Metformin and epigenetic age in non-diabetic older people with HIV in Madrid (METFORAGING): a double-blind, randomised, placebo-controlled, pilot trial.

Background: Metformin is increasingly studied as a potential geroprotective agent in the general population. We aimed to test the efficacy and safety of metformin to improve epigenetic age in older, well-controlled, non-diabetic people living with HIV. Methods: METFORAGING was a single-centre, double-blind, randomised, parallel-group, placebo-controlled pilot trial. Non-diabetic participants living with HIV who were aged 50 years or older, virologically suppressed, on a stable antiretroviral regimen with undetectable viral load for at least 12 months, and had CD4 Findings: Between March 2, and Oct 2, 2022, 55 individuals were screened, and 40 were randomly assigned to metformin (n = 19) or placebo (n = 21). Enrolment was closed at 40 participants because of slow recruitment, below the pragmatic target of 60 outlined in the study protocol. Median age was 56.4 years (IQR 53.0-60.8), 12 (30%) were female, and 35 (87.5%) self-identified as White. Mean adherence by pill count was 97.5% in both groups. 35 (87.5%) of 40 participants continued treatment to 96 weeks (n = 17 in the metformin group and n = 18 in the placebo group; per-protocol population). At week 96, the adjusted between-group difference (metformin vs. placebo) for PhenoAge EAA was -1.02 years (95% confidence interval [CI] -5.30 to 3.26; p = 0.627). 48 adverse events occurred in 16 (84%) of 19 participants who received metformin and 48 adverse events occurred in 19 (90%) of 21 participants who received placebo. In the metformin group, no serious adverse events were attributed to the medication and no deaths or hospitalisation occurred. Interpretation: Although no significant difference was noted in the primary outcome between groups, these preliminary findings support the feasibility of geroscience-trials in this population and support further investigation of metformin in larger, adequately powered studies to determine whether metformin can modify biological ageing in people with HIV. Funding: Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, and the European Union.