# Chlorthalidone linked to 2.72-fold higher hypokalemia hazard than hydrochlorothiazide in cohort study

- Published: 2026-11-08 22:52 UTC
- Section: Life & Health › Medicine
- Tags: chlorthalidone, hydrochlorothiazide, thiazide diuretic, hypertension treatment, hypokalemia, hyponatremia, LEGEND study, JAMA Internal Medicine, observational cohort
- URL: https://realtech.media/news/rt-07fb58e9a5a14195710bbc1d_chlorthalidone_linked_to/

**In an observational study of 730 225 first-time users, the two diuretics did not differ in cardiovascular outcomes, but chlorthalidone was linked to more electrolyte and renal events.**

![Chlorthalidone linked to 2.72-fold higher hypokalemia hazard than hydrochlorothiazide in cohort study](https://realtech.media/media/2026/11/223079b61a8d057d.jpg)
*Dmitry G, Wikimedia Commons, Public domain*

An observational comparative cohort study published in JAMA Internal Medicine compared chlorthalidone and hydrochlorothiazide as first-line therapy for hypertension in real-world practice in the United States. The authors analyzed 730 225 first-time users of antihypertensive monotherapy, drawn from two administrative claims databases and one collection of electronic health records covering January 2001 through December 2018. [1] Of these, 36 918 were dispensed or prescribed chlorthalidone and 693 337 hydrochlorothiazide. [1]

The mean age of participants was 51.5 years (SD 13.3), and 450 100 (61.6%) were women. Chlorthalidone is currently recommended as the preferred thiazide diuretic for hypertension, but no trials have directly compared the risks and benefits of the two drugs. The study is part of the LEGEND project and used large-scale propensity score stratification with negative-control and synthetic positive-control calibration.

## Cardiovascular outcomes

The primary outcomes were acute myocardial infarction, hospitalization for heart failure, ischemic or hemorrhagic stroke, and a composite cardiovascular outcome that also included sudden cardiac death. The chlorthalidone group had 149 composite events and the hydrochlorothiazide group had 3089. [1]

No significant difference was found in the risk of myocardial infarction, hospitalized heart failure or stroke. The calibrated hazard ratio for the composite outcome was 1.00 for chlorthalidone compared with hydrochlorothiazide (95% CI, 0.85–1.17). [1]

## Electrolyte and renal outcomes

Chlorthalidone was associated with a significantly higher risk of hypokalemia (HR, 2.72; 95% CI, 2.38–3.12) and hyponatremia (HR, 1.31; 95% CI, 1.16–1.47). [1] It was also associated with higher risk of acute renal failure (HR, 1.37; 95% CI, 1.15–1.63), chronic kidney disease (HR, 1.24; 95% CI, 1.09–1.42) and type 2 diabetes mellitus (HR, 1.21; 95% CI, 1.12–1.30). [1] Diagnosed abnormal weight gain was less likely with chlorthalidone (HR, 0.73; 95% CI, 0.61–0.86). [1]

The authors concluded that chlorthalidone was not associated with significant cardiovascular benefit compared with hydrochlorothiazide, while its use was associated with greater risk of renal and electrolyte abnormalities. In their view, the findings do not support current recommendations to prefer chlorthalidone over hydrochlorothiazide in first-time users. [1]

The design is observational, so the results describe associations. The authors used sensitivity analyses and diagnostics but note the possibility of residual confounding and the limited length of observation periods, and say further study is warranted. [1]

## Sources

1. [JAMA Internal Medicine](https://doi.org/10.1001/jamainternmed.2019.7454)
2. [knowridge.com](https://knowridge.com/2026/11/one-common-water-pill-may-lower-potassium-more-than-another)

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Source: RealTech, realtech.media — https://realtech.media/news/rt-07fb58e9a5a14195710bbc1d_chlorthalidone_linked_to/