Lack of funding

Obesity is common (>30% of US adults), contributes to substantial morbidity and mortality, but is difficult to treat. Partly this is due to the transient, arduous and modest nature of lifestyle interventions. Partly it is due to the limited efficacy and safety problems of existing pharmacotherapy. Only one drug, orlistat, is approved for long-term use in obesity; but its effects on weight are relatively small. There are drugs that have been approved for other diseases but which also reduce weight. One promising approach to treating obesity is combination therapy with orlistat and one or more of these other agents. The investigators propose an innovative approach to developing new therapies for obesity coupling the use of combination therapy with rigorous assessment of cardiovascular safety. Vascular function is a quantitative surrogate clinical endpoint that has been strongly and independently linked to future cardiovascular events.

Our hypothesis is that combination pharmacotherapy will reduce weight and improve vascular function in obese human subjects. The co-primary endpoints will be weight and vascular function.

Inclusion Criteria:

• Age 40 to 75 years
• Male or postmenopausal female
• BMI ≥ 30 kg/m2
• One or more major cardiovascular (CV) risk factors (hypertension, dyslipidemia, impaired glucose tolerance OR metabolic syndrome)

Exclusion Criteria:

• Congestive heart failure
• Renal impairment
• History of bariatric surgery (i.e. lap-band, Roux-en-Y or biliopancreatic diversion)
• Type I diabetes mellitus
• Weight loss > 10% in the past 6 months
• Recurrent nephrolithiasis
• Current treatment for seizure disorder
• Hepatic cirrhosis
• Current use of study medications
• Current use of oral estrogen
• History of smoking cessation in the past three months
• Current cholestasis or malabsorption syndrome
• Planned use of any herbal or over-the-counter supplements for weight loss
• History of allergic reactions to metformin, topiramate, orlistat or any of ingredients
• Medical conditions requiring continuous use of phosphodiesterase inhibitors and/or the inability to withhold phosphodiesterase inhibitors for 48 hours
• Participation in another clinical drug study within four weeks prior to this investigation.
• Participation in any other weight loss or rigorous exercise program.
• Any disease or condition that in the opinion of the investigator may interfere with completion of the study