RCT: Chlorthalidone Shows No Renal Advantage Over Hydrochlorothiazide Under Equivalent Dosing in Older Adults With Hypertension

Background: Hypertension is a critical factor in chronic kidney disease (CKD) progression and cardiovascular risk. Thiazide-type diuretics, such as chlorthalidone and hydrochlorothiazide, are first-line antihypertensive treatments. However, whether one agent confers stronger renal protection remains contested, especially at doses considered pharmacologically comparable. Prior observational studies suggested potential discrepancies in kidney outcomes and hypokalemia incidence. This secondary analysis of the Diuretic Comparison Project (DCP) further clarifies the comparative effectiveness of chlorthalidone versus hydrochlorothiazide on renal endpoints.

Objective: To evaluate whether chlorthalidone (12.5–25 mg/day) prevents CKD progression more effectively than hydrochlorothiazide (25–50 mg/day) in adults ≥65 years with hypertension and no pre-specified exclusion by renal function.

Methods: The DCP is a pragmatic, open-label randomized clinical trial embedded in Veterans Affairs (VA) facilities across the United States. Between June 1, 2016, and December 31, 2023, patients already receiving hydrochlorothiazide (25 or 50 mg/day) for hypertension were randomized either to continue that medication or switch to chlorthalidone (12.5–25 mg/day), reflecting equivalent potency.
The prespecified primary kidney outcome was a composite of doubling of serum creatinine, a terminal estimated glomerular filtration rate (eGFR) <15 mL/min, or dialysis initiation. Secondary measures included ≥40% eGFR decline, incident CKD (new eGFR <60 mL/min), eGFR slope, and relevant adverse events. Laboratory data were obtained through usual clinical care rather than protocol-driven testing.

Results: Among 13,523 randomized participants, 12,265 had analyzable renal data (mean [SD] age, 71 [4] years; 96.8% male). The mean (SD) follow-up was 3.9 (1.3) years. Chlorthalidone did not demonstrate superiority over hydrochlorothiazide for the composite kidney endpoint (6.0% vs 6.4%; hazard ratio, 0.94; 95% CI, 0.81–1.08; P=.37). Additional analyses showed no differences in CKD incidence, ≥40% eGFR decline, or eGFR slope. Hypokalemia occurred more frequently in chlorthalidone users (overall ~2% higher rate of low potassium measurements), and hospitalizations for hypokalemia also trended higher.

Conclusions: Under dosing regimens designed to achieve equivalent antihypertensive potency, chlorthalidone provided no measurable renal benefit over hydrochlorothiazide but posed a modestly elevated risk of hypokalemia. These findings reinforce the clinical interchangeability of both agents for long-term blood pressure management in older adults, provided serum potassium is monitored.

Implications for Practice: Clinicians can confidently employ either chlorthalidone or hydrochlorothiazide in older patients with hypertension, including those with mild or moderate CKD, since renal deterioration rates did not differ significantly. Importantly, the trial used half the milligram amount of chlorthalidone (12.5–25 mg/day) to match the usual doses of hydrochlorothiazide (25–50 mg/day). Recognizing this equivalence helps guide therapy transitions and dosing decisions. Vigilant monitoring of electrolytes remains essential, particularly when prescribing chlorthalidone, given the slightly higher incidence of hypokalemia.

Study Strengths and Limitations: Strengths include the randomized design, broad participant inclusion, and pragmatic structure that mirrors real-world prescribing. Limitations involve potential underestimation or overestimation of renal events due to reliance on routine (rather than scheduled) lab tests. Also, nearly all participants had prior hydrochlorothiazide exposure, which may have influenced tolerance and adherence patterns.

Future Research: Further clinical trials focusing on more advanced CKD stages, distinct comorbidities, or combination regimens (e.g., with potassium-sparing agents) would expand our understanding of how thiazide-type diuretics influence long-term kidney outcomes. Extended follow-up or additional subgroup analyses could also shed light on the interplay of dose-response effects in highly vulnerable populations.

Reference: Ishani A, Hau C, Raju S, et al. “Chlorthalidone vs Hydrochlorothiazide and Kidney Outcomes in Patients With Hypertension: A Secondary Analysis of a Randomized Clinical Trial.” JAMA Netw Open. 2024;7(12):e2449576. DOI: http://doi.org/10.1001/jamanetworkopen.2024.49576