Diet and Exercise Plus Metformin to Treat Frailty in Obese Seniors

Phase 3

Active, not recruiting

• Conditions: Sarcopenic Obesity; Aging; Frailty
• Interventions: Behavioral: Lifestyle therapy; Drug: Metformin Hydrochloride; Drug: Placebo; Behavioral: Healthy Lifestyle

• Registration Number: NCT04221750
• Lead Sponsor: VA Office of Research and Development

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.

Study Timeline

• Study First Submitted: 2020-01-02
• Study First Submitted QC: 2020-01-06
• Study First Posted: 2020-01-09
• Study Start: 2021-05-14
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-17
• Last Update Posted: 2025-01-22
• Primary Completion: 2026-09-30
• Study Completion: 2027-09-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 114

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Lifestyle Therapy plus Metformin	Lifestyle therapy	Diet-induced weight loss and Exercise Training plus Metformin 1500 mg daily
Lifestyle Therapy plus Metformin	Metformin Hydrochloride	Diet-induced weight loss and Exercise Training plus Metformin 1500 mg daily
Lifestyle Therapy plus Placebo	Lifestyle therapy	Diet-induced weight loss and Exercise Training plus Placebo
Lifestyle Therapy plus Placebo	Placebo	Diet-induced weight loss and Exercise Training plus Placebo
Healthy lifestyle plus Metformin	Metformin Hydrochloride	Healthy lifestyle and Metformin 1500 mg daily
Healthy lifestyle plus Metformin	Healthy Lifestyle	Healthy lifestyle and Metformin 1500 mg daily

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
Change in muscle strength	6 months	Assessed by biodex dynamometer and1-repetition maximum
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 serum parathyroid hormone	6 months	Assessed by immunoassay
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 satellite cells and fiber typing	6 months	Assessed by by immunofluorescence
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

Trial Locations

Locations (1)

Michael E. DeBakey VA Medical Center, Houston, TX; 🇺🇸 Houston, Texas, United States