induce insulin resistance and impair
β-cell function, with increased levels observed in both obesity and T2DM.
Insulin resistance has also been shown to arise in healthy subjects in
response to high plasma NEFA levels induced through diet, suggesting an
association between insulin resistance and obesity.

A possible mechanism for the β-cell dysfunction associated with obesity that may
also contribute to the pathogenesis of T2DM is lipid (triglyceride) accumulation in
pancreatic β-cells . In addition, the secretion of an adipokine, adiponectin, which is
associated with positive metabolic and vascular effects, is reduced in obesity and
may contribute to the pathogenesis of metabolic syndrome, T2DM, and
atherosclerosis .It has been suggested that proinflammatory cytokines,
such as TNF-α secreted by macrophages present in adipose tissue,
play a significant role in obesity-related insulin resistance .(17)

Obese patients with T2DM have been reported to show significantly

increased serum levels of total cholesterol, low-density lipoprotein (LDL)
cholesterol, very-low-density lipoprotein (VLDL) cholesterol, and triglycerides
and decreased high-density lipoprotein (HDL) cholesterol compared with non-
obese patients with T2DM.(18)

Research in monozygotic twins has shown that acquired obesity is associated

with increased activity of fibrinogen and coagulation markers, which are strongly
correlated with inflammation and insulin resistance and, as such, may increase risk
of thrombosis and cardiovascular events.(19)

Hypertension is also commonly seen with both T2DM and obesity and is a major
risk factor for CVD and microvascular complications. Due to the synergistic
effects of hypertension and T2DM, the diagnostic cutoff for hypertension is lower
for those with concurrent T2DM (≥130/80 mm Hg) vs those without (≥140/90 mm
Hg).(20)
RECOMMENDATIONS FOR SCREENING
Summary of Major Recommendations for Screening for Type
2 Diabetes Mellitus
• Testing to detect T2DM and to assess risk for future diabetes
should be considered in asymptomatic adults of any age who are
overweight or obese (BMI ≥25 kg/m2 or ≥23 kg/m2 in Asian
Americans) and who have one or more additional risk factors for
diabetes (see Table 31-3).
• In those without risk factors for T2DM, testing should begin at age
30-45 yr.
• If test results are normal, repeat testing should be carried out at
3- to 5-yr intervals.
• Any of the following tests is appropriate: HbA1c, FPG, 2-hr 75-g
OGTT.
• In those found to have increased risk for future diabetes, identify
and, if appropriate, treat other CVD risk factors.((13)
.

Criteria for the diagnosis of diabetes

FPG >126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least
8 h.*
OR
2-h PG>200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed
as described by the WHO, using a glucose load containing the equivalent of 75 g
anhydrous glucose dissolved in water.*

OR
A1C>6.5% (48 mmol/mol). The test should be performed in a laboratory using a
method that is NGSP certified and standardized to the DCCT assay.*

OR
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a
randomplasma glucose >200 mg/dL (11.1 mmol/L).

*In the absence of unequivocal hyperglycemia, results should be confirmed by

repeat testing.(21) .
MANAGEMENT

Lifestyle management is a fundamental aspect of diabetes care and includes

diabetes self-management education (DSME), diabetes self-management support
(DSMS), nutrition therapy, physical activity, smoking cessation counseling, and
psychosocial care.

Weight Management

Body weight management is important for overweight and obese people with
type 1 and type 2 diabetes for which lifestyle intervention programs should be
intensive with frequent follow-up to achieve significant reductions in excess body
weight and improve clinical indicators.

There is strong and consistent evidence that persistent modest weight loss( defined
as sustained reduction of 5% of initial body weight,) in overweight and obese
patients with type 2 diabetes can delay the progression from pre diabetes to type 2
diabetes , beneficial to the management of type 2 diabetes with improvement in
glycemic control and reduce the need for glucose-lowering medications.

Sustained weight loss can be attained with lifestyle programs that achieve a 500–
750 kcal/day energy deficit or provide 1,200–1,500 kcal/day for women and
1,500–1,800 kcal/day for men, adjusted for the individual’s baseline body weight
which is challenging in long term maintainance.

For many obese individuals with type 2 diabetes, weight loss of 5% is needed to
produce beneficial outcomes in glycemic control, lipids, and blood pressure, and
sustained weight loss of >7% is optimal.(21) .
Benefits of weight loss in the prevention and management of T2DM

In the United States, the Diabetes Prevention Program study showed that
overweight adults who had elevated blood glucose levels (impaired glucose
tolerance) could delay the onset of T2DM, or decrease the risk of T2DM, by losing
weight (via dietary changes and exercise), with results sustained over a 10-year
follow-up period (22)).

In the Finnish Diabetes Prevention Study, adults at high risk of developing T2DM
who were randomised to intensive dietary and exercise counselling had a 58%
reduction in the risk of developing diabetes after 4 years compared with the usual
care group (who received general information about lifestyle and diabetes risk) .
A legacy effect was seen after a 13-year follow-up, with intensive lifestyle
intervention associated with a significantly reduced risk of developing diabetes.
The intensive lifestyle intervention group also sustained lower body weights,
fasting plasma glucose (FPG) levels and 2-h postprandial plasma glucose levels
(23).

The benefit of weight loss in the prevention of T2DM are clear, and based on the
available evidence, the American Diabetes Association recommend that all patients
with impaired glucose tolerance, impaired FPG, or HbA1c 5.7–6.4% should aim
for a weight loss of 7% of body weight and increased physical activity to at least
150 min per week of moderate activity (such as walking) to prevent or delay the
onset of T2DM (24).

The landmark UK Prospective Diabetes Study (UKPDS) clearly demonstrated the

benefits of tight glycaemic control (as measured by HbA1c and FPG over
prolonged periods). The study tested whether treatment to near-normal FPG (< 6.0
mmol/l) would prevent cardiovascular events, using insulin, sulfonylurea,
metformin or diet. More than 5000 patients recently diagnosed with T2DM were
randomised, and intensive blood glucose control reduced the risk of vascular
complications in both the short- and long term, despite weight gain in the intensive
control group (probably because of sulfonylureas and insulin) (29). The inference
is that if improved glycaemia reduces cardiovascular risk, and weight loss
improves glycaemia, weight loss would be expected to provide long-term benefits
to patients.(25)
The Look AHEAD study was designed specifically to examine the effect of weight
loss on a primary outcome of cardiovascular events in overweight and obese
patients with T2DM .

Of 5145 people enrolled at 16 centres across the United States, half were randomly
assigned to receive an intensive lifestyle intervention and the other half to a general
programme of diabetes support and education. Both groups received routine
medical care from their own healthcare providers.

Analysis after 1 year showed a mean 8.6% weight loss with the intensive lifestyle
intervention compared with 0.7% for the diabetes support and education group.
The additional weight loss in intensive lifestyle intervention group was also
associated with a signifi cant reduction of glycosylated haemoglobin (HbA1c)
levels and improvement in several other cardiovascular risk factors compared with
the standard group and these results were partly sustained at 4 years .
A correlation seemed to exist between weight loss and improvements in
cardiovascular risk factors, with larger weight losses associated with greater
benefits across all patients.
. Despite these initial improvements in weight loss, and corresponding
improvements in glycaemia and other cardiovascular risk factors, the difference
between groups in cardiovascular event rates was lower than expected and the
study was terminated prematurely.(26) .
Summary of glycemic recommendations for many nonpregnant adults
with diabetes

A1C ,7.0 < (53 mmol/mol)*

Preprandial capillary plasma glucose 80–130 mg/dL* (4.4–7.2 mmol/L)

Peak postprandial capillary plasma glucose† <180 mg/dL* (10.0 mmol/L)

*More or less stringent glycemic goals may be appropriate for individual patients.
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.
†Postprandial glucose may be targeted if A1C goals are not met despite reaching
preprandial glucose goals. Postprandial glucose measurements should be made 1–2
h after the beginning of the meal, generally peak levels in patients with
diabetes.(21)

Though life style modification and physical activity plays important role in
management of diabetes almost all patients will eventually require
pharmacotheraphy to achieve target glycemic control.

Effects of glucose-lowering treatments

on weight

While lifestyle modification is the first-line therapy to improve glycaemia in new-

onset diabetes, it is unusual for patients to achieve target HbA1c values via weight
loss alone. Thus, most patients will require oral glucose-lowering drugs and,
because of the progressive nature of T2DM, many patients eventually will require
insulin. Although these therapies are effective in reducing HbA1c, many can lead
to unwanted weight gain, which could offset the benefits.

Currently, there are several different classes of drugs available to control blood
glucose and effects on weight vary among the classes.
For a patient who needs to avoid weight gain or to lose weight, metformin, any of
the dipeptidyl peptidase-4 (DPP-4) inhibitors, bile-acid sequestrants, and alpha-
glucosidase inhibitors are weight-neutral.
On the other hand, the commonly used second- line drugs, sulfonylureas,
meglitinides, thiazolidinediones and insulin are associated with significant
weight gain.

Of the widely available drug classes, two groups are associated with weight loss.
The glucagon-like peptide-1 (GLP-1) receptor agonists are are injectable agents
and recently approved new drug class , the sodium glucose co-transporter 2
(SGLT2) inhibitors which offers the promise of oral glucose-lowering drugs
associated with weight reduction(27).
Sodium–Glucose Co‑transporter Inhibitors

The European Medicines Agency (EMA) and Food and Drug Administration
(FDA) have approved SGLT2i (canagliflozin, dapagliflozin, and empagliflozin) as
monotherapy and as add‑on to other antihyperglycemic agents (AHAs).(28)

Glucose homeostasis in circulation through the kidneys is maintained by three

processes renal gluconeogenisis renal glucose reabsorbtion and renal glucose
utilization.
In healthy individuals, the well functioning kidneys filter approximately 180 g of
glucose daily and all of this glucose is reabsorbed in the proximal convoluted
tubule (PCT) , thus leaving urine free of glucose. Though kidneys contribute
significantly to gluconeogenesis the amount of glucose utilized by the kidneys for
their own metabolism equates to a comparable proportion. Thus, the mechanism of
renal glucose reabsorption exerts greater influence on blood glucose homeostasis,
as compared to renal gluconeogenesis.
Glucose reabsorption in the kidneys occurs through the PCT; approximately 90%
reabsorption is through SGLT2 and remaining 10% is through SGLT1.
The glucose transported in the PCT by SGLT mediation is released into circulation
by a passive transport across membranes through facilitative glucose transporters
(GLUTs).(29)

In patients with T2DM, the SGLT2 transporter expression and activity is

upregulated in the PCT leading to an increase in the renal threshold consequently
urinary glucose reabsorption is increased despite the elevated plasma glucose
levels and this leads to an increase in the hyperglycemic condition.

These transporters are inhibited by the SGLT2‑inhibiting agents which results in

an immediate effect of lowering of hyperglycemia through reduced renal glucose
reabsorption and greater urinary glucose excretion (UGE) .

Following ongoing SGLT2i therapy, the persistent calorie loss results

in metabolic adaptations that lead to weight loss, reduction in β‑cell stress and
hyperinsulinemia, improved insulin sensitivity, and insulin secretion rate. These
mechanisms ensure control of the plasma glucose levels on a sustained basis,
regardless of insulin resistance or β‑cell dysfunction, leading to improvement of
glycemic parameters.

As the plasma glucose concentrations decrease, the renal filtration of glucose

reduces, and proportionately lesser amount of glucose is eliminated; hence the risk
of hypoglycemia is very low with the SGLT2i agents.
Mechanism of action and effects of sodium–glucose co-transporter 2 inhibitors on
the body. BP: Blood pressure, GLUTs: Glucose transporters,
LDL-C: Low-density lipoproteins, SGLTs: Sodium–glucose co-transporters
Renal threshold for glucose is decresead in Type 2 Diabetes Mellitus patients on
treatment with SGLT2 Inhibitors.(30)
With the SGLT2i therapy, the calorie deficit and subsequent metabolic adaptations
result in net weight loss, even in combination with insulin, SU, and PIO. The
weight loss with SGLT2i therapy includes reductions in total body fat mass,
visceral and subcutaneous adipose tissue.(31)

Yang et al did a pooled analysis from eight phase IIb/III double-blind trials with
durations of up to 24 weeks examining treatments with placebo (N = 497), 5 mg of
dapagliflozin (N = 491), or 10 mg of dapagliflozin (N = 465) and demonstrated
the safety, efficacy, and tolerability of dapagliflozin in an Asian population.(32)

Kaku et al assessed the safety and efficacy of dapagliflozin when used as a

monotherapy after the failure of diet and exercise in Japanese patients. They
showed greater reductions in mean HbA1c level with dapagliflozin (5 mg, -0.41%;
10 mg, -0.45%) than with placebo (-0.06%) at week 24.
Furthermore, fasting plasma glucose (FPG) was also significantly reduced with
dapagliflozin (5 mg, -8.6 mg/dL; 10 mg, -13.7 mg/dL) compared with placebo (±
5.8 mg/dL). It significantly reduced body weight as well (5 mg, -2.13 kg; 10 mg, -
2.22 kg) compared with placebo (-0.84 kg) (33)

In a study conducted by L.Zahang, etal. on Dapagliflozin treatment in patients

with different stages of T2DM, effects on glycaemic control and body weight,
HbA1c level and body weight were measured at baseline and at weeks 4, 6, 8, 10
and 12. Urinary glucose was measured at baseline and at weeks 6 and 12.
Evaluable HbA1c, body weight and urinary glucose measurements were analysed.
At week 12, all Dapagliflozin-treated patients in the early-stage and the late-stage
groups achieved a reduction in body weight. Dapagliflozin treatment at 10 and 20
mg QD for 12 weeks resulted in clinically significant improvements in glycaemic
control and weight reduction in both early-stage and late-stage patients with
T2DM.
 The beneficial effects of dapagliflozin treatment were observed in both patient
populations despite the differences in disease status and background medications.
The results suggest that Dapagliflozin's insulin-independent mechanism could be
a promising treatment option across the different stages of clinical progression of
T2DM.(34)

kanako kato et al studied the effects of short-term administration of the sodium

glucose cotransporter 2 (SGLT-2) inhibitor, dapagliflozin, on visceral fat area
(VFA) in Japanese patients with type 2 diabetes. In that study they randomly
divided obese diabetic patients in to two groups(n1 =27 and n2=29) , group 1
received drug for first 12 weeks and group for the next 12 weeks . They assessed
the drug effect on body weight , Hba1c,lipid profile and blood pressure as
secondary end points and concluded that dapagliflozin led to decreases in VFA
and, consequently, body weight after a short treatment period. However, these
effects were largely reversed by the cessation of dapagliflozin, suggesting that this
agent should be administered continuously to maintain clinical usefulness in
overweight patients with type 2 diabetes.(35)

SUMMARY: Most of the thye 2 diabetes mellitus patients are either over weight
or obese and are at cardiovascular risk. Over weight and obesity not only
predisposes to diabetes but also affects effective management. Benefits of weight
loss in diabetic patients are established in many studies. Weight loss is difficult to
achieve and more challenging to sustain in diabetic patients as most of the glucose
lowering drugs are associated with weight gain. SGLT2 Inhibitors are new class of
oral glucose lowering drugs recently launched in Indian market, showed
promising weight loss in diabetic patients at all stages , as mono theraphy and
combination theraphy apart from good glycemic control.

Weight reduction effect of SGLT2 Inhibitors was assessed as secondary end point
in many previous studies and there are very few studies on SGLT2 Inhibitors in
Indian patients hence we conducted this proposed study to primarily asses weight
reducing effect of SGLT2 Inhibitors in indian Tpye2 Diabetes Mellitus patients.

AIMS AND OBJECTIVES

AIM

To evaluate and quantify weight loss in patients with Type 2 Diabetes Mellitus
treated with Dapagliflozin 10 milligrams daily (SGLT2 inhibitor) over a period of
three months.

OBJECTIVES:

1. To asses proportion of patients achieving weight loss of 2 to 5% and >5% of

initial weight.
2. To evaluate changes from baseline in glycaemic control (HbA1c), fasting
plasma glucose, lipid profile (total cholesterol, low-density lipoprotein
cholesterol, high-density lipoprotein cholesterol, triglycerides), waist
circumference and blood pressure.
To evaluate if SGLT2 inhibitors can be recommended in diabetic patients as oral
hypoglycaemic agents with significant weight reduction potential
 MATERIAL AND METHODS

Study area:

Patients with T2DM seen in the outpatient department in the Department of Medicine, CSI
HOLDSWORTH MEMORIAL HOSPITAL, MYSURU.

Study population:

Patients with T2DM on treatment for more than 2 years will be recruited over a period two
years and followed up over a study period of six months

Study design:

A prospective randomized, crossover, controlled, open label study.

SAMPLE SIZE:

Sample size (S) is calculated according to the following formula.

S= Z2PQ/D2

= 1.96 x1.96 x 0.07(0.93) / 0.08 x 0.08

= 39

Z = Z value (1.96 for 95% confidence level)

P = Prevalence of T2DM in India

Q = 1- Prevalence

D= margin of error at 8% (standard value of 0.08)

From the above calculation sample size is 39. We plan to take 40 patients.
kanako kato et al studied the effects of short-term administration of the sodium
glucose cotransporter 2 (SGLT-2) inhibitor, dapagliflozin, on visceral fat area
(VFA) in Japanese patients with type 2 diabetes with a sample size of 56 patients.

Study period:

This study will be done over a period of 24 months from July 2015 to June 2017.

INCLUSION CRITERIA:

1. Type 2 DM patients on treatment for more than two years and Hba1c >7%
2. Patients aged 20 to 60 years
3. Any patient for whom the treating physician considers SGLT-2 inhibitor
treatment to be appropriate
4 Renal status as follows

Estimated glomerular filtration rate >60 ml/mint/1.73mtr2
 Serum creatinine <1.5 mg /dl in men and <1.4 mg/dl in women
 Urine micro albumin to creatinine ratio <300 mg /gram
EXCLUSION CRITERIA:

1. Severe renal failure

2. Recurrent urinary tract infections and obstructive uropathy
3. Patients with history of diabetic ketoacidosis
4. Patients with dehydration.
5. T1DM
6. Gestational diabetes
7. possible or actual pregnancy or nursing
8. chronic heart failure

METHODOLOGY:

T2DM patients presented to out patient department are screened and those satisfying the
inclusion/exclusion criteria are recruited for the study. The study participants are randomly
divided in to two groups Group A the preceding group and Group B the following group.

The preceding group patients received drug tablet Dapagliflozin10 mg once a day every
morning for the first 12 weeks and placebo (tablet supradyn which.contains vitamin A ,B,C and
D, Calcium and Zinc) once a day every morning for the following 12 weeks as add on therapy.
The following group patients received placebo once a day every morning for the first 12 weeks
and tablet Dapagliflozin10 mg once a day every morning for the following 12 weeks as add on
therapy. In this study drug and placebo is crossed over between two groups after 12 weeks where
preceding group received drug in the first 12 weeks and following group received drug in
follwing 12 weeks period. Here following group patients served as control to preceding group
patients during first 12 weeks and vise versa during next 12 weeks. Patients in both the groups
continued their current anti diabetic medication during entire study period and are not given
any additional dietary advices or life style modifications other than regular advice for diabetic
patients as before.
The participants were followed up every month for tolerance and side effects of drug.
All participants weight, waist circumference,FBS, HbA1C, Lipid profile, and blood Pressure
were measured at the time of recruitment ( 0 weeks) and these measurements were repeated at
the end of 12 weeks and 24 weeks.
Measurements of weight , waist circumference and blood pressure of right arm in supine position
were taken by the same nursing staff for all participants with the same instruments.
Biochemical parameters of all participants were measured in our hospital lab using standard
methods.
Data was analysedl using SPSS2. The data will be tabulated and analysed to make
recommendations for use of SGLT 2 inhibitors

STATISTICAL METHODS:

1. Descriptive statistics

2. Paired samples‘t’ test.

3. Chi- square test.

 Study Proforma

Patient OP No:

1. Age :
2. Sex :
Presenting complaint:
Past history:
Treatment details:
Clinical examination:

At the beginning of A the end of 12 At the end of 24

study weeks weeks
Weight in kilograms
Waist circumference in
centimeters
HbA1C
Lipid profile

Fasting plasma glucose

Blood pressure
1. DeFronzo RA. From the Triumvirate to the Ominous Octet: A New Paradigm
for the Treatment of Type 2 Diabetes Mellitus. Diabetes Care.
2009;58(4):773–95.
2. Joshi SR, Parikh RM. India - Diabetes capital of the world: Now heading
towards hypertension. Journal of Association of Physicians of India.
2007;55(MAY):323–4.
3. Wild S, Roglic G, Green A, Sicree R, King H. Global Prevalence of
Diabetes: Estimates for the year 2000 and projections for 2030. Diabetes
Care. 2004;27(5):1047–53.
4. Leibowitz G, Bachar E, Shaked M, Sinai a, Ketzinel-Gilad M, Cerasi E, et
al. Glucose regulation of β-cell stress in type 2 diabetes. Diabetes Obes
Metab [Internet]. 2010;12 Suppl 2:66–75. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/21029302
5. Vaccine I, Licensed N. Prevalence of overweight and obesity among adults
with diagnosed diabetes--United States, 1988-1994 and 1999-2002. MMWR
Morb Mortal Wkly Rep [Internet]. 2004;53(45):1066–8. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/15549021
6. Feldstein AC, Bachman K, Nichols GA, Rosales AG, Smith DH, Perrin N, et
al. Weight change in diabetes and glycemic and blood pressure control.
Diabetes Care. 2008;31(10):1960–5.
7. Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin
Monotherapy in Type 2 Diabetic Patients With Inadequate Glycemic Control
by Diet and Exercise. Diabete Care. 2010;33(10):2217–24.
8. HARRISONS PRINCIPLES OF INTERNAL MEDICINE. 2399 p.
9. International Diabetes Federation. IDF Diabetes Atlas Sixth edition. idf.org.
2013;1–2.
10. Ramachandran A, Snehalatha C, Ma RCW. Diabetes in South-East Asia: An
update. Diabetes Res Clin Pract. 2014;103(2):231–7.
11. American Diabetes Association. Diagnosis and classification of diabetes
mellitus. Diabetes Care [Internet]. 2014;37(SUPPL.1):S81-90. Available
from: http://www.ncbi.nlm.nih.gov/pubmed/24357215
12. Anjana, R.M., Pradeepa, R., Deepa M et al. Prevalence of diabetes and
prediabetes in urban and rural India - phase I results of the Indian Council of
Medical Research-INdia DIABetes (ICMR-INDIAB) study..pdf.
Diabetologia. 2011;54(12):3022–7.
13. American Diabetes Association. Standards of Medical Care in Diabetes-
2015. Diabetes Care. 2015;38(1):1–94.
14. 2 Guh DP, Zhang W, Bansback N et al. No Title. Incid co-morbidities Relat
to Obes overweight a Syst Rev meta-analysis BMC Public Heal. 2009;9:88.
15. Landin K, Krotkiewski M, Smith U. Importance of obesity for the metabolic
 abnormalities associated with an abdominal fat distribution. Metabolism
[Internet]. 1989;38(6):572–6. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/2657328
16. De Ferranti S, Mozaffarian D. The perfect storm: Obesity, adipocyte
dysfunction, and metabolic consequences. Vol. 54, Clinical Chemistry. 2008.
p. 945–55.
17. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin
resistance and type 2 diabetes. Nature [Internet]. 2006;444(7121):840–6.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/17167471
18. .( Saxena, M., Agrawal, C. G., Gautam, S., Bid, H. K., & Banerjee M. No
Title. ) Overt Diabet Complicat obese type 2 diabetes Mellit patients from
North India. 2009;1:57–66.
19. Kaye SM, Pietiläinen KH, Kotronen A, Joutsi-Korhonen L, Kaprio J, Yki-
Järvinen H, et al. Obesity-Related Derangements of Coagulation and
Fibrinolysis: A Study of Obesity-Discordant Monozygotic Twin Pairs.
Obesity [Internet]. 2012;20(1):88–94. Available from:
http://doi.wiley.com/10.1038/oby.2011.287
20. American Diabetes Association. Standards of medical care in diabetes -
2012. Diabetes Care. 2012;35(Suppl 1):S11–63.
21. American Diabetes Association. No Title. Stand Med care diabetes.
2017;1:11 to 24.
22. Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ,
Brenneman AT, et al. 10-year follow-up of diabetes incidence and weight
loss in the Diabetes Prevention Program Outcomes Study. Lancet [Internet].
2009;374(9702):1677–86. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/19878986
23. Lindström J, Peltonen M, Eriksson JG, Ilanne-Parikka P, Aunola S,
Keinänen-Kiukaanniemi S, et al. Improved lifestyle and decreased diabetes
risk over 13 years: Long-term follow-up of the randomised Finnish Diabetes
Prevention Study (DPS). Diabetologia. 2013;56(2):284–93.
24. American Diabetes Association. Standards of medical care in diabetes--2013.
Diabetes Care. 2013;36(Suppl 1):S11-66.
25. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-
up of intensive glucose control in type 2 diabetes. N Engl J Med [Internet].
2008;359(15):1577–89. Available from:
http://www.nejm.org/doi/full/10.1056/nejmoa0806470%5Cnhttp://www.nej
m.org/doi/pdf/10.1056/NEJMoa0806470
26. Pi-Sunyer X, Blackburn G, Brancati FL et al. No Title. Reduct Weight
Cardiovasc Dis risk factors Individ with type 2 diabetes one-year results
Look AHEAD trial. 2007;30:1374–83.
27. . Inzucchi SE, Bergenstal RM, Buse JB et al. No TitleManagement of
hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: Updat
to a position statement Am Diabetes Assoc Eur Assoc Study Diabetes
Diabetes Care 2015. 2015;38:140–9.
28. Nauck MA. Update on developments with SGLT2 inhibitors in the
management of type 2 diabetes. Drug Des Devel Ther [Internet].
2014;8:1335–80. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/25246775
29. Gerich JE. Role of the kidney in normal glucose homeostasis and in the
hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med
[Internet]. 2010;27(2):136–42. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/20546255
30. Kalra S. Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors: A Review of
Their Basic and Clinical Pharmacology. Vol. 5, Diabetes Therapy. 2014. p.
355–66.
31. Bolinder J, Ljunggren Ö, Johansson L, Wilding J, Langkilde AM, Sjöström
CD, et al. Dapagliflozin maintains glycaemic control while reducing weight
and body fat mass over 2 years in patients with type 2 diabetes mellitus
inadequately controlled on metformin. Diabetes, Obes Metab [Internet].
2014;16(2):159–69. Available from:
http://doi.wiley.com/10.1111/dom.12189
32. Yang W, Ji L, Zhou Z, Cain VA, Johnsson KM, Sj??str??m CD. Efficacy and
safety of dapagliflozin in Asian patients: A pooled analysis. Journal of
Diabetes. 2016;
33. Kaku K, Kiyosue A, Inoue S, Ueda N, Tokudome T, Yang J, et al. Efficacy
and safety of dapagliflozin monotherapy in Japanese patients with type 2
diabetes inadequately controlled by diet and exercise. Diabetes Obes Metab
[Internet]. 2014;16(11):1102–10. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/24909293
34. Zhang L, Feng Y, List J, Kasichayanula S, Pfister M. Dapagliflozin treatment
in patients with different stages of type 2 diabetes mellitus: effects on
glycaemic control and body weight. Diab Obes Metab. 2010;12:510–6.
35. Kato K, Suzuki K, Aoki C, Sagara M, Niitani T, Wakamatsu S, et al. The
effects of intermittent use of the SGLT-2 inhibitor, dapagliflozin, in
overweight patients with type 2 diabetes in Japan: a randomized, crossover,
controlled clinical trial. Expert Opin Pharmacother [Internet]. 2017;1–9.
Available from:
https://www.tandfonline.com/doi/full/10.1080/14656566.2017.1317748
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13) Diabetes Care 2017;40(Suppl. 1):S11–S24

1. DeFronzo RA. From the Triumvirate to the Ominous Octet: A New Paradigm
for the Treatment of Type 2 Diabetes Mellitus. Diabetes Care.
2009;58(4):773–95.
2. Joshi SR, Parikh RM. India - Diabetes capital of the world: Now heading
towards hypertension. Journal of Association of Physicians of India.
2007;55(MAY):323–4.
3. Wild S, Roglic G, Green A, Sicree R, King H. Global Prevalence of
Diabetes: Estimates for the year 2000 and projections for 2030. Diabetes
Care. 2004;27(5):1047–53.
4. Leibowitz G, Bachar E, Shaked M, Sinai a, Ketzinel-Gilad M, Cerasi E, et
al. Glucose regulation of β-cell stress in type 2 diabetes. Diabetes Obes
Metab [Internet]. 2010;12 Suppl 2:66–75. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/21029302
5. Vaccine I, Licensed N. Prevalence of overweight and obesity among adults
with diagnosed diabetes--United States, 1988-1994 and 1999-2002. MMWR
Morb Mortal Wkly Rep [Internet]. 2004;53(45):1066–8. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/15549021
6. Feldstein AC, Bachman K, Nichols GA, Rosales AG, Smith DH, Perrin N, et
al. Weight change in diabetes and glycemic and blood pressure control.
Diabetes Care. 2008;31(10):1960–5.
7. Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin
Monotherapy in Type 2 Diabetic Patients With Inadequate Glycemic Control
by Diet and Exercise. Diabete Care. 2010;33(10):2217–24.
8. HARRISONS PRINCIPLES OF INTERNAL MEDICINE. 2399 p.
9. International Diabetes Federation. IDF Diabetes Atlas Sixth edition. idf.org.
2013;1–2.
10. Ramachandran A, Snehalatha C, Ma RCW. Diabetes in South-East Asia: An
update. Diabetes Res Clin Pract. 2014;103(2):231–7.
11. American Diabetes Association. Diagnosis and classification of diabetes
mellitus. Diabetes Care [Internet]. 2014;37(SUPPL.1):S81-90. Available
from: http://www.ncbi.nlm.nih.gov/pubmed/24357215
12. Anjana, R.M., Pradeepa, R., Deepa M et al. Prevalence of diabetes and
prediabetes in urban and rural India - phase I results of the Indian Council of
Medical Research-INdia DIABetes (ICMR-INDIAB) study..pdf.
Diabetologia. 2011;54(12):3022–7.
13. American Diabetes Association. Standards of Medical Care in Diabetes-
2015. Diabetes Care. 2015;38(1):1–94.
14. 2 Guh DP, Zhang W, Bansback N et al. No Title. Incid co-morbidities Relat
 to Obes overweight a Syst Rev meta-analysis BMC Public Heal. 2009;9:88.
15. Landin K, Krotkiewski M, Smith U. Importance of obesity for the metabolic
abnormalities associated with an abdominal fat distribution. Metabolism
[Internet]. 1989;38(6):572–6. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/2657328
16. De Ferranti S, Mozaffarian D. The perfect storm: Obesity, adipocyte
dysfunction, and metabolic consequences. Vol. 54, Clinical Chemistry. 2008.
p. 945–55.
17. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin
resistance and type 2 diabetes. Nature [Internet]. 2006;444(7121):840–6.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/17167471
18. .( Saxena, M., Agrawal, C. G., Gautam, S., Bid, H. K., & Banerjee M. No
Title. ) Overt Diabet Complicat obese type 2 diabetes Mellit patients from
North India. 2009;1:57–66.
19. Kaye SM, Pietiläinen KH, Kotronen A, Joutsi-Korhonen L, Kaprio J, Yki-
Järvinen H, et al. Obesity-Related Derangements of Coagulation and
Fibrinolysis: A Study of Obesity-Discordant Monozygotic Twin Pairs.
Obesity [Internet]. 2012;20(1):88–94. Available from:
http://doi.wiley.com/10.1038/oby.2011.287
20. American Diabetes Association. Standards of medical care in diabetes -
2012. Diabetes Care. 2012;35(Suppl 1):S11–63.
21. American Diabetes Association. No Title. Stand Med care diabetes.
2017;1:11 to 24.
22. Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ,
Brenneman AT, et al. 10-year follow-up of diabetes incidence and weight
loss in the Diabetes Prevention Program Outcomes Study. Lancet [Internet].
2009;374(9702):1677–86. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/19878986
23. Lindström J, Peltonen M, Eriksson JG, Ilanne-Parikka P, Aunola S,
Keinänen-Kiukaanniemi S, et al. Improved lifestyle and decreased diabetes
risk over 13 years: Long-term follow-up of the randomised Finnish Diabetes
Prevention Study (DPS). Diabetologia. 2013;56(2):284–93.
24. American Diabetes Association. Standards of medical care in diabetes--2013.
Diabetes Care. 2013;36(Suppl 1):S11-66.
25. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-
up of intensive glucose control in type 2 diabetes. N Engl J Med [Internet].
2008;359(15):1577–89. Available from:
http://www.nejm.org/doi/full/10.1056/nejmoa0806470%5Cnhttp://www.nej
m.org/doi/pdf/10.1056/NEJMoa0806470
26. Pi-Sunyer X, Blackburn G, Brancati FL et al. No Title. Reduct Weight
 Cardiovasc Dis risk factors Individ with type 2 diabetes one-year results
Look AHEAD trial. 2007;30:1374–83.
27. . Inzucchi SE, Bergenstal RM, Buse JB et al. No TitleManagement of
hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: Updat
to a position statement Am Diabetes Assoc Eur Assoc Study Diabetes
Diabetes Care 2015. 2015;38:140–9.
28. Nauck MA. Update on developments with SGLT2 inhibitors in the
management of type 2 diabetes. Drug Des Devel Ther [Internet].
2014;8:1335–80. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/25246775
29. Gerich JE. Role of the kidney in normal glucose homeostasis and in the
hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med
[Internet]. 2010;27(2):136–42. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/20546255
30. Kalra S. Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors: A Review of
Their Basic and Clinical Pharmacology. Vol. 5, Diabetes Therapy. 2014. p.
355–66.
31. Bolinder J, Ljunggren Ö, Johansson L, Wilding J, Langkilde AM, Sjöström
CD, et al. Dapagliflozin maintains glycaemic control while reducing weight
and body fat mass over 2 years in patients with type 2 diabetes mellitus
inadequately controlled on metformin. Diabetes, Obes Metab [Internet].
2014;16(2):159–69. Available from:
http://doi.wiley.com/10.1111/dom.12189
32. Yang W, Ji L, Zhou Z, Cain VA, Johnsson KM, Sj??str??m CD. Efficacy and
safety of dapagliflozin in Asian patients: A pooled analysis. Journal of
Diabetes. 2016;
33. Kaku K, Kiyosue A, Inoue S, Ueda N, Tokudome T, Yang J, et al. Efficacy
and safety of dapagliflozin monotherapy in Japanese patients with type 2
diabetes inadequately controlled by diet and exercise. Diabetes Obes Metab
[Internet]. 2014;16(11):1102–10. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/24909293
34. Zhang L, Feng Y, List J, Kasichayanula S, Pfister M. Dapagliflozin treatment
in patients with different stages of type 2 diabetes mellitus: effects on
glycaemic control and body weight. Diab Obes Metab. 2010;12:510–6.
35. Kato K, Suzuki K, Aoki C, Sagara M, Niitani T, Wakamatsu S, et al. The
effects of intermittent use of the SGLT-2 inhibitor, dapagliflozin, in
overweight patients with type 2 diabetes in Japan: a randomized, crossover,
controlled clinical trial. Expert Opin Pharmacother [Internet]. 2017;1–9.
Available from:
https://www.tandfonline.com/doi/full/10.1080/14656566.2017.1317748
1. DeFronzo RA. From the Triumvirate to the Ominous Octet: A New Paradigm
for the Treatment of Type 2 Diabetes Mellitus. Diabetes Care.
2009;58(4):773–95.
2. Joshi SR, Parikh RM. India - Diabetes capital of the world: Now heading
towards hypertension. Journal of Association of Physicians of India.
2007;55(MAY):323–4.
3. Wild S, Roglic G, Green A, Sicree R, King H. Global Prevalence of
Diabetes: Estimates for the year 2000 and projections for 2030. Diabetes
Care. 2004;27(5):1047–53.
4. Leibowitz G, Bachar E, Shaked M, Sinai a, Ketzinel-Gilad M, Cerasi E, et
al. Glucose regulation of β-cell stress in type 2 diabetes. Diabetes Obes
Metab [Internet]. 2010;12 Suppl 2:66–75. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/21029302
5. Vaccine I, Licensed N. Prevalence of overweight and obesity among adults
with diagnosed diabetes--United States, 1988-1994 and 1999-2002. MMWR
Morb Mortal Wkly Rep [Internet]. 2004;53(45):1066–8. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/15549021
6. Feldstein AC, Bachman K, Nichols GA, Rosales AG, Smith DH, Perrin N, et
al. Weight change in diabetes and glycemic and blood pressure control.
Diabetes Care. 2008;31(10):1960–5.
7. Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin
Monotherapy in Type 2 Diabetic Patients With Inadequate Glycemic Control
by Diet and Exercise. Diabete Care. 2010;33(10):2217–24.
8. HARRISONS PRINCIPLES OF INTERNAL MEDICINE. 2399 p.
9. International Diabetes Federation. IDF Diabetes Atlas Sixth edition. idf.org.
2013;1–2.
10. Ramachandran A, Snehalatha C, Ma RCW. Diabetes in South-East Asia: An
update. Diabetes Res Clin Pract. 2014;103(2):231–7.
11. American Diabetes Association. Diagnosis and classification of diabetes
mellitus. Diabetes Care [Internet]. 2014;37(SUPPL.1):S81-90. Available
from: http://www.ncbi.nlm.nih.gov/pubmed/24357215
12. Anjana, R.M., Pradeepa, R., Deepa M et al. Prevalence of diabetes and
prediabetes in urban and rural India - phase I results of the Indian Council of
Medical Research-INdia DIABetes (ICMR-INDIAB) study..pdf.
Diabetologia. 2011;54(12):3022–7.
13. American Diabetes Association. Standards of Medical Care in Diabetes-
2015. Diabetes Care. 2015;38(1):1–94.
14. 2 Guh DP, Zhang W, Bansback N et al. No Title. Incid co-morbidities Relat
to Obes overweight a Syst Rev meta-analysis BMC Public Heal. 2009;9:88.
15. Landin K, Krotkiewski M, Smith U. Importance of obesity for the metabolic
abnormalities associated with an abdominal fat distribution. Metabolism
[Internet]. 1989;38(6):572–6. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/2657328
16. De Ferranti S, Mozaffarian D. The perfect storm: Obesity, adipocyte
dysfunction, and metabolic consequences. Vol. 54, Clinical Chemistry. 2008.
p. 945–55.
17. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin
resistance and type 2 diabetes. Nature [Internet]. 2006;444(7121):840–6.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/17167471
18. .( Saxena, M., Agrawal, C. G., Gautam, S., Bid, H. K., & Banerjee M. No
Title. ) Overt Diabet Complicat obese type 2 diabetes Mellit patients from
North India. 2009;1:57–66.
19. Kaye SM, Pietiläinen KH, Kotronen A, Joutsi-Korhonen L, Kaprio J, Yki-
Järvinen H, et al. Obesity-Related Derangements of Coagulation and
Fibrinolysis: A Study of Obesity-Discordant Monozygotic Twin Pairs.
Obesity [Internet]. 2012;20(1):88–94. Available from:
http://doi.wiley.com/10.1038/oby.2011.287
20. American Diabetes Association. Standards of medical care in diabetes -
2012. Diabetes Care. 2012;35(Suppl 1):S11–63.
21. American Diabetes Association. No Title. Stand Med care diabetes.
2017;1:11 to 24.
22. Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ,
Brenneman AT, et al. 10-year follow-up of diabetes incidence and weight
loss in the Diabetes Prevention Program Outcomes Study. Lancet [Internet].
2009;374(9702):1677–86. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/19878986
23. Lindström J, Peltonen M, Eriksson JG, Ilanne-Parikka P, Aunola S,
Keinänen-Kiukaanniemi S, et al. Improved lifestyle and decreased diabetes
risk over 13 years: Long-term follow-up of the randomised Finnish Diabetes
Prevention Study (DPS). Diabetologia. 2013;56(2):284–93.
24. American Diabetes Association. Standards of medical care in diabetes--2013.
Diabetes Care. 2013;36(Suppl 1):S11-66.
25. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-
up of intensive glucose control in type 2 diabetes. N Engl J Med [Internet].
2008;359(15):1577–89. Available from:
 http://www.nejm.org/doi/full/10.1056/nejmoa0806470%5Cnhttp://www.nej
m.org/doi/pdf/10.1056/NEJMoa0806470
26. Pi-Sunyer X, Blackburn G, Brancati FL et al. No Title. Reduct Weight
Cardiovasc Dis risk factors Individ with type 2 diabetes one-year results
Look AHEAD trial. 2007;30:1374–83.
27. . Inzucchi SE, Bergenstal RM, Buse JB et al. No TitleManagement of
hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: Updat
to a position statement Am Diabetes Assoc Eur Assoc Study Diabetes
Diabetes Care 2015. 2015;38:140–9.
28. Nauck MA. Update on developments with SGLT2 inhibitors in the
management of type 2 diabetes. Drug Des Devel Ther [Internet].
2014;8:1335–80. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/25246775
29. Gerich JE. Role of the kidney in normal glucose homeostasis and in the
hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med
[Internet]. 2010;27(2):136–42. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/20546255
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