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PURPOSE: 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.EXPERIMENTAL DESIGN: 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.RESULTS: 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.CONCLUSIONS: 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.