Diet and Exercise Plus Metformin to Treat Frailty in Obese Seniors (DEMFOS)

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

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.

Study Overview

• Status: Completed
• Conditions: Frailty; Aging; Sarcopenic Obesity
• Intervention / Treatment: Behavioral: Lifestyle therapy; Drug: Metformin Hydrochloride; Drug: Placebo; Behavioral: Healthy Lifestyle

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.

• Study Type: Interventional
• Enrollment (Actual): 114
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030-4211
      • Michael E. DeBakey VA Medical Center, Houston, TX

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years to 85 years (Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Lifestyle Therapy plus Placebo; Diet-induced weight loss and Exercise Training plus Placebo	Behavioral: Lifestyle 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; Other Names: Diet-induced weight loss and exercise training; Drug: Placebo; 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.
Experimental: Lifestyle Therapy plus Metformin; Diet-induced weight loss and Exercise Training plus Metformin 1500 mg daily	Behavioral: Lifestyle 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; Other Names: Diet-induced weight loss and exercise training; Drug: Metformin 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.
Active Comparator: Healthy lifestyle plus Metformin; Healthy lifestyle and Metformin 1500 mg daily	Drug: Metformin 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.; Behavioral: Healthy Lifestyle; Group educational sessions that focus on healthy diet, exercise, and social support once a month

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 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 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 serum C-telopeptide	Assessed by immunoassay	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 procollagen type 1 N propeptide	Assessed by radioimmunoassay	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 high-sensitivity c-reactive protein	Assessed by immunoassay	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 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 telomere length	Assessed by Q-PCR	6 months
Change in p16 and other markers of cell arrest	Assessed by immunohistochemistry	6 months
Change in protein expression of senescence associated secretory phenotype	Assessed by elisa or western blotting	6 months
Change in gait speed	Assessed by time need to walk a certain distance	6 months
Change in blood pressure	Assessed by sphygmomanometry	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in Senescent Associated Secretory Phenotype (SASP)	Measured by immunoassay-based platform; results will be expressed as composite factor score	6 months

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: Baylor College of Medicine; Michael E. DeBakey VA Medical Center
• Investigators: Principal Investigator: Dennis T Villareal, MD, Michael E. DeBakey VA Medical Center, Houston, TX

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2021
• Primary Completion (Actual): July 31, 2025
• Study Completion (Actual): July 31, 2025

Study Registration Dates

• First Submitted: January 2, 2020
• First Submitted That Met QC Criteria: January 6, 2020
• First Posted (Actual): January 9, 2020

Study Record Updates

• Last Update Posted (Actual): January 5, 2026
• Last Update Submitted That Met QC Criteria: December 31, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Pathological Conditions, Signs and Symptoms; Frailty; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Organic Chemicals; Biguanides; Guanidines; Amidines; Metformin; Exercise
• Other Study ID Numbers: ENDA-007-19F; H-46970 (Other Grant/Funding Number: VA Office of Research and Development)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Publications from this research will be made available to the public through the National Library of Medicine PubMed Central website within one year after the date of publication (guidance is provided on the ORD website).

MEDVAMC will not provide unrestricted, open public access to large scale health related datasets because of re-identification concerns and the obligation to protect Veterans' private information. However, controlled public access will be provided to the greatest extent possible under specific DUAs or other written agreements, and open access will be provided to the final datasets underlying peer-reviewed publications (aggregated data that can be released with privacy and confidentiality risks).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No