Cardiovascular outcomes and safety of chlorthalidone versus hydrochlorothiazide: A systematic review and meta-analysis

Abstract

Background: For decades, chlorthalidone (CTD) was favoured over hydrochlorothiazide (HCTZ) based on its longer half-life and historical efficacy data. However, recent high-powered pragmatic trials and large-scale observational cohorts challenge this preference. We aimed to synthesise contemporary evidence comparing the cardiovascular efficacy and metabolic safety of these two thiazide-type diuretics in patients with hypertension. Methods: We conducted a systematic review and meta-analysis of contemporary evidence. A comprehensive literature search was performed across PubMed, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception through March 2026, supplemented by manual reference mining. Data were pooled using a random effects model to account for heterogeneity. For the primary outcome of major adverse cardiovascular events (MACE), we synthesised data from a large, randomised controlled trial (RCT) and 2 international observational cohorts. Secondary safety and renal outcomes were pooled from 4 studies. Heterogeneity was assessed using the I² statistic. Results: Seven studies (> 700 000 patients) were included. There was no significant difference in MACE between CTD and HCTZ (risk ratio [RR] 1.01, 95% confidence interval [CI] 0.83 to 1.24, moderate certainty). Renal outcomes were also similar. However, CTD was associated with a higher risk of hypokalaemia (RR 1.55, 95% CI 0.90 to 2.66, low certainty). Conclusion: CTD does not provide superior cardiovascular or renal protection compared with HCTZ. Given the higher risk of hypokalaemia and monitoring burden, HCTZ remains a pragmatic first-line option in hypertension.