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LONG BEACH, Calif. -- Chlorthalidone was no better than hydrochlorothiazide for reducing the incidence of major renal outcomes in patients with hypertension, a secondary analysis of the randomized Diuretic Comparison Project showed.

In a population of older veterans, a similar proportion of chlorthalidone-treated patients and hydrochlorothiazide-treated patients experienced the primary composite renal outcome, defined as a 40% reduction in estimated glomerular filtration rate (eGFR), a terminal eGFR below 15 mL/min/1.73 m², or the development of kidney failure requiring treatment, at 2.4 years (12.7% vs 13.3%; adjusted HR 0.97, 95% CI 0.88-1.07), reported Areef Ishani, MD, MS, of the University of Minnesota in Minneapolis.

The same was true when using a slightly different composite outcome -- a doubling of serum creatinine from baseline, a terminal eGFR below 15 mL/min/1.73 m², or treatment-requiring kidney failure (6% vs 6.4%; HR 0.95, 95% CI 0.82-1.09).

"Either drug can be used to prevent progression of kidney disease in those with and without chronic kidney disease," Ishani explained during a late-breaking presentation at the National Kidney Foundation Spring Clinical Meeting.

Session Chair Joseph Vassalotti, MD, of the Icahn School of Medicine at Mount Sinai in New York City, noted that while the study was negative, "we thought it was innovative. The trial design was innovative [and the study used] these two commonly used medications that are readily available."

None of the individual composite outcome components were significantly different for patients who received chlorthalidone or hydrochlorothiazide:

• Doubling of serum creatinine: 5.4% vs 5.7%
• eGFR decline of 40% or more: 12.2% vs 12.8%
• eGFR under 15 mL/min/1.73 m²: 4.2% vs 4.2%
• Dialysis initiation: 0.3% vs 0.3%

Ishani's group also looked at two additional outcomes -- incident chronic kidney disease and the median eGFR slope -- finding no differences between the groups.

The only difference that emerged was that chlorthalidone was linked with a modest but significantly higher risk of hypokalemia compared with hydrochlorothiazide in patients with a baseline eGFR ≥60 mL/min/1.73 m² (9.2% vs 7%, P<0.001). There was a similar trend among those with an eGFR below 60 mL/min/1.73 m², but the difference wasn't significant (8.1% vs 6.8%, P=0.18).

There were no differences in hypokalemia-related or acute kidney injury-related hospitalizations between the groups.

When broken down into various subgroups -- chronic kidney disease status, age, race, sex, diabetes status, history of myocardial infarction or stroke, and baseline systolic blood pressure -- only age mattered. For people 72 and younger, there was a 17% lower risk for the primary renal outcome with chlorthalidone. However, "this is an interaction in a subgroup in a secondary analysis," Ishani said. "It's unclear what to make of this, but I'd probably say just ignore it."

The pragmatic Diuretic Comparison Project previously showed that chlorthalidone was no better than hydrochlorothiazide for reducing cardiovascular risk in veterans with hypertension.

For this analysis, Ishani's group recruited patients already on 25 or 50 mg of hydrochlorothiazide. Of the 13,523 patients randomized, 6,767 continued on hydrochlorothiazide and 6,756 were switched over to chlorthalidone at doses of 12.5 mg or 25 mg; 95% of both groups were on the lower of the two doses.

"Although I've been a fan of chlorthalidone in the past, it's a little bit of a headache to prescribe in terms of the dosing," Vassalotti said.

Ishani noted that "primary studies have all used higher doses of chlorthalidone, as well as hydrochlorothiazide, to evaluate any potential benefit. It's typically 50 mg of hydrochlorothiazide or 25 mg of chlorthalidone."

"My co-chair on this one, he doesn't believe the results of the study," he added. "He'll still prescribe chlorthalidone for every single patient and the reason is because he thinks we underdosed in this trial. A 12.5 [mg dose] has never been shown to demonstrate benefit and 95% of our population was on that dose, so that is one of the limitations of this trial."

He noted that chlorthalidone isn't available in 12.5-mg pills, and tablet splitters were provided. "Now I've got 7,000 people taking pill dust every day," he said. "The thing that really astonishes me is their entry blood pressure is about 139 [mm Hg] in this study and their exit blood pressure is 139. Nobody said, instead of taking pill dust, just take the whole pill."

"I think a simple and practical thing is if you have a patient who's on 25 mg of hydrochlorothiazide, it's an easy switch to get them on 25 mg of chlorthalidone," he noted.

The median age of participants was 71, baseline body mass index was 31, and nearly all were men -- a limitation common in veteran cohorts. Nearly half had diabetes at baseline, and median eGFR was 71 mL/min/1.73 m². About 65% of both groups were also on an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker at baseline, and less than 3% were on a loop diuretic or SGLT2 inhibitor.

Ishani said his group is currently collecting more data to look into kidney stone outcomes with both therapies.

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