Incretin mimetics are quickly gaining popularity for the treatment of type 2 diabetes. Exenatide is associated with a reduction in hemoglobin A1C of 0.5–0.8% and liraglutide with a reduction of 1.1–1.5% (11
). Of interest, a consistent finding in large clinical studies is that hemoglobin A1C levels declined but then plateaued while weight loss continued (18
). Data on weight loss with exenatide in individuals without diabetes are limited. One group reported ~3.3 kg placebo-corrected weight loss over 24 weeks (15
). Astrup et al. (16
) showed that 1.2–3.0 mg liraglutide daily plus aggressive lifestyle intervention for 20 weeks was associated with dose-dependent, placebo-corrected weight loss, ranging from 2.0 to 4.4 kg among nondiabetic obese individuals. Neither study commented on individual responses to treatment.
Our cohort of women lost, on average, 2.5 kg after 16 weeks of exenatide treatment, and we observed significant weight loss after only 2 weeks. Importantly, we observed that 30% of our study population lost 8% of their body weight during exenatide treatment, whereas another 31% did not lose any weight or gained weight. The variable response to exenatide was apparent as early as 4 weeks. To our knowledge, this is the first study to report stratified weight loss in response to exenatide treatment in obese, nondiabetic individuals. Although we did not identify baseline characteristics that predicted the degree of response to exenatide treatment, our observation that significant weight loss was seen as early as 2 weeks and that high responders could be identified by 4 weeks has important clinical ramifications and demonstrates the value of a short clinical trial to assess the effectiveness in a given individual. A larger prospective study designed to investigate predictors of weight loss with exenatide is an important area for future investigation.
The mechanisms of weight loss with exenatide are not fully understood but may include changes in energy expenditure, changes in leptin sensitivity, or nausea resulting in decreased food intake. Significant weight loss is usually associated with a decrease in REE that favors weight regain (19
). Leibel et al. (20
) observed that a hypocaloric diet producing 10% weight loss resulted in a decrease in REE of ~130 kcal/day, and Pereira et al. (21
) found that a low-fat diet producing 10% weight loss was associated with a decrease in REE of 176 kcal/day, compared with 96 kcal/day with a low–glycemic index diet producing the same degree of weight loss. Dietary or pharmacologic interventions that blunt the decrease in REE with weight loss are in great clinical demand. We identified a potential effect of exenatide on REE because those who had the most robust weight loss with exenatide did not have the expected decrease in this parameter. Rodent and human studies support a relationship between GLP-1 and energy expenditure, possibly by activating the sympathetic nervous system. In rats, both peripheral and central administration of GLP-1 receptor agonists increased blood pressure and heart rate by activating autonomic regulatory sites in the rat brain (22
). In lean, healthy males, peripheral GLP-1 administration during a hyperglycemic clamp was associated with increased REE, and the GLP-1 analog liraglutide has been associated with increased heart rate (23
Another mechanism through which exenatide may produce weight loss is by increasing leptin sensitivity. Obesity is considered to be a state of leptin resistance, and weight loss is thought to improve leptin sensitivity. There currently is no technique for measuring leptin sensitivity in humans, and the decrease in leptin levels seen with weight loss generally is used as indirect evidence of increased leptin sensitivity. Although there was no significant change in leptin levels during exenatide treatment when we analyzed our data in aggregate, we noted that leptin levels decreased significantly among exenatide high responders compared with nonresponders. However, this effect may be attributed to weight loss, per se, rather than exenatide treatment. A comparator group with calorie-restricted weight loss would help answer this question in future studies. Nausea, the most common adverse effect of exenatide, also may contribute to weight loss. Although exenatide was associated with more nausea than placebo, the severity of nausea decreased over time and nausea scores were not higher among exenatide high responders.
Our study included a small cohort of generally healthy obese women, which limits the generalizability of our findings. The overall drop-out rate was 35%, with 17% dropping out prior to being randomly assigned and 18% dropping out after being randomly assigned. There was no significant difference in baseline weight or BMI among dropouts versus completers. A crossover study design introduces the possibility of both an order effect and a carryover effect. Our statistical analysis was adjusted for possible treatment order effects. Given the short half-life of exenatide and normal renal function among study participants, a 3-week washout period should have been sufficient to exclude a carryover effect. Our study was powered for the primary outcome of weight loss during exenatide versus placebo treatment. Retrospective analysis revealed that weight loss among our cohort could be grouped as ≥5% body weight, <5% body weight, or weight gain. A larger, prospective study will be required to examine the metabolic parameters that may predict the degree of response to exenatide treatment.
The trend in obesity literature typically has been to report the average response of an entire study population to a particular dietary or pharmacologic intervention. However, the analysis and reporting of weight loss data in aggregate can obscure individual responses to treatment. Our study is the first study to describe weight loss variability with a GLP-1 receptor agonist and demonstrates that a subset of women have a robust response to exenatide treatment that can be identified very early in the course of therapy. Future studies examining the duration and magnitude of weight loss among individuals who have a robust response to exenatide treatment, as well as characteristics that predict response, may guide us toward a more personalized approach to pharmacotherapy for the treatment of obesity.