Diet and Exercise Plus Metformin to Treat Frailty in Obese Seniors

Aging Clinical Trial

— DEMFOS  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04221750
• Other study ID #: ENDA-007-19F
• Secondary ID: H-46970
• Status: Recruiting
• Phase: Phase 3
• Start date: May 14, 2021
• Est. completion date: September 30, 2026

Study information

• Verified date: January 2024
• Source: VA Office of Research and Development
• Contact: Dennis T Villareal, MD
• Phone: (713) 794-7151
• Email: Dennis.Villareal[@]va.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 114
• Est. completion date: September 30, 2026
• Est. primary completion date: September 30, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 65 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Aging
• Frailty
• Obesity
• Sarcopenic Obesity

Intervention

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

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.
• 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.

Behavioral:
• Healthy Lifesylte
Group educational sessions that focus on healthy diet, exercise, and social support once a month

Locations

Country	Name	City	State
United States	Michael E. DeBakey VA Medical Center, Houston, TX	Houston	Texas

Sponsors (3)

Lead Sponsor	Collaborator
VA Office of Research and Development	Baylor College of Medicine, Michael E. DeBakey VA Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Change in muscle strength	Assessed by biodex dynamometer and1-repetition maximum	6 months
Secondary	Change in gait speed	Assessed by time need to walk 25 ft	6 months
Secondary	Change in peak aerobic power	Assessed by indirect calorimetry during a graded exercise test	6 months
Secondary	Change in lean body mass	Assessed by dual-energy x-ray absorptiometry (DXA)	6 months
Secondary	Chang in body fat	Assessed by DXA	6 months
Secondary	Change in thigh muscle	Assessed by magnetic resonance imaging (MRI)	6 months
Secondary	Change in thigh fat	Assessed by MRI	6 months
Secondary	Change in bone microarchitecture	Assessed by high-resolution peripheral quantitative computed tomograph (HR-pQCT)	6 months
Secondary	Change in bone strength	Assessed by finite-element analyses	6 months
Secondary	Change in hip, lumbar spine, and wrist bone mineral density (BMD)	Assessed by DXA	6 months
Secondary	Change in serum C-telopeptide	Assessed by immunoassay	6 months
Secondary	Change in subjective ability to function	Assessed by Functional Status Questionnaire (score range: 0 to 36 with higher scores indicating better function)	6 months
Secondary	Change in telomere length	Assessed by Q-PCR	6 months
Secondary	Change in mood	Assessed by geriatric depression scale (score range: 0 to 30, where lower scores indicating better mood)	6 months
Secondary	Change in serum osteocalcin	Assessed by ELISA	6 months
Secondary	Changed in concentration of targeted metabolites	Assessed by liquid chromatography hyphenated with mass spectrometry techniques	6 months
Secondary	Change in serum procollagen type 1 N propeptide	Assessed by radioimmunoassay	6 months
Secondary	Change in serum sclerostin	Assessed by ELISA	6 months
Secondary	Change in serum 25-OH vitamin D	Assessed by immunoassay	6 months
Secondary	Change in serum parathyroid hormone	Assessed by immunoassay	6 months
Secondary	Change in serum Interleukin 6 and other inflammatory markers	Assessed by immunoassay	6 months
Secondary	Change in high-sensitivity c-reactive protein	Assessed by immunoassay	6 months
Secondary	Change in p16 and other markers of cell arrest	Assessed by immunohistochemistry	6 months
Secondary	Change in satellite cells	Assessed by by immunofluorescence	6 months
Secondary	Change in fiber cross sectional area	Assessed by immunohistochemistry	6 months
Secondary	Change in fiber type-specific response	Assessed by immunofluorescence	6 months
Secondary	Change in protein expression of senescence associated secretory phenotype	Assessed by elisa or western blotting	6 months
Secondary	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
Secondary	Change in Impact of Weight on Quality of Life_Lite (IWQOL-lite) score	Assessed by IWQO-liteL questionnaire	6 months
Secondary	Change in serum adiponectin	Assessed by ELISA	6 months
Secondary	Change in serum leptin	Assessed by ELISA	6 months
Secondary	Change in fasting serum insulin	Assessed by immunoassay	6 months
Secondary	Change in fasting serum glucose	Assessed by glucose oxidase method	6 months
Secondary	Change in blood pressure	Assessed by sphygmonanometry	6 months
Secondary	Change in serum lipids	Assessed by automated enzymatic/colorimetric assays	6 months
Secondary	Change in insulin growth factor 1	Assessed by immunoassay	6 months
Secondary	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