The Effect of Exenatide on Weight and Hunger in Obese, Healthy Women

The Effect of Exenatide on Body Weight, Energy Expenditure and Hunger in Obese Women Without Diabetes Mellitus

This study will look at the effect of exenatide, a drug which has been approved for the treatment of type 2 diabetes, on body weight, appetite and energy expenditure among moderately obese women without diabetes.

The study is 35 weeks long and includes 19 outpatient visits. Participants will receive exenatide for 16 weeks and placebo for 16 weeks with a 3 week rest period in between. Neither participants nor investigators will know whether exenatide or placebo is being administered. Participants will be started randomly on either exenatide or placebo.

Our hypothesis is that treatment with exenatide will curb appetite and lead to weight loss and may lead to changes in energy expenditure.

This study will examine the effect of exenatide on body weight, energy expenditure, satiety, sleep, and metabolic parameters in healthy, moderately obese women (BMI 28-35 kg/m2). We will look at 2 populations of women, one with normal glucose metabolism and one with impaired glucose homeostasis (IGH)--either impaired fasting glucose (IFG, fasting glucose 101-125 mg/dL) or impaired glucose tolerance (IGT, glucose 140-199 mg/dL 2h after a 75g oral glucose load). This is a randomized, double blind, crossover study with two 16-week treatment periods separated by a 3-week washout period. There are 19 study visits over 35 weeks.

The goals of this study are 1) to examine the effect of exenatide on body weight and dysglycemia in populations in which this medication has not been studied, namely obese women with and without IGH and 2) to investigate possible mechanisms of weight loss through measurements of energy expenditure, hunger, satiety, nausea, and sleep.

The primary outcome of this study is weight loss. We will calculate absolute and relative change in body weight from baseline to week 16 (the first treatment period) and from week 19 to week 35 (the second treatment period). Body weight will be measured at every study visit which will also allow us to assess the absolute and relative change from baseline throughout the entire study.

Inclusion Criteria:

1. Females aged 25-60
2. BMI 28-35 kg/m2
3. No known diagnosis of diabetes
4. No known diagnosis of coronary heart disease
5. Self-described sedentary lifestyle with minimal regular cardiovascular exercise (no more than 1 hour per week)
6. Stable weight (variation < 3 kg within 6 months of screening visit)
7. Ability to give informed consent
8. Ability to follow verbal and written instructions
9. Use of medically approved form of contraception (monophasic oral contraception, intra uterine device, surgical sterilization or 2 combined barrier methods)
10. Nonsmoker (tobacco, marijuana)
11. Outpatient visits every 2 weeks throughout the study period are required. While most of these visits are short (15 minutes)ability to commute to the performance site in Boston, on a regular basis, is necessary.

Exclusion Criteria:

1. Type 1 or type 2 diabetes mellitus diagnosed according to American Diabetes Association criteria
2. Coronary heart disease (history of myocardial infarction or unstable angina pectoris)
3. Uncontrolled hypertension hypertension (BP > 150/90 mmHg on or off antihypertensive medication)
4. Uncontrolled dyslipidemia (LDL > 200 or TG > 400 on or off lipid lowering medication)
5. Tobacco, marijuana or intravenous drug use
6. Shift workers (night shift or alternating day/night shifts)
7. Recent weight loss (> 3 kg within 4 months of the screening visit)
8. Gastroparesis
9. Inflammatory bowel disease
10. Malignancy treated with chemotherapy within the past 3 years
11. History of pancreatitis
12. Depression requiring hospitalization or diagnosis of psychosis
13. Renal insufficiency (creatinine clearance < 50 ml/min)
14. Transaminases > 2x above the normal range
15. Pregnancy within 6 months of the screening visit
16. Breastfeeding
17. Failure to use medically approved contraceptive methods
18. History of an eating disorder (anorexia, bulimia or laxative abuse)
19. History of surgery for the treatment of obesity (gastric banding, gastric bypass, gastric stapling)
20. New diagnosis of hypo or hyperthyroidism within 1 year of screening visit
21. Previous participation in a clinical study with exenatide
22. Presence or history of allergic reaction to multiple drugs