Antiprotozoal drug exposure and reduced long-term mortality and morbidity: a multi-cohort pharmacoepidemiologic study

Introduction Medications may affect age-related morbidity and overall survival beyond their original indications. Systematic identification of such effects may inform drug repurposing strategies for healthy aging. We aimed to identify medications associated with longevity and reduced age-related morbidity using large-scale electronic health record data. Methods We conducted a stepwise pharmacoepidemiologic investigation in two independent healthcare systems. Using electronic health records from a nationwide health provider, we performed an exploratory medication-wide case-control screen comparing medication exposure during a 10-year window between 14,986 individuals who died before sex-specific median life expectancy and matched controls who survived beyond their life expectancy. Two leading candidate drugs, atovaquone-proguanil and mefloquine, are antiprotozoal agents with activity against Toxoplasma gondii. Their effects on mortality and age-related morbidity were further evaluated within a historical cohort of 3,876 exposed individuals and 77,520 matched controls using Cox proportional hazards models adjusted for baseline characteristics. External validation was performed in the United States-based TriNetX network, including cohorts exposed to atovaquone-proguanil (n = 24,498), mefloquine (n = 3,400), and nirmatrelvir-ritonavir (n = 124,681), each matched to unexposed controls. Results Atovaquone-proguanil and mefloquine, together with nirmatrelvir-ritonavir, a protease inhibitor with reported antiprotozoal effects, were associated with consistent reductions in all-cause mortality across cohorts and lower incidence of multiple age-related conditions, including dementia, diabetes mellitus, cardiovascular disease, chronic kidney disease, and selected malignancies. Consistent increases in specific conditions were also observed, including hearing loss, Sjögren’s syndrome/dry eye, and lichen planus, suggesting shared underlying mechanisms, although confounding cannot be excluded. Discussion Findings were consistent across healthcare systems and drug classes, including in populations exposed to non-travel-associated medications. While causality cannot be established, these results support further investigation into potential links between chronic protozoal infections and aging-related diseases.