REVIEWS

Proton-pump inhibitors: understanding

the complications and risks
Peter Malfertheiner, Arne Kandulski and Marino Venerito
Abstract | Proton-pump inhibitors (PPIs) are the most effective therapy for the full spectrum
of gastric-acid-related diseases. However, in the past decade, a steadily increasing list of
complications following long-term use of PPIs has been reported. Their potent acid-suppressive
action induces several structural and functional changes within the gastric mucosa, including
fundic gland polyps, enterochromaffin-like cell hyperplasia and hypergastrinaemia, which can
be exaggerated in the presence of Helicobacter pylori infection. As discussed in this Review, most
associations of PPIs with severe adverse events are not based on sufficient evidence because
of confounding factors and a lack of plausible mechanisms. Thus, a causal relationship remains
unproven in most associations, and further studies are needed. Awareness of PPI-associated risks
should not lead to anxiety in patients but rather should induce the physician to consider the
appropriate dosing and duration of PPI therapy, including long-term monitoring strategies
in selected groups of patients because of their individual comorbidities and risk factors.

Proton-pump inhibitors (PPIs) became available in of acid-inhibiting agents (that is, histamine H2 receptor

clinical practice 25 years ago and have since added a
new successful therapeutic option to the management
of gastric-­acid-related diseases. These agents are among
the most commonly used drugs in the world, and their
wide use is best exemplified by sales of PPIs — one
­single PPI, esomeprazole, was reported to have more
than US$5 ­billion in sales worldwide in 2015 (REFS 1,2).
PPI therapy addressed previously unmet needs, such as
healing and preventing peptic ulcerations, and helped
optimize the management of GERD. The clinical use
of PPIs has been extended to all diseases in which
gastric acid has either a primary or contributory role
(BOX 1). Depending on the nature of the disease, PPIs
are prescribed for short-term (2–8 weeks) or long-term
(>8 weeks) periods, with either continuous, intermittent
or on‑demand intake. With the increasing use of PPIs,
a series of important therapeutic challenges, adverse
effects and complications have emerged. In the past
Department of
decade, concerns have increasingly been raised about
Gastroenterology, the long-term use of PPIs. Many of the adverse events
Hepatology and Infectious and complications of long-term PPI use have led to
Diseases, Otto von Guericke controversial results and have greatly contributed to
University Hospital, Leipziger
the insecurity of prescribing physicians and the anxiety
Strasse 44, 39120
Magdeburg, Germany. of patients. When PPIs were brought to market, initial
Correspondence to P.M. 
concerns were related to PPI toxicity. Claims such as the
peter.malfertheiner@ induction of vasculitis and anterior optical neuropathy
med.ovgu.de due to omeprazole were abandoned because of lack of
doi:10.1038/nrgastro.2017.117 causality 3. Indeed, some of the concerns raised in regard
Published online 20 Sep 2017 to PPI safety were a result of the highly competitive field
antagonists) ­battling for the sales market at the time.
In our opinion, PPI-related adverse effects are, to a minor
extent, substance-­related, but most are due to the induc-
tion of gastric hypo­chlorhydria. In this Review, we will
address the most rele­vant adverse events claimed with
PPI use, reported from patient cohorts and population-­
based and community-­based studies, and indicate how
they might be r­ elevant to clinical practice (TABLE 1).
Stomach
PPIs and structural or functional abnormalities.
PPIs taken over a prolonged period of time lead to
substantial changes in the structure and function of
the stomach (BOX 2). The most consistent structural
changes in the gastric mucosa are the development of
parietal cell hyperplasia and hypertrophy 4,5. Parietal cell
protrusion and swelling are reported after 3 months
on omeprazole6.
Experienced pathologists, therefore, might identify a
patient on long-term PPI therapy solely on the finding
of parietal cell morphology in the oxyntic mucosa, even
in the absence of any clinical information. Parietal cell
hyperplasia is related to the trophic, cell-­proliferation-
inducing effect of hypergastrinaemia, which is most
often moderately increased in patients on long-term
PPI therapy 7,8. Hypergastrinaemia is paralleled by a
decrease in somatostatin levels consequent to the potent
PPI-induced acid suppression (hypochlorhydria) 9,
regu­lated by an acid-driven negative feedback system.

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY ADVANCE ONLINE PUBLICATION | 1

©
2
0
1
7
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

Key points acid-suppression therapy (PPIs and/or H2 receptor

• Proton-pump inhibitors (PPIs) induce structural and functional changes in the gastric
mucosa related to potent acid suppression, which are exaggerated during
Helicobacter pylori infection; PPIs alone are unlikely to be related to gastric
and gastrointestinal malignancies
• The list of adverse events associated with PPI intake is increasing; few of these
associations are plausible or proven to have a causal relationship
• The risk of bacterial enteric infections with Clostridium difficile, Salmonella and
Campylobacter is increased in patients on PPI therapy — this risk is low to modest
• PPI use can rarely cause acute kidney injury and other morbid conditions related
to idiosyncratic effects
• Long-term PPI intake interferes with magnesium and calcium homeostasis in small
subsets of patients with chronic kidney disease on diuretic therapy; the prevalence
of bone fractures attributable to PPIs in older patients is low
• The debate on whether PPIs increase the risk of coronary events in patients on
clopidogrel seems to be resolved; the FDA recommends avoiding omeprazole
in patients taking clopidogrel
An important clinical effect of parietal cell hyperplasia
is acid rebound, which occurs with a sudden stop of PPI
use after 8 weeks of continuous intake10. This abrupt
withdrawal of a PPI after prolonged intake can lead to
acid-related symptoms or their relapse, and therefore,
patients should be instructed on how to taper down
PPI intake if PPIs were taken for a prolonged period of
time. No guidelines are available for how to proceed with
tapering, but in individual case management, PPI paus-
ing can be started with a 1‑day intermission with gradual
prolongation of the intervals, and an attempt to stop PPIs
can be made after 2–4 weeks. In a subset of patients,
PPIs can lead to the development of so‑called cystic
glands, defined as fundic gland polyps (FGPs) because
of their polyp-like endoscopic appearance (FIG. 1). FGPs,
although detected in ~2% of the general population,
are 2–4 times more frequent in patients with long-term
PPI use, and there is a positive correlation between the
development of FGPs and the length of PPI exposure11,12.
A systematic review with meta-analysis concluded from
a subanalysis that the use of PPIs for at least 12 months
is necessary for FGP development 13.
According to current literature, PPI-associated
FGPs have not been shown to develop into gastric
cancer. Extremely rare sporadic FGPs, independent of
PPI use, presenting with a mutation in β‑catenin with
a genetically predetermined risk of malignant pro-
gression have been identified14,15. The benign nature
of FGPs and the exceptional reports of endoscopically
non-­distinguishable FGPs at risk of malignancy do not
justify including examination for FGPs in regular gastric
biopsy protocols.
Development of enterochromaffin-like (ECL) cell
hyperplasia in the oxyntic mucosa is found in 10–20%
of patients on long-term PPIs5.The underlying mech-
anism is a direct effect of gastrin (hypergastrinaemia),
and the dynamics of ECL cell proliferation are reflected
by increased serum levels of chromogranin A16. ECL
cell hyperplasia is of small clinical relevance and rarely
progresses to linear or even micronodular hyper­plasia.
To date, 11 cases of carcinoid tumours in patients on
antago­nists) have been reported17. However, careful
documentation and discussion of the underlying mech­
anism have been provided for only two of these cases
of gastric carcinoids on long-term PPIs18,19. In one of
these two patients, the gastric carcinoid was endo­
scopically removed, whereas it regressed spontaneously
in the other patient 16. In both patients, ECL cell hyper­
plasia regressed after cessation of PPI therapy. A modest
increase in levels of gastrin and chromogranin is induced
by PPIs, starting from day 5, and the levels return to
­normal within a few days after PPI w ­ ithdrawal20 (FIG. 2).
The diagnosis of gastrinoma can be delayed or pre-
vented by PPIs. The assumption is that PPIs can lead
to complete symptom control and, therefore, mask the
endocrine neoplasia21. However, long-term PPI use is
the appropriate therapy for most patients with this endo-
crine tumour. An increased risk of gastric cancer with
PPI use is often discussed but has never been proven.
Claims have even been made, on the basis of experi­
mental studies, that PPIs might exert several poten-
tial anti-carcinogenic actions, including the induction
of apoptosis and inhibition of inflammatory signals
and of angiogenic activities by blocking gastrin recep-
tor binding 22. Nevertheless, the clinical suspicion of a
carcino­genic effect of PPIs in humans has been fuelled by
a population-based cohort study. The incidence of gas-
tric cancer was increased among PPI users with the most
prescriptions and longest follow‑up23. Furthermore, the
gastric cancer incidence was more frequent in those on
PPIs that had received Helicobacter pylori eradication,
but information on whether H. pylori eradication had
been successful in these patients was missing. Whether
preneoplastic or early neoplastic changes had already
existed in patients developing gastric cancer during
PPI intake cannot be extrapolated from the report.
H. pylori as a major confounding factor, in addition
to others (such as dietary habits or family history of
gastric cancer), was not taken into account in three
other observational studies, and therefore, the estim­
ated risk of PPI-associated and drug-related gastric
Box 1 | Clinical use of PPIs
• Peptic ulcer disease
• Zollinger–Ellison syndrome
• Stress ulcer prophylaxis
• Prevention of NSAID-induced or ASA-induced
gastroduodenopathy
• Helicobacter pylori eradication
• Upper gastrointestinal bleeding
• GERD (symptomatic)
• Oesophagitis, Barrett oesophagus and peptic stricture
• Uninvestigated dyspepsia and functional dyspepsia
• Oesophageal eosinophilia and suspected eosinophilic
oesophagitis
• Exocrine pancreatic insufficiency*
*Combined with enzyme replacement. ASA, acetylsalicylic
acid; PPI, proton-pump inhibitor.

2 | ADVANCE ONLINE PUBLICATION www.nature.com/nrgastro

©
2
0
1
7
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 REVIEWS

Table 1 | Evidence levels for the association between PPIs and various complications
Complications associated Level of Key findings
with PPI use evidence*
Structural or functional 2a Increased risk of fundic gland polyps
abnormalities
2a Increase in parietal cell mass
2b Hypergastrinaemia, hyperchromograninaemia
1c Enterochromaffin-like cell hyperplasia
Effects on Helicobacter 1c Shift from antrum-predominant to corpus-predominant gastritis,
pylori gastritis exaggerated increase in gastrin
Gastrointestinal infection 2a Increased risk of Clostridium difficile infection (OR 1.5–1.8)
2a/b For other pathogenic bacteria, >2–4‑fold increased risk
Pneumonia 2a/2b/2c Conflicting data, all from retrospective studies
2a/2b In large retrospective RCT and cohort studies, increased risk not confirmed
AIN 2b Considerable (fivefold increased) risk of AIN, re‑exposure to be avoided
CKD 2b Low risk of development of CKD
Hypomagnesaemia 3b Consider PPIs as a cause of hypomagnesaemia in patients with CKD
on diuretic therapy
Hypocalcaemia 4 No population-based or controlled studies
Fractures and osteoporosis 2a • PPI dose and duration dependency in older patients (aged >65 years)
• Low risk in patients without any other risk factors
Myopathies 4 • Possibly idiosyncratic reaction
• The underlying mechanisms leading to rhabdomyolysis with PPI use
are unclear but are possibly related to interactions with concomitantly
administered drugs such as HMG-CoA reductase inhibitors (statins).
Reduced clopidogrel 1c No increase of risk in randomized clinical trials
activation with increased
cardiovascular risks 2a Slightly increased risk in retrospective cohort studies.

Dementia 3b Increased risk (OR 1.6) with high bias

*Interpretation: 1a, systematic review of a randomized controlled trial (RCT) of good methodological quality and with
homogeneity; 1b, individual RCT with narrow 95% CI; 1c, individual RCT with risk of bias; 2a, systematic review of cohort studies
(with homogeneity); 2b, individual cohort study (including low-quality RCT, for example, <80% follow‑up); 2c, non-controlled
cohort studies or ecological studies; 3a, systematic review of case–control studies (with homogeneity); 3b, individual case–control
study; 4, case series or poor-quality cohort or case–control studies. AIN, acute interstitial nephritis; CKD, chronic kidney disease;
HMG-CoA, 3‑hydroxy‑3‑methylglutaryl-coenzyme A; OR, odds ratio; PPI, proton-pump inhibitor.

cancer (relative risk (RR) 1.43, 95% CI 1.23–1.66) 13
should not, in our opinion, cause concern at this time.
Further investigations of this important relationship
should be conducted before drawing a final conclusion.
Ideally, study design should be prospective and include
a large cohort of patients newly starting on PPIs with an
anticipated requirement for long-term PPI therapy for
follow-up. Most importantly, patients should be free or
cured from H. pylori gastritis and should have no pre-
neoplastic gastric mucosal lesions and no familial his-
tory of gastric cancer at inclusion; a control group with
no PPI use should also be included. Patient follow‑up
will require a decade or more. There is no indication
of increased risk of structural abnormalities in the mid
and lower gastrointestinal tract, including colorectal
adenoma and colorectal cancer, in patients on long-term
PPI therapy 24,25. A statistically significant positive associ­
ation with pancreatic cancer was reported for active
PPI users (short-term and long-term): in a cohort of
4,113 cases with pancreatic cancer and 16,012 matched
controls, the prevalence of PPI use was 53% and 26%,
respectively 26. The increased mortality in short-term
users is addressed by the study authors as an example of
reverse causality and can be explained by the assump-
tion that patients most likely started PPIs shortly after,
or at the time of, pancreatic cancer diagnosis.
PPIs and H. pylori gastritis. The interaction between
PPIs and H. pylori is complex and depends on the pheno­
type of gastritis. In patients requiring PPIs, H. pylori gas-
tritis is mostly antrum predominant27–29. With long-term
PPI intake, levels of inflammation and bacterial coloniza­
tion in the antrum decline, whereas the inflammation in
the corpus and fundus was found to increase5,30,31 (FIG. 3).
Several studies have demonstrated that use of PPIs in
H. pylori-infected patients is associated with the develop­
ment of corpus-predominant gastritis32–34. Over the long
term, this process can lead to an accelerated loss of o
­ xyntic
glands and development of atrophic gastritis, impaired
acid output, colonization of the stomach by other bacteria
(mainly those from the oral flora) and gastric hormone
dysregulation26–28. The European Maastricht V/Florence
consensus report recommended that H. pylori infection
be cured in patients requiring long-term PPI therapy to
prevent the development of gastric mucosa abnormalities
and progression to atrophic gastritis35.

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY ADVANCE ONLINE PUBLICATION | 3

©
2
0
1
7
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

Gastrointestinal tract
Gastric and intestinal microbiota. The effect of PPIs on
the gastric microbiota is primarily related to H. pylori.
Microorganisms other than H. pylori are usually not
detectable on the gastric mucosa but have been cul-
tured from gastric biopsy samples and aspirates
obtained from patients on PPIs36. The gastric micro­
biota p
­ attern on PPIs is similar to that seen in patients
with hypochlor­hydria associated with severe atrophic
gastritis37. The microbial colonization in the small and
large bowel is also subject to variations in gastric acidity.
Gut microbiota composition is altered by PPI intake,
according to a series of studies. In a crossover trial of
12 healthy individ­uals off and on PPIs, taxa (that is
Enterococcaceae and Streptococcaceae) associated
with Clostridium difficile became prominent ­colonizers
of the lower gut, whereas Clostridiales decreased in
abundance38. Microbial diversity was reported to be
lower in patients on PPIs than in those not taking PPIs,
according to a large twin cohort study 39. In a study of a
large cohort from the Netherlands, the gut microbiota
assemblage was predisposing to C. difficile infection40.
A decrease in Bacteroides and an increase in Firmicutes
abundance and the detection of Holdemania filiformis
were reported in a small cohort of 32 patients on long-
term PPI use compared with 22 healthy individuals41.
The clinical importance of these findings needs to be
further explored. Changes in gut microbiota compo-
sition because of long-term PPI use might predispose
patients to dysbiosis and enteric infections.
Small intestinal bacterial overgrowth. An increase
in the number (colony forming units >1 × 105/ml) of
endogenous symbiotic bacterial flora normally coloniz-
ing the colon defines the diagnosis of small intestinal
bacterial overgrowth (SIBO). The increase in gastric pH
by PPIs is the postulated mechanism of SIBO. At high
pH, the amount of bacteria normally transiting the
stomach and colonizing the small bowel is probably
increased. An increased risk of SIBO with PPI intake
Box 2 | Stomach-related PPI complications
• Hypochlorhydria
• Hypergastrinaemia
• Parietal cell hyperplasia
• Fundic gland polyps (FGPs)
• Enterochromaffin-like (ECL) cell hyperplasia along with
hyperchromograninaemia
• Gastric carcinoids (rare)
Proton-pump inhibitor (PPI) intake results in various
degrees of acid suppression depending on dose, duration
and individual responses. This process leads to a series of
functional and structural consequences. The initial
response to impaired acid production is an increase of
gastrin, which is intended as a compensating mechanism
to stimulate the oxyntic gland’s components to produce
acid and results in cellular increase (parietal cells, ECL
cells). FGPs are four times more frequently detected.
Gastric carcinoids are rare.
has been reported42, but another study did not confirm
this association43. Nearly all studies on the relation­
ship of PPIs with SIBO were based on glucose-H2
breath tests, and most of them reported no statistically
signifi­cant association, as reported in a meta-analysis44.
H2-based breath tests are less accurate than duodenal
aspirate sampling. A study based on duodenal aspir­
ates demonstrated a significantly increased preva-
lence of bacterial and fungal overgrowth in patients on
PPIs (P <0.0063), and that PPI use was an independ-
ent risk factor for this overgrowth45. A study with the
same methodology conducted in 713 patients on PPIs
reported an association between SIBO and IBS, but this
association was not affected by PPI intake46.
The assessment of SIBO and its clinical relevance
must be readdressed by studies that will make use
of next-generation sequencing and of the analysis of
meta­bolic products of the microorganisms colonizing
the small bowel. Symptomatic SIBO developing during
PPI intake is, according to all available evidence, best
handled on an individual basis.
Enteric infections. A threefold increased risk of enteric
infections on PPI use, including by Salmonella and
Campylobacter spp., has been summarized in sys­tematic
reviews of mostly observational and retrospective stud-
ies (six studies, 11,280 patients), highlighting substan-
tial heterogeneity 47. A case–control study reported a
fourfold increase in Salmonella enterica subsp. enter-
ica Enteritidis infection and an eightfold increase in
Salmonella enterica subsp. enterica Typhimurium
infection with recent, even short-term, use of PPIs48.
Campylobacter jejuni diarrhoea has been reported with
an odds ratio of 2.9–11.7 from four studies49. Although
the increased risk of enteric infection has been estab-
lished, the magnitude is heterogeneous and is estimated
to be on the order of 2–3‑fold. In a prospective Dutch
population-based cohort study with 14,926 individ­
uals aged >45 years and a 24‑year follow‑up, PPI intake
was associated with an increased risk (OR 1.94, 95% CI
1.15–3.25) of bacterial gastroenteritis50. Strong acid
inhibition might also facilitate traveller’s diarrhoea
induced by common enteropathogens (such as toxigenic
Escherichia coli or Shigella spp.)49, but properly designed
prospective studies are not available. In clinical practice,
patients are advised to first observe hygienic recom­
mendations, but, in addition, they should reduce PPI
intake to a minimum effective required dose when visit­
ing subtropical or tropical regions with well-known risk
of enteric infections.
The risk of developing C.  difficile infection is
increased by 1.5–2‑fold even after recent PPI use. Two
meta-analyses based on 42 (30 case–control, 12 cohort)
and 51 (37 case–control, 14 cohort) studies showed that
the risk of developing C. difficile infection in patients on
PPIs is modest (OR 1.74, 95% CI 1.47–2.85 and OR 1.65,
95% CI 1.47–1.85, respectively)51,52. These meta-­analyses
noted several shortcomings related to the nature of the
studies — mostly observational, monocentric and retro­
spective, with no adjustment for comorbidity and no
report on the duration of PPI exposure or antibiotic

4 | ADVANCE ONLINE PUBLICATION www.nature.com/nrgastro

©
2
0
1
7
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 REVIEWS

a b Extraintestinal complications
Pneumonia. In critically ill patients, stress ulcer prophy­
laxis with PPIs was reported to be associated with an
increased risk of pneumonia (OR 1.3–2.7)62. However,
the putative mechanism of ascending bacterial coloniza­
tion from the hypoacidic stomach with transfer to the
* lung because of high intragastric pH is unproven and
lacks plausibility, except in aspiration pneumonia.
In a systematic review and meta-analysis published
in 2016, pneumonia and mortality were not found
to be s­ ignificantly increased in critically ill patients
|
Figure 1 Endoscopic appearance of fundic Naturegland polyps.
Reviews Characteristic&endoscopic
| Gastroenterology Hepatology taking PPIs63.
images of multiple fundic gland polyps of the oxyntic mucosa. a | Multiple fundic gland
polyps (arrow). b | Histomorphological characteristics of a cystic gland dilatation After the first report of community-acquired pneu­
(asterisk). These polyps are located in the fundic or corpus mucosa between gastric rugal monia by use of PPIs in an outpatient setting 64, a meta-
folds. They can also appear in a single polypoid structure. The size varies from a few analysis of five observational studies corrobor­ated this
millimetres up to 10 mm. The underlying lesion is not a mucosal neoformation, but a early observation65. However, later studies did not con-
cystic gland dilatation (histomorphology). Part b courtesy of D. Jechorek, University of firm an increased risk of community-acquired pneu-
Magdeburg, Germany, in collaboration with P. M. monia in patients on PPIs. A study involving eight
Canadian centres with >4 million patients newly pre-
scribed NSAIDs found that those exposed to PPIs were
intake — and concluded that a cause–effect relation- not more frequently affected by pneumonia than those
ship cannot be supported based on these findings. not exposed to PPIs66. No association between treatment
A meta-analysis published in 2016 based on 23 obser- with a PPI (esomeprazole) and community-­acquired
vational studies including 186,033 individuals con- respiratory tract infections (including pneumonia)
firmed the modest magnitude of the PPI-related risk of was reported in a retrospective analysis from 24 ran­
hospital-acquired C. difficile infection but emphasized domized double-blind clinical ­trials of patients receiving
the notable health and economic burden53. Notably, the esomepra­zole67. An overview of 33 sys­tematic reviews
coadministration of a PPI with antibiotics has an addi- on PPI-related adverse events underlines the finding
tive increased risk, and therefore, prescription of PPIs that the strongest association of community-­acquired
should be checked for ­appropriateness to minimize the pneumonia was most strongly associated with PPI
risk of C. difficile infection54. intake in the first 7–30 days68. This finding can be taken
as a hint that PPIs are more likely prov­ided to patients at
Microscopic colitis. An association between PPIs and the onset of pneumonia rather than as an adjunct med­
microscopic colitis has been reported in a series of ication. These latest studies seem to largely outweigh the
case reports55,56. In a retrospective analysis of 95 well-­ claim that PPI use increases the risk of pneumonia.
documented cases of microscopic colitis, exposure to
PPIs was identified as a risk factor 57. The magnitude of PPIs and dementia. The risk of incidental dementia
the risk associated with PPIs was low, but PPI intake as from PPI therapy was reported in a large p ­ rospective
a rare cause of diarrhoea should be remembered. The observational longitudinal study from Germany
risk of microscopic colitis is statistically significant for (OR 1.44, 95% CI 1.36–1.52)69. Notably, at inclusion,
concomitant PPI and NSAID therapy 58, although the patients had no dementia and a minimum age of
underlying mechanisms are unknown. 75 years. In this study, PPI intake was found to have
a similar degree of association with cognitive impair-
Spontaneous bacterial peritonitis and the liver. The ment as with age, depression and polypharmacy. Even
association between the risk of spontaneous bacterial after exclusion of these factors, the association of regu­
peritonitis (SBP) and PPI use is controversial. In a sys- lar PPI intake with dementia in this elderly population
tematic review including 12 articles and five confer- remained statistically significant. However, in a large
ence abstracts, the odds ratio for SBP was 2.17 (95% CI case–control study of primary care in patients with
1.46–3.23)59. In a prospective multicentre study, there dementia (mean age of 80 years), PPIs were associ-
was no evidence of an increased incidence of SBP60. In a ated with a reduced risk of dementia (OR 0.93, 95% CI
further study of a post-hoc analysis of different thera- 0.90–0.97). A similar effect was shown with statins and
peutic ­trials in an international patient cohort, the odds antihypertensive drugs70.
ratio for SBP was 1.72 (95% CI 1.10–2.69), and the risk Data on the association of PPIs and dementia are
of hepatic encephalopathy was also increased61. In our controversial, with either a modest or even reduced risk.
opinion, the appropriate use of PPIs in patients with Confounding factors such as patient characteristics,
liver cirrhosis is of no concern and should follow the comorbidities and polypharmacy are the most likely
usual established indications for PPIs. Inappropriate explanation for this discrepancy. In our opinion, stud-
use includes long-term PPI therapy in patients with ies that have so far been conducted only in patients with
oesophageal varices in the absence of GERD, as there is dementia in advanced age should not cause any worries
no evidence for protection from oesophageal variceal concerning the use of PPIs but rather should remind us
bleeding with long-term PPI intake. about their responsible use for proper indications.

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY ADVANCE ONLINE PUBLICATION | 5

©
2
0
1
7
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

and series have documented this association72. The

PPIs
Parietal cell
H+
+ patients without any underlying kidney disease showed
↑ Gastrin
Blood
vessel
↑ Chromogranin
↓ H+
↑ ECL cell
↑ pH
Hypergastrinaemia
↑ Gastrin
+ + Parietal cell
hyperplasia
↓ D cell
• 2-4-fold
increased
risk of fundic
↑ G cell gland polyps
Figure 2 | Effect of PPIs on gastric physiology. The pathway of acid impairment by
Nature Reviews | Gastroenterology & Hepatology
proton-pump inhibitors (PPIs) is illustrated (dotted lines indicate putative pathways).
Hypochlorhydria interferes with antral D and G cells, resulting in increased gastrin
and chromogranin that activates a hyperplastic reaction in enterochromaffin-like (ECL)
cells and parietal cells.
Myopathies. According to a review of the WHO adverse
drug reaction database (VigiBase), PPI use might,
although rarely, be associated with the occurrence of myo-
pathies, including rhabdomyolysis71. In total, the search
identified 292 reports of various myopathies in association
with PPIs. In one-third of the cases, the PPI was the only
administered drug, whereas in 57% of the reports, the PPI
was the only suspected drug by the reporter despite the
fact that concomitant medication was used. The strength
of the association between PPI intake and myopathies
is based on the temporality, that is, that the occurrence
of myopathy is associated with the timing of when PPIs
are taken. In a further report, the same patient took three
different PPIs (lansoprazole, esomeprazole and rabepra-
zole) at different time periods, with myalgia and muscle
weakness occurring with all three drugs71. Furthermore,
the time to onset after PPI intake was provided in 17 of the
cases of patients with rhabdomyolysis. The complication
occurred during the first week in nine cases and between
14 days to 3 months after treatment in a further three
patients. Notably, in 12 of these patients, a concomi­tant
intake of a 3‑hydroxy‑3‑­methylglutaryl-coenzyme A
(HMG‑CoA) reductase inhibitor (­statin) was recorded.
Kidney disease. PPI intake has been associated with
acute interstitial nephritis (AIN). Since the first report
of omeprazole-induced AIN in 1992, other case reports
most reason­able pathophysiological mechanism of PPI-
induced AIN seems to be an idiosyncratic reaction73. In a
case series of 133 patients with biopsy-proven AIN, 12%
of the cases were PPI-induced74. Thus, the widespread
prescription of PPIs requires awareness of this possible
PPI complication75. A population-based nested case–­
control study from New Zealand including 572,661
a fivefold increased risk of AIN on PPI therapy, especially
in older patients (aged >60 years of age)76. In another
population-­based study from the USA, >290,000 patients
who took PPI medication within 120 days before hos-
pital admission due to acute kidney injury (AKI) were
matched to an equal number of sex-matched and age-
matched controls who did not receive PPI medica-
tion77. Propensity score matching was used to establish
a highly comparable reference group of control patients.
PPI intake was associated with an increased risk of AKI
(HR 2.52, 95% CI 2.27–2.79) and AIN (HR 3.0, 95% CI
1.47–6.14), again with higher ­frequency in older patients.
Early detection of AIN prompts drug withdrawal with
recovery of renal function. Progression of PPI-induced
AIN to chronic kidney disease (CKD) after an episode
of AIN is possible78. In a prospective survey of a large
cohort of patients with 10,482 participants, self-reported
PPI intake was associated with an increased risk of
CKD development (HR 1.50, 95% CI 1.14–1.96), with a
­number needed to harm of 30 patients. The risk of CKD
was higher among patients taking PPIs twice daily than
those taking them once daily 79. In a study published in
2016 including 172,321 patients, the risk attributed to
PPI intake for developing AKI was moderately increased
(HR 2.15, 95% CI 2.00–2.32); the incidence of CKD was
not of clinical concern80.
All studies on the relationship of PPI intake and
increased risk of CKD have been performed in large
cohorts of patients with robust statistical methods, but
with relevant limitations. A substantial bias exists owing
to patient selection, concomitant drugs and cardio­
vascular comorbidity. The association of CKD with PPIs
(HR <2.0) is of low magnitude, but awareness of PPIs as
a possible cause for renal disease is important. In patients
with new-onset AKI due to AIN, early withdrawal of
PPIs is mandatory to restore kidney function. In patients
at increased risk of PPI-induced AIN (that is, patients
>60 years), monitoring of renal function in the first few
months might be worth considering.
Death. In older patients (≥65 years) discharged from
acute care hospitals, the association between PPI intake
and 1‑year mortality at low doses of PPIs was not statis­
tically significant, whereas high-dose PPI treatment was
associated with an increased 1‑year mortality (OR 2.59)81.
PPIs in high doses are considered an indicator of high
morbidity and polymorbidity with an associated higher
risk of mortality 81. A direct causality has not been
established. In a meta-analysis of 20 randomized clin-
ical trials, there was no difference in all-cause mortal-
ity between patients receiving PPI therapy and those
receiving placebo82.

6 | ADVANCE ONLINE PUBLICATION www.nature.com/nrgastro

©
2
0
1
7
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 REVIEWS

Vitamin and mineral deficiency
Vitamin B12 deficiency. In a case–control study within
the Kaiser Permanente Northern California popula-
tion, a ≥2‑year supply of PPIs was dispensed to 12%
of patients with vitamin B12 deficiency compared with
7.2% of patients in the control group without vitamin B12
deficiency 83. A ≥2‑year supply of PPIs (OR 1.65, 95% CI
1.58–1.73) was associated with an increased risk of vita-
min B12 deficiency. There is a plausible mech­anism for
some patients with an inadequate nutritional supply:
gastric acid is important for the release of vitamin B12
from ingested nutrients84. Gastric parietal cells are also
the source of intrinsic factor, which is essential for B12
binding 85; therefore, high PPI doses might contribute to
the critical reduction of intrinsic factor. Determination
of serum vitamin B12 levels (including peripheral red
blood cell analysis) at biannual intervals seems appro-
priate in long-term PPI users, especially if they are on
high-dose PPIs and have dietary restrictions (such as
strict vegetarians and vegans).
Hypomagnesaemia. Clinical manifestations of hypo-
magnesaemia include neuromuscular disturbances
(for example, tetany and seizures) and cardiac arrhyth-
mias86. Hypomagnesaemia with depletion of total body
magnesium stores in patients with long-term PPI use
deserves consideration, because if it occurs, it is of
important clinical concern. Initial case reports were
published in 2006, followed by other single case reports
and case series87–89. The prevalence of hypomagnesae-
mia follow­ing long-term PPI use might have been
underestimated, especially in male patients, as reported
in a critical assessment of the FDA adverse event
databank with ~1% of the patients taking long-term
PPI med­ication. The issue here is possible confound-
ing factors (that is, impaired renal function or the use
of diuretics)90. The homeostasis of the serum magne­
sium level is balanced by intestinal absorption and
renal excretion91. The postulated patho­physiological
background of PPI-associated hypomagnesaemia is
apparently caused by reduced intestinal magnesium
absorption by inhib­ition of the TRPM6 and TRPM7
channel-dependent paracellular magnesium transpor-
tation92. In patients with chronic renal insufficiency and
receiving haemo­dialysis, renal excretion is addition-
ally disturbed, and magnesium homeostasis is mainly
regu­lated by intestinal reabsorption93. Diuretics repre-
sent independent risk factors for hypomagnesaemia,
as they increase, per se, the renal loss of magnesium
and other electrolytes. Large cross-­sectional trials sug-
gest that PPI-associated hypo­magnesaemia can occur,
­especially in patients with chronic renal insufficiency
on diuretic therapy 94–97.
In patients without chronic renal insufficiency and
without concomitant diuretic therapy, the associ­ation
of PPIs and hypomagnesaemia has not been proven98.
In line with these results, a case–control study includ-
ing 154 outpatients on long-term PPI therapy and
84 matched controls not using PPIs showed no differ­
ences in serum magnesium levels99. Thus, evidence
is lacking to recommend routine screening for hypo­
magnesaemia in patients without risk factors on PPI
therapy or before initiating long-term PPI use. Monitor­
ing for hypomagnesaemia is worth considering for
those patients with additional risk factors (that is, renal
insufficiency or concomitant diuretic therapy) and is

Antrum-predominant gastritis Develops into corpus-predominant gastritis

PPIs

• ↑ IL-1β
• ↑ NH4
• ↑ other microorganisms
• Accelerate development of atrophy
Helicobacter in the fundus–corpus region
pylori

Figure 3 | Effect of acid inhibition with PPIs on Helicobacter pylori gastritis.

Nature Reviews | Gastroenterology
A shift from & Hepatology
antrum-predominant
inflammation to fundus–corpus-predominant inflammation occurs with acid inhibition via proton-pump inhibitors (PPIs).
The occurrence of Helicobacter pylori gastritis varies according to H. pylori virulence and host susceptibility genes and
is related to diverse clinical outcomes. Corpus-predominant gastritis is associated with a markedly higher risk of
developing malignancy than antrum-predominant gastritis. PPIs alter the gastric milieu by contributing to increased
IL‑1β, a potent pro-inflammatory factor, and ammonia (NH4). The catalytic activity of H. pylori urease on urea leads to
the formation of NH4, and PPIs could further promote the production of ammonia through the biological nitrogen
cycle involving other gut bacteria. IL‑1β and NH4 contribute to as well as result from the fact that H. pylori shifts from
the antrum to the corpus. Consequently, H. pylori might even totally disappear from the antrum, but it increases the
inflammation in the fundus–corpus.

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY ADVANCE ONLINE PUBLICATION | 7

©
2
0
1
7
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

recommended in those suspected to have symptoms
potentially due to hypomagnesaemia, such as cramps,
paresthesias and cardiac arrhythmias.
Hypocalcaemia. PPI-induced hypocalcaemia is
described in case reports related to PPI-associated
hypomagnesaemia100,101. The clinical importance of
PPI-associated hypocalcaemia has been emphasized
and critically discussed in studies showing an increased
risk of bone fractures among patients on long-term PPI
therapy 102. The existing data are conflicting, and the
exact pathophysiological mechanism of PPI-induced
hypocalcaemia is still unclear. Experimental evidence
indicates that PPIs might inhibit paracellular calcium
transport by increasing the luminal pH, similar to the
interference with the intestinal absorption of magne-
sium103–105. With short-term acid inhibition, PPI intake
does not influence calcium absorption. In a randomized,
placebo-controlled trial including 12 healthy volunteers
in a crossover design, inhibition of gastric acid secretion
by PPI intake did not affect the absorption of calcium.
All patients received standardized meals with defined
amounts of protein, phosphate and calcium. Gastric
acid suppression under PPI intake was monitored by
gastric pH-metry 106. Another prospective study included
21 postmenopausal women and did not find effects on
calcium absorption after 30 days of PPI-induced gas-
tric acid inhibition107. Population-based studies investi­
gating the long-term effect of PPI therapy on calcium
homeo­stasis are still lacking. However, in the analysis of
the LOTUS and SOPRAN cohorts comparing anti-reflux
surgery with long-term PPI intake for 5 and 12 years,
respectively, no differences in calcium and vitamin D
serum levels were observed between groups with or
without PPI use108. Thus, the available evidence currently
does not support that impaired calcium absorption is a
relevant PPI-associated mechanism.
Fractures and osteoporosis. The association of PPI
intake with impaired bone mineralization has been the
subject of many investigations with disparate outcomes
(TABLE 2). An increased risk of osteoporosis with hip
fractures was first reported in two observational studies
from the UK and Denmark in 2006 (REF. 109). An early
study reported an adjusted odds ratio of 1.44 (95% CI
1.30–1.59) for hip fracture in patients >65 years of age
on PPIs for >1 year 110. The findings were strengthened
by the dose-dependent and time-dependent effect of
PPI intake (adjusted OR 2.65, 95% CI 1.80–3.90). In a
large retrospective Canadian study of 15,792 patients
with osteoporosis-related fractures and 47,289 matched
controls, no increased risk of osteoporotic fractures was
observed in patients taking PPIs for <6 years. For PPI
intake >6 years, a 1.62‑fold risk of hip fracture (95% CI
1.02–2.58) was calculated111.
Two different meta-analyses confirmed only a mar-
ginally increased risk of hip fractures (OR 1.25) in older
patients on long-term PPI therapy. A meta-analysis of

Table 2 | Association between long-term PPI intake and osteoporotic changes and risk of fractures*
Reference End point of the study and results Type of study
Yang et al. 110
• Risk of hip fractures Observational,
• OR 1.44 (95% CI 1.30–1.59): older patients (>65 years); duration of PPI case–control study
intake >1 year
• Dose- and time-dependent effects: adjusted OR 2.65 (95% CI 1.8–3.90)
Vestergaard • Risk of hip fractures Observational,
et al.109 • OR 1.45 (95% CI 1.28–1.65) for PPI intake within the last year case–control study
• OR 0.69 (95% CI 0.57–0.84) for H2 receptor antagonist intake within
the last year
Targownik et al.111 • Risk of hip fractures Observational,
• OR 1.62 (95% CI 1.02–2.58); only in patients on PPIs >6 years case–control study
• No risk for patients on PPIs <6 years
Ye et al.112 • Risk of hip fractures Meta-analysis, seven
• OR 1.24 (95% CI 1.15–1.34) observational studies
Ngamruengphong • Risk of hip fractures Meta-analysis, ten
et al.113 • OR 1.25 (95% CI 1.14–1.37) observational studies
Corley et al.114 • Risk of hip fractures Observational,
• OR 1.30 (95% CI 1.21–1.39): on PPIs and H2 receptor antagonists; case–control study
only in the presence of other risk factors (that is, pre-existing osteoporosis
or chronic steroid therapy)
Kaye & Jick115 • Risk of hip fractures Observational,
• No risk in the absence of other risk factors case–control study
Targownik et al.116 • Risk of osteoporotic changes and bone mineral density loss Observational,
• No effect of PPIs on bone mineral density case–control study
Chen et al.117 • Risk of osteoporosis Observational,
• HR 1.5 (95% CI 1.39–1.62) for osteoporosis case–control study
• No risk of fractures
*Authors’ bias of most important studies investigating the association between PPI intake and risk of fractures and
osteoporotic changes based on study design, enrolled patients and robustness of data. HR, hazard ratio; OR, odds ratio;
PPI, proton-pump inhibitor.

8 | ADVANCE ONLINE PUBLICATION www.nature.com/nrgastro

©
2
0
1
7
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 REVIEWS

a Clopidogrel (Prodrug) therapy should be aware of this risk association and can
consider on an individual basis whether measures (that
Cytochrome P450 Oxidation is, bone mineral density measurement and adequate
(CYP2C19) Hydrolysis
therapy) are required. We caution against the general
Active metabolite unjustified alarm of a risk to bone health by PPI intake.

b Drug interactions
Clopidogrel (Prodrug) Interaction of PPIs with clopidogrel. A number of
Cytochrome P450 Oxidation retrospective analyses suggest an association of PPI
(CYP2C19) Hydrolysis ­co‑medication with an increased rate of adverse cardio­
vascular events — composite ischaemic end points,
Loss-of-function mutations Active metabolite
all-cause mortality, non-fatal myocardial infarction,
stroke, revascularization and stent thrombosis — in
c PPIs Clopidogrel (Prodrug) patients on clopidogrel 118–120. PPIs and clopidogrel
are both metabolized via the same cytochrome P450
Cytochrome P450 Oxidation pathway (CYP2C19) and, therefore, a competition for
Hydroxy-metabolites (CYP2C19) Hydrolysis
and the same pathway has been hypothesized121,122 (FIG. 4).
5-O-desmethyl-metabolites Active metabolite Ex vivo studies showed that, in contrast to omeprazole,
neither pantoprazole nor esomeprazole or lansoprazole
Normal activation Reduced activation influence the antiplatelet effects of clopidogrel123,124.
These data suggest that drug interaction between clopi-
Figure 4 | Activation of clopidogrel via cytochrome
Nature ReviewsP450. a | Normal activation
| Gastroenterology of
& Hepatology
dogrel and PPIs might be agent-specific rather than
clopidogrel occurs via CYP2C19. b | Loss‑of‑function mutation of CYP2C19 leads to
reduced activation of clopidogrel. c | A possible reduced activation of clopidogrel has class-­specific. Consequently, the FDA and European
been suggested in patients on proton-pump inhibitor (PPI) therapy (particularly for Medicines Agency warned in 2009 against combin-
omeprazole) due to competition for the same pathway. ing clopidogrel with PPIs (particularly omeprazole).
However, in randomized controlled trials, omepra-
zole did not increase the risk of adverse cardiovascular
seven observational studies found a pooled odds ratio events compared with placebo but did reduce upper
of 1.24 (95% CI 1.15–1.34)112. This finding was repli- gastrointestinal bleeding 125,126. Despite these new data,
cated in another meta-analysis that included ten studies on 10 March 2016, the FDA published a reminder to
(OR 1.25, 95% CI 1.14–1.37)113. avoid the concomitant use of clopidogrel and omepra-
Another large case–control study similarly des­ zole127, emphasizing that this r­ ecommendation applies
cribed a low increased risk of hip fractures in patients only to omeprazole and not to all PPIs.
on PPI medication as well as on H2 receptor antagonists The interindividual CYP2C19 genetic variability is
(OR 1.30, 95% CI 1.21–1.39) but only in patients with at an additive factor responsible for a reduced activation
least one other risk factor (pre-existing osteoporosis or of clopidogrel, with a number of loss‑of‑function muta-
chronic steroid therapy). In the absence of other addi- tions of the CYP2C19 gene128. The frequencies of these
tional risk factors, no association between PPI intake polymorphic alleles show marked interethnic variation
and an increased risk of hip fractures was observed114,115. (up to 35% in the Chinese, Japanese and Indian popu­
The discussion on the possible association between lation and up to 15% in the white European popula-
PPI intake and an increased risk of both osteoporosis tion)129,130. This aspect was not taken into consideration
and accelerated loss of bone mineral density remains in many of the early studies on the interaction between
open. In a North American study, PPI use was not clopidogrel and PPIs. Data from the TRIUMPH obser-
associated with either an increased risk of osteoporosis vational cohort study showed an association between
or an accelerated loss of bone mineral density 116. The PPI use and the risk of cardiac rehospitalization among
authors concluded that hip fractures in older patients clopidogrel-treated white patients who had a myo­cardial
on long-term PPI therapy might occur independently infarction and were carriers of the CYP2C19*17 variant
from the occurrence of osteoporotic changes. In con- (HR 1.62, 95% CI 1.19–2.19)131; therefore, ­genotyping
trast to that study, a Taiwanese investigation including could be considered for all patients.
>10,000 patients with GERD on long-term therapy The conflicting results with respect to the interaction
with PPIs and 20,000 controls matched by sex-, age- between clopidogrel and omeprazole can be summarized
and comorbidities without GERD found an increased as follows: ex vivo analyses showed that omeprazole (but
risk of osteoporosis in patients with GERD taking PPIs not other PPIs) influenced the antiplatelet effects of
(HR 1.5, 95% CI 1.39–1.62), but no association with clopidogrel; retrospective studies suggested that all PPIs
hip fractures117. (class-specific effect) increased cardiovascular events
All studies show important limitations of retro­ in patients on clopidogrel; and prospective trials found
spective, observational studies. No prospective no interaction between omeprazole and clopidogrel.
studies evaluating the pharmacological effect of acid-­ Thus, the debate on whether PPIs (including omepra-
suppressive therapy on hip fractures are available. zole) increase the risk of coronary events in patients on
At present, phys­icians involved in the medical care of clopidogrel is far from resolved. Both clopidogrel and
patients with severe comorbidities on long-term PPI omeprazole have short plasma half-lives (1–2 h)130,132;

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY ADVANCE ONLINE PUBLICATION | 9

©
2
0
1
7
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

Table 3 | Key recommendations for the management of PPI-related adverse effects

Issue, concern or effect Management
Long-term PPI intake • Keep dose and duration to the essential to reduce the risk of possible adverse effects
• Test for and treat Helicobacter pylori gastritis to prevent the shift from
antrum-predominant to corpus-predominant gastritis
AIN • After early detection of AIN, PPI withdrawal leads to recovery of renal function
• Avoid PPI re‑exposure
CKD • Search for known aetiologies of CKD before assuming a role for PPI intake
• PPI withdrawal could be considered in individual cases
Hypomagnesaemia • Consider PPIs as a cause of hypomagnesaemia and hypocalcaemia in patients with CKD
and hypocalcaemia on diuretic therapy
• Consider monitoring for hypomagnesaemia and electrolytes in patients with risk factors
and long-term PPI intake
• In patients with risk factors for osteoporotic changes (that is, pre-existing osteoporosis,
steroid therapy or malabsorption), calcium and vitamin D supplementation is required
Fractures and • Consider PPI intake at the minimally effective dose, especially in elderly patients
osteoporosis • Vitamin D supplementation in case of deficiency
Myopathies • Exclude other aetiological factors
• In patients who recover from an episode of rhabdomyolysis possibly related to PPI
intake and have a definite indication for ongoing PPI treatment, the PPI should not
be coadministered with statins
Cardiovascular risk • Prescribe a PPI other than omeprazole to patients on clopidogrel
AIN, acute interstitial nephritis; CKD, chronic kidney disease; PPI, proton-pump inhibitor.

therefore, separating the timing of clopidogrel and
omepra­zole administration has been proposed as a
strategy to attenuate the potential for drug–drug com-
petition. However, the success of this strategy is under-
mined by the increased bioavailability of omeprazole due
to repeated dosing. The FDA discourages this strategy
as well133. For the time being, and taking into consider-
ation the lack of updated clinical guidelines, adherence
to authorities’ recommendations is best practice. PPIs
other than omeprazole can be prescribed to patients
on clopidogrel whenever indicated and at the lowest
effective dose.
Drug absorption. A systematic review identified
16 high-­quality randomized crossover studies investi-
gating whether acid suppression during anti-­secretory
therapy through PPIs or H 2 receptor antagonists
might impair absorption of coadministered drugs134.
Suppression of gastric acidity reduced the absorption
of ketoconazole, itraconazole, atazanavir, cefpodoxime,
L‑thyroxin, α‑methyldopa, enoxacin and dipyridamole
(with a median reduction of the maximum observed
concentration of 66.5%). Furthermore, anti-secretory
therapy enhanced the absorption of nifedipine and
digoxin (with an increase in the median area under the
curve (AUC) of 10%) and induced a twofold increase
in alendronate bioavailability 134. PPIs are reported
to potentiate the anticoagulation effect of vitamin K
antagonists by enhancing absorption as a consequence
of elevated intragastric pH135,136. However, in healthy
volunteers, dexlansoprazole once daily, compared with
placebo, did not influence the peak plasma concentra-
tion or AUC of warfarin nor international normalized
ratio values137. Furthermore, although PPIs and warfarin
are both metabolized by hepatic CYP enzymes, a study
including 305 warfarin users found no evidence of a
clinically meaningful drug–drug interaction between
PPIs and warfarin138.
PPI intake impairs tyrosine kinase inhibitor efficacy
by reducing drug absorption. In a retrospective study
of nearly 200 patients with advanced renal cell cancer
treated with sunitinib, coadministration of PPIs was
associ­ated with poorer progression-free survival and
overall survival than in those not taking PPIs139. A simi­lar
finding was demonstrated in >500 patients with advanced
non-small-cell lung cancer treated with erlotinib140.
Furthermore, effects related to tyrosine kinase inhibition
were markedly less toxic in patients with non-small-cell
lung cancer concomitantly receiving PPIs with erlo-
tinib than in patients not taking PPIs. Interestingly,
erlotinib absorption in patients on PPIs was improved
when administering the drug with an acidic beverage,
such as cola141.
A possible negative effect of PPIs on the absorption
of the oral chemotherapeutic agent capecitabine in the
context of a complex chemotherapeutic regimen has
been suggested to be responsible for the observed statis-
tically significant decrease in progression-free survival
and reduced overall survival in patients with advanced
gastro-oesophageal cancer 142. This finding has not been
observed with oral fluoropyrimidine S-1 (REF. 143). These
emerging data demand high-quality studies in this area.
PPIs and endothelial homeostasis
According to experimental data, the off-target effects of
PPIs observed in vitro provide new insights into the direct
effects of PPIs on vascular homeostasis, which could
account for cardiovascular, renal and neuro­vascular
complications. The presumed mechanism is a direct
interference of PPIs with the endothelial homeo­stasis
of asymmetric dimethylarginine (ADMA), an endo­
genous inhibitor of nitric oxide synthase (NOS)144.

10 | ADVANCE ONLINE PUBLICATION www.nature.com/nrgastro

©
2
0
1
7
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 REVIEWS

Several clinical studies have indicated that elevated
ADMA plasma levels are associated with increased
cardio­vascular risk. ADMA correlates with disease
severity, major adverse cardiovascular events and all-
cause mortality in patients with peripheral arterial dis-
ease and is discussed as an independent risk factor for
mortality in patients with peripheral arterial disease145,146.
Studies have examined ADMA and arginine deriv­
atives in relation to vascular function in the general
popu­lation. In a controlled trial, 4 weeks of PPI use did
not markedly increase serum ADMA levels compared
with placebo; however, substantial changes might occur
with long-term PPI treatment 147. Another mechanism
that might explain the association of chronic PPI intake
with cardiovascular, renal and neurological adverse
effects is an acceleration of endothelial senescence by
impaired lysosomal activity, disrupted proteostasis in
endothelial cells and telomere shortening 148–151. The
in vitro effects of PPIs on endothelial cell ageing prov­
ides stimulating hypotheses, but they are not ready for
translation into a clinical setting.
Conclusions
In acid-related diseases, the benefits of PPI intake out-
weigh their potential harms. TABLE 3 outlines key recom­
mendations on how to manage and possibly prevent
PPI-related complications. PPIs should not be withheld
in patients with an appropriate indication, but dose and
duration should be kept to the minimum. Among the
long and continuously increasing list of adverse events
Acute kidney
Structural and injury Chronic kidney
functional changes disease
in the gastric mucosa
Dementia
Enteric infections*
Gastrointestinal
SIBO malignancies
PPIs
Clostridium difficile Cardiovascular events,
infection negative effect
on clopidogrel‡
Vitamin B12
deficiency Pneumonia
Hypomagnesaemia Osteoporosis
Hypocalcaemia Bone fractures
Causal relationship
Low evidence for causality
Insufficient evidence for causality
Figure 5 | PPIs and adverse events with proven
Nature and unproven
Reviews causality. The
| Gastroenterology number
& Hepatology
of complications associated with proton-pump inhibitors (PPIs) is high. This figure shows
the adverse events linked to PPI use, with indicators of the evidence supporting causality.
Those events with proposed major importance in clinical practice are shown according
to the scientific evidence and grading as per TABLE 1. *Enteric infections with
Salmonella enterica subsp. enterica serovar Enteritidis, Salmonella enterica subsp. enterica
serovar Typhimurium and Campylobacter jejuni. ‡Association restricted to omeprazole;
the FDA recommends avoiding the concomitant use of clopidogrel and omeprazole127.
SIBO, small intestinal bacterial overgrowth.
reported in association with long-term PPI intake, only
a few have proven causality and/or are based on potential
pathophysiological mechanisms induced by PPIs (FIG. 5).
The effects of PPIs on their therapeutic target organ, the
stomach, and the consequences of acid suppression on
the gastric mucosa structure and physiology are plausible
and evidence-based. The few reports on an increased risk
of gastric and other gastrointestinal malignancies due to
PPIs have important biases and confounding variables.
The association of PPIs with a variety of gastrointestinal
infections has been established, and the mechanism is
plausible. Furthermore, PPIs induce changes in the gut
microbiota composition with unknown health-related
consequences. Several studies have failed to confirm
an increased risk of community- and hospital-acquired
pneumonia in patients taking PPIs.
PPIs rarely affect vitamin B12 absorption, magne-
sium and calcium homeostasis. The association of
osteoporosis and bone fractures with PPI intake is of
low degree and mostly confounded by clinically signifi­
cant comorbidities. PPIs are a rare cause of AIN and
other idiosyncrasy-­related events. Omeprazole (but
not other PPIs) can increase the risk of coronary events
in patients on clopidogrel. Beyond metabolic drug–
drug ­interactions, PPIs also impair the absorption of
certain drugs.
In spite of the fact that most associations between
PPI intake and adverse events have substantial intrinsic
weaknesses due to the inclusion of retrospective cohorts
and insufficient adjustment for comorbidities, co‑­
medications and the dose and duration of PPI exposure,
we should remain alert to capture any possible relevant
event associated with PPI intake. However, premature
conclusions should not be drawn before these associ­
ations are investigated in depth and a causal relationship
has been considered.
In clinical practice, it is important to carefully assess
the individual management of our patients requiring
long-term PPI therapy without causing alarm about
possible dangers induced by PPIs. This aspect is
particu­larly important in the context of the u ­ ncritical
release of media reports on the inherent risks of PPI
intake. For the clinical management of patients on
long-term PPI therapy, general surveillance of blood
chemistry para­meters is not mandatory, but we sug-
gest monitoring renal function, serum electrolytes and
micronutrients according to the management of their
individual comorbidities. H. pylori gastritis should be
cured in patients requiring long-term PPI therapy to
prevent progression to ­preneoplastic changes in the
gastric mucosa.
There is a continued need for strong acid suppression
now and in the future to control the substantial mor-
bidity and mortality in acid-related diseases. Clinical
studies will have to include prospective population-­
based outcome studies in patients on long-term PPI
treatment, starting by including patients at the time
when they are first exposed to a PPI. These studies
should include pharmacogenomics and should investi­
gate adverse events by involving interdisciplinary
medical expertise.

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY ADVANCE ONLINE PUBLICATION | 11

©
2
0
1
7
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

1. Turner, T. Proton pump inhibitors. Drugwatch https://
www.drugwatch.com/proton-pump-inhibitors/ (2017).
2. Statista. Top 20 pharmaceutical products by sales
worldwide in 2014 (in billions US dollars). Statista
https://www.statista.com/statistics/258022/top-10-
pharmaceutical-products-by-global-sales-2011/ (2017).
3. Lessell, S. Omeprazole (correction of omepraxole)
and ocular damage. Concerns on safety of drug are
unwarranted. BMJ 316, 7124–7167 (1998).
4. Stolte, M., Bethke, B., Rühl, G. & Ritter, M.
Omeprazole-induced pseudohypertrophy of gastric
parietal cells. Z. Gastroenterol. 30, 134–138 (1992).
5. Fiocca, R. et al. Gastric exocrine and endocrine cell
morphology under prolonged acid inhibition therapy:
results of a 5‑year follow‑up in the LOTUS trial.
Aliment. Pharmacol. Ther. 36, 959–971 (2012).
A controlled study on the long-term effect of PPIs
on endocrine and exocrine gastric cells.
6. Cats, A. et al. Parietal cell protrusions and fundic
gland cysts during omeprazole maintenance
treatment. Hum. Pathol. 31, 684–690 (2000).
7. Lamberts, R., Brunner, G. & Solcia, E. Effects of very
long (up to 10 years) proton pump blockade on human
gastric mucosa. Digestion 64, 205–213 (2001).
8. Lundell, L., Vieth, M., Gibson, F., Nagy, P.
& Kahrilas, P. J. Systematic review: the effects of
long‑term proton pump inhibitor use on serum gastrin
levels and gastric histology. Aliment. Pharmacol. Ther.
42, 649–663 (2015).
This systematic review reports on long-term
PPI-induced moderate hypergastrinaemia in
most patients and an increased prevalence of
enterochromaffin-like cell hyperplasia; Helicobacter
pylori-positive patients receiving long-term PPI
therapy were exposed to a higher risk of corpus
atrophy than were H. pylori-negative patients.
9. Schubert, M. L. Gastric acid secretion. Curr. Opin.
Gastroenterol. 32, 452–460 (2016).
10. Reimer, C., Søndergaard, B., Hilsted, L. & Bytzer, P.
Proton-pump inhibitor therapy induces acid-related
symptoms in healthy volunteers after withdrawal
of therapy. Gastroenterology 137, 80–87 (2009).
11. Hongo, M., Fujimoto, K. & Gastric Polyps Study
Group. Incidence and risk factor of fundic gland polyp
and hyperplastic polyp in long-term proton pump
inhibitor therapy: a prospective study in Japan.
J. Gastroenterol. 45, 618–624 (2010).
12. Martin, F. C., Chenevix-Trench, G. & Yeomans, N. D.
Systematic review with meta-analysis: fundic
gland polyps and proton pump inhibitors.
Aliment. Pharmacol. Ther. 44, 915–925 (2016).
13. Tran-Duy, A., Spaetgens, B., Hoes, A. W., de Wit, N. J.
& Stehouwer, C. D. Use of proton pump inhibitors
and risks of fundic gland polyps and gastric
cancer: systematic review and meta-analysis.
Clin. Gastroenterol. Hepatol. 14, 1706–1719 (2016).
The latest systematic review and meta-analysis
reporting that PPI use increases the incidence
of fundic gland polyps; a small effect on gastric
cancer is biased by confounding factors.
14. Worthley, D. L. et al. Gastric adenocarcinoma and
proximal polyposis of the stomach (GAPPS): a new
autosomal dominant syndrome. Gut 61, 774–779
(2012).
15. Yanaru-Fujisawa, R. et al. Familial fundic gland
polyposis with gastric cancer. Gut 61, 1103–1104
(2012).
16. Sanduleanu, S. et al. Serum chromogranin A as a
screening test for gastric enterochromaffin-like cell
hyperplasia during acid-suppressive therapy.
Eur. J. Clin. Invest. 31, 802–811 (2001).
17. Savarino, V., Dulbecco, P. & Savarino, E. Are proton
pump inhibitors really so dangerous? Dig. Liver Dis.
48, 851–859 (2016).
18. Waldum, H. L., Hauso, Ø., Brenna, E., Qvigstad, G.
& Fossmark, R. Does long-term profound inhibition
of gastric acid secretion increase the risk of ECL cell-
derived tumors in man? Scand. J. Gastroenterol. 51,
767–773 (2016).
19. Jianu, C. S. et al. Gastric carcinoids after long-term
use of a proton pump inhibitor. Aliment. Pharmacol.
Ther. 36, 644–649 (2012).
20. Pregun, I. et al. Effect of proton-pump inhibitor
therapy on serum chromogranin a level. Digestion 84,
22–28 (2011).
21. Wong, H. et al. PPI-delayed diagnosis of gastrinoma:
oncologic victim of pharmacologic success.
Pathol. Oncol. Res. 16, 87–91 (2010).
22. Han, Y. M. et al. Role of proton pump inhibitors
in preventing hypergastrinemia-associated
carcinogenesis and in antagonizing the trophic
effect of gastrin. J. Physiol. Pharmacol. 66, 159–167
(2015).
Experimental evidence of anti-carcinogenetic
effects of PPIs — these results are awaiting clinical
confirmation.
23. Poulsen, A. H. et al. Proton pump inhibitors and risk
of gastric cancer: a population-based cohort study.
Br. J. Cancer. 100, 1503–1507 (2009).
24. Singh, M., Dhindsa, G., Friedland, S.
& Triadafilopoulos, G. Long-term use of proton pump
inhibitors does not affect the frequency, growth,
or histologic caracteristics of colon adenomas.
Aliment. Pharmacol. Ther. 26, 1051–1061 (2007).
25. Robertson, D. J. et al. Proton pump inhibitor use
and risk of colorectal cancer: a population-based, case-
control study. Gastroenterology 133, 755–760 (2007).
26. Kearns, M. D., Boursi, B. & Yang, Y. X. Proton pump
inhibitors on pancreatic cancer risk and survival.
Cancer Epidemiol. 46, 80–84 (2017).
27. Kuipers, E. J. et al. Increase of Helicobacter pylori-
associated corpus gastritis during acid suppressive
therapy: implications for long-term safety.
Am. J. Gastroenterol. 90, 1401–1406 (1995).
28. Malfertheiner, P., Chan, F. K. & McColl, K. E. Peptic
ulcer disease. Lancet 374, 1449–1461 (2009).
29. Hunt, R. H. et al. The stomach in health and disease.
Gut 64, 1650–1668 (2015).
A comprehensive update on all aspects of gastric
functions.
30. Logan, R. P. et al. Changes in the intragastric
distribution of H. pylori during treatment with
omeprazole. Gut 36, 12–16 (1995).
31. Stolte, M., Meining, A., Schmitz, J. M., Alexandridis, T.
& Seifert, E. Changes in Helicobacter pylori-induced
gastritis in the antrum and corpus during 12 months
of treatment with omeprazole and lansoprazole in
patients with gastro-oesophageal reflux disease.
Aliment. Pharmacol. Ther. 12, 247–253 (1998).
32. Kuipers, E. J. et al. Atrophic gastritis and Helicobacter
pylori infection in patients with reflux esophagitis
treated with omeprazole or fundoplication. N. Engl.
J. Med. 334, 1018–1022 (1996).
33. Eissele, R., Brunner, G., Simon, B., Solcia, E.
& Arnold, R. Gastric mucosa during treatment
with lansoprazole: Helicobacter pylori is a risk factor
for argyrophil cell hyperplasia. Gastroenterology 112,
707–717 (1997).
34. Lundell, L. et al. Changes of gastric mucosal
architecture during long-term omeprazole
therapy: results of a randomized clinical trial.
Aliment. Pharmacol. Ther. 23, 639–647 (2006).
35. Malfertheiner, P. et al. Management of Helicobacter
pylori infection-the Maastricht V/Florence Consensus
Report. Gut 66, 6–30 (2017).
This manuscript presents the latest
recommendations on the management of
Helicobacter pylori infection and the role of PPIs.
36. Sanduleanu, S., Jonkers, D., De Bruïne, A.,
Hameeteman, W. & Stockbrügger, R. W. Double
gastric infection with Helicobacter pylori and non-
Helicobacter pylori bacteria during acid-suppressive
therapy: increase of pro-inflammatory cytokines and
development of atrophic gastritis. Aliment. Pharmacol.
Ther. 8, 1163–1175 (2001).
37. Schulz, C., Koch, N., Schütte, K., Pieper, D. H.
& Malfertheiner, P. H. pylori and its modulation of
gastrointestinal microbiota. J. Dig. Dis. 16, 109–117
(2015).
38. Freedberg, D. E. et al. Proton pump inhibitors
alter specific taxa in the human gastrointestinal
microbiome: a crossover trial. Gastroenterology 149,
883–885 (2015).
39. Jackson, M. A. et al. Proton pump inhibitors alter the
composition of the gut microbiota. Gut 65, 749–756
(2016).
References 37 and 38 provide novel insights into
the effect of PPIs on gut microbiota composition.
40. Imhann, F. et al. Proton pump inhibitors affect the gut
microbiome. Gut 65, 740–748 (2016).
41. Clooney, A. G. et al. A comparison of the gut
microbiome between long-term users and non-users
of proton pump inhibitors. Aliment. Pharmacol. Ther.
43, 974–984 (2016).
42. Lombardo, L., Foti, M., Ruggia, O. & Chiecchio, A.
Increased incidence of small intestinal bacterial
overgrowth during proton pump inhibitor therapy.
Clin. Gastroenterol. Hepatol. 8, 504–508 (2010).
43. Ratuapli, S. K. et al. Proton pump inhibitor therapy
use does not predispose to small intestinal bacterial
overgrowth. Am. J. Gastroenterol.107, 730–735
(2012).
44. Lo, W. K. & Chan, W. W. Proton pump inhibitor use
and the risk of small intestinal bacterial overgrowth:
a meta-analysis. Clin. Gastroenterol. Hepatol. 11,
483–490 (2013).
45. Jacobs, C., Coss Adame, E., Attaluri, A., Valestin, J.
& Rao, S. S. Dysmotility and proton pump
inhibitor use are independent risk factors for small
intestinal bacterial and/or fungal overgrowth.
Aliment. Pharmacol. Ther. 37, 1103–1111 (2013).
46. Giamarellos-Bourboulis, E. J., Pyleris, E.,
Barbatzas, C., Pistiki, A. & Pimentel, M. Small
intestinal bacterial overgrowth is associated with
irritable bowel syndrome and is independent of proton
pump inhibitor usage. BMC Gastroenterol. 16, 67
(2016).
47. Leonard, J., Marshall, J. K. & Moayyedi, P.
Systematic review of the risk of enteric
infection in patients taking acid suppression.
Am. J. Gastroenterol. 102, 2047–2056 (2007).
48. Doorduyn, Y., Van Den Brandhof, W. E.,
Van Duynhoven, Y. T., Wannet, W. J. & Van Pelt, W.
Risk factors for Salmonella Enteritidis and
Typhimurium (DT104 and non‑DT104) infections
in the Netherlands: predominant roles for raw eggs in
Enteritidis and sandboxes in Typhimurium infections.
Epidemiol. Infect. 134, 617–626 (2006).
49. Bavishi, C. & Dupont, H. L. Systematic review: the use
of proton pump inhibitors and increased susceptibility
to enteric infection. Aliment. Pharmacol. Ther. 34,
1269–1281 (2011).
50. Hassing, R. J., Verbon, A., de Visser, H., Hofman, A.
& Stricker, B. H. Proton pump inhibitors and
gastroenteritis. Eur. J. Epidemiol. 31, 1057–1063
(2016).
51. Kwok, C. S. et al. Risk of Clostridium difficile infection
with acid suppressing drugs and antibiotics: meta-
analysis. Am. J. Gastroenterol. 107, 1011–1019
(2012).
52. Tleyjeh, I. M. et al. Association between proton pump
inhibitor therapy and clostridium difficile infection:
a contemporary systematic review and meta-analysis.
PLoS ONE 7, e50836 (2012).
53. Arriola, V. et al. Assessing the risk of hospital-acquired
Clostridium difficile infection with proton pump
inhibitor use: a meta-analysis. Infect. Control Hosp.
Epidemiol. 28, 1–10 (2016).
A meta-analysis suggesting an almost twofold
increased risk of hospital-acquired Clostridium
difficile infection in patients on PPIs.
54. Kandel, C. E., Gill, S. E.,McCready, J., Matelski, J.
& Powis, J. E. Reducing co‑administration of proton
pump inhibitors and antibiotics using a computerized
order entry alert and prospective audit and feedback.
BMC Infect. Dis. 16, 355 (2016).
55. Chande, N. & Driman, D. K. Microscopic colitis
associated with lansoprazole: report of two cases
and a review of the literature. Scand. J. Gastroenterol.
42, 530–533 (2007).
56. Wilcox, G. M. & Mattia, A. R. Microscopic colitis
associated with omeprazole and esomeprazole
exposure. J. Clin. Gastroenterol. 43, 551–553
(2009).
57. Keszthelyi, D. et al. Proton pump inhibitor use is
associated with an increased risk for microscopic
colitis: a case-control study. Aliment. Pharmacol. Ther.
32, 1124–1128 (2010).
58. Verhaegh, B. P. et al. High risk of drug-induced
microscopic colitis with concomitant use of NSAIDs
and proton pump inhibitors. Aliment. Pharmacol. Ther.
43, 1004–1013 (2016).
59. Xu, H. B. et al. Proton pump inhibitor use and risk of
spontaneous bacterial peritonitis in cirrhotic patients:
a systematic review and meta-analysis. Genet. Mol.
Res. 14, 7490–7501 (2015).
60. Terg, R. et al. Proton pump inhibitor therapy does
not increase the incidence of spontaneous bacterial
peritonitis in cirrhosis: a multicenter prospective
study. J. Hepatol. 62, 1056–1060 (2015).
61. Dam, G., Vilstrup, H., Watson, H. & Jepsen, P.
Proton pump inhibitors as a risk factor for hepatic
encephalopathy and spontaneous bacterial peritonitis
in patients with cirrhosis with ascites. Hepatology 64,
1265–1272 (2016).
A relevant study showing that PPIs increase
the risk of developing hepatic encephalopathy
and spontaneous bacterial peritonitis in patients
with liver cirrhosis.
62. Fohl, A. L. & Regal, R. E. Proton pump inhibitor-
associated pneumonia: not a breath of fresh air after
all? World J. Gastrointest. Pharmacol. Ther. 2, 17–26
(2011).

12 | ADVANCE ONLINE PUBLICATION www.nature.com/nrgastro

©
2
0
1
7
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 REVIEWS

63. Alshamsi, F. et al. Efficacy and safety of proton pump
inhibitors for stress ulcer prophylaxis in critically ill
patients: a systematic review and meta-analysis
of randomized trials. Crit. Care 20, 120 (2016).
64. Laheij, R. J., Van Ijzendoorn, M. C., Janssen, M. J.
& Jansen, J. B. Gastric acid-suppressive therapy
and community-acquired respiratory infections.
Aliment. Pharmacol. Ther. 18, 847–851 (2003).
65. Eom, C. S. et al. Use of acid-suppressive drugs and risk
of pneumonia: a systematic review and meta-analysis.
CMAJ 183, 310–319 (2011).
66. Filion, K. B. et al. Proton pump inhibitors and the risk
of hospitalisation for community-acquired pneumonia:
replicated cohort studies with meta-analysis. Gut 63,
552–558 (2014).
67. Estborn, L. & Joelson, S. Frequency and time to onset
of community-acquired respiratory tract infections
in patients receiving esomeprazole: a retrospective
analysis of patient-level data in placebo-controlled
studies. Aliment. Pharmacol. Ther. 42, 607–613
(2015).
A large cohort study of a PPI (esomeprazole)
that disproves the risk of community-acquired
pneumonia.
68. Abramowitz, J. et al. Adverse event reporting for
proton pump inhibitor therapy: an overview of
systematic reviews. Otolaryngol. Head Neck Surg.
155, 547–554 (2016).
69. Gomm, W. et al. Association of proton pump inhibitors
with risk of dementia: a pharmacoepidemiological
claims data analysis. JAMA Neurol. 73, 410–416
(2016).
This study was an adverse event report showing a
significantly increased risk of incident dementia in
conjunction with PPI use; this report caused great
concern in the general public.
70. Booker, A., Jacob, L. E., Rapp, M., Bohlken, J.
& Kostev, K. Risk factors for dementia diagnosis in
German primary care practices. Int. Psychogeriatr. 28,
1059–1065 (2016).
71. Clark, D. W. & Strandell, J. Myopathy including
polymyositis: a likely class adverse effect of proton
pump inhibitors? Eur. J. Clin. Pharmacol. 62,
473–479 (2006).
72. Ruffenach, S. J., Siskind, M. S. & Lien, Y. H. Acute
interstitial nephritis due to omeprazole. Am. J. Med.
93, 472–473 (1992).
73. Perazella, M. A. & Markowitz, G. S. Drug-induced
acute interstitial nephritis. Nat. Rev. Nephrol. 6,
461–470 (2010).
74. Muriithi, A. K. et al. Biopsy-proven acute interstitial
nephritis, 1993‑2011: a case series. Am. J. Kidney
Dis. 64, 558–566 (2014).
75. Moledina, D.,G. & Perazella, M. A. PPIs and kidney
disease: from AIN to CKD. J. Nephrol. 29, 611–616
(2016).
76. 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. Kidney Int. 86, 837–844
(2014).
77. Antoniou, T. et al. Proton pump inhibitors and the risk
of acute kidney injury in older patients: a population-
based cohort study. CMAJ Open 3, E166–E171
(2015).
78. Geevasinga, N., Coleman, P. L., Webster, A. C.
& Roger, S. D. Proton pump inhibitors and acute
interstitial nephritis. Clin. Gastroenterol. Hepatol. 4,
597–604 (2006).
79. Lazarus, B. et al. Proton pump inhibitor use and
the risk of chronic kidney disease. JAMA Intern. Med.
176, 238–246 (2016).
This study report comprehensive data showing
that PPI use is associated with a low risk of incident
chronic kidney disease.
80. Xie, Y. et al. Proton pump inhibitors and risk of
incident CKD and progression to ESRD. J. Am.
Soc. Nephrol. 10, 3153–3163 (2016).
81. Maggio, M. et al. Proton pump inhibitors and risk of
1‑year mortality and rehospitalization in older patients
discharged from acute care hospitals. JAMA Intern.
Med. 173, 518–523 (2013).
82. Leontiadis, G. I., Sharma, V. K. & Howden, C. W.
Proton pump inhibitor therapy for peptic ulcer
bleeding: Cochrane collaboration meta-analysis of
randomized controlled trials. Mayo Clin. Proc. 82,
286–296 (2007).
83. Lam, J. R., Schneider, J. L., Zhao, W. & Corley, D. A.
Proton pump inhibitor and histamine 2 receptor
antagonist use and vitamine B12 deficiency. JAMA
310, 2435–2442 (2013).
84. McColl, K. E. Effect of proton pump inhibitors on
vitamins and iron. Am. J. Gastroenterol. 104, S5–S9
(2009).
85. Venerito, M. et al. Oxyntic gastric atrophy in
Helicobacter pylori gastritis is distinct from
autoimmune gastritis. J. Clin. Pathol. 69, 677–685
(2016).
86. al‑Ghamdi, S. M., Cameron, E. C. & Sutton, R. A.
Magnesium deficiency: pathophysiologic and clinical
overview. Am. J. Kidney Dis. 24, 737–752 (1994).
87. Epstein, M., McGrath, S. & Law, F. Proton-pump
inhibitors and hypomagnesemic hypoparathyroidism.
N. Engl. J. Med. 355, 1834–1836 (2006).
88. Hoorn, E. J. et al. A case series of proton pump
inhibitor-induced hypomagnesemia. Am. J. Kidney Dis.
56, 112–116 (2010).
89. Mackay, J. D. & Bladon, P. T. Hypomagnesaemia due
to proton-pump inhibitor therapy: a clinical case
series. QJM 103, 387–395 (2010).
90. Luk, C. P., Parsons, R., Lee, Y. P. & Hughes, J. D.
Proton pump inhibitor-associated hypomagnesemia:
what do FDA data tell us? Ann. Pharmacother. 47,
773–780 (2013).
91. Quamme, G. A. Recent developments in intestinal
magnesium absorption. Curr. Opin. Gastroenterol. 24,
230–235 (2008).
92. Voets, T. et al. TRPM6 forms the Mg2+ influx channel
involved in intestinal and renal Mg2+ absorption.
J. Biol. Chem. 279, 19–25 (2004).
93. Schlingmann, K. P. et al. Hypomagnesemia with
secondary hypocalcemia is caused by mutations in
TRPM6, a new member of the TRPM gene family.
Nat. Genet. 31, 166–170 (2002).
94. Zipursky, J. et al. Proton pump inhibitors and
hospitalization with hypomagnesemia: a population-
based case-control study. PLoS Med. 11, e1001736
(2014).
A population-based case–control study showing
an increased risk of hospitalization with
hypomagnesaemia in patients on PPIs that
are also receiving diuretics.
95. Sumukadas, D., McMurdo, M. E. T. & Habicht, D.
Proton pump inhibitors are associated with lower
magnesium levels in older people with chronic kidney
disease. J. Am. Geriatr. Soc. 60, 392–393 (2012).
96. Danziger, J. et al. Proton-pump inhibitor use is
associated with low serum magnesium concentrations.
Kidney Int. 83, 692–699 (2013).
97. Misra, P. S., Alam, A., Lipman, M. L. & Nessim, S. J.
The relationship between proton pump inhibitor
use and serum magnesium concentration among
hemodialysis patients: a cross-sectional study.
BMC Nephrol. 16, 136 (2015).
98. Sharara, A. I. et al. Low prevalence of
hypomagnesemia in long-term recipients of proton
pump inhibitors in a managed care cohort.
Clin. Gastroenterol. Hepatol. 14, 317–321 (2016).
An important study showing that, in the absence
of known precipitating factors (concomitant diuretic
intake, chronic diarrhoea, chronic kidney disease
and malignancies), chronic PPI use is not
associated with hypomagnesaemia.
99. Biyik, M. et al. Hypomagnesemia among outpatient
long-term proton pump inhibitor users. Am. J. Ther.
24, e52–e55 (2017).
100. Negri, A. L. & Valle, E. E. Hypomagnesaemia/
hypokalemia associated with the use of esomeprazole.
Curr. Drug Saf. 6, 204–206 (2011).
101. Deroux, A., Khouri, C., Chabre, O., Bouillet, L.
& Casez, O. Severe acute neurological symptoms
related to proton pump inhibitors induced
hypomagnesemia responsible for profound
hypoparathyroidism with hypocalcemia. Clin. Res.
Hepatol. Gastroenterol. 38, e103–e105 (2014).
102. Leontiadis, G. I. & Moayyedi, P. Proton pump
inhibitors and risk of bone fractures. Curr. Treat.
Options Gastroenterol. 12, 414–423 (2014).
103. Thongon, N. & Krishnamra, N. Apical acidity decreases
inhibitory effect of omeprazole on Mg(2+) absorption
and claudin‑7 and -12 expression in Caco‑2
monolayers. Exp. Mol. Med. 44, 684–693 (2012).
104. Lameris, A. L. L., Hess, M. W., van Kruijsbergen, I.,
Hoenderop, J. G. J. & Bindels, R. J. M. Omeprazole
enhances the colonic expression of the Mg(2+)
transporter TRPM6. Pflugers Arch. 465, 1613–1620
(2013).
105. Hess, M. W., de Baaij, J. H. F., Gommers, L. M. M.,
Hoenderop, J. G. J. & Bindels, R. J. M. Dietary inulin
fibers prevent proton-pump inhibitor (PPI)-induced
hypocalcemia in mice. PLoS ONE 10, e0138881
(2015).
106. Wright, M. J. et al. Inhibiting gastric acid production
does not affect intestinal calcium absorption in young,
healthy individuals: a randomized, crossover,
controlled clinical trial. J. Bone Miner. Res. 25,
2205–2211 (2010).
107. Hansen, K. E. et al. Do proton pump inhibitors
decrease calcium absorption? J. Bone Miner. Res. 25,
2786–2795 (2010).
108. Attwood, S. E. et al. Long-term safety of proton pump
inhibitor therapy assessed under controlled,
randomised clinical trial conditions: data from the
SOPRAN and LOTUS studies. Aliment. Pharmacol.
Ther. 41, 1162–1174 (2015).
This study shows data from controlled randomized
trials with reassuring findings on long-term PPI use,
electrolytes and micronutrients.
109. Vestergaard, P., Rejnmark, L. & Mosekilde, L. Proton
pump inhibitors, histamine H2 receptor antagonists,
and other antacid medications and the risk of fracture.
Calcif. Tissue Int. 79, 76–83 (2006).
110. Yang, Y. X., Lewis, J. D., Epstein, S. & Metz, D. C.
Long-term proton pump inhibitor therapy and risk
of hip fracture. JAMA 296, 2947–2953 (2006).
111. Targownik, L. E. et al. Use of proton pump inhibitors
and risk of osteoporosis-related fractures. CMAJ 179,
319–326 (2008).
112. Ye, X. et al. Proton pump inhibitors therapy and
risk of hip fracture: a systematic review and meta-
analysis. Eur. J. Gastroenterol. Hepatol. 9, 794–800
(2011).
113. Ngamruengphong, S., Leontiadis, G., Radhi, S.,
Dentino, A. & Nugent, K. Proton pump inhibitors and
risk of fracture: a systematic review and meta-analysis
of observational studies. Am. J. Gastroenterol. 106,
1209–1218 (2011).
114. Corley, D. A., Kubo, A., Zhao, W. & Quesenberry, C.
Proton pump inhibitors and histamine‑2 receptor
antagonists are associated with hip fractures among
at‑risk patients. Gastroenterology 139, 93–101
(2010).
115. Kaye, J. A. & Jick, H. Proton pump inhibitor use and
risk of hip fractures in patients without major risk
factors. Pharmacotherapy 28, 951–959 (2008).
116. Targownik, L. E., Lix, L. M., Leung, S. & Leslie, W. D.
Proton-pump inhibitor use is not associated with
osteoporosis or accelerated bone mineral density loss.
Gastroenterology 138, 896–904 (2010).
An accurate study shedding light on the association
between PPIs and osteoporosis or accelerated
bone mineral density loss.
117. Chen, C. H., Lin, C. L. & Kao, C. H. Gastroesophageal
reflux disease with proton pump inhibitor use is
associated with an increased risk of osteoporosis:
a nationwide population-based analysis.
Osteoporos. Int. 27, 2117–2126 (2016).
118. Serbin, M. A., Guzauskas, G. F. & Veenstra, D. L.
Clopidogrel-proton pump inhibitor drug-drug
interaction and risk of adverse clinical outcomes
among PCI-treated ACS patients: a meta-analysis.
J. Manag. Care Spec. Pharm. 22, 939–947 (2016).
A meta-analysis of randomized controlled trials
and observational studies, showing that
concomitant clopidogrel–PPI therapy following
percutaneous coronary intervention is significantly
associated with adverse cardiovascular events.
119. Sherwood, M. W. et al. Individual proton pump
inhibitors and outcomes in patients with coronary
artery disease on dual antiplatelet therapy:
a systematic review. J. Am. Heart Assoc. 4, e002245
(2015).
120. Melloni, C. et al. Conflicting results between
randomized trials and observational studies on the
impact of proton pump inhibitors on cardiovascular
events when coadministered with dual antiplatelet
therapy: systematic review. Circ. Cardiovasc. Qual.
Outcomes 8, 47–55 (2015).
121. Gilard, M., Arnaud, B., le Gal, G., Abgrall, J. F.
& Boschat, J. Influence of omeprazol on the
antiplatelet action of clopidogrel associated to aspirin.
J. Thromb. Haemost. 4, 2508–2509 (2006).
122. Focks, J. J. et al. Concomitant use of clopidogrel
and proton pump inhibitors: impact on platelet
function and clinical outcome: a systematic review.
Heart 99, 520–527 (2013).
123. Siller-Matula, J. M. et al. Effects of pantoprazole and
esomeprazole on platelet inhibition by clopidogrel.
Am. Heart J. 157, 148.e1–148.e5 (2009).
124. Small, D. S. et al. Effects of the proton pump inhibitor
lansoprazole on the pharmacokinetics and
pharmacodynamics of prasugrel and clopidogrel.
J. Clin. Pharmacol. 48, 475–484 (2008).

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY ADVANCE ONLINE PUBLICATION | 13

©
2
0
1
7
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

125. Bhatt, D. L., et al. Clopidogrel with or without
omeprazole in coronary artery disease. N. Engl.
J. Med. 363, 1909–1917 (2010).
126. Gao, Q. P. Sun, Y., Sun, Y. X., Wang, L. F. & Fu, L.
Early use of omeprazole benefits patients with acute
myocardial infarction. J. Thromb. Thrombolysis 28,
282–287 (2009).
127. FDA. FDA reminder to avoid concomitant use of Plavix
(clopidogrel) and omeprazole. FDA https://www.fda.gov/
Drugs/DrugSafety/ucm231161.htm (2016).
128. Simon, T. et al. Genetic determinants of response to
clopidogrel and cardiovascular events. N. Engl. J. Med.
360, 363–375 (2009).
129. Rosemary, J. & Adithan, C. The pharmacogenetics of
CYP 2C9 and CYP2C19: ethnic variation and clinical
significance. Curr. Clin. Pharmacol. 2, 93–109
(2007).
130. Venerito, M., Kandulski, A. & Malfertheiner, P.
Dilemma between gastroprotection and
cardiovascular prevention. Dtsch. Med. Wochenschr.
135, 2193–2198 (2010).
131. Depta, J. P. et al. Clinical outcomes associated with
proton pump inhibitor use among clopidogrel-treated
patients within CYP2C19 genotype groups following
acute myocardial infarction. Pharmacogenomics J. 15,
20–25 (2015).
132. Laine, L. & Hennekens, C. Proton pump inhibitor
and clopidogrel interaction: fact or fiction?
Am. J. Gastroenterol. 105, 34–41 (2010).
133. FDA. Information for healthcare professionals: update
to the labeling of clopidogrel bisulfate (marketed as
Plavix) to alert healthcare professionals about a drug
interaction with omeprazole (marketed as Prilosec
and Prilosec OTC). FDA https://www.fda.gov/Drugs/
DrugSafety/PostmarketDrugSafetyInformationfor
PatientsandProviders/DrugSafetyInformationforHeath
careProfessionals/ucm190787.htm (2009).
134. Lahner, E., Annibale, B. & Delle Fave, G. Systematic
review: impaired drug absorption related to the
co‑administration of antisecretory therapy.
Aliment. Pharmacol. Ther. 29, 1219–1229 (2009).
135. Julkunen, R. J. The absorption of warfarin from the rat
stomach in situ. Med. Biol. 54, 260–263 (1976).
136. Scarpignato, C. et al. Effective and safe proton pump
inhibitor therapy in acid-related diseases - a position
paper addressing benefits and potential harms of acid
suppression. BMC Med. 14, 179 (2016).
A position statement on the benefits, harms
and appropriateness of PPI use.
137. Vakily, M., Lee, R. D., Wu, J., Gunawardhana, L.
& Mulford, D. Drug interaction studies with
dexlansoprazole modified release (TAK‑390MR),
a proton pump inhibitor with a dual delayed-release
formulation: results of four randomized, double-blind,
crossover, placebo-controlled, single-centre studies.
Clin. Drug Investig. 29, 35–50 (2009).
138. Henriksen, D. P. et al. The potential drug-drug
interaction between proton pump inhibitors
and warfarin. Pharmacoepidemiol. Drug Saf. 24,
1337–1340 (2015).
139. Ha, V. H. et al. Does gastric acid suppression affect
sunitinib efficacy in patients with advanced or
metastatic renal cell cancer? J. Oncol. Pharm. Pract.
21, 194–200 (2015).
140. Chu, M. P. et al. Gastric acid suppression is
associated with decreased erlotinib efficacy in non-
small-cell lung cancer. Clin. Lung Cancer 16, 33–39
(2015).
141. van Leeuwen, R. W. et al. Influence of the acidic
beverage cola on the absorption of erlotinib in
patients with non-small-cell lung cancer. J. Clin. Oncol.
34, 1309–1314 (2016).
142. Chu, M. P. et al. Association of proton pump
inhibitors and capecitabine efficacy in advanced
gastroesophageal cancer: secondary analysis
of the TRIO‑013/LOGiC randomized clinical trial.
JAMA Oncol. 3, 767–773 (2017).
A secondary analysis of a phase III randomized
trial, showing that PPIs negatively affect
capecitabine efficacy, possibly by raising gastric
pH levels; PPI-treated patients with advanced
gastro-oesophageal cancer receiving
capecitabine-based polychemotherapy had poorer
progression-free survival and overall survival than
those not treated with PPIs.
143. Scheulen, M. E. et al. Effect of food and a proton pump
inhibitor on the pharmacokinetics of S-1 following oral
administration of S-1 in patients with advanced solid
tumors. Cancer Chemother. Pharmacol. 69, 753–761
(2012).
144. Ghebremariam, Y. T. et al. Unexpected effect of proton
pump inhibitors: elevation of the cardiovascular risk
factor asymmetric dimethylarginine. Circulation 128,
845–853 (2013).
145. Wilson, A. M. et al. Asymmetric dimethylarginine
correlates with measures of disease severity, major
adverse cardiovascular events and all-cause mortality
in patients with peripheral arterial disease. Vasc. Med.
15, 267–274 (2010).
146. Böger, R. H. et al. Asymmetric dimethylarginine as an
independent risk marker for mortality in ambulatory
patients with peripheral arterial disease. J. Intern.
Med. 269, 349–361 (2011).
147. Ghebremariam, Y. T. et al. Proton pump inhibitors and
vascular function: a prospective cross-over pilot study.
Vasc. Med. 4, 309–316 (2015).
148. Yepuri, G. et al. Proton pump inhibitors accelerate
endothelial senescence. Circ. Res. 118, e36–e42 (2016).
149. Goligorsky, M. S. Pathogenesis of endothelial cell
dysfunction in chronic kidney disease: a retrospective
and what the future may hold. Kidney Res. Clin. Pract.
34, 76–82 (2015).
150. Di Marco, L. Y. et al. Vascular dysfunction in the
pathogenesis of Alzheimer’s disease — a review
of endothelium-mediated mechanisms and
ensuing vicious circles. Neurobiol. Dis. 82, 593–606
(2015).
151. Flammer, A. J. et al. The assessment of endothelial
function: from research into clinical practice.
Circulation 126, 753–767 (2012).
152. Malfertheiner, P. et al. Management of Helicobacter
pylori infection — the Maastricht IV/ Florence
Consensus Report. Gut 61, 646–664 (2012).
Author contributions
All authors contributed equally to the writing and reviewing
of the draft manuscript.
Competing interests statement
P.M. is a member of the advisory boards for Allergan, Alfa
Wassermann and Bayer and has taken part in speakers’
bureaus for Allergan, AstraZeneca, Reckitt Benckiser
and Takeda. M.V. is a member of the advisory boards for
Amgen, Lilly and Nordic and has taken part in a speakers’
bureau for Bayer and Merck Serono. A.K. declares no
competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
Review criteria
Bibliographic searches in PubMed, Embase and Medline for
literature published until 31 Dec 2016 were performed using
the term “PPI” with various complications: “gastric”, “intesti-
nal”, “infections”, “cardiovascular”, “renal”, “osteological”,
“metabolic” and “neurologic”. Some new reports were
included during the revision of the paper in April 2017.
Systematic reviews since 2010 reporting on adverse events
related to PPI use were also included. Only human studies
published in English were considered; selected experimental
studies were cited to explain mechanisms leading to compli-
cations. The strength of the supporting evidence for the asso-
ciation between PPI intake and various complications was
graded according to the system used in previous reports152
(listed in Table 1).
DATABASES
VigiBase: https://www.who-umc.org/vigibase/vigibase
ALL LINKS ARE ACTIVE IN THE ONLINE PDF

14 | ADVANCE ONLINE PUBLICATION www.nature.com/nrgastro

©
2
0
1
7
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.