Use of chlorprothixene and the risk of diabetes and major adverse cardiovascular events: A nationwide cohort study

Chlorprothixene is commonly used off‐label in low doses for sedative‐hypnotic purposes although it might carry a risk of cardiometabolic adverse events due to its pharmacodynamic profile. We investigated the risk of diabetes and major adverse cardiovascular events (MACE) with use of low‐dose chlorprothixene, compared with use of low‐dose quetiapine in a nationwide cohort study, including all new users of low‐dose chlorprothixene (n = 81 328) and low‐dose quetiapine (n = 91 163) in Denmark 2000–2017. Main outcomes were diabetes and MACE (myocardial infarction, stroke and death from cardiovascular causes). The association between cumulative dose of chlorprothixene and the outcomes was tested in a case–control analysis. Low‐dose chlorprothixene use was associated with increased risk of diabetes (intention‐to‐treat [ITT]‐hazard ratio [HR]: 1.16; 95% CI: 1.08–1.25), compared with low‐dose quetiapine use. This association strengthened when follow‐up was restricted to time on treatment (as‐treated [AT]‐HR: 1.34; 95% CI: 1.14–1.56). Low‐dose chlorprothixene use was also associated with increased risk of MACE (ITT‐HR: 1.12; 95% CI: 1.04–1.21) and stroke (ITT‐HR: 1.21; 95% CI: 1.06–1.37) but not with myocardial infarction (ITT‐HR: 1.11; 95% CI: 0.95–1.30) nor death from cardiovascular causes (ITT‐HR: 1.07; 95% CI: 0.96–1.20). Cumulative dose of chlorprothixene ≥6000 mg was associated with increased risk of diabetes (OR: 1.15–1.63; test for trend: p < 0.001), whereas cumulative dose of chlorprothixene ≥1500 mg was associated with increased risk of MACE (OR: 1.10–1.85; test for trend: p < 0.001). In conclusion, low‐dose chlorprothixene use is associated with increased risk of cardiometabolic adverse events compared with low‐dose quetiapine use.