TY - JOUR

T1 - Use of chlorprothixene and the risk of diabetes and major adverse cardiovascular events

T2 - A nationwide cohort study

AU - Højlund, Mikkel

AU - Wagner, Christina Blanner

AU - Wesselhoeft, Rikke

AU - Andersen, Kjeld

AU - Fink-Jensen, Anders

AU - Hallas, Jesper

N1 - Publisher Copyright: © 2022 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - antipsychotic agents

KW - cardiovascular diseases

KW - chlorprothixene

KW - diabetes mellitus

KW - pharmacoepidemiology

KW - quetiapine fumarate

U2 - 10.1111/bcpt.13711

DO - 10.1111/bcpt.13711

M3 - Journal article

C2 - 35122399

AN - SCOPUS:85124630830

VL - 130

SP - 501

EP - 512

JO - Basic and Clinical Pharmacology and Toxicology

JF - Basic and Clinical Pharmacology and Toxicology

SN - 1742-7835

IS - 4

ER -