Comparative efficacy of acid-suppressive therapies for gastroesophageal reflux disease: a systematic review, pairwise meta-analysis, and frequentist network meta-analysis

Background Proton pump inhibitors (PPIs) remain the standard pharmacological therapy for gastroesophageal reflux disease (GERD), but how PPIs, histamine-2 receptor antagonists (H2RAs), and the newer potassium-competitive acid blockers (P-CABs) compare across dose and outcome levels has not been thoroughly examined. Methods We conducted a systematic review, pairwise meta-analysis, and frequentist network meta-analysis of randomized controlled trials comparing PPIs, H2RAs, and P-CABs in GERD, following PRISMA and PRISMA-NMA guidance. Outcomes were endoscopic healing at 4 and 8 weeks, maintenance of healing, and symptomatic relief. PROSPERO ID CRD420261514935. Findings Fifty-four trials totaling about 29,400 patients were included. PPIs and P-CABs consistently outperformed H2RAs in endoscopic healing. Pantoprazole 40 mg ranked highest at 4 weeks (P-score 0.88), while zastaprazan 20 mg led at 8 weeks (P-score 0.87), with fexuprazan and tegoprazan close behind. Heterogeneity was low at 4 weeks and low-to-moderate at 8 weeks, with no significant global inconsistency; sensitivity analysis preserved the rankings. At 52 weeks, PPIs significantly outperformed H2RAs in maintaining healed esophagitis (RR 2.07, 95% CI 1.56–2.73). Active acid suppression improved symptomatic relief overall (RR 1.15, 95% CI 1.03–1.28), with P-CABs showing a small, consistent advantage over PPIs (RR 1.12, 95% CI 1.03–1.22; I² = 0%). No evidence of publication bias was found. Conclusions PPIs remain the foundation of GERD pharmacotherapy, while newer P-CABs — particularly zastaprazan, fexuprazan, and tegoprazan — achieve comparable or superior healing and symptom control. These findings support P-CABs as a complementary option and a basis for more individualized treatment selection.