Rationale and Study Design of a Randomized Clinical Trial of Metformin to Prevent Frailty in Older Adults With Prediabetes

Abstract

Background Frailty is a geriatric syndrome that leads to poor health outcomes with aging. Previous studies have demonstrated that insulin resistance and inflammation predict frailty onset. Metformin is a widely used, well-tolerated drug that improves insulin sensitivity and displays anti-inflammatory properties. It is also known to prevent diabetes onset in adults with prediabetes. We hypothesize that metformin in older adults with prediabetes will promote healthy aging and prevent frailty. Here we describe an ongoing placebo-controlled, double-blinded clinical trial of metformin for the prevention of frailty in older adults with prediabetes. Methods Older adults aged more than 65 years are randomized to metformin or placebo and are followed for 2 years. Prediabetes, required for inclusion, is assessed by 2-hour oral glucose tolerance test. Exclusion criteria are baseline frailty (Fried criteria), diabetes, dementia, untreated depression, active malignancy, or severe cardiovascular, pulmonary, and neurologic diseases. Primary outcome is frailty; secondary outcomes are physical function (Short Physical Performance Battery), systemic and skeletal muscle tissue inflammation, muscle insulin signaling, insulin sensitivity (insulin clamp), glucose tolerance (oral glucose tolerance test), and body composition (dual-energy x-ray absorptiometry). Subjects are followed every 3 months for safety assessments and every 6 months for frailty assessment (Fried criteria) and oral glucose tolerance test, and every 12 or 24 months for secondary outcomes. Enrollment of 120 subjects (completers) will take place over a 2-year period. Conclusion Metformin is being examined in this study as a potential therapeutic agent to prevent frailty in older adults with prediabetes. Findings from this trial may have future implications for the screening and potential treatment of prediabetes in older patients with metformin for the prevention of frailty.

Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases

“…The results indicate that metformin modulates metabolic and nonmetabolic gene expression in skeletal muscle and subcutaneous adipose tissues of older persons [110]. The phase 2 clinical trial (NCT02570672) "Metformin for Preventing Frailty in High-risk Older Adults," which considered frailty as a vital endpoint, was undertaken since 2015 [111]. Another phase 4 clinical study (NCT02915198) investigating the outcome of metformin in patients with pre-diabetes and established atherosclerotic cardiovascular disease started in February 2019.…”

Determination of Biological Age: Geriatric Assessment vs Biological Biomarkers

“…More recent research has validated frailty as a core clinical concept in assessing older adults and while representing the underlying rate of age-related accumulation of deficits, implies that this typically progressive state is dynamic and potentially modifiable [ 23 ]. Interventions that can modify frailty and by proxy the rate of biological aging include interventions grounded in the CGA [ 40 ] or with exercise [ 41 ], nutrition [ 42 ], and possibly pharmacologic or reverse pharmacologic interventions [ 43 •, 44 ]. This is likely to inform future research on frailty treatment and prevention and thereby impact on biological aging.…”

A geroscience perspective on immune resilience and infectious diseases: a potential case for metformin

“…Ample evidence links metformin to lower all-cause mortality and reduced rates of multiple disease of aging, even in nondiabetic populations [106] [107] and suggest a broad geroprotective role of metformin. Clinical trials exploring the effects of metformin in nondiabetic older adults on gerocentric outcomes are underway [108] or planned [30,31]. For example, a placebo-controlled, double-blinded clinical trial of 2-year metformin treatment for the prevention of frailty in 120 older adults with prediabetes is ongoing at University of Texas Health Science Center at San Antonio [108].…”

“…Clinical trials exploring the effects of metformin in nondiabetic older adults on gerocentric outcomes are underway [ 108 ] or planned [ 30 , 31 ]. For example, a placebo-controlled, double-blinded clinical trial of 2-year metformin treatment for the prevention of frailty in 120 older adults with prediabetes is ongoing at University of Texas Health Science Center at San Antonio [ 108 ]. The TAME trial will evaluate metformin’s effects on incidence of any new age-related disease (cardiovascular disease, mild cognitive impairment/dementia, most cancers, or death) in 3000 older adults without diabetes [ 30 , 31 ].…”