Safety of proton pump inhibitors: an overview of systematic reviews and meta-analyses

Background Proton pump inhibitors (PPIs) have been widely used for over 35 years. However, in recent decades, numerous adverse drug reactions (ADRs) have been reported, with evidence often inconsistent and heterogeneous across studies. Objective To conduct an overview of systematic reviews/meta-analyses (SR/MAs) to provide a contemporary review of the evidence for the safety of PPIs in patients using them for treating or prophylaxis, to summarise the outcome data, assess the methodological quality and rate the certainty of the evidence and to provide references for clinical decision-making and the subsequent formulation of evidence. Methods We conducted an overview of reviews following the Preferred Reporting Items for Overviews of Reviews guidelines. We identified SR/MAs regarding PPI safety through a search of multiple databases, including the China National Knowledge Infrastructure, Chinese Science and Technology Journal Database and Wanfang Database (WanFang) on 6 December 2025 as well as Embase, PubMed and the Cochrane Library database on 7 December 2025. The participants were human populations who had been administered PPIs; the intervention groups used PPI-based regimens and the control group received different PPI regimens, no-PPIs, H2-receptor antagonists (H2RAs), potassium-competitive acid blockers (P-CAB) or placebo; the outcomes mainly included the specific ADRs associated with PPI use. We used the A Measurement Tool to Assess Systematic Reviews-2 (AMSTAR-2) tool to assess the methodological quality of the included SR/MAs and employed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to evaluate the quality of evidence for the reported outcomes. The focus of the data presentation was descriptive, featuring detailed tabular presentations of characteristics and results at both the review level and the primary studies level. Main results A total of 940 studies were retrieved from various databases according to the search strategies. After eliminating duplicates and the screening process, 36 SR/MAs were finally included. Overall, there was a slight overlap (corrected covered area, CCA of 0.91%) in 483 primary studies included in the 36 SR/MAs. AMSTAR-2 evaluation results showed that 34 SR/MAs were of low quality, and the other two were of critically low quality. The GRADE evaluation results indicated that the certainty of evidence for all outcomes was low or very low . The use of PPIs might be associated with an increased risk of acute kidney injury (AKI) (relative risk (RR) 1.75, 95% CI 1.40 to 2.19), chronic kidney disease (CKD) (RR 1.35, 95% CI 1.15 to 1.56), gastric cancers (GC) (RR 1.67, 95% CI 1.39 to 2.00) and community-acquired pneumonia (CAP) (OR 1.37, 95% CI 1.22 to 1.53). PPI therapy was associated with a higher recurrence rate of Clostridioides difficile infection (CDI) (24% vs 18%) and might increase CDI risk in renal transplant recipients (RR 2.33, 95% CI 1.07 to 5.07). The use of PPIs might heighten the risk of fractures in young patients (aged <29 years) (RR 1.20, 95% CI 1.12 to 1.29). PPI therapy was also linked to hypomagnesaemia in haemodialysis patients (1/36, 2.78%) and renal transplant recipients (1/36, 2.78%). Conclusions This overview evaluates the safety profile of PPIs, noting associated risks including renal impairment, GC, fractures and infections. Most evidence comes from observational studies, resulting in low or very low certainty evidence that limits definitive causal conclusions. Clinicians and pharmacists may consider greater vigilance with PPI use, and these ADRs may not require de-escalation but de-implementation when inadequate (eg, long-term use or special group use). Future research should focus on high-quality prospective studies and investigate underlying mechanisms to better establish causality and quantify risks. PROSPERO registration number CRD420251059575.