1. While chlorthalidone is the recommended thiazide diuretic treatment for hypertension, it has no added benefits compared to hydrochlorothiazide and has significantly worse safety profile.
Evidence Rating Level: 1 (Excellent)
The American College of Cardiology/American Heart Association hypertension guideline reported in 2017 that the recommended thiazide diuretic treatment for hypertension is currently chlorthalidone. However, there are insufficient trials investigating risks and benefits. This Large-Scale Evidence Generation and Evaluation in a Network of Databases (LEGEND) observational, comparative cohort study sought to investigate the cardiovascular and safety outcomes of chlorthalidone and hydrochlorothiazide as first-line treatments for hypertension. Of 730,225 individuals (M [SD] age, 51.5 [13.3] years, 61.6% female), 36,918 were prescribed chlorthalidone with 149 composite outcome events and 693,337 were prescribed hydrochlorothiazide with 3,089 composite outcome events. No significant differences were found in associated risks of stroke, hospitalized heart failure, or myocardial infarction. The hazard ratio for composite cardiovascular outcomes was 1.00 for chlorthalidone compared to hydrochlorothiazide (95% CI 0.85 to 1.17). Chlorthalidone was associated with significantly elevated risks of type 2 diabetes (HR, 1.21, 95% CI 1.12-1.30), chronic kidney disease (HR, 1.24, 95% CI 1.09 to 1.42), acute renal failure (HR, 1.37, 95% CI 1.15 to 1.63), hyponatremia (HR, 1.31, 95% CI 1.16 to 1.47), and hypokalemia (HR, 2.72, 95% CI 2.38 to 3.12). However, chlorthalidone was also associated with a lower risk of abnormal weight gain (HR, 0.73, 95% CI 0.61 to 0.86). This study highlights concerns related to the preferred treatment for hypertension, such that chlorthalidone use not only resulted in non-significant cardiovascular benefits compared to hydrochlorothiazide but was associated with significantly greater risks of metabolite and renal abnormalities.
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