BOSTON — The prominent headline from the highly anticipated Diuretic Comparison Project (DCP), published in late 2022, was that the antihypertensive drugs chlorthalidone and hydrochlorothiazide showed no significant differences in major adverse cardiovascular events and noncancer death. Further analyses have also shown no differences in kidney outcomes. However, a new secondary analysis of the trial suggests one potential caveat — kidney stones, and more specifically, their recurrence.
In the analysis, presented at the National Kidney Foundation’s Spring Clinical Meeting 2025, there were no significant differences in the development of kidney stones between the two groups; however, among those with a history of kidney stones, patients treated with chlorthalidone had a significantly higher risk of recurring stones.
Overall, “we’ve looked at a number of outcomes with chlorthalidone and hydrochlorothiazide and found no significant differences in cardiovascular or renal outcomes,” said first author Areef Ishani, MD, director of the Primary and Specialty Care Service Line at the Minneapolis VA Health Care System, Minnesota, in presenting the late-breaking findings.
“However, the take-home message from this is, if you’ve got a patient with a history of kidney stones, you might want to pick the drug with the evidence suggesting a lower risk of recurrence, because based on the results of this randomized secondary analysis, chlorthalidone appears to increase the risk.”
The findings are notable because, even though the rates of kidney stones were low in the population overall, their prevalence has been on the rise. For those who get kidney stones, recurrence rates are high — at an estimated 40% of patients recurring within 5 years and 75% over 20 years when treatment is not effective.
Thiazides and thiazide-like diuretics have been among key choices for preventing kidney stones, yet recommendations on which thiazide diuretic is most effective are lacking.
With chlorthalidone having longer-acting effects, Ishani and colleagues theorized that the drug might offer greater stone prevention benefits vs hydrochlorothiazide.
To investigate, they conducted a secondary analysis of the DCP pragmatic trial, which was the first head-to-head comparison of hydrochlorothiazide and chlorthalidone in a randomized, prospective trial, representing an ideal place to look.
The study included 13,523 patients in the Department of Veterans Affairs health system aged 65 or older, who had hypertension and were initially treated with hydrochlorothiazide at 25 or 50 mg/d.
For the open-label study, patients were randomized to either continue treatment with hydrochlorothiazide or switch to chlorthalidone (12.5 or 25 mg).
With an average follow-up of 4.2 years, no significant differences were observed between the two groups in the development of new kidney stone events (4.9% chlorthalidone and 5.2% hydrochlorothiazide; hazard ratio 0.94; P = .43).
There were also no differences in the time to first kidney stone or the number of kidney stones.
However, in an adjusted analysis further stratifying the patients based on whether they had no history of kidney stones (n = 12,359) or a history of stones (n = 1164), those who did have a history were significantly more likely to have a recurrence when treated with chlorthalidone (n = 564) vs hydrochlorothiazide (n = 600; 18.3% vs 13.7%, respectively; P = .04).
“Hypokalemia is Trouble”
Importantly, the known higher risk of hypokalemia associated with chlorthalidone was consistent in the trial, including among those with no history of kidney stones (10.2% hypokalemia with chlorthalidone vs 8.3% with hydrochlorothiazide) and among patients with prior kidney stones (13.8% vs 11.5%, respectively).
Ishani speculated the increased hypokalemia risk could very well be the culprit behind the increased risk of stone recurrence.
“The more I do this, the more I’m convinced that hypokalemia is the root of all evil,” he quipped.
“This is hypothesis-generating, but I suspect that the higher kidney stone recurrence rate is related to hypokalemia reducing citrate in the urine and, as a result, increasing the risk of [recurring] kidney stones.”
Ishani noted that, while he once strongly preferred chlorthalidone, due to the increased hypokalemia risk, he now recommends at least using it in a combination.
“I am now convinced that hypokalemia is trouble, and if you’re going to use chlorthalidone, pay attention to the potassium,” Ishani urged. “In general, I now unfortunately try to choose hydrochlorothiazide, which [was not my preference] when I started the trial.”
Overall, he added, “either drug can be used to treat high blood pressure in patients with kidney disease – but the prescriber needs to watch for low potassium with chlorthalidone,” he added to Medscape Medical News.
“Potentially those with a prior history of kidney stones should preferentially be prescribed hydrochlorothiazide over chlorthalidone for the treatment of hypertension and/or kidney stones.”
Commenting on the study, Sankar D Navaneethan, MD, associate chief of nephrology at Baylor College of Medicine, Houston, Texas, noted that the study’s strengths include the data from the large Veteran Affairs cohort.
“Strengths included using a large pragmatic clinical trial data to answer a clinically relevant question, and they attempted to explain the results by studying the different types of potassium supplements used, especially potassium citrate, which can lower the risk of stones,” he told Medscape Medical News.
He echoed Ishani’s recommendation to use caution, based on the findings.
“Even though these data are not conclusive, given the limitations of being secondary analysis and lack of accounting of various factors influencing choice of the potassium supplements, etc., clinicians need to be cautious while using chlorthalidone for managing hypertension in those with pre-existing kidney stones.”
Ishani had no disclosures to report.