Umbrella Review of 42 Systematic Reviews With Meta-analyses

The Safety of Proton Pump Inhibitors

Elizabeth M. Salvo; Nicole C. Ferko; Sarah B. Cash; Ailish Gonzalez; Peter J. Kahrilas


Aliment Pharmacol Ther. 2021;54(2):129-143. 

In This Article

Abstract and Introduction


Background: Proton pump inhibitors (PPIs) are widely used to treat and prevent acid-related disorders. Despite high efficacy, PPI safety has been increasingly scrutinised. However, no comprehensive review summarising investigations of various adverse events is available.

Aims: To perform an umbrella review to comprehensively assess associations between adverse events and PPI use.

Methods: In accordance with PRISMA, an umbrella review of systematic reviews with meta-analyses was conducted. PubMed and EMBASE were searched from 2015 to July 2019. AMSTAR 2 and GRADE were used to assess quality and certainty of evidence. Author-reported quality assessments were also reviewed.

Results: Forty-two systematic reviews with meta-analyses, supported predominantly by observational evidence, were included. The most comprehensive studies reported statistically significant associations with PPI use for several outcomes, including: fractures (eg, hip; RR = 1.20; 95% CI = 1.14–1.28; n = 2 103 800), kidney disease (eg, acute kidney injury; RR = 1.61; 95% CI = 1.16–2.22; n = 2 396 640), infections (eg, Clostridioides difficile; OR = 1.99; 95% CI = 1.73–2.30; n = 356 683), gastric cancer (OR = 2.50; 95% CI = 1.74–3.85; n = 943 070) and gastrointestinal events (eg, fundic gland polyps; OR = 2.46; 95% CI = 1.42–4.27; n = 40 218). No associations with non-gastric cancers, or neurological disease were concluded, with conflicting evidence for cardiovascular outcomes. Certainty based on GRADE was very low for most outcomes.

Conclusions: This review identified several published associations between PPIs and adverse outcomes, however, further investigation is needed to understand their clinical significance and the likelihood of causal relationship. If higher quality evidence is generated substantiating the potential risks, it may be necessary for clinicians to consider alternative treatment strategies, especially when PPI efficacy is suboptimal.


First introduced in the late 1980s, proton pump inhibitors (PPIs) are a primary treatment for acid-related disorders.[1] PPIs currently approved by the United States Food and Drug Administration and European Medicines Agency include omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole and pantoprazole.[1,2] PPIs are administered orally or intravenously, and all varieties utilise a common mechanism to treat acid-related disorders which involves the irreversible blocking of gastric H+/K+-ATPases.[3,4]

PPIs are a common treatment option for acid-related disorders in primary care settings. They are one of the most widely utilised classes of drugs, accounting for over $25 billion in healthcare costs globally per year, based on both prescriptions and over-the-counter sales.[2] In a US study of 3600 gastroenterologists, 50% recommended over-the-counter PPIs, 33% recommended prescription PPIs and 13% recommended an H2RA for the typical acid reflux patient.[5]

Given their mechanism of action, PPIs are a standard treatment option for a number of conditions, including gastro-oesophageal reflux disease (GORD), dyspepsia, peptic ulcer disease, gastrointestinal bleeding prophylaxis and hypersecretory conditions, such as Zollinger-Ellison syndrome.[6,7] Of these conditions, GORD is the most common indication for PPI use.[6,8–10] In the treatment of GORD, PPIs are considered highly effective. However, 30%-45% of these patients report inadequate symptom relief on a standard daily dose of PPI and are considered to have failed standard dose PPI therapy.[11,12] There are a multitude of potential reasons for failure including: poor adherence, drug bioavailability, persistent weakly acidic or bile reflux, visceral hypersensitivity and misdiagnosis. While some of these mechanisms argue for use of an increased dose or alternative PPI, others argue for discontinuation and adoption of an alternative management strategy.

Along with widespread PPI use, the relationship between PPIs and adverse outcomes has been increasingly scrutinised in recent literature. Although RCTs are the gold standard for evaluation of treatment efficacy, they are usually underpowered to detect uncommon adverse events and too short to detect long-term adverse events.[13–15] Conversely, many observational studies of PPIs and adverse outcomes are available, along with several recent systematic reviews with meta-analyses. However, each meta-analysis of PPI adverse outcomes typically focuses on either a single, or only a few, adverse outcomes which obscures a collective understanding of the potential impact. Umbrella reviews synthesise systematic reviews and meta-analyses on similar research questions and have become increasingly influential for highly published topics.[16] Therefore, an umbrella review was undertaken to systematically assess the relationship between adverse outcomes and PPI use across populations suffering from acid-related diseases.