Unraveling Potential Sex-Specific Effects of Cardiovascular Medications on Longevity Using Mendelian Randomization

Establishing the sex-specific efficacy of cardiovascular medications is pivotal to evidence-based clinical practice, potentially closing the gender gap in longevity. Trials large enough to establish sex differences are unavailable. This study evaluated sex-specific effects of commonly prescribed cardiovascular medications on lifespan.

In a two-sample Mendelian randomization study, established genetic variants mimicking effects of lipid-lowering drugs, antihypertensives, and diabetes drugs were applied to genetic associations with lifespan proxied by UK Biobank maternal (n=412 937) and paternal (n=415 311) attained age. Estimates were obtained using inverse variance weighting, with sensitivity analyses where possible. For lipid-lowering drugs, genetically mimicked PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors were associated with longer lifespan, particularly in men (2.39 years per SD low-density lipoprotein cholesterol reduction [95% CI, 0.42-4.36], P for interaction=0.14). Genetically mimicked treatments targeting APOC3, LPL, or possibly LDLR were associated with longer lifespan in both sexes. For antihypertensives, genetically mimicked β-blockers and calcium channel blockers were associated with longer lifespan, particularly in men (P for interaction=0.17 for β-blockers and 0.31 for calcium channel blockers). For diabetes drugs, genetically mimicked metformin was associated with longer lifespan in both sexes. No associations were found for genetically mimicked statins, ezetimibe, or angiotensin-converting enzyme inhibitors.

PCSK9 inhibitors, β-blockers, and calcium channel blockers may prolong lifespan in the general population, particularly men. Treatments targeting APOC3, LPL, or LDLR and metformin may be relevant to both sexes. Whether other null findings are attributable to lack of efficacy requires investigation. Further investigation of repurposing should be conducted.