Safety of Potassium-Competitive Acid Blockers Compared With Proton Pump Inhibitors in Patients With Gastroesophageal Reflux Disease and Peptic Ulcer Disease: A Systematic Review and Meta-Analysis

Abstract

Background and Aim: Potassium-competitive acid blockers (P-CABs) are a novel class of acid suppressants developed to overcome the limitations of proton pump inhibitors (PPIs), providing rapid and sustained acid suppression. While PPI-related adverse events (AEs) are well-documented, safety data on P-CABs remain limited. This study systematically reviewed AEs of P-CABs compared with PPIs, with a meta-analysis focusing on hypergastrinemia. Methods: Following a preregistered PROSPERO protocol (CRD42024565011), we searched for randomized controlled trials (RCTs) and observational studies comparing P-CABs and PPIs in patients with gastroesophageal reflux disease or peptic ulcer disease. Frequently reported AEs and serious AEs (SAEs) were qualitatively synthesized; hypergastrinemia was quantitatively analyzed using a random-effects model. Results: Ten RCTs and one observational study were included. Nine studies reported specific AEs, with diarrhea reported in seven studies and constipation, nasopharyngitis, and liver-related events, each reported in three. Most AEs had reporting rates below 5%, except diarrhea, nasopharyngitis, and upper respiratory tract inflammation, which exceeded 5% in both groups. Fracture demonstrated the largest relative difference between the groups, with a threefold higher rate in the P-CAB group. SAEs were observed in fewer than 10% of patients in both groups in most studies. A meta-analysis of six studies showed greater serum gastrin elevation in the P-CAB group compared with the PPI group (mean difference: 130.92 pg/mL, 95% confidence intervals: 36.37–225.47). Conclusions: P-CABs demonstrate a comparable AE risk to PPIs but monitoring for hypergastrinemia and hepatic dysfunction is essential. Further research is required to support safer clinical use. © 2025 The Author(s). Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.