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Approaches to managing obesity in type 2 diabetes: focus on incretin therapies.


The United States has experienced a concomitant increase in obesity and type 2 diabetes over the past decade that has reached epidemic proportions. Longitudinal studies confirm that increased body mass index (BMI) raises a person's lifetime risk of developing type 2 diabetes and that adults with a BMI [greater than or equal to] 30 kg/[m.sup.2] have the greatest risk. (1) Furthermore, it is estimated that 90% of type 2 diabetes cases are attributed to obesity. (2) Obesity is also a risk factor for comorbid diseases that negatively influence type 2 diabetes and its treatment, including hypertension, dyslipidemia, stroke, and coronary heart disease. (3)


The American Diabetes Association (ADA) recommends that the benefits of diet modification and increased physical activity be reinforced at each office visit and that patients with type 2 diabetes achieve a BMI [greater than or equal to] 25 kg/[m.sup.2]. (4) Weight loss in obese patients with type 2 diabetes improves beta-cell sensitivity and insulin secretion. (5) Accumulating evidence indicates that modest weight loss, defined as a 5% to 10% reduction in baseline weight, may be beneficial for glycemic control and for reducing associated complications.

The long-term efficacy of diet-based therapy was not sustained in the United Kingdom Prospective Diabetes Study (UKPDS) because observed weight loss and HbAlc improvements decreased over the course of the trial. (6,7) Although a meta-analysis of controlled trials of exercise intervention in type 2 diabetes failed to find significant differences in body mass, moderate exercise was associated with significant decreases in HbAlc levels. (8) Mobility constraints, neuropathy, or retinopathy may preclude some patients with type 2 diabetes from undertaking an exercise regimen.

The ongoing Look AHEAD trial is a long-term study of the effects of intensive lifestyle intervention, including reduced caloric intake and increased physical activity, in conjunction with individual and group counseling in overweight patients with type 2 diabetes? After 1 year, patients in the intensive therapy group lost 8.6% of their initial weight compared with 0.7% in the group receiving diabetes support and education. (9) Furthermore, resultant weight loss improved diabetes control and cardiovascular risk factors.

The benefits of weight loss extend to patients who are at high risk for developing type 2 diabetes. In the Diabetes Prevention Program, the incidence rate of type 2 diabetes decreased by 58% at 3 years with lifestyle intervention in high-risk patients who had elevated fasting and post-load glucose levels. (10) Interestingly, the effects of lifestyle intervention were greater than those observed with metformin use in this trial.


Because of progressive deterioration in beta-cell function, most patients with type 2 diabetes require pharmacological intervention with antidiabetic agents or exogenous insulin. Insulin secretagogues, insulin sensitizers, and insulin therapy are associated with weight gain, which undermines their use in obese patients with type 2 diabetes. This weight gain is attributed to decreased urinary glucose excretion and a lowered metabolic rate. (11) Patients may also increase caloric intake because of concerns about hypoglycemia. (12)

Metformin, the first-line agent used in conjunction with lifestyle modifications, is weight neutral or may result in weight loss in some patients, and has nonglycemic benefits such as decreased low-density lipoprotein cholesterol and triglycerides. (13) Although the newer sulfonylureas are associated with a lesser impact, this class of agents generally results in weight gain. Long-term clinical trials of the thiazolidinediones indicate that these agents are associated with progressive weight gain, partly because of fluid retention. (14,15) However, the thiazolidinedione pioglitazone has beneficial effects on lipid levels and appears to reduce the risk of myocardial infarction. (14)

Fear of weight gain poses a significant barrier to the initiation and intensification of insulin therapy. (16,17) Indeed, it is estimated that patients with type 2 diabetes gain 2 kg per 1% reduction in HbAlc with intensive therapy. (18) Newer basal insulin analogs appear to have less of an impact on weight gain; the mechanisms contributing this weight-sparing effect are unclear. (19)

Amylin, a hormone secreted by the pancreatic beta-cell in quantities equimolar to insulin, has also been identified as a target in type 2 diabetes because levels are attenuated or absent in these patients. (20,21) Pramlintide, an amylin analog, is approved for use in patients with type 2 diabetes who do not achieve glycemic control with insulin. Preprandial subcutaneous administration of pramlintide as an adjunct to insulin therapy reduces HbAlc levels and has modest effects on body mass in clinical trials of patients with type 2 diabetes. (22,23) A sub-analysis of overweight/obese participants in these trials found that approximately 9% of patients experienced a [greater than or equal to] 5% reduction in body weight. (24) Pramlintide, which reduces body weight by means of a satiety effect, also results in sustained weight loss when combined with lifestyle interventions in nondiabetic obese patients, but it is not currently indicated for this use. (25) Emerging data indicate that pramlintide administered in combination with a leptin analog further enhances weight loss.

Elucidation of the incretin system and its role in glucose homeostasis led to the development of new pharmacotherapies for type 2 diabetes. There are currently two therapeutic approaches to restoring glucagon-like peptide (GLP)-1 in type 2 diabetes: administration of a potent GLP-1 receptor agonist or augmentation of endogenous GLP-1 by means of a dipeptidyl peptidase (DPP)-4 inhibitor. Exenatide, the only approved GLP-1 analog available at this time, reduces HbAlc levels with concomitant decreases in body weight over time. Exenatide is administered subcutaneously twice daily, starting with 5 mcg bid and increasing administration to 10 mcg bid. (26) Participants in randomized, placebo-controlled clinical trials of exenatide in combination with metformin and/or sulfonylurea therapy experienced significant weight reductions of -1.6 to -2.8 kg regardless of the agent used in combination. (27,28) In open-label extension studies of exenatide, 81% of participants lost body weight after 2 years, with progressive reductions continuing up to 3 years (-5.3 [+ or -] 0.4 kg at year 3). (29,30)

A 26-week open-label, randomized, controlled trial of exenatide and insulin glargine demonstrated equivalent reductions in HbAlc levels that were sustained throughout the trial. (31) Insulin glargine increased body weight by 1.8 kg, whereas exenatide resulted in a 2.3 kg weight reduction. However, significantly more patients in the exenatide group experienced gastrointestinal adverse effects, accounting for more withdrawals from the study compared with the insulin glargine group (19.4% vs 9.7%). The effects of exenatide monotherapy were recently investigated in a 24-week trial of patients with type 2 diabetes who were naive to antidiabetic agents. Twice-daily 10 mcg exenatide improved a number of parameters, including HbA1c, fasting and postprandial glucose, and body weight. (32)

Although the adverse effects of exenatide are gastro-intestinal, with 20% to 30% of patients reporting mild and transient nausea, this does not account for the observed weight loss. Studies have determined that weight loss is independent of nausea. GLP-1 receptors are distributed throughout the body, including the central nervous system. (33) As such, exenatide may lead to weight loss through a broad range of actions, including promoting satiety and reducing food intake.

A number of GLP-1 agonists are in clinical development (Table 1). For example, a 15-week study of a long-acting release formulation of exenatide reported that once-weekly administration significantly reduced HbA1c levels and body weight. (34) Liraglutide, a human GLP-1 agonist in development, is a once-daily agent administered subcutaneously. A 14-week placebo-controlled study demonstrated that liraglutide monotherapy (0.65, 1.25, or 1.90 mg) significantly reduced HbAlc levels and body weight. (35) A 52-week study of patients with early type 2 diabetes reported that 1.2 mg and 1.8 mg of liraglutide exhibited greater reductions in HbAlc levels and body weight than did glimepiride. (36) Furthermore, a 26-week, randomized, parallel-group study comparing the effects of 10 mcg exenatide and 1.8 mg liraglutide reported that weight reduction was comparable in both groups despite significantly greater reduction of HbAlc in liraglutide-treated patients. (37)

Sitagliptin is the only DPP-4 inhibitor currently approved for use in the United States; however, a number of agents are in development (Table 1). Sitagliptin is administered orally with a recommended dose of 100 mg/day. (38) Dose reduction is recommended for patients with moderate to severe renal insufficiency or end-stage renal disease. Clinical trial data demonstrate that orally administered sitagliptin as monotherapy or in combination with metformin reduces HbAlc levels over time, with neutral effects on body mass. (39,40) Receptors for DPP-4 are expressed in many tissues, underscoring the importance of long-term studies with these agents.

A recent crossover trial of exenatide and sitagliptin compared several short-term effects, including rate of gastric emptying and caloric intake. (410 Exenatide reduced the rate of gastric emptying, whereas sitagliptin had no effect. After 2 weeks, exenatide resulted in significantly greater decreases in body weight compared with sitagliptin (0.8 [+ or -] 0.2 kg vs 0.3 [+ or -] 0.2 kg, P=.0056). Exenatide also significantly reduced caloric intake during an ad libitum meal compared with sitagliptin. Longer head-to-head trials are needed to confirm these findings.

Other antiobesity pharmacotherapies, including phentermine, diethylpropion, orlistat, or sibutramine, may be considered in select patient populations. Orlistat, the most studied agent, is now available over the counter. In a 1-year clinical trial of patients with type 2 diabetes, orlistat (120 mg 3 times daily) reduced body weight by 2.6 kg to -6.2 kg. (42) Orlistat is associated with gastrointestinal complaints, and its long-term safety has not been established. Sibutramine has also been demonstrated to reduce weight in patients with type 2 diabetes; however, cardiovascular events have been reported with use of this agent. (43) Patients who have not been able to reduce body weight with other interventions or who are morbidly obese may be candidates for bariatric surgery. Accumulating evidence indicates that this approach can reverse the metabolic underpinnings of the disease and reduce overall mortality. (44)


Overweight and obese patients at risk for developing type 2 diabetes should be counseled on the importance of diet and physical activity, to underscore the benefits of modest weight loss. The ADA recommends that patients with type 2 diabetes receive individualized medical nutrition therapy and, in the absence of contraindications, participate in physical activity to achieve individualized goals. (4) Including a dietitian in obesity management has been demonstrated to improve outcomes. (45) Patient readiness to initiate lifestyle modifications is also an important predictor of success. (46) A number of patient education tools are available to assist with weight management in clinical practice (Table 2).


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(10.) Knowier WC, Barrett-Conner E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

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(15.) Kahn SE, Haffner SM, Heise MA, et al. Glycemic durabil ity of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427-2443.

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(17.) Ziemer DC, Miller CD, Rhee MK, et al. Clinical inertia contributes to poor diabetes control in a primary care setting Diabetes Educ. 2005;31:564-571.

(18.) Purnell IQ, Weyer C. Weight effect of current and experimental drugs for diabetes mellitus: from promotion to alleviation of obesity. Treat Endocrinol. 2003;2:33-47.

(19.) Hermansen K, Davies M. Does insulin detemir have a role in reducing risk of insulin-associated weight gain? Diabetes Obes Metab. 2007;9:209-217.

(20.) Kruger DE Gatcomb PM, Owen SK. Clinical implications of amylin and amytin deficiency. Diabetes Educ. 1999;25:389-397.

(21.) Rushing PA. Central amylin signaling and the regulation of energy homeostasis. Curr Pharm Des. 2003;9:819-825.

(22.) Hollander P, Ramer R, Fineman M, et al. Addition of pramlintide to insulin therapy lowers HbAlc in conjunction with weight loss in patients with type 2 diabetes approaching glycaemic targets. Diabetes Obes Metab. 2003;5:408-414.

(23.) Rather RE, Maggs D, Nielsen LL, et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2006;8:419-428.

(24.) Hollander P, Maggs DG, Ruggles JA, et al. Effect of pramlintide on weight in overweight and obese insulin-treated type 2 diabetes patients. Obes Res. 2004; 12:661-668.

(25.) Smith SR, Aronne LJ, Burns CM, et al. Sustained weight loss following 12 month pramlintide treatment as an ad junct to lifestyle intervention in obesity. Diabetes Care. 2008;31:1816-1823.

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an interim analysis of data from the open label, uncontrolled extension of three double blind, placebo-controlled trials. Clin Ther. 2007;29:139-153.

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Incretin-related therapies in clinical development

Agent                                      Status

GLP-1 agonists

Liraglutide                                Filed
Exenatide LAR                              Filed
AVE0010                                    Phase 3
Taspoglutide                               Phase 3
Albiglutide                                Phase 2
CJC-1134-PC                                Phase 2

DPP-4 inhibitors

Vildagliptin                               Filed
Saxagliptin                                Phase 3
Alogliptin                                 Phase 3
ARI-2243                                   Phase 1

GLP-1, glucagon-like peptide 1; DPP-4, dipeptidyl peptidase.


Resources for the management of obesity
in type 2 diabetes

The Practical Guide: Identification, Evaluation, and Treatment of
Overweight and Obesity in Adults was developed by a panel convened
by the North American Association for the Study of Obesity and the
National Heart, Lung, and Blood Institute. The Guide, based on
clinical guidelines for identifying and managing obesity, gives
health care practitioners tools for helping patients lose weight
effectively. Available at: http://www.nhlbi.

The Weight-Control Information Network, a website sponsored by the
National Institute of Diabetes and Digestive and Kidney Diseases,
is a resource for clinicians and patients that provides information
on weight control, nutrition, healthy eating, and physical
activity. The site includes downloadable patient publications in
English and Spanish. Available at:

Small Steps. Big Rewards. Your GAME PLAN for Preventing Type 2
Diabetes: Health Care Provider's Toolkit. Developed by the National
Diabetes Education Program, this 32-page booklet provides the
latest evidence-based tools and techniques to help physicians start
their own personalized diabetes prevention programs. Information in
the booklet is based on strategies used in the Diabetes Prevention
Program, sponsored by the National Institutes of Health. Available

4 Steps to Control Your Diabetes, For Life., a booklet from the
National Diabetes Education Program, summarizes diabetes and its
comorbidities and outlines patient tactics for managing the
disease. Available at:
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Article Details
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Author:Ridge, Terry
Publication:Journal of Family Practice
Article Type:Report
Geographic Code:1USA
Date:Feb 1, 2009
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