Lifestyle Intervention Plus Metformin to Treat Frailty in Older Veterans With Obesity
Overview
- Phase
- Phase 3
- Intervention
- Lifestyle therapy
- Conditions
- Frailty
- Sponsor
- VA Office of Research and Development
- Enrollment
- 114
- Locations
- 1
- Primary Endpoint
- Change in the modified Physical Performance Test (PPT)
- Status
- Completed
- Last Updated
- 3 months ago
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 - 85 years) Veterans with physical frailty.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age 65 - 85 years
- •BMI = or \> 30 kg/m2
- •Mild to moderate frailty (score of 18 to 31 in the modified Physical Performance Test)
- •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)
Arms & Interventions
Lifestyle Therapy plus Metformin
Diet-induced weight loss and Exercise Training plus Metformin 1500 mg daily
Intervention: Lifestyle therapy
Lifestyle Therapy plus Metformin
Diet-induced weight loss and Exercise Training plus Metformin 1500 mg daily
Intervention: Metformin Hydrochloride
Lifestyle Therapy plus Placebo
Diet-induced weight loss and Exercise Training plus Placebo
Intervention: Lifestyle therapy
Lifestyle Therapy plus Placebo
Diet-induced weight loss and Exercise Training plus Placebo
Intervention: Placebo
Healthy lifestyle plus Metformin
Healthy lifestyle and Metformin 1500 mg daily
Intervention: Metformin Hydrochloride
Healthy lifestyle plus Metformin
Healthy lifestyle and Metformin 1500 mg daily
Intervention: Healthy Lifestyle
Outcomes
Primary Outcomes
Change in the modified Physical Performance Test (PPT)
Time Frame: 6 months
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.
Secondary Outcomes
- Change in muscle strength(6 months)
- Change in peak aerobic power(6 months)
- Change in high-sensitivity c-reactive protein(6 months)
- Change in gait speed(6 months)
- Change in lean body mass(6 months)
- Change in hip, lumbar spine, and wrist bone mineral density (BMD)(6 months)
- Change in serum C-telopeptide(6 months)
- Chang in body fat(6 months)
- Change in p16 and other markers of cell arrest(6 months)
- Change in protein expression of senescence associated secretory phenotype(6 months)
- Change in Impact of Weight on Quality of Life_Lite (IWQOL-lite) score(6 months)
- Change in fasting serum insulin(6 months)
- Change in fasting serum glucose(6 months)
- Change in thigh muscle(6 months)
- Change in insulin growth factor 1(6 months)
- Change in bone microarchitecture(6 months)
- Change in bone strength(6 months)
- Change in mood(6 months)
- Change in serum parathyroid hormone(6 months)
- Change in Medical Outcomes 36-Item short form Health survey (SF-36)(6 months)
- Change in serum adiponectin(6 months)
- Change in serum lipids(6 months)
- Change in telomere length(6 months)
- Change in serum procollagen type 1 N propeptide(6 months)
- Change in serum 25-OH vitamin D(6 months)
- Change in serum leptin(6 months)
- Change in blood pressure(6 months)
- Change in Cognitive composite scores(6 months)