Drug Repurposing Signals for Abdominal Aortic Aneurysms.

Abstract

Drug repurposing offers a cost effective approach to identify therapies for abdominal aortic aneurysm (AAA), which lacks proven medical treatment. This study assessed associations between long term cumulative drug exposure and AAA events (first time rupture or surgical repair). This was a matched nested case-control study using nationwide Danish registries (1996 - 2021). Cases were first time AAA rupture or surgery; controls were individuals with AAA who were event free at the index date and matched 1:20 by sex and birth year. Drug exposure was assessed in defined daily doses at the Anatomical Therapeutic Chemical system chemical subgroup level. Associations were evaluated using log₂ transformed unconditional logistic regression, adjusted for comorbidities and socioeconomic status. Identified associations were independently classified into four pre-defined hypothesis generating categories based on plausibility, bias, and relevance to AAA risk. The study included 17 536 cases (mean age 73.8 years; 80.8% male), each matched to approximately 20 controls. Of 181 chemical subgroups analysed, 29 presented significant dose-response associations. Dose doubling of statins and metformin was associated with lower odds of AAA events: odds ratio (OR) 0.93 (95% confidence interval [CI] 0.92 - 0.94) and OR 0.96 (95% CI 0.93 - 0.99), respectively. Additional inverse associations were observed with caries prophylactic agents (OR 0.91, 95% CI 0.84 - 0.99), proton pump inhibitors (OR 0.97, 95% CI 0.96 - 0.98), and antibiotic subgroups. Signals suggesting potential direct effects were observed for several additional drug classes, including antiplatelet agents, β blockers, testosterone inhibitors, non-steroidal anti-inflammatory drugs, and bisphosphonates. Overall, expert review classified 12 associations (41%) as suggestive of a direct or indirect drug effect. The findings suggest a substantial role of chronic infection in AAA pathogenesis. These findings identify several dose dependent associations between common medications and risk of AAA events, including signals consistent with protective effects of statins, metformin, and agents used for chronic infections. Chronic infection may represent a mechanistic pathway warranting further investigation.