Comparative efficacy and safety of chlorthalidone vs hydrochlorothiazide in hypertension management: A systematic review and meta-analysis

Abstract

BACKGROUND

Hypertension is among the leading causes of cardiovascular diseases, including myocardial infarction (MI), stroke, and heart failure. The thiazide diuretics of chlorthalidone and hydrochlorothiazide are commonly prescribed in the control of blood pressure. Although they are effective, there has been debate regarding their relative efficacy and safety, particularly with respect to cardiovascular events.

AIM

To determine the relative efficacy and safety of hydrochlorothiazide vs chlorthalidone in the treatment of primary hypertension treatment in adults, isolation of their effects on systolic and diastolic blood pressure, MI, stroke, heart failure, and hypokalemia.

METHODS

PubMed and Google Scholar databases were searched for comparative studies of hydrochlorothiazide vs chlorthalidone in patients with hypertension. The inclusion criteria were randomized controlled trials, cohort studies, and clinical studies in the English language from 2005 to 2025. Eleven studies were ultimately included for meta-analysis. Statistical analysis was performed using a random-effects model, and heterogeneity was tested by I² statistics.

RESULTS

Chlorthalidone was associated with greater reductions in systolic blood pressure [mean difference: 5.18 mmHg, 95% confidence interval (CI): 4.28-6.08] and diastolic blood pressure (2.91 mmHg, 95%CI: 1.96-3.87) compared to hydrochlorothiazide. Interestingly, chlorthalidone also demonstrated superior nocturnal blood pressure control (P = 0.0002). In terms of cardiovascular outcomes, chlorthalidone showed a potential significant (P = 0.052) reduction in the risk of MI (relative risk: 1.30, 95%CI: 1.00-1.70); however, there were no differences in stroke or all-cause mortality between the two medications. A safety analysis revealed a significantly lower risk of hypokalemia associated with hydrochlorothiazide (relative risk: 0.52, 95%CI: 0.38-0.72). Both medications had similar safety profiles regarding heart failure and rates of hospitalization.

CONCLUSION

The present meta-analysis suggests that chlorthalidone is more effective than hydrochlorothiazide in reducing both systolic and diastolic blood pressure, particularly at night. Although both drugs share comparable cardiovascular event safety profiles, chlorthalidone carries a higher risk of inducing hypokalemia. These findings emphasize the need for individualized treatment strategies in the management of hypertension based on the varying efficacy and safety profiles of chlorthalidone and hydrochlorothiazide.

Keywords: Hypertension; Chlorthalidone; Hydrochlorothiazide; Blood pressure reduction; Cardiovascular outcomes

Core Tip: Hypertension is a leading cause of cardiovascular disease, chlorthalidone and hydrochlorothiazide are widely used treatments. This meta-analysis compared their efficacy and safety in adults with primary hypertension, including 11 studies published from 2005 to 2025. Chlorthalidone achieved greater reductions in both systolic blood pressure and diastolic blood pressure, as well as superior nocturnal control (P = 0.0002). Cardiovascular safety was similar, with a nonsignificant reduction in myocardial infarction risk for chlorthalidone and no difference in stroke or mortality, but hydrochlorothiazide had a lower risk of hypokalemia. The findings highlight that drug choice should be tailored to individual patient needs, balancing stronger blood pressure reduction from chlorthalidone against the lower hypokalemia risk of hydrochlorothiazide.