Metformin does not significantly alter longitudinal dynamics of clonal hematopoiesis.

Abstract

Early intervention in patients with Clonal Hematopoiesis (CH) is an area of intense investigation with no currently approved agents. With recent mechanistic data on metformin as a possible therapeutic agent in CH and its availability in clinical practice, we sought to investigate clonal dynamics of CH mutations in metformin users. We analyzed longitudinal targeted deep sequencing of 1,104 CH mutations in 863 metformin-treated type 2 diabetic participants in two longitudinal cohorts: WHI and BioVu with blood collected at a median of 15.8 and 6.1 years apart respectively. Metformin duration (per 6 months) was not significantly associated with overall CH growth rate in WHI (β = -0.05%/year; 95% confidence interval (CI): -0.11 to 0.01; P = 0.08; N = 543) and in BioVU (β = -0.09%/year; 95% CI: -0.22 to 0.05; P = 0.20; N = 561) . Inverse-variance weighted random-effect meta-analysis demonstrated a small, statistically significant association (β = -0.06%/year; 95% CI: -0.11 to -0.002; P = 0.04; N = 1,104) without significant heterogeneity (P = 0.60). These results were similar when only considering DNMT3A and DNMT3A R882 clones. In our cohorts, duration of metformin use among diabetic users was associated with a small reduction in CH growth rate (-0.06%/year), which is modest compared to typical DNMT3A clonal growth rates of 5-7% annually. Metformin's clinical utility for modulating clonal dynamics in real-world settings appear limited and its clinical use for this indication requires further investigation in prospective studies.