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The “dangers” of chronic proton pump inhibitor use

  • Rena Yadlapati
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
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  • Peter J. Kahrilas
    Correspondence
    Corresponding author: Peter J. Kahrilas, MD, Northwestern University, Feinberg School of Medicine, Division of Gastroenterology and Hepatology, Department of Medicine, 676 N St Clair St, 14th Floor, Chicago, IL 60611.
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
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      Key words

      The list of reported side effects of long-term proton pump inhibitor (PPI) therapy continues to grow. Media reports linking PPI use and life-threatening conditions, such as kidney failure, heart disease, and dementia, have caused substantial angst, and at-risk patients are increasingly demanding answers about PPI safety. Every day, clinicians across many disciplines of medicine face these queries. However, the snowballing literature surrounding this topic has overwhelmed the critical analysis of that literature. Moreover, a thoughtful physician's cautious explanation of the weak and noncausal relationship between PPI use and putative risks withers in comparison with the striking declarations of adverse effects that litter the media. What is a clinician to do?
      PPIs covalently bind to and render inactive the H+/K+ ATPase that is the final common pathway for gastric acid secretion, making them orders of magnitude more potent than H2 receptor antagonists, the drugs they supplanted in the early 1990s. Their efficacy in treating peptic ulcer disease and erosive esophagitis has nearly eliminated the need for surgery and sharply reduced disease-related morbidity and mortality with these conditions. Subsequently, their use was broadened to symptomatic reflux disease, and today, PPIs are among the most commonly used drugs worldwide. Apart from strong evidence demonstrating efficacy in treating heartburn, esophagitis, and ulcer disease, widespread PPI use is also related to a favorable safety profile, high therapeutic index, and minimal short-term side effects. However, with the exponential increase in PPI use above and beyond those core indications and the application of big data methods to query large health system databases, reports associating chronic PPI use with a variety of disorders have proliferated.
      Concerns related to chronic PPI therapy are as old as the drugs themselves. Initially, these centered on unintended consequences of pharmacologically induced hypochlorhydria or achlorhydria: hypergastrinemia, gastric cancer, gastric carcinoid tumors, loss of gastric sterility, micronutrient malabsorption, and others. Some of these effects can be demonstrated experimentally, but fortunately, there have been no instances of gastric cancers or carcinoids linked to chronic PPI therapy in human subjects.
      • Lundell L.
      • Vieth M.
      • Gibson F.
      • Nagy P.
      • Kahrilas P.J.
      Systematic review: effects of long-term proton pump inhibitor use on serum gastrin levels and gastric histology.
      On the other hand, gastric acid does facilitate iron and vitamin B12 absorption, and long-term PPI use has a dose-dependent effect on clinical iron (odds ratio, 2.49)
      • Lam J.R.
      • Schneider J.L.
      • Quesenberry C.P.
      • Corley D.A.
      Proton pump inhibitor and histamine-2 receptor antagonist use and iron deficiency.
      and vitamin B12 (hazard ratio, 1.83) deficiency.
      • Jung S.B.
      • Nagaraja V.
      • Kapur A.
      • Eslick G.D.
      Association between vitamin B12 deficiency and long-term use of acid-lowering agents: a systematic review and meta-analysis.
      PPI-induced hypochlorhydria also interferes with gastric bactericidal function, and long-term use can predispose to enteric infections, including Clostridium difficile colitis (up to 3-fold increase), Campylobacter or Salmonella gastroenteritis (2- to 6-fold increase), and small intestinal bacterial overgrowth (2- to 8-fold increase).
      • Freedberg D.E.
      • Kim L.S.
      • 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.
      Because of potential bacterial translocation, PPI use is also an independent risk factor for spontaneous bacterial peritonitis (hazard ratio, 2.17) and encephalopathy (hazard ratio, 1.88) among patients with cirrhosis.
      • Freedberg D.E.
      • Kim L.S.
      • 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.
      Conversely, despite being subject to intense scrutiny for more than 10 years, evidence does not support clinically relevant calcium malabsorption or an increased risk of community-acquired pneumonia with chronic PPI use.
      • Freedberg D.E.
      • Kim L.S.
      • 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.
      Mass population exposure to PPIs (many millions of persons worldwide) has also provided ample data on potential idiosyncratic reactions. Acute interstitial nephritis appears to be an idiosyncratic risk related to PPI use; a 2014 observational nested case-control study reported a 5-fold increased adjusted odds ratio for PPI users.
      • Blank M.L.
      • Parkin L.
      • Paul C.
      • Herbison P.
      A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use.
      Rare isolated cases of profound PPI-associated hypomagnesemia have also been reported.
      • Freedberg D.E.
      • Kim L.S.
      • 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.
      However, the mechanisms are not understood in either case, and attempts at establishing linkage between PPI use and chronic kidney disease or hypomagnesemia in population-based studies have yielded only very low hazard ratios (≤1.5), raising legitimate concern that these represent noise rather than signal.
      • Kia L.
      • Kahrilas P.J.
      Therapy: risks associated with chronic PPI use—signal or noise?.
      Similar weak associations with PPI use have been reported for dementia and myocardial infarction, where plausible, or weakly plausible mechanisms were tested in population-based epidemiology studies, meta-analyses, or both.
      • Freedberg D.E.
      • Kim L.S.
      • 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.
      • Sherwood M.W.
      • Melloni C.
      • Jones S.
      • Washam J.B.
      • Hasselblad V.
      • Dolor R.J.
      Individual proton pump inhibitors and outcomes in patients with coronary artery disease on dual antiplatelet therapy: a systematic review.
      However, in the case of myocardial infarction, this was also tested in a randomized controlled trial, the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT), which found no evidence of a clinically significant PPI-clopidogrel interaction.
      • Bhatt D.L.
      • Cryer B.L.
      • Contant C.F.
      • Cohen M.
      • Lanas A.
      • Schnitzer T.J.
      • et al.
      Clopidogrel with or without omeprazole in coronary artery disease.
      COGENT randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel and aspirin in combination with either omeprazole or placebo; cardiovascular events occurred in 4.9% of the omeprazole group compared with 5.7% in the placebo group (hazard ratio with omeprazole, 0.99; P = .96). Clearly, observational studies have their limits, and until verified by prospective controlled data, findings from observational studies, especially findings of weak association, should be viewed as hypothesis generating. These studies are inherently flawed by an inability to establish causality, unmeasured confounders, inaccurately measured confounders, and unaccounted for biases.
      • Grimes D.A.
      • Schulz K.F.
      False alarms and pseudo-epidemics: the limitations of observational epidemiology.
      Therefore, presented with these data, how should clinicians guide patients on PPI risk? Clinicians should weigh the likelihood of causation against the clinical significance of the risk. Among several guidelines surrounding the notion of causality, biological plausibility of the association and strength of association are dominant.
      • Grimes D.A.
      • Schulz K.F.
      False alarms and pseudo-epidemics: the limitations of observational epidemiology.
      Fig 1 diagrams what we know of PPI's effects and the plausibility of how these can lead to side effects. In observational epidemiology the strength of association, or the effect size, is derived from risk estimates in which an odds ratio of between 1 and 3 or relative risk of between 1 and 2 are subject to potential bias and indicate a weak association.
      • Grimes D.A.
      • Schulz K.F.
      False alarms and pseudo-epidemics: the limitations of observational epidemiology.
      Figure thumbnail gr1
      Fig 1Mechanisms of potential risks associated with PPIs. Blue boxes represent effects that are observed. Green boxes represent effects that are weakly associated with PPI use. Pink boxes represent hypothetical effects that have not been reported or observed in association with PPI use. Black arrows are established linkages, whereas red arrows are proposed unproved links. ECL, Enterochromaffin-like; SBP, spontaneous bacterial peritonitis; SIBO, small intestinal bacterial overgrowth.
      Table I attempts to describe the likelihood of causation and clinical significance of the risk. Note that in no instance is there a known mechanism, strong association, or great clinical significance. Idiosyncratic reactions can occur with any drug, and none are risk free. This emphasizes the need for some benefit to offset the risk, no matter how minuscule that risk. PPIs should have a valid indication and be used at an appropriate dose.
      • Scarpignato C.
      • Gatta L.
      • Zullo A.
      • Blandizzi C.
      SIF-AIGO-FIMMG Group, Italian Society of Pharmacology, the Italian Association of Hospital Gastroenterologists, and the Italian Federation of General Practitioners
      Effective and safe proton pump inhibitor therapy in acid-related diseases—a position paper addressing benefits and potential harms of acid suppression.
      Iron deficiency, vitamin B12 deficiency, C difficile–associated diarrhea, sequelae of bacterial translocation in cirrhosis, and small intestinal bacterial overgrowth are all mechanistically plausible, yet the risk estimates are low, the conditions are treatable, and the clinical significance is more modest. The low-quality evidence surrounding chronic kidney disease, myocardial infarction, bone fracture, and dementia is not at all compelling. Hence currently available data do not support altering evidence-based PPI use
      • Scarpignato C.
      • Gatta L.
      • Zullo A.
      • Blandizzi C.
      SIF-AIGO-FIMMG Group, Italian Society of Pharmacology, the Italian Association of Hospital Gastroenterologists, and the Italian Federation of General Practitioners
      Effective and safe proton pump inhibitor therapy in acid-related diseases—a position paper addressing benefits and potential harms of acid suppression.
      on the basis of these hypothetical risks.
      Table IPlausibility, risk estimate, and clinical significance of risks associated with PPIs
      Putative riskMechanismPlausibility of causality (+ to +++)Nature of evidenceRisk estimateClinical significance
      Acute interstitial nephritisIdiosyncratic effect, rare+++Observational (case-control)Moderate (OR, 5.16)Emphasizes need for valid PPI indication
      Iron deficiencyHypochlorhydria, poor absorption+++Observational (case-control)Low (OR, 2.49)Minimal; treatable and reversible
      Vitamin B12 deficiencyHypochlorhydria, poor absorption+++Systematic review, meta-analysisLow (HR, 1.83)Minimal; treatable and reversible
      Severe hypomagnesemiaIdiosyncratic effect, rare+++Observational (case reports)Insufficient data to calculateEmphasizes need for valid PPI indication
      Fundic gland polypHypergastrinemia+++Systematic review, meta-analysisLow (OR, 2.45)Minimal
      Small intestinal bacterial overgrowthLoss of acid-mediated gastric sterility+++Meta-analysisLow (OR, 2.28)Minimal; treatable and reversible
      Dementiaβ-Amyloid deposits++Observational (prospective cohort)Very low (HR, 1.44)Minimal; evidence is too weak
      Spontaneous bacterial peritonitis in cirrhotic patientsSIBO, bacterial translocation++Systematic review, meta-analysisLow (OR, 2.28)Minimal; emphasizes need for valid PPI indication
      Clostridium difficile–associated diarrheaLoss of acid-mediated gastric sterility++Meta-analysisLow (RR, 1.69)Minimal; emphasizes need for valid PPI indication
      Bone fractureHypochlorhydria, poor calcium absorption++Observational (case-control)Low (OR, 2.65)Minimal; standard bone health recommendations
      Hepatic encephalopathy in cirrhotic patientsSIBO, bacterial translocation++Observational (case-control)Low (HR, 1.72)Minimal; emphasizes need for valid PPI indication
      Chronic kidney diseaseNot established++Observational (population-based cohort)Low (HR, 1.50)Minimal; evidence is too weak
      Dementiaβ-Amyloid deposits++Observational (prospective cohort)Very low (HR, 1.44)Minimal; evidence is too weak
      Community-acquired pneumoniaLoss of acid-mediated gastric sterility, aspiration+Systematic review, meta-analysisVery low (OR, 1.49)Minimal; evidence is too weak
      Acute cardiovascular eventsDrug-drug interaction with hepatic metabolism of clopidogrel+Randomized controlled trialNot observed (HR, 0.99)Minimal; emphasizes need for valid PPI indication
      Plausibility of causality was graded from + to +++: + = hypothesized, not reported, or not observed; ++ = weak association observed; and +++ = causal relationship established.
      HR, Hazard ratio; OR, odds ratio; RR, relative risk; SIBO, small intestinal bacterial overgrowth.

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