Chlorthalidone trumps HCTZ for stone prevention; morning dosing preferable

Calcium stone formers prefer the long-acting and more effective chlorthalidone for stone prevention, reports a study. The time of administration appears irrelevant, but morning administration may be more effective in addressing higher postdinner calcium excretion.

On the other hand, the more common hydrochlorothiazide (HCTZ) is shorter acting, frequently dosed once daily, but falls short of reducing urine calcium excretion (UCa) with the 25-mg dosing.

“In calcium stone formers with high UCa, 25-g daily dosing of chlorthalidone produces robust reduction in urine calcium regardless of administration time, reducing supersaturations of calcium oxalate or calcium phosphate,” the investigators said.

“In a similar group of patients, 25-mg daily dosing of HCTZ did not have a significant effect on urinary calcium or supersaturations. For these reasons, we recommend daily morning dosing of chlorthalidone for stone prevention,” they added.

In this study, the investigators carried out 12-h urine collections in seven patients treated with chlorthalidone 25 mg and 10 patients who received HCTZ 25 mg. Participants completed urine collections at baseline, again after a week of morning medication administration, and again after a week of evening administration, all on repeated self-selected diets.

Chlorthalidone was effective in lowering UCa for both 12-h periods whether taken in the morning or in the evening. The morning dosing reduced urine calcium from 130 mg/g creatinine at baseline to 76 mg/g creatinine (p<0.02), while the evening dosing lowered it to 87 mg/g creatinine, which was not significant. [J Urol 2025;214:280-288]

In contrast, HCTZ failed to lower UCa regardless of dosing time. The mean 24-h UCa was 124 mg/g creatinine at baseline and 106 mg/g creatinine when the agent was administered in the morning and 117 mg/g creatinine when taken in the evening.

“Interestingly, we found that morning dosing of chlorthalidone significantly reduced nighttime UCa while evening dosing significantly reduced daytime UCa,” the investigators said. “From these data, we suggest that chlorthalidone is a more effective medication for urinary stone prevention when comparing 25-mg doses at varying administration times.”

Daytime administration

The investigators suggested that the superior effectiveness of chlorthalidone was driven by its longer duration of action. The effects of HCTZ peak 4 h after dosing and last for about 12 h, while the effects of chlorthalidone begin around 3 to 4 h after dosing and may last for 72 h. [Hypertension 2004;43:4-9]

"Therefore, daytime administration of chlorthalidone may lead to better control of nighttime UCa and could prevent stones more effectively,” the investigators said. “We assume morning dosing of chlorthalidone has been the usual manner of clinical prescription.”

These findings support those of a previous study which found chlorthalidone to have a longer duration of action and better potency as an antihypertensive agent. [Hypertension 2004;43:4-9]

The current study had some limitations. First, it only included men, so the results may not be applicable to women. Second, the number of participants was small, limiting correction for multiple comparisons. Third, the participants adhered to different dietary patterns.