Metformin and physical performance in older people with probable sarcopenia and physical prefrailty or frailty in England (MET-PREVENT): a double-blind, randomised, placebo-controlled trial

BACKGROUND: Metformin has effects on multiple biological systems relevant to ageing and has been posited as a candidate therapy for sarcopenia and physical frailty. We aimed to test the efficacy and safety of metformin, a candidate geroprotector, to improve physical performance in older people with probable sarcopenia and physical prefrailty or frailty. METHODS: In this double-blind, randomised, parallel-group, placebo-controlled trial (MET-PREVENT), participants aged 65 years and older with a 4-m walk speed of less than 0·8 m/s and probable sarcopenia, characterised by low handgrip strength (<16 kg for women and <27 kg for men) or five times sit-to-stand time of longer than 15 s (or inability to complete five sit-to-stands) were recruited from primary care and hospital clinics in Gateshead and Newcastle, UK. Participants were randomly assigned (1:1), via a web-based system with minimisation to ensure balance by sex and baseline 4-m walk speed, to receive either 500 mg oral metformin or matching placebo three times a day for 4 months. The primary outcome was the adjusted between-group difference in 4-m walk speed at 4 months. The primary outcome was analysed in the intention-to-treat population (ie, all participants randomly assigned to treatment) who had complete data, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with the ISRCTN registry, ISRCTN29932357, and is now complete. FINDINGS: Between Aug 1, 2021, and Sept 30, 2022, 268 individuals were screened for inclusion in the trial, and 72 participants were randomly assigned to either metformin (n=36) or placebo (n=36; intention-to-treat population). Mean age was 80·4 years (SD 5·7), 42 (58%) of 72 participants were female, 30 (42%) were male, and 70 (97%) were White British. 70 (97%) of 72 participants had complete follow-up data (n=34 in the metformin group and n=36 in the placebo group). Mean 4-m walk speed at 4 months was 0·57 m/s (SD 0·19) in the metformin group and 0·58 m/s (0·24) in the placebo group (adjusted treatment effect 0·001 m/s [95% CI -0·06 to 0·06]; p=0·96). 108 adverse events occurred in 35 (100%) of 35 participants who received metformin and 77 adverse events occurred in 33 (92%) of 36 participants who received placebo, and 12 (34%) of 35 participants had hospital admissions in the metformin group versus three (8%) of 36 participants in the placebo group. One death occurred, in the metformin group (one [3%] of 35), and was judged to be unrelated to study treatment. INTERPRETATION: Metformin did not improve 4-m walk speed and was poorly tolerated in this population. FUNDING: National Institute for Health and Care Research Newcastle Biomedical Research Centre.