Low-dose combination antihypertensive therapy versus standard therapy in adults with hypertension: a systematic review and meta-analysis of randomized controlled trials

Abstract Background Low-dose combination-based antihypertensive therapy has emerged as a promising strategy to improve blood pressure (BP) control while minimizing dose-related adverse effects. However, evidence comparing its efficacy and safety with conventional antihypertensive therapy remains limited. This systematic review and meta-analysis evaluated the efficacy and safety of low-dose combination-based antihypertensive therapy in adults with primary hypertension. Methods A systematic review and meta-analysis was conducted in accordance with PRISMA guidelines. PubMed/MEDLINE, Google Scholar, ScienceDirect, the Cochrane Library, and ClinicalTrials.gov were searched from inception through June 2026. Randomized controlled trials comparing low-dose combination-based antihypertensive therapy with standard antihypertensive therapy in adults with primary hypertension were included. The primary outcome was achievement of target BP control. Secondary outcomes included mean change in systolic BP, mean change in diastolic BP, treatment-emergent adverse events, serious adverse events, and treatment discontinuation due to adverse events. Study quality was assessed using the Cochrane Risk of Bias 2 tool. Random-effects meta-analyses were performed to calculate pooled risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs). Subgroup analyses were performed according to treatment strategy and CCB-containing versus non-CCB initial therapy. Results Six randomized controlled trials involving 5,759 participants were included. Compared with standard therapy, low-dose combination therapy significantly improved achievement of target BP control (RR 1.21, 95% CI 1.15–1.27; P < 0.00001; I²=0%) and produced greater reductions in systolic BP (MD − 5.59 mmHg, 95% CI − 7.33 to − 3.86; P < 0.00001; I²=85%) and diastolic BP (MD − 3.48 mmHg, 95% CI − 5.86 to − 1.10; P = 0.004; I²=97%). No significant subgroup differences were observed according to treatment strategy for SBP ( P = 0.82) or DBP ( P = 0.39), or according to CCB-containing initial therapy for SBP ( P = 0.12) or DBP ( P = 0.07). Leave-one-out sensitivity analysis showed that the pooled SBP effect remained statistically significant despite substantial heterogeneity. No significant differences were observed in treatment-emergent adverse events, serious adverse events, or treatment discontinuation due to adverse events. Conclusions Low-dose combination-based antihypertensive therapy was associated with improved BP control and greater reductions in systolic and diastolic BP without significant differences in the assessed safety outcomes compared with standard therapy. However, substantial heterogeneity was observed in the pooled BP estimates. Further randomized trials comparing specific low-dose combination strategies with contemporary standard treatment are warranted. The protocol was registered with PROSPERO (CRD420261452295).