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동국대학교 일산병원

J. Am. Coll. Cardiol., Feb 03 2026, S0735-1097(25)10559-7 | https://doi.org/10.1016/j.jacc.2025.12.028 Single-Pill Low-Dose Triple Combination Therapy vs Standard-Dose Monotherapy in Patients With Mild-to-Moderate Hypertension

Ki-Chul Sung MD, PhD ^a∗, Kyungil Park MD, PhD ^b∗, Dae-Hee Kim MD, PhD^c, Sang-Wook Lim MD, PhD ^d, Soon Jun Hong MD, PhD ^e, Jin Bae Lee MD, PhD^f, Dong-Ryeol Ryu MD, PhD ^g, Seong Hwan Kim MD, PhD ^h, Min Chul Kim MD, PhD ⁱ, Na Young Kim MPharm ^j, Gianfranco Parati MD ^k,l, Moo-Yong Rhee MD, PhD ^m the HM-APOLLO 301 and 302 Trials Investigators^†

^aDivision of Cardiology, Kangbuk Samsung Hospital, Seoul, Republic of Korea
^bDivision of Cardiology, Dong-A University Hospital, Busan, Republic of Korea
^cDivision of Cardiology, Asan Medical Center, Seoul, Republic of Korea
^dCardiology Division, CHA Bundang Medical Center, Seongnam, Republic of Korea
^eDepartment of Cardiology, Korea University Anam Hospital, Seoul, Republic of Korea
^fDepartment of Cardiology, Daegu Catholic University Medical Center, Daegu, Republic of Korea
^gDivision of Cardiology, Kangwon National University Hospital, Chuncheon, Republic of Korea
^hDivision of Cardiology, Korea University Ansan Hospital, Ansan, Gyeonggi, Republic of Korea
ⁱDivision of Cardiology, Chonnam National University Hospital, Gwangju, Republic of Korea
^jHanmi Pharmaceutical Co, Seoul, Republic of Korea
^kDepartment of Cardiovascular, Neural, and Metabolic Sciences, Istituto Auxologico Italiano IRCCS, San Luca Hospital, Milan, Italy
^lDepartment of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
^mDivision of Cardiology, Dongguk University Ilsan Hospital, Goyang-si, Gyeonggi, Republic of Korea

Address for correspondence: Prof Moo-Yong Rhee

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]).

논문소개전체 설명

[초저용량 3제 복합제를 통한 고혈압 치료 패러다임의 전환]

고혈압 초기 치료 실패의 핵심 요인은 치료 관성(therapeutic inertia), 단일제 중심의 단계적 증량 전략, 부작용으로 인한 순응도 저하 등이 있다. 이러한 한계를 극복하기 위하여 1980년대부터 저용량 복합투여(low-dose combination therapy)의 개념이 제안되었으며, 여러 연구들이 그 가능성을 보여주었다. 이 개념이 임상에 도입되기 위하여서는 체계적인 중개연구와 확증적 임상연구가 필수적인데, 이번에 발표한 APOLLO-301, 302연구는 이를 바탕으로 한 최초의 4상 랜드마크 연구로 '초저용량 복합 투여(ultra-low-dose combination therapy)'의 임상적 유용성과 안정성을 평가하였다.
본 연구는 세가지 혈압강하제(amlodipine, losartan, chlorthalidone)를 각각 표준용량의 1/3 용량(1.67 mg, 16.67 mg, 4.17 mg)으로 낮추어 3제 단일정 복합제를 개발하여 표준용량의 2가지 단일제 치료(amlodipine 5 mg, losartan 50 mg)와 직접 비교하였다(2상 임상 연구결과는 이전에 보고됨). 이 연구에서 8주간의 초저용량 복합제 치료는 표준용량의 단일치료제인 amlodipine 5mg 과 유사한 혈압강하 효과를 보였으며, losartan 50 mg과 비교하여 우월한 혈압강하 효과를 입증하였다.
이 연구의 중요성은 초저용량 3제 단일정 복합제 치료를 두가지 종류의 혈압강하제 (칼슘차단제와 안지오텐신 수요체 차단제)와 고혈압의 1차 치료로 혈압강하 효과를 비교한 체계적인 임상근거를 제시하였다는 점에 있다. 이를 통해 초저용량 복합요법은 고혈압 초기 치료 전략의 새로운 선택지로서 임상적 가능성을 확인하였다.
초저용량 단일정 복합제의 기대되는 장점은 다음과 같다. 첫째, 다중 기전을 동시에 차단함으로써 보다 신속하고 안정적인 혈압 조절을 도모할 수 있다. 둘째, 각 약제를 저용량으로 사용함으로써 용량 의존적 부작용을 최소화로 내약성 향상에 따른 복약 순응도를 향상시킬 수 있다.  셋째, 병태생리적 기전 분류가 현실적으로 어려운 일차 진료 현장에서, 여러 기전을 동시에 표적하는 접근은 환자에게 적절한 환자 맞춤 약제 선택에 대한 임상의의 부담을 줄이는 데 기여할 것으로 기대된다.

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