Single-pill low-dose combination (LDC) therapy is an emerging strategy for improving blood pressure (BP) control in patients with hypertension.¹ Two new phase III trials, HM-APOLLO-301 and HM-APOLLO-302, have evaluated the efficacy and safety of an ultra-low-dose triple combination pill compared with standard-dose monotherapy as an initial treatment for mild-to-moderate hypertension.
Methodology
The HM-APOLLO-301 and HM-APOLLO-302 studies were multicentre, randomised, double-blind, active-controlled trials conducted in South Korea. They enrolled adults with mild-to-moderate hypertension, defined as a systolic blood pressure (SBP) of 140 to <180 mmHg and a diastolic blood pressure (DBP) of <110 mmHg, following a 4-week placebo run-in period.
In HM-APOLLO-301, patients were randomised to receive either a single-pill LDC containing 1.67mg amlodipine, 16.67mg losartan potassium, and 4.17mg chlorthalidone (LDC-ALC) or standard-dose 5mg amlodipine monotherapy. In HM-APOLLO-302, patients received either LDC-ALC or standard-dose 50mg losartan potassium monotherapy. The primary endpoint for both trials was the reduction in SBP from baseline after 8 weeks of treatment.
Results
In the HM-APOLLO-301 trial, the LDC-ALC pill was noninferior to amlodipine monotherapy in reducing SBP at week 8. The least-squares mean change from baseline was −19.1 mmHg for the LDC-ALC group versus −19.9mmHg for the amlodipine group (95% CI: −1.5 to 3.1; p=0.495). Reductions in DBP and overall BP control rates were also similar between the two groups.
In the HM-APOLLO-302 trial, the LDC-ALC pill was found to be both noninferior and superior to losartan monotherapy for SBP reduction. The least-squares mean change from baseline was −19.9 mmHg with LDC-ALC compared to −16.4mmHg with losartan (95% CI: −6.6 to −0.2; p=0.037). The LDC-ALC group also demonstrated greater DBP reduction and a higher BP control rate.
Across both studies, the safety profiles were comparable. The incidence of adverse events was 11.7% for LDC-ALC versus 13.9% for amlodipine, and 6.4% for LDC-ALC versus 3.3% for losartan. Treatment withdrawal rates were low (≤1%), and no serious drug-related adverse events were reported.
In Practice
The study authors concluded that, “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 suggest that this low-dose triple combination therapy is an effective and well-tolerated alternative for the initial treatment of mild-to-moderate hypertension, offering a new option alongside established monotherapies.
This study was funded by Hanmi Pharmaceutical Co.
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References
1. Sung KC, Park K, Kim DH, et al. Single-pill low-dose triple combination therapy vs standard-dose monotherapy in patients with mild-to-moderate hypertension. J Am Coll Cardiol. 2026; [Epub ahead of print]. https://doi.org/10.1016/j.jacc.2025.12.028
2. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. Lancet. 2021;398:957-980. https://doi.org/10.1016/S0140-6736(21)01330-1