Weight Management in Type 2Diabetes: Current and EmergingApproaches to Treatment [2015]

1. Weight Management in Type 2
Diabetes: Current and Emerging
Approaches to Treatment
LUC VAN GAAL AND ANDR ´E SCHEEN
DIABETES CARE - 2015;38:1161–1172
Talha-Sami-Ul-Haque
Dept. of Endocrinology
DHAKA MEDICAL COLLEGE HOSPITAL

2. Diabetes is a growing global health concern, as is obesity.
Diabetes and obesity are intrinsically linked:
Obesity - in particular abdominal obesity is a major driver
in the development of diabetes and cardiovascular
disease.
with the increasing prevalence of obesity mirrored by the
rising prevalence of diabetes.
obesity and overweight are associated with multiple
comorbidities

3. Weight reduction, therefore, is a key therapeutic goal in
both the prevention and management of type 2
diabetes.
Although the benefits of weight loss in the prevention of
diabetes and as a critical component of managing the
condition are well established, weight reduction remains
challenging for individuals with type 2 diabetes due to a
host of metabolic and psychological factors.

4. For many patients, lifestyle intervention is not
enough to achieve weight loss, and alternative
options, such as pharmacotherapy, need to be
considered.

5. However, many traditional glucose-lowering medications
may lead to weight gain. This article focuses on the
potential of currently available pharmacological strategies
and on emerging approaches in development to support
the glycemic and weight-loss goals of individuals with type
2 diabetes.

6. Two pharmacotherapy types are considered:
 those developed primarily for blood glucose control
that have a favorable effect on body weight and
 those developed primarily to induce weight loss that
have a favorable effect on blood glucose control.
The potential of combination therapies for the
management of obese patients with type 2 diabetes is
discussed.

7. Intensive lifestyle intervention (ILI)
Weight reduction with intensive lifestyle intervention (ILI) has been
shown to reduce the incidence of diabetes by 58%.
For individuals with diabetes, studies (Look AHEAD [Action for Health
in Diabetes]) have shown that a loss of 5–10% of body weight can:
improve fitness,
reduce HbA1c levels,
improve cardiovascular disease (CVD) risk factors,
decrease use of diabetes, hypertension, and lipid-lowering
medications.
reduction of depression symptoms and
remission or reduced severity of obstructive sleep apnea.

8.  Guidelines recommend lifestyle modifications as
the foundation of weight loss.
 Although ILI produces clinically beneficial weight
loss for many patients, the reality is that ILI is
difficult to achieve and maintain over the long-
term for most patients.

9. Even in an optimal clinical trial setting, such as Look AHEAD,
one-third of all patients were unable to achieve at least 5% weight
loss after 1 year.
Most individuals with diabetes tend to lose weight over a period of
4–6 months, and lose 4–10% of their baseline weight before
experiencing a plateau in weight loss, generally followed by a
weight regain.
half of all patients who lost 5% of their body weight after 1 year of
ILI regained some or all of their initial weight loss by year 8.
pharmacotherapy, should be considered for patients who cannot
lose weight with lifestyle modification alone.

10. Why patients regain weight:
antihyperglycemic agents
antipsychotic medications
antiepileptic drug
Metabolic, psychological, and behavioral factors
homeostatic control of body weight
Functional changes within the brain
When considering combination therapies, clinicians should
remain aware of the weight gain that is often associated
with diabetes medications.

11. WEIGHT GAIN WITH
CONVENTIONAL
THERAPIES

12. WEIGHT GAIN WITH
CONVENTIONAL THERAPIES

13. WEIGHT GAIN WITH
CONVENTIONAL THERAPIES
 The resultant decrease in blood glucose levels corresponds
with a decrease in glycosuria, a major contributing factor to
the weight gain observed in patients treated with
conventional antihyperglycemic agents.
 subcutaneous delivery of insulin leads to more weight gain
than intraperitoneal delivery. [Subcutaneous administration
bypasses hepatic insulin sensors and leads to physiologically
abnormal levels of insulin exposure at peripheral tissues,
which may disrupt the homeostatic regulation of body
weight]

14. WEIGHT GAIN WITH
CONVENTIONAL THERAPIES

15. ANTIDIABETES THERAPIES
WITH
WEIGHT-LOSS POTENTIAL

16. ANTIDIABETES THERAPIES WITH
WEIGHT-LOSS POTENTIAL

17. GLP-1 Receptor Agonists
GLP-1:
GLP-1 is an endogenous peptide hormone produced in the
gut in response to nutrient absorption.
The insulinotropic action of GLP-1 is dependent on glucose,
which means its activeity should not be associated with
hypoglycemia.

18. GLP-1 exerts its effects through binding to the GLP-1 receptor
(GLP-1R), which is expressed on pancreatic b-cells. GLP-1/GLP-
1R signaling :
increases b-cell sensitivity to glucose and
suppresses glucagon secretion from pancreatic a-cells.
GLP-1 exerts extra pancreatic effects, such as:
reducing hepatic glucose production and
inhibiting gastric emptying.
GLP-1 action at the hypothalamus promotes satiety.

19. Because native GLP-1 is rapidly inactivated in vivo,
GLP-1R agonists were developed that mimic the
actions of GLP-1 in vivo but are resistant to
enzymatic degradation and inactivation by
dipeptidyl peptidase-4 (DPP-4) (41). GLP-1R
agonists exert diverse actions on multiple-target
tissues and lead to a reduction in blood glucose
and in body weight.

20. GLP-1 Receptor Agonists
The first two GLP-1R agonists available for the treatment
of type 2 diabetes:
Exenatide
Liraglutide

21. GLP-1 Receptor Agonists: Exenatide
vs Liraglutide
Exenatide [twice-daily
and once-weekly]
Liraglutide [1.8 mg q.d.]
reduction in
HbA1c from baseline
-1.1% [trial durations of 12–52
weeks]
-1.18%
weight loss -2.67 kg -3.24 kg [from baseline at 26 weeks]
Adverse events (AEs) nausea and vomiting [mild-to-
moderate severity and
transient]
gastrointestinal AEs resolved
more quickly
hypoglycemia limited occurrence of major
and minor hypoglycemia
(33.6%)
fewer cases of minor
Hypoglycemia (25.5%) [thought to
be
mainly due to the concomitant
medications used (sulfonylureas)]
Post marketing reports of acute pancreatitis with GLP- 1R agonist use have led to pancreatitis being listed
under the warnings and precautions.

22. GLP-1 Receptor Agonists: Exenatide vs Liraglutide
[in combination with insulin, metformin, sulfonylurea, metformin
plus rosiglitazone, or metformin plus glimepiride]
Exenatide Liraglutide
reduction in
HbA1c from
baseline
Significant Significant reductions in HbA1c over
baseline were observed within 8
weeks of treatment.
weight reductions Significant Liraglutide to metformin or
metformin plus rosiglitazone.
[liraglutide plus sulfonylurea
treatment was weight neutral]
Adverse events
(AEs)
nausea, diarrhea, and
nasopharyngitis
gastrointestinal in nature
hypoglycemia much lower in patients not on
concomitant sulfonylurea
therapy
Major hypoglycemia was reported
only when liraglutide was used in
combination with a sulfonylurea

23. GLP-1 Receptor Agonists
Other GLP-1 Receptor Agonists:
Lixisenatide and albiglutide have been approved in Europe
Albiglutide and dulaglutide in the U.S.
semaglutide and additional exenatide extended-release
formulations (i.e., once-monthly and once-yearly
formulations) are under clinical development

24. Sodium-Glucose Co transporter 2
Inhibitors
In individuals with type 2 diabetes, SGLT2 expression is
increased in the renal proximal tubular cells, leading to
increased renal glucose reabsorption, which ultimately
aggravates hyperglycemia. SGLT2 inhibitors reduce
blood glucose mainly through increased glycosuria,
although indirect mechanisms have also been reported.

25. Sodium-Glucose Co transporter 2
Inhibitors
Sodium-Glucose Co transporter 2 Inhibitors:
Dapagliflozin (1–50 mg per day)
Canagliflozin (100 and 300 mg q.d.)
Empagliflozin (approved in 2014 by the FDA and EMA)

26. Sodium-Glucose Co transporter 2 Inhibitors
Dapagliflozin vs Canagliflozin vs Empagliflozin
Dapagliflozin Canagliflozin Empagliflozin
reduction in baseline
HbA1c
-0.53% -0.77% (100 mg q.d.)
-1.03% (300 mg q.d.)
[After 26 weeks]
-0.62% (10 mg)
-0.66% (25 mg)
reduction in body
weight
-1.63-kg -2.2% and -3.3% after
26 weeks.
-1.85 and -1.84 kg,
with 10 and 25 mg
hypoglycemia Monotherapy did not lead to
hypoglycemia, the incidence of
hypoglycemic events increased
when dapagliflozin was
combined with sulfonylureas and
insulin
Low (~3%) -
Adverse events (AEs) increased risk of mild urinary and
genital tract infections.
mild genital mycotic
infections and urinary
tract infections (UTIs)
genital tract
infection

27. Sodium-Glucose Co transporter 2 Inhibitors
Dapagliflozin vs Canagliflozin combined with other antihyperglycemic
agents (i.e., metformin, insulin, sulfonylurea, TZD)
dapagliflozin [1–50
mg]
canagliflozin [50–300
mg]
reduce HbA1c -0.73% -0.97%
reduction in body
weight
-0.59 kg
Adverse events (AEs) genital tract infections
UTI
increased risk of
genital tract infections

28. Human Amylin: Pramlintide
 small but significant reduction in HbA1c (-0.33%)
 reduction in weight from baseline compared with control (-2.57 kg)
 associated with a higher incidence of mild-to-moderate, mainly
transient, nausea than control.
 incidence of hypoglycemia (mild to moderate) to be higher with
pramlintide versus placebo

29. ANTIOBESITY
PHARMACOTHERAPIES

30. ANTIOBESITY
PHARMACOTHERAPIES

31. Orlistat
 Orlistat functions as an antiobesity agent by inhibiting gastrointestinal
lipases, thereby reducing absorption of dietary fat.
 In [a 4-year study of] obese patients without diabetes, orlistat (120 mg
t.i.d.) plus lifestyle changes produced moderate weight loss (–5.8 kg
from baseline vs. –3.0 kg from baseline with lifestyle changes alone)
 greater reduction in the incidence of type 2 diabetes over lifestyle
changes alone (6.2% vs. 9.0%, a –37.3% reduction).

32. Orlistat
Obese patients with type 2 diabetes: After 52 weeks of
orlistat treatment (120 mg t.i.d.) combined with a reduced-
calorie diet and a weight-management program:
reduction in weight from baseline: 5.0%
HbA1c reduction: 1.1%

33. Orlistat
Better glycemic control independent of weight loss:
improvement of insulin sensitivity
slower/incomplete digestion of dietary fat
reduction of postprandial plasma nonesterified fatty
acids,
decreased visceral adipose tissue
stimulation of GLP-1 secretion

34. Orlistat
Orlistat was generally well tolerated, and gastrointestinal
effects were the most commonly reported AEs, but all
events were considered mild or moderate.

35. Lorcaserin
Lorcaserin is indicated as an adjunct to a reduced-calorie diet
and increased physical activity for chronic weight management
in adults with an initial BMI of >30 kg/m2 (obese) or >27 kg/m2
(overweight) in the presence of at least one weight-related
comorbid condition such as hypertension, dyslipidemia, or type 2
diabetes.
Lorcaserin is a selective small-molecule agonist of the 5-
hydroxytryptamine 2C serotonin receptor (5HT2C), which
regulates mechanisms related to satiety, ingestive behavior,
glucose tolerance, and hepatic insulin sensitivity.

36. Lorcaserin
 In overweight or obese patients without diabetes, lorcaserin
treatment provided a 5.81% reduction from baseline body
weight after 1 year versus 2.16% with placebo.
 type 2 diabetes treated with metformin or a sulfonylurea,
lorcaserin treatment resulted in mean weight changes of 4.5%
(twice daily) and 5.0% (once daily) compared with 1.5% with
placebo at week 52.
 HbA1c decreased 0.9% and 1.0% from baseline with lorcaserin
twice daily and once daily, respectively.

37. Lorcaserin
 Although hypoglycemia was slightly more frequent in the
lorcaserin treatment groups than in the placebo group,
no severe hypoglycemia was reported.
 Overall, the most common AEs with lorcaserin were
headache, back pain, nasopharyngitis, and nausea.

38. Phentermine Plus Topiramate
 Phentermine is a norepinephrine- and dopamine-releasing
agent approved for the short-term treatment of obesity.
 with type 2 diabetes achieved weight reductions of -6.8% [with
PHEN 7.5/TPM 46.0 ] and -8.8% [with PHEN 15.0/TPM 92.0 ] versus
-1.9% with placebo.
 For patients with diabetes, significantly greater reductions in
HbA1c (–0.4 mmol/L) were seen with both doses.
 Furthermore, in patients without diabetes, the two doses of
PHEN/TPM led to 54% and 76% reductions, respectively, in the
progression of subjects to type 2 diabetes, compared with
placebo.

39. Phentermine Plus Topiramate
 AEs: constipation, paresthesia and dry mouth. increased
risk of orofacial clefts in infants exposed to phentermine
plus topiramate during the first trimester of pregnancy.

40. Naltrexone Sustained Release Plus
Bupropion Sustained Release
 Naltrexone is an opioid receptor antagonist, whereas bupropion is a
norepinephrine and dopamine reuptake inhibitor. The combination
increases proopiomelanocortin (POMC) neuronal firing, which may
have anorectic effects.
 NB therapy significantly decreased HbA1c from baseline: –0.6%
 significantly greater weight reduction from baseline: –5.0%
 NB was associated with a higher incidence of nausea, constipation,
vomiting.
 Systolic blood pressure and pulse rate have been found to be higher
with NB.

41. Liraglutide
 Liraglutide (3.0 mg q.d.) has been shown to provide weight-
reduction benefits for obese patients; after 20 weeks, the
placebo-subtracted reduction in weight from baseline with
liraglutide (3.0 mg) treatment was –4.4 kg..
 after 1 year, weight loss of –5.8 kg
 after 2 years, weight loss of –7.8 kg

42. Safety Concerns
Recent safety concerns about an increased risk of major
cardiac AEs have led to market withdrawal of existing
antiobesity medications or a lack of new treatments being
approved. Assessment of cardiovascular safety has now
emerged as a major consideration for all new antiobesity and
glucose-lowering agents under current review by the FDA.

43. FUTURE PROSPECTS IN
CLINICAL
DEVELOPMENT
TO PROVIDE EFFECTIVE WEIGHT MANAGEMENT IN PATIENTS WITH TYPE
2 DIABETES, WHILE ALSO MINIMIZING AES.

44. FUTURE PROSPECTS IN CLINICAL
DEVELOPMENT

45. GLP-1R Agonist Combination
Therapies
Because GLP-1R agonists and basal insulins offer
complementary pharmacologic effects on prandial and
fasting glycemia.
The combination of exenatide (10 mg b.i.d.) with insulin
glargine led to greater reductions in HbA1c levels, compared
with insulin glargine alone (–1.74% vs. –1.04%).
Treatment with exenatide and insulin glargine led to a weight
decrease of –1.8 kg, whereas insulin glargine alone led to a
weight increase of 1.0 kg.

46. GLP-1R Agonist Combination
Therapies
Liraglutide with insulin degludec (IDegLira)- now approved in
Europe - is another combination currently being investigated for
the treatment of type 2 diabetes.
IDegLira led to greater reductions in HbA1c (–1.9%) versus
insulin degludec (–1.4%) or liraglutide (–1.3%) alone.
IDegLira also provided a modest weight loss of –0.5 kg from
baseline to week 26, [ –2.2 kg reduction with insulin degludec].
IDegLira also resulted in significantly fewer hypoglycemic
episodes than insulin degludec.

47. GLP-1R Agonist Combination
Therapies
A combination of insulin glargine with lixisenatide:
produced greater reductions in HbA1c (–0.32%; P , 0.0001) and
postprandial hyperglycemia compared with insulin glargine
alone.
favorable effect on body weight (difference vs. placebo –0.89
kg)
Nausea, vomiting, and symptomatic hypoglycemia were more
commonly reported with lixisenatide than with insulin glargine
alone.

48. FUTURE PROSPECTS IN
PRECLINICAL
DEVELOPMENT

49. Peptide Hormone Combination
Therapies
 combination treatment with pramlintide/ metreleptin
led to a significant earlier, sustained, and greater weight
loss than treatment with pramlintide or metreleptin
alone..
 Polyethylene glycolated (PEG)-leptin, along with PEG-
GLP-1/glucagon, may be another potential
combination therapy option.

50. Unimolecular Dual- or Triple-Incretin
Receptor Agonists
 early-stage development
 this dual agonist has the potential to enhance the
antihyperglycemic and antiobesity effects observed
with monoagonism because it affects adiposityinduced
insulin resistance and pancreatic insulin deficiency.

51. POTENTIAL THERAPEUTIC
TARGETS
Owing to the complex pathophysiology of diabetes, additional
therapeutic targets are under investigation as potential agents for
glycemic control, many in combination with GLP-1R agonists.
These possible agents—
GLP-1R agonist/PYY, [PYY is an incretin hormone that also has a role in
satiety]
fibroblast growth factor 21 with or without GLP-1R agonist, [factor 21 has
broad metabolic effects, including enhancing insulin sensitivity,
decreasing triglyceride concentrations, and inducing weight loss]
GLP-1R/ glucagon coagonists. [fat loss, decreased food intake, and
increased energy expenditure, while minimizing hypoglycemic risk]

52. CONCLUSIONS
The management of type 2 diabetes and the benefits of weight
reduction are irrefutable, most patients remain overweight or obese.
A shift in the approach to weight management in people with type
2 diabetes is clearly needed.
For patients struggling to achieve or maintain their weight-
management objectives, concomitant antiobesity medications can
be considered, with the aim of reducing patients’ body weight and
glycemic targets.

53. The emergence of a range of pharmacotherapies with
varying modes of action, coupled with ongoing
improvements in our knowledge of the physiology of
appetite and energy homeostasis, provides the prospect of
a rational combination therapy that is both effective and
tolerable.

54. Thank You