By Joseph Scherger, MD, MPH

Vice President, Primary Care, Eisenhower Medical Center; Clinical Professor, Keck School of Medicine, University of Southern California

Dr. Scherger reports no financial relationships relevant to this field of study.

SYNOPSIS: An observational study of a Veterans Affairs population showed that the use of proton pump inhibitors over a median 5.7-year follow-up period increased the risk of death by 25% compared with the use of H2 blockers or no medication.

SOURCE: Xie Y, Bowe B, Li T, et al. Risk of death among users of proton pump inhibitors: A longitudinal observational cohort study of United States veterans. BMJ Open 2017;7:e015735.

Investigators studied patient data from the U.S. Department of Veterans Affairs (VA) collected between October 2006 and September 2008. Among 3.5 million veterans, about 350,000 received proton pump inhibitors (PPIs) for ongoing suppression of gastric acid. This cohort was compared with veterans who received histamine 2 (H2) blockers and with veterans who did not receive medication. Otherwise, the three groups were matched by age and overall health. The group that received PPIs demonstrated a higher relative risk of death (hazard ratio, 1.2-1.25, depending on the comparison group). The cause of death was not evaluated. The results of this study were reported widely as a 25% increase in death from PPI medications. To put the results in perspective, those given PPIs experienced a death rate of 4.7 per 100 veterans per year, comparted with 3.3 deaths per 100 in the group that took H2 blockers. The death rate for veterans on no medication was similar to those given H2 blockers.


Since their entry into the market decades ago, PPIs have been indicated for short-term use. PPIs are effective, and the main problem they treat, gastroesophageal reflux disease (GERD), is a chronic health problem. Since PPIs do not produce immediate side effects in most patients, they often are taken long term. Adverse health consequences of long-term PPI use are piling up and are quite serious. An article published in The New York Times in March summarized the research documenting the complications of PPIs as nutrient deficiencies (vitamin B12, vitamin C, calcium, iron, and magnesium), joint pain, infections (including C. difficile) bone fractures, heart attacks, and dementia.1 Studies published in the past two years described in greater detail the relationship between PPIs and many of these health complications.2-4 Previous research revealed increased one-year mortality in institutionalized patients on PPIs.5,6

Xie et al carried out the first longitudinal study of a cohort over a longer period. Based on all this research, long-term use of PPIs should occur with great caution and with the patient’s informed consent. Before PPIs, the H2 blockers were among the most prescribed drugs in the world. They are effective and, based on the Xie et al study, are as safe from mortality as no medication. However, H2 blockers suppress the acid environment of the stomach, which may produce adverse consequences over time, such as proliferation of H. pylori and other gastric flora as well as cellular changes that may lead to gastric cancer.7,8 There is a nutritional solution to consider for patients with GERD, dyspepsia, and irritable bowel syndrome (IBS). These conditions are often a reflection of dysbiosis, an unhealthy gut microbiome. The gut microbiome depends on what we eat. Reducing or eliminating inflammatory foods such as those containing gluten and fructans have been shown to relieve these problems in some patients.9,10 Gluten is an inflammatory protein complex found in wheat, barley, and rye. Fructans are oligosaccharides and polysaccharides that are in some vegetables, grains, and fruits. Fructans also are known as FODMAPS, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols.

I suspect we will hear much more about nutritional solutions in the future if the research is funded to generate high-quality clinical trials. Meanwhile, look for patients taking long-term PPIs and speak with them about alternatives. You may be saving their lives.


  1. Brody JE. Pop a Pill for Heartburn? Try Diet and Exercise Instead. The New York Times, March 20, 2017. Available at: Accessed July 19, 2017.
  2. Schoenfeld AJ, Grady D. Adverse effects associated with proton pump inhibitors. JAMA Intern Med 2016;176:172-174.
  3. Xie Y, Bowe B, Li T, et al. Proton pump inhibitors and risk of incident CKD and progression to ESRD. J Am Soc Nephrol 2016;27:3153-3163.
  4. Klepser DG, Collier DS, Cochran GL. Proton pump inhibitors and acute kidney injury: A nested case-control study. BMC Nephrol 2013;14:150. doi: 10.1186/1471-2369-14-150.
  5. Bell JS, Strandberg TE, Teramura-Gronblad M, et al. Use of proton pump inhibitors and mortality among institutionalized older people. Arch Intern Med 2010;170:1604-1605.
  6. Maggio M, Corsonello A, Ceda GP, et al. Proton pump inhibitors and risk of 1-year mortality and rehospitalization in older patients discharged from acute care hospitals. JAMA Intern Med 2013;173:518-523.
  7. Sabesin SM. Safety issues relating to long-term treatment with histamine H2-receptor antagonists. Aliment Pharmacol Ther 1993;7(Suppl 2):35-40.
  8. Parikh N, Howden CW. The safety of drugs used in acid-related disorders and functional gastrointestinal disorders. Gastroenterol Clin North Am 2010;3:529-542.
  9. Fedewa A, Rao SSC. Dietary fructose intolerance, fructan intolerance and FODMAPS. Curr Gastroenterol Rep 2014;16:370.
  10. Ford AC, Lacy BE, Talley NJ. Irritable Bowel Syndrome. N Engl J Med 2017;376:2566-2578.