A polypill containing valsartan, amlodipine, and chlorthalidone (KDF1901) works better than the valsartan–amlodipine combination for improving blood pressure (BP) control in Asians with essential hypertension, according to a phase III study from South Korea.
After 8 weeks of treatment, the primary endpoint of mean sitting systolic BP decreased by 22.8 mm Hg in the triple combination group vs 16.7 mm Hg in the dual combination group (between-group difference, –6.1 mm Hg; p<0.0001), reported Dr Hae-Young Lee from Seoul National University Hospital, Seoul, South Korea, and colleagues. [Clin Ther 2026;48:989-996]
Treatment with the triple vs dual combination also yielded greater reductions in mean sitting diastolic BP (–11.6 vs –8.5 mm Hg; p=0.0006), Lee and colleagues added.
By week 8, significantly more participants in the triple combination group achieved BP normalization (mean sitting BP lower than 140/90 mm Hg: 75.9 percent vs 54.5 percent; p<0.0001) and response (≥20-mm Hg reduction in mean sitting systolic BP or ≥10-mm Hg reduction in mean sitting diastolic BP: 73.8 percent vs 51.7 percent; p<0.0001) compared with those in the dual combination group.
“Importantly, these efficacy advantages did not come at the expense of safety profile, as the overall incidence of adverse events (AEs) was comparable between groups,” Lee and colleagues said.
Treatment-emergent AEs occurred in 24.7 percent of participants in the triple combination group vs 21.5 percent in the dual combination group (p=0.5783). Dizziness, fatigue, and peripheral oedema were the most common AEs.
No extreme electrolyte abnormalities
Lee and colleagues attributed the study’s positive findings to the efficacy and tolerability of chlorthalidone as part of triple combination therapy in a single-pill format.
“Chlorthalidone is known for its potent BP-lowering effects and extended half-life compared with hydrochlorothiazide, thus providing better 24-h BP control and potentially reducing cardiovascular risk. However, clinical use has often been limited due to concerns regarding its metabolic side effects, especially electrolyte disturbances,” they said.
In the study, greater changes in sodium, potassium, and uric acid levels occurred with KDF1901 vs the valsartan–amlodipine combination. Nevertheless, clinically meaningful extreme electrolyte abnormalities were rare in both groups, and the overall laboratory profile remained acceptable, the authors noted. This finding is consistent with previous research demonstrating that chlorthalidone-based regimens do not result in a significantly higher incidence of clinically meaningful electrolyte abnormalities compared with hydrochlorothiazide-based therapies, they added. [Cureus 2024;16:e68802; Cardiol Ther 2025;14:231-247]
Taken together, the data “suggest that concerns over chlorthalidone-induced electrolyte abnormalities may be overstated, particularly when used as part of an appropriately dosed single-pill combination therapy in East Asian populations,” according to Lee and colleagues.
Polypill to improve treatment persistence
“Our study reinforces current clinical guideline recommendation that prompts escalation to triple therapy for patients who remain uncontrolled on dual antihypertensive regimens. Recent guidelines from the European Society of Hypertension and the Korean Society of Hypertension emphasize rapid attainment of BP targets, ideally through single-pill combinations to enhance adherence and treatment persistence,” Lee and colleagues said.
Polypills, they noted, simplify treatment and improve patient adherence. This is important, given that “poor adherence is a critical barrier to optimal BP control, especially in patients requiring multiple medications,” they continued.
“The findings from the study support the wider use of chlorthalidone-based triple single-pill combinations, especially in hypertensive patients who fail to achieve adequate BP control with conventional dual combinations,” Lee and colleagues concluded.
The study included 294 patients (mean age 60.2 years, 74.8 percent male, mean BMI 27.1 kg/m2) with essential hypertension who had inadequately controlled BP after a 4-week run-in phase with valsartan/amlodipine (80/5 mg). They were randomly assigned to receive treatment with KDF1901 (valsartan/amlodipine/chlorthalidone 160/10/25 mg, n=147) or valsartan/amlodipine at 160/10 mg (n=147) daily for 8 weeks.