Aging, Frailty, Sarcopenic Obesity
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
VA Office of Research and Development
Michael E. DeBakey VA Medical Center
Baylor College of Medicine
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; lowest score is 0 and a perfect score would be 36. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Muscle Strength | 6 months | Knee extension muscle strength measured using a Biodex dynamometer |
| Change in Gait Speed | 6 months | Gait speed was calculated from the time required to walk 4 meters at the participant's usual walking pace and expressed in meters per minute. |
| 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) |
| Change in Body Fat | 6 months | Assessed by using dual energy x-ray absorptiometry |
| Change in Thigh Muscle | 6 months | Assessed by magnetic resonance imaging (MRI) |
| Change in Distal Tibia Bone Microarchitecture: Cortical Thickness | 6 months | Assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal tibia |
| Change in Bone Strength | 6 months | Assessed as distal tibia failure load estimated using finite-element analysis of HR-pQCT scans. |
| Change in Bone Mineral Density (BMD) at the Total Hip | 6 months | Assessed by dual-energy X-ray absorptiometry (DXA) at the total hip site |
| Change in Bone Mineral Density at the Lumbar Spine | 6 months | Assessed by dual-energy X-ray absorptiometry (DXA) at the lumbar spine site |
| Change in Serum C-telopeptide | 6 months | Bone resorption marker assessed by electrochemiluminescence immunoassay. Values represent least-squares mean ratios of 6-month to baseline C-telopeptide derived from mixed-effects models (exp\[post - pre\]). |
| 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 | Bone formation marker assessed in fasting serum samples by radioimmunoassay (RIA). Values represent least-squares mean ratios of 6-month to baseline procollagen type 1 N propeptide derived from mixed-effects models (exp\[post - pre\]). |
| Change in Serum 25-OH Vitamin D | 6 months | Measured by automated immunoassay |
| Change in Serum Parathyroid Hormone | 6 months | Assessed by Beckman Coulter immunoassay |
| Change in High-sensitivity C-reactive Protein | 6 months | Assessed by immunoturbidimetric assay. CRP was log-transformed prior to analysis. Values represent least-squares mean ratios of 6-month to baseline CRP derived from mixed-effects models (exp\[post - pre\]). |
| Change in Medical Outcomes 36-Item Short Form Health Survey (SF-36) | 6 months | Assessed by Physical component summary 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 Impact of Weight on Quality of Life-Lite (IWQOL-lite) questionnaire. Score ranges from 0 to 100, with higher scores indicating better weight-related quality of life. |
| Change in Serum Adiponectin | 6 months | Assessed by enzyme linked immunosorbent assay (ELISA) |
| Change in Serum Leptin | 6 months | Assessed by radioimmunoassay |
| Change in Fasting Serum Insulin | 6 months | Assessed by chemiluminescent immunoassay |
| Change in Fasting Serum Glucose | 6 months | Assessed by glucose oxidase method |
| Change in Systolic Blood Pressure | 6 months | Seated systolic blood pressure assessed using an oscillometric blood pressure monitor. |
| Change in Serum Lipids: Triglycerides | 6 months | Assessed by automated enzymatic/colorimetric assays: triglycerides are reported. |
| Change in Serum Insulin Growth Factor 1 | 6 months | Measured using an automated immunochemiluminometric assay (ICMA) |
| Change in Cognitive Function Composite Score | 6 months | Global cognitive function was assessed using the NIH Toolbox Cognition Battery Total Cognition Composite Score, a standardized measure of overall cognitive performance. Age-Corrected Standard Scores were used. These scores are standardized relative to individuals of the same age, with a normative mean of 100 and a standard deviation of 15. Higher scores indicate better cognitive performance. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORDennis T Villareal, MD
Michael E. DeBakey VA Medical Center, Houston, TX
Participant flow
Recruitment details
Participants were recruited from the Michael E. DeBakey Veterans Affairs Medical Center and surrounding community through clinic referrals, advertisements, mailings, and research registries. Interested individuals underwent telephone prescreening followed by in-person clinical screening to determine eligibility
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 72.8 years STANDARD_DEVIATION 4.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 50 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 38 | 2 / 38 | 0 / 38 |
| other Total, other adverse events | 14 / 38 | 11 / 38 | 10 / 38 |
| serious Total, serious adverse events | 4 / 38 | 6 / 38 | 5 / 38 |
Outcome results
None listed