Single-Pill Low-Dose Triple Combination Therapy vs Standard-Dose Monotherapy in Patients With Mild-to-Moderate Hypertension

Clinical Snapshot

Key Findings

• P Value: Study 301: P = 0.495 (non-significant); Study 302: P = 0.037 (significant superiority)

• Effect Size: Non-inferior to amlodipine (difference 0.8 mmHg); superior to losartan (difference 3.5 mmHg)

• Primary Outcome: SBP reduction at 8 weeks: LDC-ALC achieved -19.1 mmHg vs amlodipine -19.9 mmHg (Study 301) and -19.9 mmHg vs losartan -16.4 mmHg (Study 302)

• Nnt Or Sensitivity: Cannot calculate NNT from available data; adverse event rates 6.4-11.7% vs 3.3-13.9% for comparators

• Confidence Interval: Study 301: 95% CI -1.5 to 3.1 mmHg; Study 302: 95% CI -6.6 to -0.2 mmHg

Clinical Application

Single-pill combination may improve medication adherence compared to multiple pills; requires availability of specific low-dose formulation Aligns with RACGP guidelines supporting combination therapy for hypertension. TGA approval would be required for this specific formulation. May be cost-effective if PBS-listed compared to multiple separate medications Adults with mild-to-moderate hypertension (140-180/110 mmHg) suitable for initial antihypertensive therapy

Abstract

BACKGROUND: Single-pill low-dose combination (LDC) antihypertensive therapy is an emerging strategy for improving blood pressure (BP) control. Although previous phase II and pragmatic studies suggested promise, these are the first phase III, double-blind, active-controlled trials comparing a single-pill ultra-low-dose triple combination with standard-dose monotherapy. OBJECTIVES: In these studies, we sought to compare a single-pill combination of 1.67 mg amlodipine, 16.67 mg losartan potassium, and 4.17 mg chlorthalidone (LDC-ALC) with standard-dose monotherapy-5 mg amlodipine or 50 mg losartan potassium-in patients with mild-to-moderate hypertension. METHODS: HM-APOLLO-301 (Study 301, May 2022-June 2023) and HM-APOLLO-302 (Study 302, March-December 2024) were multicenter, randomized, double-blind, active-controlled, phase III studies in South Korea. Study 301 compared LDC-ALC and amlodipine; Study 302 compared LDC-ALC and losartan. Adults (≥19 years of age) with systolic blood pressure (SBP) 140 to <180 mm Hg and diastolic blood pressure (DBP) <110 mm Hg after 4-week placebo run-in were randomized to 8 weeks of treatment. The primary endpoint was SBP reduction at week 8, assessed first for noninferiority, then for superiority. RESULTS: In Study 301, LDC-ALC exhibited noninferiority to amlodipine in reducing SBP at week 8 (upper bound of 1-sided 97.5% CI: 2.8 mm Hg [<3 mm Hg noninferiority margin]), and similar efficacy (least-squares mean change: -19.1 vs -19.9 mm Hg; 95% CI: -1.5 to 3.1; P = 0.495), with similar DBP reduction and blood pressure control rate. In Study 302, LDC-ALC was both noninferior (upper bound of one-sided 97.5% CI: -0.6 mm Hg) and superior to losartan (least-squares mean change: -19.9 vs -16.4 mm Hg; 95% CI: -6.6 to -0.2; P = 0.037) in SBP reduction at week 8, with greater DBP reduction and a higher blood pressure control rate than losartan. Adverse events were similar between groups (LDC-ALC vs amlodipine: 11.7% vs 13.9%; LDC-ALC vs losartan: 6.4% vs 3.3%), with ≤1% treatment withdrawals and no serious drug-related events. CONCLUSIONS: Single-pill LDC-ALC achieved BP reductions similar to those with amlodipine and greater than those with losartan monotherapy over 8 weeks, with similar short-term tolerability. These findings support LDC-ALC as an effective and well tolerated alternative initial therapy for mild-to-moderate hypertension, expanding the set of validated strategies alongside established monotherapies. (A Study to Evaluate Efficacy and Safety of HCP1803 in Patients With Essential Hypertension [HM-APOLLO-301; NCT05362110]; A Study to Evaluate Efficacy and Safety of HCP1803 Compared to RLD2001-1 in Patients with Essential Hypertension [HM-APOLLO-302, NCT06438172]).

References

1. 1.Sung, K. C., Park, K., Kim, D. H., Lim, S. W., Hong, S. J., Lee, J. B., Ryu, D. R., Kim, S. H., Kim, M. C., Kim, N. Y., Parati, G., & Rhee, M. Y. (2026). Single-pill low-dose triple combination therapy vs standard-dose monotherapy in patients with mild-to-moderate hypertension. Journal of the American College of Cardiology. https://doi.org/10.1016/j.jacc.2025.12.028