Both chlorthalidone and hydrochlorothiazide are diuretic medications used to treat high blood pressure (hypertension). Chlorthalidone is the recommended medication to treat hypertension, but its risks and benefits, as compared with hydrochlorothiazide, are not established. This study aims to compare the safety outcomes and efficacy of chlorthalidone and hydrochlorothiazide as first-line therapies for hypertension.

This observational comparative cohort study included a total of 730,255 individuals (mean age 51.5 years) with hypertension. Of the participants, 36,918 were prescribed or dispensed chlorthalidone, and 693,337 were prescribed or dispensed hydrochlorothiazide. The primary outcomes of the study were adverse cardiac events (myocardial infarction, hospitalization for heart failure, ischemic or hemorrhagic stroke), safety outcomes, and overall efficacy.

A total of 149 composite outcome events (0.004%) among patients who received chlorthalidone, and 3,089 composite outcome events (0.004%) occurred among those who received hydrochlorothiazide. No significant difference between the risk of cardiac events was found between the two medications. However, chlorthalidone was associated with a higher risk of hypokalemia (HR 2.72), hyponatremia (1.31), acute renal failure (1.37), chronic kidney disease (1.24), and type 2 diabetes mellitus (1.21).

The research concluded that both chlorthalidone and hydrochlorothiazide were associated with similar cardiovascular benefits; however, chlorthalidone resulted in a higher risk of hypokalemia, hyponatremia, and kidney disease.