What does this research mean for the field?

Triple-combination antihypertensive therapy achieves significantly greater blood pressure reduction and higher control rates than dual-combination therapy with an acceptable overall safety profile. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.NEUTRAL.

May 15, 2026Frontiers in PharmacologyOpen Access

Comparative efficacy and safety of dual-combination vs. triple-combination antihypertensive therapies in hypertensive patients: an updated meta-analysis of randomized controlled trials

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Why the study?

Combination therapy is often needed for hypertension, but the comparative efficacy and safety of triple versus dual antihypertensive regimens required clarification with updated evidence-based data.

Does triple antihypertensive therapy reduce mean seated blood pressure in adult patients with primary hypertension compared to dual therapy?

Structured PICO

Does triple antihypertensive therapy reduce mean seated blood pressure in adult patients with primary hypertension compared to dual therapy?

Population

17,669 adult patients with poorly controlled primary hypertension or stage 2 hypertension and above across 21 RCTs. Mean age 56.6 in triple therapy group, 56.9 in dual therapy group.

Intervention

Triple antihypertensive therapy (primarily calcium channel blockers + angiotensin II receptor blockers + diuretics)

Comparator

Dual antihypertensive therapy

Outcome

Mean seated blood pressure (systolic and diastolic)surrogate

Compared with dual-drug regimens, triple-drug antihypertensive regimens are more effective for short-term blood pressure control with an acceptable safety profile.

Limitations

Significant heterogeneity remains
Subgroup analyses represent exploratory findings only
Small number of included studies for adverse events with imprecise effect estimates and design flaws in some studies

Implication

Supports triple therapy escalation in primary hypertension; extends RCT evidence via meta-analysis.

Abstract

Background: Combination therapy is often required for treating hypertension,but the comparative efficacy and safety of triple versus dual antihypertensive regimens remain to be clarified by the latest evidence-based medical data. This meta-analysis aims to compare the efficacy and safety of dual versus triple antihypertensive drug therapy for adult primary hypertension, providing updated evidence to support clinical decision-making. Methods: A systematic search was conducted across four databases-PubMed, Embase, Cochrane, and Web of Science-up to July 2025 to identify randomized controlled trials comparing dual antihypertensive therapy with triple antihypertensive therapy for treating adult primary hypertension. The primary outcome was mean seated blood pressure; secondary outcomes included blood pressure control rates and adverse events. Screening, data extraction, and quality assessment were performed by two independent researchers.The Cochrane Risk of Bias Assessment Tool was used to evaluate study quality; data analysis was conducted using Stata 15.1 software. Results: A total of 21 studies involving 17,669 patients were ultimately included. Of these, 6,918 patients received triple therapy and 10,751 patients received dual therapy. Triple therapy reduced systolic blood pressure [WMD: -5.98 mmHg, (95% CI: -7.04, -4.92)] and diastolic blood pressure [WMD: -3.34 mmHg, (95% CI: -4.03, -2.65)]. In the ARB subgroup, valsartan-based triple therapy demonstrated significant blood pressure-lowering effects on systolic blood pressure [WMD = -7.41 mmHg, (95% CI: -8.91 to -5.91)] and diastolic blood pressure [WMD = -4.57 mmHg, (95% CI: -5.65 to -3.49)]. An evaluation of 14 adverse reaction symptoms revealed that triple therapy improved patient fatigue [RR: 0.80, (95% CI: 0.67, 0.96)]. Triple therapy increased the rate of blood pressure control [RR: 1.31, (95% CI: 1.23, 1.39)]. Conclusion: Compared with the dual-drug regimen, the triple-drug antihypertensive regimen may be more effective for short-term blood pressure control, and its overall safety profile is acceptable. However, the subgroup analyses in this study represent exploratory findings only and cannot be directly used to guide clinical drug selection. Given that, although the evidence for the primary efficacy outcome is of moderate certainty, significant heterogeneity remains, the results should be interpreted with caution.