Short-term Exenatide Treatment Leads to Significant Weight Loss in a Subset of Obese Women Without Diabetes

Jody Dushay, MD; Chuanyun Gao, MD; Gosala S. Gopalakrishnan, PHD; Meghan Crawley, MS; Emilie K. Mitten, BA; Elissa Wilker, PHD; Janet Mullington, PHD; Eleftheria Maratos-Flier, MD

Disclosures

Diabetes Care. 2012;35(1):4-11. 

In This Article

Abstract and Introduction

Abstract

Objective–To investigate the effect of treatment with the glucagon-like peptide 1 receptor agonist exenatide on weight loss and metabolic parameters in obese nondiabetic women.
Research Design and Methods–Forty-one obese women (aged 48 ± 11 years and BMI 33.1 ± 4.1 kg/m2) participated in a 35-week randomized, double-blind, placebo-controlled, crossover study, including two 16-week treatment periods separated by a 3-week washout period. There was no lifestyle intervention. The primary outcome was change in body weight.
Results–Subjects treated with exenatide lost an average of 2.49 ± 0.66 kg compared with a 0.43 ± 0.63 kg weight gain during placebo treatment. Weight loss with exenatide treatment was noted at 2 weeks. The degree of weight loss could be stratified. A total of 30% of subjects were high responders who lost ≥5% body weight (−7.96 ± 0.52%), 39% were moderate responders who lost <5% body weight (−2.43 ± 0.45%), and 31% were nonresponders who gained weight (1.93 ± 0.53%). Waist circumference also decreased significantly with exenatide treatment. Subjects experienced more nausea during exenatide treatment compared with placebo, but the severity decreased over time and did not correlate with weight loss.
Conclusions–Short-term exenatide treatment was associated with modest weight loss and decreased waist circumference in a cohort of obese nondiabetic women. A subset of individuals demonstrated robust weight loss that was detected very early in the course of treatment.

Introduction

The recent withdrawal of sibutramine from the market leaves only two Food and Drug Administration–approved pharmacologic agents for the treatment of obesity, phentermine and orlistat.[1] From this limited armamentarium, clinicians attempt medical management of a chronic disease that has substantial economic, physical, and emotional consequences. Although many studies have shown that weight loss can be achieved through highly supervised dietary interventions, weight regain following these interventions is almost universal.[2–4] A recent meta-analysis showed that 25–88% (mean 54%) of weight loss achieved immediately after the intervention was maintained after 1 year of unsupervised follow-up.[5] After 2 years, the percentage of maintained weight loss diminishes even more.[6] In contrast, bariatric surgery is the most successful intervention for achieving long-term weight loss in morbid obesity.[7] However, widespread use of a surgical intervention for obesity is problematic because many people who would benefit do not choose this approach, nor is it routinely available to individuals with BMI <39.9 kg/m2 and no other metabolic complications. Given the lack of long-term success with dieting, the invasive nature of bariatric surgery, and the limited pharmacologic options for the medical management of obesity, studies designed to investigate weight loss with agents approved for other primary indications have potentially high clinical value.

Glucagon-like peptide (GLP)-1 is an incretin hormone secreted by the enteroendocrine L cells of the small intestine in response to food intake. The major physiologic effects of GLP-1 include increased postprandial insulin secretion, decreased postprandial glucagon secretion, and delayed gastric emptying.[8] Early studies of human GLP-1 showed that continuous peripheral infusion was associated with decreased appetite and increased satiety.[9] Continuous infusion of GLP-1 also was shown to improve insulin sensitivity, glycemic control, and β-cell function in individuals with type 2 diabetes.[10] Incretin mimetics evolved as therapeutic options for the treatment of type 2 diabetes primarily because of their effects on insulin and glucagon secretion, with weight loss as an additional benefit.

Weight loss ranging from 2 to 6 kg has been a consistent finding in studies designed to investigate the glycemic benefits of incretin mimetics in individuals with type 2 diabetes.[11–14] There are very limited data on weight loss in nondiabetic individuals treated with these agents.[15,16] To evaluate the effects of exenatide treatment in obese, nondiabetic women, we designed a randomized, placebo-controlled, crossover study. To minimize the placebo effect and study the effect of exenatide in a real-world setting, we did not include any lifestyle modifications, and we discouraged any change in diet or physical activity. To avoid confounding factors of body fat distribution, we enrolled only women.

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