Understanding the Risks Associated With Long-Term Use of PPI Therapy

By Basem M. Ratrout, MD
Internist, Mayo Clinic, Rochester, Minnesota

About 3 decades ago, proton-pump inhibitor (PPI) therapy was introduced to the market for the treatment of gastric acid-related diseases such as gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), Zollinger-Ellison syndrome, and idiopathic gastric acid hypersecretion. Currently, a few PPIs are available as prescription only, but 2 are available as over-the-counter (OTC) medications: omeprazole and lansoprazole. Many Americans use OTC antacids, histamine type 2 receptor antagonists (H₂ blockers), and PPIs to treat common gastrointestinal (GI) tract symptoms. PPIs are the most potent inhibitors of gastric acid secretion and are more effective in relieving GERD symptoms. In general, the rate of adverse effects of PPI use is quite low, with 1% to 2% of users experiencing abdominal pain, diarrhea, headache, lightheadedness, and nausea.

Although many patients may take prescribed PPIs as a long-term treatment, they may not truly understand why they are on this therapy. In addition, many patients worry about potential long-term complications such as dementia and fractures. For this reason, it is important for health care providers to understand and properly convey the risks associated with PPI therapy.

Practice guidelines from the American Gastroenterological Association (AGA)¹ give us a clearer understanding of the associated risks as well as recommendations for prescribing PPI therapy. Several studies included in the literature review used to construct the guidelines conclude that PPI use may increase the risk for fracture, vitamin B₁₂ deficiency, hypomagnesemia, iron-deficiency anemia, small intestinal bacterial overgrowth (SIBO), Clostridium difficile infection, and pneumonias. Other studies included in the review suggest an increased risk of kidney disease, cardiovascular disease, and dementia.^2,3,4,5

Practice guidelines from the American Society for Gastrointestinal Endoscopy⁶ recommend upper endoscopy in patients with GERD with alarm symptoms such as dysphagia, GI bleeding or anemia, unintentional weight loss, recurrent vomiting, or symptoms that are refractory to an empiric trial of PPI therapy. Guidelines from the American College of Physicians recommend assessing the healing of erosive esophagitis after 2 months of PPI therapy.⁷ Furthermore, several risk factors associated with Barrett esophagus may indicate the need for upper endoscopy in this at-risk population. The risk factors include white race, male sex, GERD symptoms lasting more than 5 years, older than 50 years of age, and having additional risk factors such as high body mass index and family history of Barrett esophagus.⁶

PPIs are typically prescribed for 4 to 8 weeks as empiric therapy to relieve symptoms of GERD. PPI on-demand therapy for GERD symptoms was added to the treatment options in 2017.¹ PPI maintenance therapy should be considered in patients with certain conditions—such as erosive esophagitis, eosinophilic esophagitis, Barrett esophagus, and Zollinger-Ellison syndrome—and in those on antiplatelet therapy or nonsteroidal anti-inflammatory drugs who are at high risk for ulcer-related bleeding.¹ Implementing lifestyle modifications from the time of GERD diagnosis may also improve symptoms if a clear dietary trigger had been found to exacerbate symptoms.

In conclusion, it is important for physicians to perform medication reconciliations with patients at every visit to assess the need for PPIs, to evaluate the most effective dosage, and to address any medication interactions. If patients are hesitant to initiate PPI therapy, they can be reassured of the low adverse event rate for long-term use. Alternatively, therapy can be stepped down to a cheaper H₂ blocker or even on-demand treatment, such as OTC antacids. Discontinuing treatment all together would likely worsen patients’ symptoms and carry a risk of developing other conditions. Physicians should take these points into consideration when discussing treatment options with patients.

References:

1. Freedberg DE, Kim LS, Yang Y-X. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology. 2017;152(4):706-715. http://dx.doi.org/10.1053/j.gastro.2017.01.031.
2. Pello Lázaro AM, Cristóbal C, Franco-Peláez JA, et al. Use of proton-pump inhibitors predicts heart failure and death in patients with coronary artery disease. PLoS One. 2017;12(1):e0169826. doi:10.1371/journal.pone.0169826.
3. Wang Y-F, Chen Y-T, Luo J-C, Chen T-J, Wu J-C, Wang S-J. Proton-pump inhibitor use and the risk of first-time ischemic stroke in the general population: a nationwide population-based study [published online April 11, 2017]. Am J Gastroenterol. doi:10.1038/ajg.2017.101.
4. Sun S, Cui Z, Zhou M, et al. Proton pump inhibitor monotherapy and the risk of cardiovascular events in patients with gastro-esophageal reflux disease: a meta-analysis. Neurogastroenterol Motil. 2017;29(2): e12926. doi:10.1111/nmo.12926.
5. Niu Q, Wang Z, Zhang Y, et al. Combination use of clopidogrel and proton pump inhibitors increases major adverse cardiovascular events in patients with coronary artery disease: a meta-analysis. J Cardiovasc Pharmacol Ther. 2017;22(2):142-152. doi:10.1177/1074248416663647.
6. Muthusamy VR, Lightdale JR, Acosta RD, et al; ASGE Standards of Practice Committee. “The role of endoscopy in the management of GERD.” Gastrointestinal Endoscopy. 2015;81(6):1305-1310. http://dx.doi.org/10.1016/j.gie.2015.02.021.
7. Shaheen NJ, Weinberg DS, Denberg TD, et al; Clinical Guidelines Committee of the American College of Physicians. Upper endoscopy for gastroesophageal reflux disease: best practice advice from the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med. 2012;157(11):808-816. doi:10.7326/0003-4819-157-11-201212040-00008.