Paradigms and perspectives
The ‘‘dangers’’ of chronic proton pump inhibitor use
Rena Yadlapati, MD, MSHS, and Peter J. Kahrilas, MD
Key words: Proton pump inhibitor, gastroesophageal reflux disease,
adverse events, safety
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 H1/K1 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
From the Division of Gastroenterology and Hepatology, Department of Medicine,
Northwestern University Feinberg School of Medicine.
P.J.K. was supported by grant R01 DK092217 from the Public Health Service. R.Y. was
supported by National Institutes of Health grant T32DK101363.
Disclosure of potential conflict of interest: The authors declare that they have no relevant
conflict of interests.
Received for publication April 21, 2017; revised June 1, 2017; accepted for publication
June 13, 2017.
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. E-mail: p-kahrilas@
northwestern.edu.
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Chicago, Ill
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.1 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)2 and vitamin B12 (hazard ratio, 1.83)
deficiency.3 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).4 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.4 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.4
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.5 Rare isolated cases of profound
PPI-associated hypomagnesemia have also been reported.4
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.6 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.4,7 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.8
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 5 .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.9
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
1
2 YADLAPATI AND KAHRILAS J ALLERGY CLIN IMMUNOL
nnn 2017

Observed effect
SIBO
S EEsophageal cancer Hypothesized effect, not observed
Traveller’s
T diarrhea Pneumonia
eumo Reported weak associa on
SSalmonella, shigella
C.
C difficile coli s C
Chronic Brain β–
B B
Brain β–
kkidney amyloid (mice)
oid (m aamyloid Demen a
D
Encephalopathy
E disease ((human)
and
a SBP in cirrho css

ECL cell hyperplasia Gastric

G Unknown
Fundic gland polyps sterility
sterilit mechanism Hypersensi vity
Rebound hypersecre on reac
ac ons
o
Rat carcinoids
oids
H+/K+ ATPase Acute
Chronic Id
Idiosyncra c
G
Gastrin inhibi on, inters
in al
PPI use reac ons
gastric
g acid nephri s
Human
H n carcinoids
Colon cancer Severe
Sever
H. pylori
pylo Compe
mpe ve hypomagnesemia
IIron Nutrient
N pangastri s inhibi on of
deficiency
d fi y absorp
ab on CYP450
anemia
Gastri
Gastric
G
Drug-drug
Calcium
Calcium cancer
c Clopidogrel
pidog
B12 interac ons: dilan n,
absorp
ab on ac
a va on in-
deficiency
d fi coumadin, diazepam
vitro
anemia
Bone
fracture
fr Cardiovascular
C ascula events

FIG 1. Mechanisms 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. Plausibility, risk estimate, and clinical significance of risks associated with PPIs
Plausibility
of causality
Putative risk Mechanism (1 to 111) Nature of evidence Risk estimate Clinical significance

Acute interstitial nephritis Idiosyncratic effect, rare 111 Observational Moderate (OR, 5.16) Emphasizes need for
(case-control) valid PPI indication
Iron deficiency Hypochlorhydria, 111 Observational Low (OR, 2.49) Minimal; treatable and
poor absorption (case-control) reversible
Vitamin B12 deficiency Hypochlorhydria, 111 Systematic review, Low (HR, 1.83) Minimal; treatable and
poor absorption meta-analysis reversible
Severe hypomagnesemia Idiosyncratic effect, rare 111 Observational Insufficient data to Emphasizes need for valid
(case reports) calculate PPI indication
Fundic gland polyp Hypergastrinemia 111 Systematic review, Low (OR, 2.45) Minimal
meta-analysis
Small intestinal bacterial Loss of acid-mediated 111 Meta-analysis Low (OR, 2.28) Minimal; treatable and
overgrowth gastric sterility reversible
Dementia b-Amyloid deposits 11 Observational Very low (HR, 1.44) Minimal; evidence is too
(prospective cohort) weak
Spontaneous bacterial SIBO, bacterial 11 Systematic review, Low (OR, 2.28) Minimal; emphasizes need
peritonitis in cirrhotic translocation meta-analysis for valid PPI indication
patients
Clostridium Loss of acid-mediated 11 Meta-analysis Low (RR, 1.69) Minimal; emphasizes need
difficile–associated gastric sterility for valid PPI indication
diarrhea
(Continued on next page)
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VOLUME nnn, NUMBER nn

TABLE I. (Continued )
Plausibility
of causality
Putative risk Mechanism (1 to 111) Nature of evidence Risk estimate Clinical significance
Bone fracture Hypochlorhydria, poor 11 Observational Low (OR, 2.65) Minimal; standard bone
calcium absorption (case-control) health recommendations
Hepatic encephalopathy SIBO, bacterial 11 Observational Low (HR, 1.72) Minimal; emphasizes need
in cirrhotic patients translocation (case-control) for valid PPI indication
Chronic kidney disease Not established 11 Observational Low (HR, 1.50) Minimal; evidence is too
(population-based weak
cohort)
Dementia b-Amyloid deposits 11 Observational Very low (HR, 1.44) Minimal; evidence is too
(prospective cohort) weak
Community-acquired Loss of acid-mediated 1 Systematic review, Very low (OR, 1.49) Minimal; evidence is too
pneumonia gastric sterility, meta-analysis weak
aspiration
Acute cardiovascular Drug-drug interaction 1 Randomized controlled Not observed Minimal; emphasizes need
events with hepatic metabolism trial (HR, 0.99) for valid PPI indication
of clopidogrel

Plausibility of causality was graded from 1 to 111: 1 5 hypothesized, not reported, or not observed; 11 5 weak association observed; and 111 5 causal relationship
established.
HR, Hazard ratio; OR, odds ratio; RR, relative risk; SIBO, small intestinal bacterial overgrowth.

several guidelines surrounding the notion of causality, biological REFERENCES

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Table I attempts to describe the likelihood of causation and
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data do not support altering evidence-based PPI use10 on the
basis of these hypothetical risks.
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