First-line diuretic associated with greater risk of hypokalemia than second-choice alternative

Researchers have determined that chlorthalidone – the guideline-recommended diuretic to lower blood pressure – is associated with greater risks of adverse side effects, including hypokalemia, compared with hydrochlorothiazide, which appears similarly effective at reducing blood pressure.

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Researchers from Columbia University Irving Medical Center (NY, USA) have analyzed data on more than 730,225 individuals and determined that chlorthalidone – the guideline-recommended diuretic for use as a hypertensive treatment – is associated with greater risks of adverse side effects, such as hypokalemia, compared with hydrochlorothiazide, which appears similarly effective at lowering blood pressure.

Hypokalemia – low circulating levels of potassium in the blood – is a common side effect associated with diuretic use to manage hypertension; hypokalemia can, in turn, result in various additional adverse medical conditions, including cardiac dysrhythmias, kidney failure and Type 2 diabetes.

In 2017, based on indirect evidence suggesting that chlorthalidone is more effective at lowering cardiovascular risk, the American College of Cardiology (DC, USA) and American Heart Association (TX, USA) issued new guidelines recommending chlorthalidone as the diuretic of choice for hypertension treatment.

In this study, researchers employed the Large-scale Evidence Generation and Evaluation in a Network of Databases (LEGEND) Hypertension study, which enables the analysis of vast amounts of electronic health record data, to investigate the comparative cardiovascular and safety outcomes associated with the first-time use of chlorthalidone versus hydrochlorothiazide monotherapy for the treatment of hypertension. Both chlorthalidone and hydrochlorothiazide are members of the thiazide/thiazide-like class of diuretics.

Study co-author Patrick Ryan (Columbia University) stated: “LEGEND is a novel approach that could transform the way we use real-world evidence in healthcare…LEGEND provides a systematic framework that can reproducibly generate evidence by applying advanced analytics across a network of disparate databases for a wide array of exposures and outcomes.”

Researchers observed chlorthalidone and hydrochlorothiazide to be similarly effective at preventing the study's primary outcomes – acute myocardial infarction, hospitalization for heart failure and stroke. However, individuals who received chlorthalidone had significantly increased risks of side effects including hypokalemia – the hazard ratio of individuals experiencing hypokalemia who had received chlorthalidone versus hydrochlorothiazide was 2.72.

In the study, the authors concluded: “This study found that chlorthalidone use was not associated with significant cardiovascular benefits when compared with hydrochlorothiazide, while its use was associated with greater risk of renal and electrolyte abnormalities. These findings do not support current recommendations to prefer chlorthalidone vs hydrochlorothiazide for hypertension treatment in first-time users…”

However, lead study author George Hripcsak (Columbia University Medical Center) cautioned: “Until we have more studies directly comparing the two diuretics, we don't really know whether the risk of the side effects seen in observational studies outweighs the potential cardiovascular benefits.”

Limitations of the study include the possibility of residual confounding, common amongst real-world evidence investigations. Additionally, the results of this study, which contrast the indirect evidence that prompted the revised guidelines recommending chlorthalidone, may result from the fact that researchers were specifically investigating the outcomes associated with first-time use of the two monotherapy regimens. Individuals included in this study were thus more likely to present with milder hypertension and reduced cardiovascular disease risk at baseline, compared with individuals included in previous clinical trials.

The limited length of observation periods in this investigation represent a further shortcoming; to help resolve the debate, the Veteran Affairs Office of Research and Development (DC, USA) is to conduct a randomized clinical trial investigating the comparative effectiveness and safety of chlorthalidone over hydrochlorothiazide.


Hripcsak G, Suchard MA, Shea S et al. Comparison of cardiovascular and safety outcomes of chlorthalidone vs hydrochlorothiazide to treat hypertension. JAMA Intern Med. doi:10.1001/jamainternmed.2019.7454 (2020) (Epub ahead of print);

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Ilana Landau

Assistant Editor, Future Science Group

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