Adverse Effects of Proton Pump Inhibitors: Fact or Fake News?

Mitchell L. Schubert


Curr Opin Gastroenterol. 2018;34(6):451-457. 

In This Article

Abstract and Introduction


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

Recent findings: Proton pump inhibitors are amongst the most widely prescribed and overprescribed medications worldwide. Although generally considered well tolerated, epidemiologic studies mining large databases have reported a panoply of purported serious adverse effects associated with proton pump inhibitors, including chronic kidney disease, cognitive decline, myocardial infarction, stroke, bone fracture and even death. It should be noted that the quality of the evidence underlying these associations is very low and these studies, by design, cannot ascribe cause and effect. Nonetheless, these associations have been sensationalized in the media and misinterpreted by patients and providers. Unintended consequences of the fake news are that patients are not being prescribed and/or taking clinical guideline-recommended proton pump inhibitors to prevent and treat complications from gastroesophageal reflux disease and upper gastrointestinal bleeding precipitated by NSAIDs and dual antiplatelet therapies. In addition, physicians, who already have limited time to interact with their patients, are spending an inordinate amount of additional time placing these findings into proper perspective and reassuring their patients when initiating treatment as well as on every follow-up visit.

Summary: Most of the recent highly publicized serious adverse effects ascribed to proton pump inhibitors are not based on demonstrable evidence. Nevertheless, when proton pump inhibitors are prescribed long-term, they should be used at the lowest effective dose and the need for their use periodically reassessed.


Gastric acid secretion is precisely regulated to maximize benefits and minimize harms. Acid kills ingested microorganisms, renders the stomach and small intestine relatively sterile, modulates the gut microbiome, assists in protein digestion and facilitates the absorption of nonheme iron, calcium and vitamin B12, and enhances the bioavailability of certain medications (e.g. ketoconazole, itraconazole, thyroid hormone and atazanavir). However, when levels of acid (and pepsin) overwhelm mucosal defense mechanisms, gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD) may occur.

The development of proton pump inhibitors (PPIs; omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole and dexlansoprazole), medications that block the parietal cell acid pump, has revolutionized the management of GERD and PUD. These potent antisecretory medications have reduced complications and hospitalizations as well as improved the quality of life for patients suffering from acid-peptic disorders. PPIs have also become the gold standard in the prevention of NSAID-induced gastroduodenal ulcer, prevention of NSAID-induced upper gastrointestinal (UGI) bleeding and Helicobacter pylori eradication regimens. Consequently, PPIs are one of the most commonly prescribed (and overprescribed) medications. In the United States, nearly 15% of adults have used a PPI within the last year, with even greater use in the elderly.[1,2] The use and overuse of PPIs is a world-wide phenomenon, with similar results reported in a drug-utilization study conducted in Iceland.[3] Over a 13-year period, the overall outpatient prescription for PPIs doubled and patients were increasingly treated with higher doses for longer durations than recommended by clinical guidelines.

Although PPIs have long been considered well tolerated medications, there have been numerous recent publications purporting potential harms. These reports, published in the medical literature and sensationalized in the media, have caused alarm and angst amongst patients and providers. An unintended consequence of the adverse publicity is that PPIs are now often underprescribed for conditions necessitating their use such as erosive esophagitis and prevention of NSAID-induced UGI bleeding, particularly in patients taking dual antiplatelet therapies.

There is now a long list of dozens of potential serious adverse effects associated with PPI therapy, including alterations in gut microbiome, enteric infection, micronutrient deficiencies, fundic gland polyps, gastrointestinal malignancy, chronic kidney disease (CKD), cognitive dysfunction, myocardial infarction (MI), bacterial overgrowth, bacterial peritonitis, pneumonia, bone fracture, drug interactions and death. There is relatively strong evidence, including biologic plausibility, linking PPIs with alterations in gut microbiome, micronutrient deficiencies (e.g. magnesium, vitamin B12, iron and calcium), fundic gland polyps and enteric infection. Increasing basic science data suggest a possible association with carcinogenesis that is mediated by PPI-induced hypergastrinaemia.[4–7] The quality of the evidence, however, underlying the other associations is very low and often inconsistent.[8,9] The aim of this chapter is to critically review the recent literature, published within the past year, regarding potential adverse effects of PPIs and place the findings in proper perspective.