weight management in type 2diabetes: 2015

Weight Management in Type 2Diabetes: Current and EmergingApproaches to TreatmentLUC VAN GAAL AND ANDR ´E SCHEENDIABETES CARE - 2015;38:1161–1172

Talha-Sami-Ul-HaqueDept. of Endocrinology

DHAKA MEDICAL COLLEGE HOSPITAL

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

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.

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

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.

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.

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.

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.

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.

Why patients regain weight:antihyperglycemic agentsantipsychotic medicationsantiepileptic drugMetabolic, psychological, and behavioral factorshomeostatic control of body weightFunctional changes within the brain

When considering combination therapies, clinicians should remain aware of the weight gain that is often associated with diabetes medications.

WEIGHT GAIN WITHCONVENTIONAL THERAPIES

WEIGHT GAIN WITHCONVENTIONAL THERAPIES

WEIGHT GAIN WITHCONVENTIONAL 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]

WEIGHT GAIN WITHCONVENTIONAL THERAPIES

ANTIDIABETES THERAPIES WITHWEIGHT-LOSS POTENTIAL

ANTIDIABETES THERAPIES WITHWEIGHT-LOSS POTENTIAL

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.

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.

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.

GLP-1 Receptor Agonists

The first two GLP-1R agonists available for the treatment of type 2 diabetes:ExenatideLiraglutide

GLP-1 Receptor Agonists: Exenatide vs Liraglutide

Exenatide [twice-dailyand once-weekly]

Liraglutide [1.8 mg q.d.]

reduction inHbA1c 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 resolvedmore quickly

hypoglycemia limited occurrence of major and minor hypoglycemia

(33.6%)

fewer cases of minorHypoglycemia (25.5%) [thought to

bemainly 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.

GLP-1 Receptor Agonists: Exenatide vs Liraglutide [in combination with insulin, metformin, sulfonylurea, metformin plus rosiglitazone, or metformin plus glimepiride]Exenatide Liraglutide

reduction inHbA1c 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

nasopharyngitisgastrointestinal 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

GLP-1 Receptor Agonists

Other GLP-1 Receptor Agonists:Lixisenatide and albiglutide have been approved in EuropeAlbiglutide 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

Sodium-Glucose Co transporter 2Inhibitors

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.

Sodium-Glucose Co transporter 2Inhibitors

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)

Sodium-Glucose Co transporter 2 InhibitorsDapagliflozin 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

Sodium-Glucose Co transporter 2 InhibitorsDapagliflozin 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

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

ANTIOBESITYPHARMACOTHERAPIES

ANTIOBESITYPHARMACOTHERAPIES

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).

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%

Orlistat

Better glycemic control independent of weight loss:improvement of insulin sensitivityslower/incomplete digestion of dietary fatreduction of postprandial plasma nonesterified fatty acids,decreased visceral adipose tissuestimulation of GLP-1 secretion

Orlistat

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

LorcaserinLorcaserin 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.

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.

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.

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.

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.

Naltrexone Sustained Release PlusBupropion 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.

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

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.

FUTURE PROSPECTS IN CLINICALDEVELOPMENT

TO PROVIDE EFFECTIVE WEIGHT MANAGEMENT IN PATIENTS WITH TYPE 2 DIABETES, WHILE ALSO MINIMIZING AES.

FUTURE PROSPECTS IN CLINICALDEVELOPMENT

GLP-1R Agonist CombinationTherapiesBecause 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.

GLP-1R Agonist CombinationTherapies

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.

GLP-1R Agonist CombinationTherapies

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.

FUTURE PROSPECTS INPRECLINICAL DEVELOPMENT

Peptide Hormone CombinationTherapies

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.

Unimolecular Dual- or Triple-IncretinReceptor 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.

POTENTIAL THERAPEUTICTARGETSOwing 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]

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.

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.

Thank You