A Randomized Clinical Trial of Metformin to Reduce Frailty in Older Adults with Glucose Intolerance

Abstract Importance Preclinical and human observational studies suggest that metformin may decrease age-related pathology, including frailty. Objective Determine whether metformin reduces frailty progression and biological age in older adults with glucose intolerance, a population at increased risk of becoming frail. Design, Setting and Participants Randomized, double-blind, placebo-controlled trial of metformin in 145 non-frail or pre-frail older adults. Participants (72±5 years, 48% female, 94% White, 35% Hispanic) were randomized to metformin vs . placebo for two years. Main Outcomes and Measures Effect on frailty was primarily determined using generalized estimating equations by change in the Fried frailty phenotype score (based on weight loss, exhaustion, physical activity, gait speed, and grip strength). Because metformin can cause significant weight loss, effects on the Fried score were assessed with and without the weight loss criterion. Frailty also was assessed by change in the frailty index (composite of 95 deficits). Biological age was estimated by DNA methylation-based epigenetic clocks in blood. Results Metformin led to a non-linear response in the Fried score rate of change, with an upward trajectory in year 1 (0.72±0.22 per year vs. placebo, p=0.0011) and stabilization in year 2 (−0.33±0.17 per year vs. placebo, p=0.056). Metformin led to more weight loss than placebo (−5.7±5.2 vs . −2.3±5.4 kg, p=0.0002); thus, when assessing effect on Fried score without the weight loss criterion, no difference was observed, indicating that weight loss in year 1 accounted for the change in Fried score. Notably, metformin caused a steady improvement in the frailty index (−0.006±0.0026 per year vs. placebo, p=0.0222) that persisted with covariates adjustment including body mass index. Metformin reduced biological age estimated by PC-Horvath2 (−0.40±0.16 per year, p=0.014) and PC-Hannum (−0.33±0.16 per year, p=0.047) clocks. Metformin was well tolerated. Conclusions and Relevance Metformin halts the progression of the deficit accumulation frailty index and reduces biological age, suggesting potential benefit for extending healthspan. Trial Registration ClinicalTrials.gov : NCT02570672 . Key Points Question Does metformin slow progression of frailty and biological aging in older adults? Findings In this randomized, placebo-controlled clinical trial of 145 non-frail or pre-frail older adults with glucose intolerance (prediabetes), metformin led to a significant reduction in the deficit accumulation frailty index but not the Fried frailty phenotype. Metformin also reduced biological age estimated by the epigenetic clocks PC-Horvath2 and PC-Hannum in peripheral blood. Meaning Metformin treatment in older adults improves frailty index and indicators of biological age, suggesting potential benefits for extending healthspan.