Received: 12 June 2023 Revised: 29 October 2023 Accepted: 6 November 2023

DOI: 10.1111/bcp.15960

COMMENTARY

Proton pump inhibitors: Weighing the benefits and risks across

various health conditions

Luka Sizgoric 1 | Robert Likic 1,2

1
University of Zagreb Medical School, Zagreb, Croatia
2
Division of Clinical Pharmacology and Therapeutics, Department of Internal Medicine, Clinical Hospital Centre Zagreb, Zagreb, Croatia

Correspondence
Robert Likic, Unit of Clinical Pharmacology, Department of Internal Medicine, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia.
Email: [email protected]; [email protected]

K E Y W O R D S : chronic kidney disease, COVID-19, drug interactions, effects, gastric acid secretion, glycemic dysregulation, proton pump
inhibitors

Proton pump inhibitors (PPIs) are a group of medicines prescribed to observed consistently among different ethnic groups and individual
treat disorders related to stomach acid. Their mechanism of action OAC compounds, except for edoxaban. Additionally, intensive care
involves inhibiting the hydrogen-potassium ATPase enzyme pump in unit (ICU) patients who are at an increased risk of developing
the parietal cells of the gastric mucosa, thereby reducing gastric acid stress ulcers and bleeding are commonly taking PPIs as a preventive
secretion. While PPIs are generally considered safe and effective, therapy. However, Barkun and Bardou in their study12 (NEJM 2018)
recent research has raised concerns about potential risks associated found limited benefit of this approach. In their view, considering the
with their use. There have been several recent articles in The British low incidence of clinically important upper GIB in the ICU patients,
Journal of Clinical Pharmacology assessing the benefits and risks of PPI prophylaxis with a PPI, if started, should be reserved only for severely
use and their interactions with other drugs in various health condi- ill patients with an increased risk for this complication (Figure 1).
tions. This Spotlight Commentary aims to highlight some of these In a population-based cohort study, Schmilovitz-Weiss et al.14
1
studies' key findings. (BJCP 2020) evaluated 29 639 patients (with no history of stroke
The adverse effects discussed include all-cause and cause-specific and/or use of antiplatelet aggregation drugs) with a mean age of 82.2
mortality, incidence of type 2 diabetes, elevated risk of sensorineural ± 5.5 years who were using PPIs. They discovered that the risk for a
hearing loss and adverse outcomes in patients with chronic kidney first-time ischemic stroke was significantly lower in those using PPIs
disease (see Table 1). Negative drug interactions and problems with at any dose and for any time period compared to non-users. The
drug clearance as well as increased risk of COVID-19 adverse clinical authors suggested that the protective effect of PPIs might be due to
outcomes were also highlighted. It is important to note that evidence their ability to improve endothelial function and reduce platelet
of any association with adverse effects remains weak and rigorous aggregation.
evaluation is lacking. Recent randomized trials suggested that the link Conversely, several recent studies have reported links between
between PPI use and various diseases likely appeared due to bias and PPI use and increased risks of all-cause and cause-specific mortality,
residual confounding and that these drugs seem to be safe apart from incident type 2 diabetes, and poor outcomes in patients with chronic
a possible elevated risk of enteric infections. PPIs ought to be kidney disease. Brown et al.4 (BJCP 2021) described an association
prescribed at the lowest effective dose and for the shortest time between PPI use and both all-cause (weighted hazard ratio 1.38, 95%
period possible. They are still a relatively safe group of drugs but CI 1.33–1.44) and cause-specific mortality. However, their findings
should be prescribed only in their registered indications.10 also highlighted significant differences between PPI users and
PPIs have been shown to lower the risk of upper gastrointestinal comparator groups on characteristics predictive of death.
bleeding, especially among patients on oral anticoagulants (OACs). A Recent studies have explored the correlation between PPI use
systematic review and meta-analysis of 10 studies by Ahn et al.11 and type 2 diabetes mellitus. Czarniak et al.3 (BJCP 2021) assessed
(BJCP 2022), including 1 970 931 patients, demonstrated that concur- this relationship and its dose-dependence. They conducted a Cox
rent PPI therapy in patients taking OACs is linked with a decreased proportional hazard regression analysis to assess the time-varying
incidence of total gastrointestinal bleeding (GIB) and major GIB. The effect of incident PPI use on type 2 DM during follow-up. After
beneficial effect of PPI was mainly associated with upper GIB and was adjusting for risk factors, PPI use was found to be connected with an

388 © 2023 British Pharmacological Society. wileyonlinelibrary.com/journal/bcp Br J Clin Pharmacol. 2024;90:388–391.

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COMMENTARY 389

TABLE 1 Overview of system/organ based adverse effects associated with PPI use.

System/organ Adverse effect Key findings Study

Auditory Elevated likelihood of sensorineural auditory Consumption of PPI correlated with a Yee et al.2 (BJCP 2022)
system impairment heightened likelihood of sensorineural
hearing loss (SNHL) or tinnitus, especially
with current or recent use and high average
daily doses.
Endocrine Incidence of type 2 diabetes PPI use was found to be linked with an Czarniak et al.3 (BJCP 2021)
system increased likelihood of developing type 2
DM, with the effect being highly dose
dependent.
General health Mortality from all causes and specific causes Correlation between PPI prescription and both Brown et al.4 (BJCP 2021)
all-cause (weighted hazard ratio 1.38, 95% CI
1.33–1.44) and cause-specific mortality.
Significant differences between PPI users
and comparator groups on characteristics
predictive of death.
General health Elevated risk of COVID-19 adverse clinical PPI use was linked to a significantly higher Li et al.5 (Gut 2020)
outcomes likelihood of poorer COVID-19 outcomes
compared to no PPI use.
General health Decrease in voriconazole plasma concentration Use of PPIs led to a significant decrease in Blanco Dorado et al.6 (BJCP
voriconazole plasma concentration. These 2020)
subtherapeutic levels could potentially
compromise the efficacy of antifungal
therapy.
Metabolic Problems with drug clearance Presence of drug clearance variability, El Rouby et al.7 (EODMT
system particularly concerning CYP2C19 genetic 2018)
polymorphism, in certain proton pump
inhibitors (PPIs).
Renal system Adverse outcomes in patients with chronic Heightened likelihood of sudden kidney Liabeuf et al.8 (BJCP 2021)
kidney disease damage, disease progression, and death
among patients with chronic kidney disease
who consistently used PPIs over an
extended period of time.
Respiratory Increased mortality risk in patients with In these patients, PPI consumption was linked Wei et al.9 (BJCP 2022)
system advanced non-small cell lung cancer (NSCLC) to a heightened risk of death. There are also
on systemic anti-tumour therapy possible drug–drug interactions that could
lower TKI absorption.

increased risk of incident type 2 DM, with the effect being highly risk of disease progression, acute kidney injury and mortality among
dose-dependent. Although the mechanism of glycaemic dysregulation patients with chronic kidney disease who were long-term users of PPIs.
connected to PPI use requires additional investigation, the authors A significant discussion point is the association between PPI use
suggested that low magnesium and glucagon-like peptide-1 blood and COVID-19 outcomes. To compare and critically appraise the
levels could be potential contributors. Furthermore, type 2 diabetes existing scientific literature, Veettil et al.15 (BJCP 2021) conducted a
mellitus patients on PPI therapy appeared more susceptible to hearing comprehensive umbrella review of multiple meta-analyses. Their pri-
loss. Yee et al.2 (BJCP 2022) described a link between PPI use and an mary goal was to summarize the evidence related to adverse clinical
increased risk of sensorineural hearing loss (SNHL) or tinnitus, outcomes associated with PPI use, including those related to
especially among patients with current or recent PPI use and high COVID-19, while also understanding the level of certainty in the exist-
average daily dose consumption. ing evidence. However, their conclusions were contested by Wu
Long-term use of PPIs has been shown to have not only ototoxic et al.16 (BJCP 2021), whose meta-analysis was included in Veettil's
effects but also to contribute significantly to nephrotoxicity. umbrella review. They cited misinterpretation of the number of stud-
Liabeuf et al.8 (BJCP 2021) proposed limiting the use of PPIs in ies analysed, adjustment for confounding variables, and misinterpreta-
self-medication among patients with chronic kidney disease and tion of the link between PPI use and COVID-19 adverse clinical
considering deprescribing PPIs in patients without an indication. This outcomes. According to the original meta-analysis, Li et al.5 (Gut
recommendation arised from their findings, which showed an elevated 2020) found that current or regular PPI use was significantly
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390 COMMENTARY

remains unclear, the concurrent use of tyrosine kinase inhibitors

(TKIs) and PPIs is a significant concern due to possible drug–drug
interactions that could decrease TKI uptake. As the solubility of these
drugs decreases between pH 4 and 5, patients are advised to take
TKIs with acidic beverages, such as Coca-Cola™, to temporarily acidify
the stomach and enhance TKI absorption during PPI use.
In a study by Sharma et al.17 (BJCP 2022), degassed Coca-Cola™
was used to deliver a suspension of acalabrutinib (whose solubility is
also pH-dependent) via a nasogastric tube in healthy subjects during PPI
administration. The authors found that the systemic exposure to acalab-
rutinib and its active metabolite after nasogastric administration of an
acalabrutinib suspension in degassed Coca-Cola™ was similar to that
achieved after oral administration of an acalabrutinib capsule with
water.
Today, there is limited criticism regarding how PPIs are pre-
scribed. In fact, overuse remains a critical point. PPI consumption
trends indicated that 37.5% of patients continued their original ther-
apy course for over a year, contrary to recommendations18 (BJGP
2022). Additionally, a recent study by El Rouby et al.7 (EODMT 2018)
highlighted drug clearance variability, particularly concerning
CYP2C19 genetic polymorphism, in certain proton pump inhibitors
(PPIs). The authors stated that large epidemiological studies demon-
strated an association between dose and PPI-related adverse events,
which suggested a possible connection between CYP2C19, PPI drug
concentrations and adverse events (PEDIATRICS 2019).19 The study
also reported that genotype-guided dosing could offer a way towards
improving therapeutic outcomes and minimizing adverse events.
Further potential drug interactions were explored by Blanco
F I G U R E 1 Functional principles of proton pump inhibitors. The Dorado et al.6 (BJCP 2020). In their multicentre prospective study,
enzyme H/K-ATPase, responsible for secreting stomach acid, is they evaluated the effect of omeprazole and pantoprazole, two com-
initially located in the intracellular tubules during the inactive phase monly prescribed PPIs, on the plasma concentrations of voriconazole,
and subsequently relocates to the microvilli of the enlarged secretory an antifungal drug. They found a higher CYP inhibitory capacity of
canaliculus when the parietal cell is activated. In this active phase, the
omeprazole compared to pantoprazole regardless of the CYP2C19
gastric H/K-ATPase transitions from the tubulovesicles to the
topmost membrane in the canaliculus, facilitating stomach acid polymorphism and that the use of PPIs led to a significant decrease in
release through an isoelectric, ATP-driven exchange of hydrogen and voriconazole plasma concentration. These subtherapeutic levels could
potassium ions. This process employs extracellular K+ to expel acid, potentially compromise the efficacy of antifungal therapy.
swapping internal hydronium ions with K+. The charged particle is In conclusion, the research papers discussed in this commentary
transported to the luminal face of the ATPase via the incorporation of
underscore the importance of using PPIs judiciously. While PPIs have
K+ Cl channels into the microvillus membrane. Proton pump
proven effective in the treatment of numerous gastrointestinal prob-
inhibitors (PPIs) obstruct the function of gastric H/K-ATPase, thereby
reducing stomach acid production.13 The image has been created with lems, there is some evidence of adverse outcomes and detrimental
BioRender.com. interactions with other drugs, despite problems with confounding.
Emphasis should be placed on the significant challenges of dose selec-
associated with an increased risk of severe COVID-19 outcomes com- tion and treatment duration. PPIs are often obtained over the counter,
pared to no PPI use. This finding underscores the need for further and many complications arise from issues related to inadequate medi-
research into the risks associated with PPI use, particularly in the con- cation prescribing protocols, including insufficient patient education.
text of existing and emerging infectious diseases such as COVID-19. Compelling evidence highlights the need for a patient-centric and vigi-
Another concern is the interaction of PPIs with other drugs under lant approach, as well as the importance of deprescribing practices. As
various health conditions. Wei et al.9 (BJCP 2022) investigated the we continue to understand the intricacies of PPI use, it is crucial to
relationship between PPIs and survival outcomes of patients with adopt rational PPI prescribing practices to offer patients the best
advanced non-small cell lung cancer (NSCLC) undergoing systemic possible care.
anti-tumour therapy. Their analysis revealed that PPI use in these
patients was associated with an elevated mortality risk. While the AUTHOR CONTRIBU TIONS
mechanism underlying PPI use and mortality risk in NSCLC patients Both authors equally participated in writing the manuscript.
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COMMENTARY 391

CONF LICT OF IN TE RE ST ST AT E MENT 10. Kanno T, Moayyedi P. Proton pump inhibitors in the elderly, balancing
None to disclose. risk and benefit: an age-old problem. Curr Gastroenterol Rep. 2019;
21(12):65. doi:10.1007/s11894-019-0732-3
11. Ahn H, Lee SR, Choi EK, et al. Protective effect of proton-pump
DATA AVAI LAB ILITY S TATEMENT inhibitor against gastrointestinal bleeding in patients receiving oral
Data related to this study may be available from the corresponding anticoagulants: a systematic review and meta-analysis. Br J Clin
author upon a reasonable request. Pharmacol. 2022;88(11):4676-4687. doi:10.1111/bcp.15478
12. Barkun A, Bardou M. Proton-pump inhibitor prophylaxis in the
ICU—benefits worth the risks? N Engl J Med. 2018;379(23):
ORCID 2263-2264. doi:10.1056/NEJMe1810021
Robert Likic https://orcid.org/0000-0003-1413-4862 13. Shin JM, Sachs G. Pharmacology of proton pump inhibitors. Curr
Gastroenterol Rep. 2008;10(6):528-534. doi:10.1007/s11894-008-
0098-4
RE FE R ENC E S
14. Schmilovitz-Weiss H, Gingold-Belfer R, Peleg N, et al. Use of proton
1. Webb AJ. Spotlight—introducing a new Commentary series for the pump inhibitors is associated with lower rates of first-time ischemic
BJCP. Br J Clin Pharmacol. 2019;85(7):1387-1388. doi:10.1111/bcp. stroke in community-dwelling elderly. Br J Clin Pharmacol. 2020;87(3):
13930.Epub 1187-1193. doi:10.1111/bcp.14488
2. Yee J, Han HW, Gwak HS. Proton pump inhibitor use and hearing loss 15. Veettil SK, Sadoyu S, Bald EM, et al. Association of proton-pump
in patients with type 2 diabetes: evidence from a hospital-based inhibitor use with adverse health outcomes: a systematic umbrella
case-control study and a population-based cohort study. Br J Clin review of meta-analyses of cohort studies and randomised controlled
Pharmacol. 2022;88(6):2738-2746. doi:10.1111/bcp.15210 trials. Br J Clin Pharmacol. 2021;88(4):1551-1566. doi:10.1111/bcp.
3. Czarniak P, Ahmadizar F, Hughes J, et al. Proton pump inhibitors are 15103
associated with incident type 2 diabetes mellitus in a prospective 16. Wu D, Li G, Yu G. Use of proton pump inhibitors and adverse clinical
population-based cohort study. Br J Clin Pharmacol. 2021;88(6): outcomes. Br J Clin Pharmacol. 2021;88(5):2452-2453. doi:10.1111/
2718-2726. doi:10.1111/bcp.15182 bcp.15161
4. Brown JP, Tazare JR, Williamson E, et al. Proton pump inhibitors and 17. Sharma S, Pepin X, Cheung J, et al. Bioavailability of acalabrutinib
risk of all-cause and cause-specific mortality: a cohort study. Br J Clin suspension delivered via nasogastric tube in the presence or absence
Pharmacol. 2021;87(8):3150-3161. doi:10.1111/bcp.14728 of a proton pump inhibitor in healthy subjects. Br J Clin Pharmacol.
5. Li G-F, An XX, Yu Y, et al. Do proton pump inhibitors influence 2022;88(10):4573-4584. doi:10.1111/bcp.15362
SARS-COV-2 related outcomes? A meta-analysis. Gut. 2020;70(9): 18. Savarino E, Anastasiou F, Labenz J, Hungin APS, Mendive J. Holistic
1806-1808. doi:10.1136/gutjnl-2020-323366 management of symptomatic reflux: rising to the challenge of proton
6. Blanco Dorado S, Maroñas Amigo O, Latorre-Pellicer A, et al. A pump inhibitor overuse. Br J Gen Pract. 2022;72(724):541-544. doi:
multicentre prospective study evaluating the impact of proton-pump 10.3399/bjgp22X721157
inhibitors omeprazole and pantoprazole on Voriconazole plasma 19. Bernal CJ, Aka I, Carroll RJ, et al. CYP2C19 phenotype and risk of
concentrations. Br J Clin Pharmacol. 2020;86(8):1661-16FF66. doi:10. proton pump inhibitor-associated infections. Pediatrics. 2019;144(6):
1111/bcp.14267 e20190857. doi:10.1542/peds.2019-0857
7. El Rouby N, Lima JJ, Johnson JA. Proton pump inhibitors: from
CYP2C19 pharmacogenetics to precision medicine. Expert Opin Drug
Metab Toxicol. 2018;14(4):447-460. doi:10.1080/17425255.2018.
1461835
8. Liabeuf S, Lambert O, Metzger M, et al. Adverse outcomes of
How to cite this article: Sizgoric L, Likic R. Proton pump
proton pump inhibitors in patients with chronic kidney disease: the inhibitors: Weighing the benefits and risks across various
CKD-Rein cohort study. Br J Clin Pharmacol. 2021;87(7):2967-2976. health conditions. Br J Clin Pharmacol. 2024;90(2):388‐391.
doi:10.1111/bcp.14713 doi:10.1111/bcp.15960
9. Wei N, Zheng B, Que W, Zhang J, Liu M. The association between
proton pump inhibitor use and systemic anti-tumour therapy on sur-
vival outcomes in patients with advanced non-small cell lung cancer: a
systematic review and meta-analysis. Br J Clin Pharmacol. 2022;88(7):
3052-3063. doi:10.1111/bcp.15276