Frailty, Sarcopenic Obesity, Aging
Conditions
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.
Interventions
BEHAVIORALLifestyle therapy
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
DRUGMetformin Hydrochloride
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.
DRUGPlacebo
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.
BEHAVIORALHealthy Lifestyle
Group educational sessions that focus on healthy diet, exercise, and social support once a month
Sponsors
Michael E. DeBakey VA Medical Center
Baylor College of Medicine
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Placebo controlled
Eligibility
Sex/Gender
ALL
Age
65 Years to 85 Years
Healthy volunteers
Yes
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) * 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, 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the modified Physical Performance Test (PPT) | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in gait speed | 6 months | Assessed by time need to walk a certain distance |
| Change in peak aerobic power | 6 months | Assessed by indirect calorimetry during a graded exercise test |
| Change in lean body mass | 6 months | Assessed by dual-energy x-ray absorptiometry (DXA) |
| Chang in body fat | 6 months | Assessed by DXA |
| Change in thigh muscle | 6 months | Assessed by magnetic resonance imaging (MRI) |
| Change in bone microarchitecture | 6 months | Assessed by high-resolution peripheral quantitative computed tomograph (HR-pQCT) |
| Change in bone strength | 6 months | Assessed by finite-element analyses |
| Change in hip, lumbar spine, and wrist bone mineral density (BMD) | 6 months | Assessed by DXA |
| Change in serum C-telopeptide | 6 months | Assessed by immunoassay |
| Change in telomere length | 6 months | Assessed by Q-PCR |
| Change in mood | 6 months | Assessed by geriatric depression scale (score range: 0 to 30, where lower scores indicating better mood) |
| Change in serum procollagen type 1 N propeptide | 6 months | Assessed by radioimmunoassay |
| Change in serum 25-OH vitamin D | 6 months | Assessed by immunoassay |
| Change in muscle strength | 6 months | Assessed by biodex dynamometer and1-repetition maximum |
| Change in high-sensitivity c-reactive protein | 6 months | Assessed by immunoassay |
| Change in p16 and other markers of cell arrest | 6 months | Assessed by immunohistochemistry |
| Change in protein expression of senescence associated secretory phenotype | 6 months | Assessed by elisa or western blotting |
| Change in Medical Outcomes 36-Item short form Health survey (SF-36) | 6 months | Assessed by Physical component summary and mental component summary score (score range 0 to 100, with higher scores indicating better health status) |
| Change in Impact of Weight on Quality of Life_Lite (IWQOL-lite) score | 6 months | Assessed by IWQO-liteL questionnaire |
| Change in serum adiponectin | 6 months | Assessed by ELISA |
| Change in serum leptin | 6 months | Assessed by ELISA |
| Change in fasting serum insulin | 6 months | Assessed by immunoassay |
| Change in fasting serum glucose | 6 months | Assessed by glucose oxidase method |
| Change in blood pressure | 6 months | Assessed by sphygmomanometry |
| Change in serum lipids | 6 months | Assessed by automated enzymatic/colorimetric assays |
| Change in insulin growth factor 1 | 6 months | Assessed by immunoassay |
| Change in Cognitive composite scores | 6 months | 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 |
| Change in serum parathyroid hormone | 6 months | Assessed by immunoassay |
Countries
United States
Outcome results
None listed