Christopher T Rentsch, Vanessa A Palzes, Mingjian Shi, Michael R Setzer, Samantha G Malone, Andrea H Kline-Simon, Emma L Winterlind, Lorenzo Leggio, Vincent Lo Re, David A Fiellin, John Tazare, Mehdi Farokhnia, Stacy Sterling, Henry R Kranzler, Joshua C Gray
In two large, preregistered EHR-based cohorts, we found no evidence that BP-LTCCBs were associated with reduced drinking relative to comparators. Despite compelling genetic and preclinical evidence, these findings do not support repurposing BP-LTCCBs for AUD and instead prioritize alternative pharmacologic targets.
PURPOSE: Alcohol use disorder (AUD) remains a major public health problem, with few effective treatments. L-type calcium channel blockers (LTCCBs) have genetic and preclinical support as potential treatments for AUD.
METHODS: We evaluated whether brain penetrant (BP)-LTCCBs are associated with reduced alcohol consumption in two preregistered observational cohort studies using electronic health records from the US Department of Veterans Affairs (VA) and Kaiser Permanente Northern California (KPNC). New users of BP-LTCCBs (nifedipine or felodipine) were compared with new users of a non-BP-LTCCB (amlodipine) and with unexposed patients from the same clinics, requiring a 180-day washout and ≥ 60 days' supply. Propensity score matching was performed across all exposure contrasts. The primary outcome was change in drinks per week from pre-index to end of follow-up using difference-in-differences (DiD) models, with prespecified subgroup analyses by AUD diagnosis, drinking level, and sex.
RESULTS: Across both health systems, BP-LTCCB initiation was not associated with greater reductions in drinks per week than either comparator, with broadly consistent findings across all subgroups; though some subgroups were small and imprecise. In the VA, the DiD comparing BP-LTCCB with non-BP-LTCCB was 0.14 drinks/week (95% CI -0.06, 0.34), and versus unexposed was 0.00 (95% CI -0.18, 0.19). Similar results were observed in KPNC (BP-LTCCB vs. non-BP-LTCCB: 0.31, 95% CI -0.48, 1.11; BP-LTCCB vs. unexposed: 0.16, 95% CI -0.67, 0.99).
CONCLUSIONS: In two large, preregistered EHR-based cohorts, we found no evidence that BP-LTCCBs were associated with reduced drinking relative to comparators. Despite compelling genetic and preclinical evidence, these findings do not support repurposing BP-LTCCBs for AUD and instead prioritize alternative pharmacologic targets.