Clonal Hematopoiesis of Indeterminate Potential (CHIP) is characterized by age-related acquisition and expansion of somatic mutations in hematopoietic stem cells without overt hematologic malignancy. DNMT3A mutations, among the more prevalent genetic alterations in CHIP, have been implicated in cardiovascular risk due to their pro-inflammatory effects and altered epigenetic regulation. Recent experimental and clinical observations indicate that DNMT3A-mutant HSCs are dependent on altered metabolic processes, including augmented mitochondrial oxidative phosphorylation, which may present a unique vulnerability that therapeutic interventions could exploit.
Metformin, a well-established Type 2 Diabetes (T2D) medication with documented cardiovascular benefits, was surprisingly shown in mechanistic studies to inhibit mitochondrial complex I, a key dependency of DNMT3A-mutant HSCs. Disrupting this metabolic advantage through treatment with metformin reduced clonal expansion and presents a compelling therapeutic strategy to mitigate CHIP-associated cardiovascular risks.
Preliminary observational evidence from large-scale cohorts such as UK Biobank demonstrates that after controlling for confounders such as BMI, diabetes status, and glycemic control, metformin use is associated with a significantly lower prevalence of DNMT3AR882H-driven CHIP. This suggests a potential therapeutic role for metformin mediated through suppression of clonal hematopoiesis. However, comprehensive evaluations assessing metformin’s effects on reducing incident cardiovascular events specifically in DNMT3A-mutant CHIP patients remain lacking.
Given these promising recent findings and mechanistic support, our study aims to address this gap using existing cohort data from UK Biobank. We hypothesize that metformin will reduce incident cardiovascular disease (including atherosclerosis, stroke, myocardial infarction, and heart failure) in patients harboring CHIP driver mutations, specifically DNMT3A.
