Clinical trial NCT04221750: Diet and Exercise Plus Metformin to Treat Frailty in Obese Seniors
Official title: Lifestyle Intervention Plus Metformin to Treat Frailty in Older Veterans With Obesity
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Frailty
Sarcopenic Obesity
Aging
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: Michael E. DeBakey VA Medical Center
name: Baylor College of Medicine
First posted: 2020-01-09
Enrollment: 114
Sex: ALL
Minimum age (years): 65
Maximum age (years): 85
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in the modified Physical Performance Test (PPT)
timeFrame: 6 months
Secondary outcomes:
measure: Change in muscle strength
timeFrame: 6 months
measure: Change in gait speed
timeFrame: 6 months
measure: Change in peak aerobic power
timeFrame: 6 months
measure: Change in lean body mass
timeFrame: 6 months
measure: Chang in body fat
timeFrame: 6 months
measure: Change in thigh muscle
timeFrame: 6 months
measure: Change in bone microarchitecture
timeFrame: 6 months
measure: Change in bone strength
timeFrame: 6 months
measure: Change in hip, lumbar spine, and wrist bone mineral density (BMD)
timeFrame: 6 months
measure: Change in serum C-telopeptide
timeFrame: 6 months
measure: Change in telomere length
timeFrame: 6 months
measure: Change in mood
timeFrame: 6 months
measure: Change in serum procollagen type 1 N propeptide
timeFrame: 6 months
measure: Change in serum 25-OH vitamin D
timeFrame: 6 months
measure: Change in serum parathyroid hormone
timeFrame: 6 months
measure: Change in high-sensitivity c-reactive protein
timeFrame: 6 months
measure: Change in p16 and other markers of cell arrest
timeFrame: 6 months
measure: Change in satellite cells and fiber typing
timeFrame: 6 months
measure: Change in protein expression of senescence associated secretory phenotype
timeFrame: 6 months
measure: Change in Medical Outcomes 36-Item short form Health survey (SF-36)
timeFrame: 6 months
measure: Change in Impact of Weight on Quality of Life_Lite (IWQOL-lite) score
timeFrame: 6 months
measure: Change in serum adiponectin
timeFrame: 6 months
measure: Change in serum leptin
timeFrame: 6 months
measure: Change in fasting serum insulin
timeFrame: 6 months
measure: Change in fasting serum glucose
timeFrame: 6 months
measure: Change in blood pressure
timeFrame: 6 months
measure: Change in serum lipids
timeFrame: 6 months
measure: Change in insulin growth factor 1
timeFrame: 6 months
measure: Change in Cognitive composite scores
timeFrame: 6 months
Other outcomes:
measure: change in Senescent Associated Secretory Phenotype (SASP)
timeFrame: 6 months
Locations:
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center, Houston, TX
state: Texas
Study officials:
affiliation: Michael E. DeBakey VA Medical Center, Houston, TX
name: Dennis T Villareal, MD
role: PRINCIPAL_INVESTIGATOR
References: