Proton Pump Inhibitors: Placing Putative Adverse Effects in Proper Perspective

Mitchell L. Schubert


Curr Opin Gastroenterol. 2019;35(6):509-516. 

In This Article

Abstract and Introduction


Purpose of review: This review summarizes the past year's literature, both clinical and basic science, regarding potential adverse effects of proton pump inhibitors (PPIs).

Recent findings: PPIs are amongst the most widely prescribed and over-prescribed medications worldwide. Although generally considered well tolerated, epidemiologic studies that mine large databases have reported a panoply of putative adverse effects associated with PPIs. It should be emphasized that the quality of the evidence underlying most of these associations is very low and the studies, by design, cannot ascribe cause and effect. These associations continue to be sensationalized in the media and misinterpreted by providers and patients. The unintended consequences are that patients who require PPIs, such as those taking dual antiplatelet agents, are not being prescribed or taking these necessary medications. In addition, physicians are spending an inordinate amount of additional time placing these findings into proper perspective for their patients and reassuring them upon initiating PPI treatment as well as at every follow-up visit.

Summary: Most of the recent publicized putative serious adverse effects attributed to PPIs rely on observational data and have not been confirmed in prospective randomized trials. Nevertheless, PPIs should be prescribed for valid indications and when prescribed long-term, they should be used at the lowest effective dose and the need for their use periodically reassessed.


Proton pump inhibitors (PPIs: omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, and dexlansoprazole) continue to be the most commonly prescribed (and over-prescribed) medications in the world. PPIs inhibit H+,K+-ATPase (HKA), the proton pump located on the luminal membrane of acid-secreting gastric parietal cells.[1] The HKA acidifies the stomach by pumping hydrogen ions into the gastric lumen against a million-fold proton concentration gradient while counter-transporting potassium from the lumen using ATP as the energy source. In a nationwide population-based drug-utilization study of adults in Iceland between 2003 and 2015, a considerable increase in the overall outpatient use of PPIs over a 13-year period was observed, particularly among older adults.[2] The annual prevalence increased to 15.5 per 100 persons and, disturbingly, patients were increasingly treated with higher doses and longer durations than recommended by clinical guidelines.

PPIs have revolutionized the management of acid-peptic disorders and are indicated for treatment of peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD). In GERD, they are indicated for erosive esophagitis as well as nonerosive reflux disease (NERD) with excess acid in the esophagus or increased sensitivity of the esophagus to acid. PPIs are also indicated for prevention of NSAID-induced and aspirin (ASA)-induced gastroduodenal ulcer, prevention and treatment of NSAID-induced upper gastrointestinal (UGI) bleeding; prevention of stress ulcer bleeding in patients in ICUs who require mechanical ventilation or have coagulopathy, acute renal or hepatic decompensation, sepsis, or history of PUD; treatment of hypersecretory disorders such as gastrinoma; Helicobacter pylori eradication regimens; and esophageal eosinophilia to determine PPI responsiveness.[3–5] In a meta-analysis of nine studies for gastrointestinal bleeding and eight studies for ulcer formation, PPIs were more effective than histamine-2 receptor antagonists (H2RAs) in preventing low-dose aspirin (ASA)-induced ulcer and bleeding.[6] Risk factors indicating need for PPI prophylaxis to prevent NSAID-induced or ASA-induced PUD complications include: history of PUD, age greater than 65 years, NSAID at high doses or in combination with other potentially gastrotoxic drugs, such as multiple NSAIDs, anticoagulants, steroids, or serotonin re-uptake inhibitors (SSRIs), and ASA, even at low doses, in elderly patients or when combined with NSAIDs, steroids, anticoagulants, or antiplatelet agents, such as clopidogrel or ticlopidine.[5] Although selective cyclooxygenase-2 (COX-2) inhibitors (celecoxib, rofecoxib, and etoricoxib) and preferential COX-2 inhibitors (meloxicam) are safer on the gastrointestinal tract than traditional NSAIDs, they reduce the risk of gastroduodenal lesions by only ~50% compared with traditional NSAIDs. PPI prophylaxis is generally recommended in patients using COX-2 inhibitors who manifest the above-mentioned risk factors, including concomitant use of low-dose ASA.

Despite 30 years of accepted safety, database-driven articles purporting putative serious adverse effects from PPIs continue to be published and publicized. The reports are largely retrospective observational studies, as well as meta-analyses of the same studies, that, by definition, have serious limitations and cannot establish cause-and-effect relationships because of inherent confounding and channeling bias. Confounding and channeling are similar biases because of nonrandom assignment such that PPI use is much more common amongst older and sicker patients whose underlying comorbidities, rather than PPI exposure itself, are most likely the cause of the adverse effect. Most reported associations are weak [odds ratios (OR) <2 to 3) and false. The minority that are true are often exaggerated.[7] When the magnitude of an association unearthed by such studies is small (OR or hazard ratio <4), it is not possible to discern whether the association is valid or because of residual confounding and bias. In general, observational studies with OR or hazard ratio less than 4 should not be considered credible.

An unintended consequence of the adverse publicity is that PPIs are now often under-prescribed for conditions necessitating their use, such as erosive esophagitis and prevention of NSAID-induced UGI bleeding, particularly in patients taking dual antiplatelet therapies. The present chapter critically reviews the recent literature, published within the past year, regarding potential adverse effects of PPIs in an effort to better inform providers and patients.