The Effects of Exenatide (Byetta ) on Energy Expenditure and Weight Loss in Nondiabetic Obese Subjects

Obesity can lead to a number of health problems including diabetes, heart disease, stroke,
low back pain, fatty liver disease, and osteoarthritis. The medical treatments currently
available for obesity are limited. Exenatide is an injectable medication approved for
treatment of type 2 diabetes that causes weight loss in some diabetic subjects. The reasons
exenatide is thought to cause weight loss include decreased food intake, increased feelings
of fullness and nausea. Because levels of a human gut hormone (glucagon like peptide 1) that
is similar to exenatide have been shown to be related to resting energy expenditure, it is
also possible that exenatide may have effects on a person s metabolism, a.k.a. energy
expenditure, but any effect of exenatide on energy expenditure has yet to be evaluated. Even
though exenatide is used to treat diabetes, administration of exenatide to non-diabetic lean
individuals did not cause frankly low blood sugars.

The primary goal of this study is to investigate the way in which exenatide given twice a day
to obese (BMI >= 30 kg/m^2) people without diabetes might lead to weight loss. Because
response to weight loss treatment can be highly variable between individuals, we will look at
the role of exenatide in changing food intake and energy expenditure as possible explanations
for weight loss. We will also assess the safety profile of exenatide in non-diabetic obese
people.

This study will involve the use of exenatide or placebo, determined randomly, in obese
individuals without diabetes over a 5 week period. The primary measurements will include
effects of exenatide on energy expenditure and food intake. We will also look at changes in
body fat and the levels of hormones involved in the sensations of hunger and fullness. We
will assess if any exenatide-induced changes can predict which individuals lose weight over
the 5 weeks. The safety and side effects of exenatide in non-diabetic individuals during this
time will also be determined. Findings from this study would help to determine how exenatide
works to cause weight loss in people without diabetes, who might benefit most, and would help
to improve understanding of why some people respond better to weight loss treatment than
others.

- INCLUSION CRITERIA:

- Premenopausal women and men < 55 years of age

- BMI >30 kg/m(2)

- Expressed desire for weight loss

- Stable weight (variation < 2.3 kg within past 6 months)

- Ability to provide informed consent

- Ability to follow verbal and written instructions

- Nonsmoker

- Ability to commute to study site on a regular basis for short outpatient visits over 5
weeks

- For females, use of a medically approved form of contraception. For oral
contraceptives, subjects will need to be on an established dose for at least 3 months
to ensure stable weight and will be asked not to switch contraceptive methods during
study participation.

EXCLUSION CRITERIA:

- Age < 18 years

- Use of other medications to treat obesity including medications obtained over the
counter or internet, orlistat (Xenical, Alli), sibutramine (Meridia), topiramate (with
or without phentermine (Qsymia), phentermine (Adipex P) or lorcaserin (Belviq) within
the past 6 months

- History of an eating disorder including anorexia or bulimia

- History of surgery for the treatment of obesity (gastric banding, gastric bypass)

- Diagnosis of type 1 or type 2 diabetes mellitus according to American Diabetes
Association guidelines

- Previous exposure to exenatide

- Uncontrolled hypertension as defined by a blood pressure of 150/90 on two or more
occasions or use of antihypertensive medications which may affect energy expenditure
including alpha blockers, beta blockers, angiotensin receptor blockers or inhibitors
of angiotensin converting enzyme

- Current use of tobacco products, marijuana, amphetamines, cocaine or intravenous drug
use

- Chronic ethanol use (> 3 drinks /day)

- Endocrine disorders including hypo or hyperthyroidism (including subclinical disease),
Cushing s disease, growth hormone deficiency or other pituitary diseases

- History of pancreatitis

- Personal or family history of multiple endocrine neoplasia (MEN)-2 or medullary
thyroid cancer

- History of unresolved gallstones

- Hyperamylasemia

- Fasting triglyceride level greater than or equal to 500

- Gastroparesis

- Inflammatory bowel disease or malabsorption disorders

- Malignancy treated with chemotherapy or radiation within the past 5 years

- Current clinical depression, diagnosis of psychosis or recent use of psychotropic
medication

- Pregnancy within past 6 months

- Breastfeeding

- Failure to use medically approved contraceptive methods if subject is female

- Liver function abnormalities (transaminases greater than twice normal)

- Renal insufficiency (creatinine clearance < 50 ml/min)

- History of chronic infection including tuberculosis, coccidiomycoses, lyme disease or
HIV infection

- Pulmonary disorders, including chronic obstructive pulmonary disease, which would
limit ability to follow the protocol (investigator judgment)

- Cardiovascular disease including history of myocardial infarction, unstable angina or
heart failure

- Central nervous system disease, including history of cerebrovascular accidents,
dementia, and neurodegenerative disorders

- Weight <450 pounds (maximum weight of the DXA machine as per manufacturer s manual)

- Sensitivity to exenatide or any inert components in its formulation

- Sensitivity to acetaminophen

- Conditions not specifically mentioned above may serve as criteria for exclusion at the
discretion of the investigators