Diet and Exercise Plus Metformin to Treat Frailty in Obese Seniors

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
Lifestyle Intervention Plus Metformin to Treat Frailty in Older Veterans With Obesity

Conditions
-----------------
Frailty, Sarcopenic Obesity, Aging

Intervention / Treatment
-----------------
* Behavioral: Lifestyle therapy
* Drug: Metformin Hydrochloride
* Drug: Placebo
* Behavioral: Healthy Lifesylte


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 65 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lifestyle Therapy plus Metformin<br>Diet-induced weight loss and Exercise Training plus Metformin 1 gm bid | Behavioral: Lifestyle therapy<br>* Weight management program, in which participants are prescribed a balanced diet that provides and energy deficit of 500 to 750 kcal per day to induced  10% weight loss plus Supervised combined aerobic and resistance exercise training three times weekly<br>* Other names: Diet-induced weight loss and exercise training;Drug: Metformin Hydrochloride<br>* Given orally starting at 500 mg (one tablet) taken orally once a day with meals. After a week, the dose of metformin will be increased to 1000 mg (two tablets) daily. After another week, the dose of metformin will be increased to 1500 mg (three tablets) daily.<br>|
| Placebo Comparator: Lifestyle Therapy plus Placebo<br>Diet-induced weight loss and Exercise Training plus Placebo | Behavioral: Lifestyle therapy<br>* Weight management program, in which participants are prescribed a balanced diet that provides and energy deficit of 500 to 750 kcal per day to induced  10% weight loss plus Supervised combined aerobic and resistance exercise training three times weekly<br>* Other names: Diet-induced weight loss and exercise training;Drug: Placebo<br>* Given orally starting at 500 mg (one tablet) taken orally once a day with meals. After a week, the dose of placebo will be increased to 1000 mg (two tablets) daily. After another week, the dose of placebo will be increased to 1500 mg (three tablets) daily.<br>|
| Active Comparator: Healthy lifestyle plus Metformin<br>Healthy lifestyle and Metformin 1 gm bid | Drug: Metformin Hydrochloride<br>* Given orally starting at 500 mg (one tablet) taken orally once a day with meals. After a week, the dose of metformin will be increased to 1000 mg (two tablets) daily. After another week, the dose of metformin will be increased to 1500 mg (three tablets) daily.<br>Behavioral: Healthy Lifesylte<br>* Group educational sessions that focus on healthy diet, exercise, and social support once a month<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the modified Physical Performance Test (PPT) | The Physical Performance Test includes seven standardized tasks (walking 15.2 m [50 ft], putting on and removing a coat, picking up a penny, standing up from a chair, lifting a book, climbing one flight of stairs, and performing a progressive Romberg test) plus two additional tasks (going up and down four flights of stairs and making a 360-degree turn). The score for each task ranges from 0 to 4, with higher scores indicating better physical performance; a perfect score would be 36. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in muscle strength | Assessed by biodex dynamometer and1-repetition maximum | 6 months | 
| Change in dynamic balance | Assessed by the obstacle course | 6 months | 
| Change in static balance | Assessed by one leg stance | 6 months | 
| Change in gait speed | Assessed by time need to walk 25 ft | 6 months | 
| Change in peak aerobic power | Assessed by indirect calorimetry during a graded exercise test | 6 months | 
| Change in lean body mass | Assessed by dual-energy x-ray absorptiometry (DXA) | 6 months | 
| Chang in body fat | Assessed by DXA | 6 months | 
| Change in thigh muscle | Assessed by magnetic resonance imaging (MRI) | 6 months | 
| Change in thigh fat | Assessed by MRI | 6 months | 
| Change in muscle quality | Assessed by ratio of skeletal strength per unit of skeletal muscle | 6 months | 
| Change in bone microarchitecture | Assessed by high-resolution peripheral quantitative computed tomograph (HR-pQCT) | 6 months | 
| Change in bone strength | Assessed by finite-element analyses | 6 months | 
| Change in hip, lumbar spine, and wrist bone mineral density (BMD) | Assessed by DXA | 6 months | 
| Change in wrist and tibial cortical and trabecular BMD | Assessed by HR-pQCT | 6 months | 
| Change in serum C-telopeptide | Assessed by immunoassay | 6 months | 
| Change in subjective ability to function | Assessed by Functional Status Questionnaire (score range: 0 to 36 with higher scores indicating better function) | 6 months | 
| Change in telomere length in skeletal muscles and whole blood | Assessed by Q-PCR | 6 months | 
| Change in mood | Assessed by geriatric depression scale (score range: 0 to 30, where lower scores indicating better mood) | 6 months | 
| Change in serum osteocalcin | Assessed by ELISA | 6 months | 
| Changed in concentration of targeted metabolites | Assessed by liquid chromatography hyphenated with mass spectrometry techniques | 6 months | 
| Change in serum procollagen type 1 N propeptide | Assessed by radioimmunoassay | 6 months | 
| Change in serum sclerostin | Assessed by ELISA | 6 months | 
| Change in serum 25-OH vitamin D | Assessed by immunoassay | 6 months | 
| Change in serum parathyroid hormone | Assessed by immunoassay | 6 months | 
| Change in serum Interleukin 6 | Assessed by immunoassay | 6 months | 
| Change in Tumor necrosis factor | Assessed by immunoassay | 6 months | 
| Change in high-sensitivity c-reactive protein | Assessed by immunoassay | 6 months | 
| Change in p16 | Assessed by immunohistochemistry | 6 months | 
| Change in p21 | Assessed by immmnohistochemistry | 6 months | 
| Change in satellite cells | Assessed by by immunofluorescence | 6 months | 
| Change in fiber cross sectional area | Assessed by immunohistochemistry | 6 months | 
| Change in fiber type-specific response | Assessed by immunofluorescence | 6 months | 
| Change in gene expression of senescence associated secretory phenotype | Assessed by RT-PCR | 6 months | 
| Change in protein expression of senescence associated secretory phenotype | Assessed by western blotting | 6 months | 
| Change in Medical Outcomes 36-Item short form Health survey (SF-36) | Assessed by Physical component summary and mental component summary score (score range 0 to 100, with higher scores indicating better health status) | 6 months | 
| Change in Impact of Weight on Quality of Life_Lite (IWQOL-lite) score | Assessed by IWQO-liteL questionnaire | 6 months | 
| Change in serum adiponectin | Assessed by ELISA | 6 months | 
| Change in serum leptin | Assessed by ELISA | 6 months | 
| Change in fasting serum insulin | Assessed by immunoassay | 6 months | 
| Change in fasting serum glucose | Assessed by glucose oxidase method | 6 months | 
| Change in blood pressure | Assessed by sphygmonanometry | 6 months | 
| Change in serum lipids | Assessed by automated enzymatic/colorimetric assays | 6 months | 
| Change in insulin growth factor 1 | Assessed by immunoassay | 6 months | 
| Change in Cognitive composite scores | Using cognitive toolbox which yields the following summary scores: Cognitive Function Composite Score, Fluid Cognition Composite Score, and Crystallized Cognition Composite Score (score range: -3 to +3 for each with higher scores indicating better cognitive status | 6 months | 
| Change in habitual physical activity assessed by questionnaires | Using the Stanford physical activity questionnaire (score range: 0 to 40 with higher scores indicating higher physical activity levels) | 6 months | 
| Change in habitual physical activity measured objectively | Using accelerometers | 6 months |