Diet and Exercise Plus Metformin to Treat Frailty in Obese Seniors

The continuing increase in prevalence of obesity in older adults including many older Veterans has become a major health concern. The clinical trial will test the central hypothesis that a multicomponent intervention consisting of lifestyle therapy (diet-induced weight loss and exercise training) plus metformin will be the most effective strategy for reversing sarcopenic obesity and frailty in older Veterans with obesity.

The growing prevalence of obesity in older adults including many older Veterans, has become a major concern in the US already strained health care system in general and in the VA in particular. In older adults, obesity exacerbates the age-related decline in physical function resulting in frailty, decrease in quality of life, loss of independence, and increase in nursing home admissions. The investigators' group demonstrated that weight loss from lifestyle therapy improves physical function and ameliorates frailty but the improvement was modest at best and most obese older adults remained frail. More importantly, there are concerns that the weight-loss induced loss of muscle and bone mass could worsen underlying age-related sarcopenia and osteopenia in the subset of frail obese elderly. Metformin, a biguanide, is a widely available drug used as first line treatment of type 2 diabetes. Animal studies suggest that metformin improves health span and increases lifespan, hence may represent a novel intervention for frailty. Because metformin reduces cellular senescence and senescence-associated phenotype (SASP), it is believed to retard accelerated aging most especially in older adults with obesity. The objective is to conduct a head-head comparative efficacy, placebo controlled, randomized controlled trial to test the hypothesis that lifestyle therapy + metformin for six months will be more effective than lifestyle therapy alone or metformin alone in improving physical function and preventing the weight loss-induced reduction in muscle and bone mass in obese (BMI \> 30 kg/m2) older (age 65 years) Veterans with physical frailty.

Eligibility Criteria:
Inclusion Criteria:

* BMI = or \> 30 kg/m2
* Stable body weight (plus/minus 2 kg) during the past 6 months
* Sedentary (regular exercise \<1 h/wk or \<2 x/wk for the last 6 months)
* Willing to provide informed consent

Exclusion Criteria:

* Any major chronic diseases, or any condition that would interfere with exercise or dietary restriction, or use of metformin, in which exercise, dietary restrictions, or metformin are contraindicated, or that would interfere with interpretation of results
* Cardiopulmonary disease (e.g. recent MI, unstable angina, stroke) or unstable disease (e.g., NYHA Class III or IV congestive heart failure, severe pulmonary disease requiring steroid pills or the use of supplemental oxygen) that would contraindicate exercise or dietary restriction
* Severe orthopedic (e.g. awaiting joint replacement) and/or neuromuscular (e.g. multiple sclerosis, active rheumatoid arthritis) disease or impairments that would contraindicate participation in exercise
* Renal impairment as defined by an estimated glomerular filtration rate (eGFR of less than 30 mL/min/1.73 m2) in which metformin is contraindicated
* Other significant co-morbid disease that would impair ability to participate in the exercise intervention (e.g. severe psychiatric disorder \[e.g. bipolar, schizophrenia\], excess alcohol use \[\>14 drinks per week\])
* Severe visual or hearing impairments that would interfere with following directions
* Significant cognitive impairment, defined as a known diagnosis of dementia or positive screening test for dementia using the Mini-Mental State Exam (i.e. MMSE score \<24)69
* Uncontrolled hypertension (BP\>160/90 mm Hg)
* History of malignancy during the past 5 years (except non-melanoma skin cancers)
* Current use of bone acting drugs (e.g. use of estrogen, or androgen containing compound,raloxifene, calcitonin, parathyroid hormone during the past year or bisphosphonates during the last two years)
* Osteoporosis (T-score -2.5 and below on hip or spine scan) or history of fragility fractures
* Known history of diabetes mellitus or any of the following:

  * fasting blood glucose of 126 mg/dl, 2-h blood glucose 200 mg/dl in the OGTT, or HbA1c of 6.5% or \>
* Terminal illness with life expectancy less than 12 months, as determined by a physician
* Use of any drugs or natural products designed to induce weight loss within past three months
* History of excessive alcohol consumption (e.g. 8 or more drinks a week for women and 15 or more drinks a week for men)
* Positive exercise stress test for ischemia or any indication for early termination of exercise stress testing
* Taking metformin or any other glucose lowering drug
* Lives outside of the study site or is planning to move out of the area in the next 2 years