Efficacy and Safety of Initial Low-Dose Triple Combination Therapy for Hypertension: A Systematic Review and Meta-Analysis

Objective: Single-pill triple low-dose combination (triple-LDC) antihypertensive drugs have become available for clinical use as an alternative initial therapy for hypertension, expanding options beyond conventional monotherapy. We evaluated the efficacy and safety of triple-LDC therapy compared with placebo or standard-dose (SD) monotherapy. Design and method: This systematic review and meta-analysis followed a prespecified PROSPERO-registered protocol and PRISMA guidelines. Randomized controlled trials comparing triple-LDC therapy (<=50% of the SD per component) with placebo or SD monotherapy were identified through MEDLINE, EMBASE, and CENTRAL. Pooled estimates were calculated using random-effects inverse-variance models with restricted maximum likelihood. The Hartung–Knapp–Sidik–Jonkman (HKSJ) method was applied for primary inference, with Wald-type confidence intervals for sensitivity analyses. Results: Eight randomized controlled trials from seven publications (1,749 participants) were included. Compared with placebo, triple-LDC significantly reduced systolic blood pressure (BP) by -13.76 mmHg (95% CI, -19.28 to -8.23) and diastolic BP by -7.45 mmHg (95% CI, -10.85 to -4.04), more than doubling BP control rates (risk ratio [RR] 2.27, 95% CI, 1.37 to 3.75). Compared with SD monotherapy, triple-LDC achieved an additional systolic BP reduction of -3.65 mmHg (95% CI, -7.40 to 0.11). Although not statistically significant in the primary HKSJ model, this effect was significant in Wald-based sensitivity analyses (95% CI, -6.53 to -0.77). Diastolic BP was lower with triple-LDC than with monotherapy, but the difference did not reach statistical significance (-1.39 mmHg; 95% CI, -3.35 to 0.58). BP control rates were higher with triple-LDC (RR 1.25, 95% CI, 1.00 to 1.56). Triple-LDC was superior to angiotensin receptor blocker but comparable to calcium channel blocker monotherapy. Both low-dose (sum of dose fraction >1.0 SD) and ultra-low-dose (sum of dose fraction <=1.0 SD) regimens were superior to placebo, with no differences between doses. Versus SD monotherapy, low-dose therapy was superior, whereas ultra-low-dose therapy showed comparable efficacy. Findings were consistent in sensitivity analyses. Treatment-emergent adverse events and withdrawal rates were similar across groups.Conclusions: Triple-LDC therapy provides substantial BP reduction compared with placebo and modest additional benefit over SD monotherapy without increased adverse events, supporting its role as an effective initial treatment strategy for hypertension.