What is the update on long-term safety evidence with proton pump inhibitor use?

Introduction
Since their introduction more than 25 years ago, proton pump inhibitors (PPIs), a widely used class of medications for acid secretion-related disorders, have become a mainstay of treatment for conditions such gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), peptic ulcer-related gastrointestinal bleeding, eradication of Helicobacter pylori infection, prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal ulcers, erosive esophagitis due to GERD, and Zollinger-Ellison syndrome.^1,2 In 2019, an all-time high of nearly 84 million Medicare monthly prescription claims were processed for PPIs, although this number may underestimate how truly widespread their use is, since many can be purchased over the counter (OTC).³ Since their inception, PPIs have generally been considered safe; however, the association of certain adverse events with long-term use has resulted in increased concern with the prolonged use of these agents.¹ Since 2010, several safety warnings have been issued by the Food and Drug Administration (FDA) regarding the potential for Clostridium dificile-associated diarrhea, hypomagnesemia, possible increased risk of hip, wrist, and spine fractures, vitamin B deficiency, acute interstitial nephritis (AIN), and cutaneous and systemic lupus erythematous.^4,5 Concerns have also been raised that long-term use may be associated with the development of pneumonia, dementia, and certain cancers. Since the issuance of these warnings, new evidence has been published, therefore, the aim of this review is provide an evidence update regarding the safety of long-term PPI use.

Guideline Recommendations
The 2022 American College of Gastroenterology (ACG) GERD management guideline currently recommends a duration of PPI for 8 weeks, with maintenance therapy recommended indefinitely for patients with Los Angeles (LA) grade C or D esophagitis.⁶ For those patients who do not have erosive esophagitis or Barrett’s esophagus and whose symptoms are resolved with PPI therapy, the guidelines recommend attempting PPI discontinuation, or switching to on-demand PPI therapy. Similarly, the American Gastroenterological Association (AGA) recommends that patients with Barrett’s esophagus, eosinophilic esophagitis, or idiopathic pulmonary fibrosis not be considered for the deprescribing of PPIs.⁷ The guideline states that patients with complicated GERD, which includes those with a history of severe erosive esophagitis, esophageal ulcer, or peptic stricture, should also generally not be considered for discontinuation of PPIs, and that the decision to discontinue a PPI should be based on a lack of indication for use, rather than concern for the risk of adverse events. The AGA recommends that if PPI therapy is continued in patients with unproven GERD, the appropriateness and dosing of PPI therapy should be evaluated 12 months after initiation, with endoscopy and prolonged wireless reflux monitoring offered off PPI therapy to establish whether long-term therapy is appropriate.⁸ Recommended durations of PPI use for other indications not mentioned in the guidelines range from 5 days to 8 weeks.^2,6 However, there are many instances where patients continue PPIs to control symptoms of refractory GERD or providers simply do not discontinue the medication past the recommended duration.

The ACG guidelines for GERD acknowledge the concerns with long-term PPI use and recommend counseling patients regarding the lack of definitive data to establish a cause-and-effect relationship between PPI use and certain adverse effects.⁶ The authors acknowledge that while some studies demonstrated an association with long-term use and adverse events, these studies had flaws, and higher quality data have not demonstrated an increased risk for pneumonia, stomach cancer, osteoporosis-related bone fractures, chronic kidney disease, vitamin and mineral deficiencies, heart attack, stroke, dementia, and mortality, although an increased risk of intestinal infections has been observed with long-term PPI use. The ACG guideline states that long-term PPI use carries more inherent benefits than risks, but that the possibility of the adverse events identified in observational studies cannot be completely excluded. The guideline provides several recommendations during long-term PPI use. In patients without risk factors for bone disease, the intake of vitamin D and calcium does not need to be increased, and routine bone mineral density monitoring is not necessary. In patients without risk factors for vitamin B12 deficiency, routine monitoring of vitamin B12 and vitamin B12 supplementation is not necessary. Additionally, in patients without risk factors for kidney disease, the routine monitoring of serum creatinine levels is not necessary; however, in the presence of diagnosed renal insufficiency, close monitoring and consultation is recommended with a nephrologist. The ACG guideline also states that in patients on clopidogrel with LA grade C or D esophagitis or whose GERD is not well-controlled with other therapies, the benefits of PPI therapy outweigh their questionable cardiovascular (CV) risk.

Adverse Effects
Most adverse events associated with long-term PPI use do not have known mechanisms of action, but previous observational studies have hypothesized their pathophysiology, and their major proposed mechanisms are discussed in the ACG guidelines.⁶ For gastric cancer, it is proposed that PPIs promote gastric atrophy and inflammation in patients with H. pylori, resulting in a predisposition to malignancy. Additionally, PPI use has been correlated with increases in N-nitrosamine serum levels compared to baseline, which may be carcinogenic. Hypergastrinemia has also been suggested to cause gastric epithelial cell proliferation which may be carcinogenic. Vitamin B12 deficiency is a result of decreased absorption in the stomach.^6,9 The same mechanism also affects the absorption of magnesium and calcium, which may result in hypomagnesemia and bone fractures, respectively.

There are also concerns that the increase in pH caused by PPIs may allow for greater non-Helicobacter pylori growth, which can colonize in the lung and cause pneumonia or, in the case of C. dificile or small intestinal bacterial overgrowth, colonization in the gastrointestinal tract.⁶

An increased risk of CV events has been associated with PPI blockade of asymmetric dimethylarginine (ADMA, an L-analogue of arginine) metabolism, which results in downstream effects that block nitric oxide needed to maintain the vascular system. The proposed mechanism for dementia has been attributed to the inhibition of H+ ATPase needed to acidify microglial lysosomes, which prevents the degradation of cerebral amyloid-ß peptide; a deficiency in vitamin B12 may also be a contributing factor. Lastly, the develop of AIN is suggested to be an idiosyncratic drug reaction that progresses to chronic kidney disease.

Recent Literature
Several recent meta-analyses published since the 2022 ACG guideline have evaluated the causal relationship of long-term PPI use with the adverse events previously discussed.^6,10-14 The impact of PPI use on the development of dementia was recently assessed in a meta-analysis (MA) of 9 observational studies by Ahn et al.¹⁰ The authors of the MA concluded that there was no decisive evidence to determine that PPIs were associated with dementia. The included studies in the MA ranged in follow-up from 4 to 14 years. The risk of developing dementia was not significantly increased with long-term PPI use versus non-use (RR, 1.16; 95% CI, 1.00 to 1.35); however, after adjustment for small-study bias using the Rucker’s shrinkage method and Copas selection model, the risk was increased (RR, 1.15; 95% CI, 1.13 to 1.17 and RR, 1.16; 95% CI, 1.01 to 1.32, respectively), with significant heterogeneity estimated using the Rucker’s method (I²=97.4%).

In the MA of 22 observational studies by Gao et al that evaluated the incidence of gastric cancer in patients on PPIs and H2RAs, PPI use was associated with an increased incidence of gastric cancer (OR, 1.94; 95% CI, 1.43 to 2.65) compared to non-PPI users, but when evaluated against H2RAs, there was no difference in risk (OR, 1.65; 95% CI, 0.92 to 2.97).¹¹ The observational studies included in this MA had a variable range of follow-up, which ranged in duration from 3 to 29 years. Additionally, 2 studies in the MA had a serious risk of bias, 12 studies had a moderate risk of bias, and 6 had a low risk of bias. When the duration of PPI therapy was evaluated for the risk of gastric cancer development, no increases in gastric cancer risk were observed with longer durations of therapy. In patients receiving PPIs for $ < $1 year (OR, 6.33; 95% CI, 3.76 to 10.65), 1 to 3 years (OR, 1.82; 95% CI, 1.30 to 2.55), and $ > $3 years (OR, 1.25; 95% CI, 1.00 to 1.56) a time-dependent increase in gastric cancer risk was not observed.

In the MA of 8 studies from Mohammadi et al that evaluated the use of PPIs and H2RAs in kidney transplant recipients, no significant differences were found in graft loss, biopsy proven acute rejection (BPAR), mortality, C. diff infection, or rates of pneumonia between groups.¹² The estimated glomerular filtration rate (eGFR) after 12 months was significantly lower in patients receiving PPIs versus H2RAs (weighted mean difference [WMD], -1.01; 95% CI, -1.89 to -0.12 mL/min/1.73m²), and PPI versus H2RA therapy was associated with higher rates of antibody-mediated rejection (AMR) (OR, 1.87; 95% CI, 1.03 to 3.04). Hypomagnesemia was also significantly increased in PPI patients versus those receiving an H2RA (OR, 2.16; 95% CI, 1.46 to 3.20).

Two MAs evaluating CV outcomes in patients receiving PPI therapy found no increased CV risk in patients receiving PPI therapy.^13,14 In the MA of randomized controlled trials by Shang et al in patients with coronary artery disease (CAD) receiving antithrombotics, the use of PPI therapy was not associated with an increased risk of major adverse cardiovascular and cerebrovascular events (MACCE), all-cause death, CV death, myocardial infarction (MI), stent thrombosis, or gastroduodenal ulceration, compared to no PPI treatment.¹³ In addition, PPI therapy was noted as beneficial for the risk of GI events (RR, 0.34; 95% CI, 0.21 to 0.54) and significant bleeding from gastroduodenal lesions (RR, 0.09; 95% CI, 0.03 to 0.28) versus no PPI treatment. In this MA, when bias was assessed, 5 trials had a high risk due to evidence of detection and performance bias while 12 trials had some concerns for bias due to not reporting their process used for randomization and allocation, which may limit the findings of this data. In the MA of observational studies by Nolde et al, the risk of first MI, ischemic stroke, and first CV event was not increased versus comparator treatment (H2RA or placebo).¹⁴ Additionally, the pooled risk of CV mortality was not increased with PPI use versus comparator after adjustment for bias. The authors state that limitations of this data include the dilution of data on the long-term effects of PPI use by short-term studies that were included.

Since prior observational data has linked PPI therapy in cirrhotic patients with an increased risk for infection, hepatic encephalopathy, hospitalization, and mortality, the STOPPIT trial is currently evaluating the discontinuation of long-term PPI therapy and its effects on the composite endpoint of re-hospitalization and/or death in recently hospitalized cirrhotic patients.¹⁵  In the study, patients without an evidence-based indication for long-term PPI treatment will be randomized to either continuation of long-term PPI therapy, or removal of PPI treatment for 360 days. Based on findings from this study, either a more liberal or restrictive PPI prescribing strategy may be warranted in cirrhotic patients in the future.

Conclusion
Higher quality data since the ACG guidelines are lacking regarding the association of long-term PPI use and adverse event development. Although long-term PPI use carries more inherent benefits than risks, the possibility of adverse events identified in observational studies cannot be completely excluded. Randomized, confirmatory clinical trials are still needed to elucidate whether long-term PPI therapy may be associated with the development of adverse events.

References

1. Strand DS, Kim D, Peura DA. 25 years of proton pump inhibitors: A comprehensive review. Gut Liver. 2017;11(1):27-37. doi:10.5009/gnl15502
2. Omeprazole. [Package insert]. Covis Pharma US, Inc. 2022.
3. Toth JM, Jadhav S, Holmes HM, Sharma M. Prescribing trends of proton pump inhibitors, antipsychotics and benzodiazepines of Medicare part D providers. BMC Geriatr. 2022;22(1):306. doi:10.1186/s12877-022-02971-2
4. Ambizas EM, Etzel JV. Proton pump inhibitors: Considerations with long-term use. US Pharmacist. Published July 19, 2017. Accessed March 28, 2023. https://www.uspharmacist.com/article/proton-pump-inhibitors-considerations-with-longterm-use
5. Islam MM, Poly TN, Walther BA, et al. Adverse outcomes of long-term use of proton pump inhibitors: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2018;30(12):1395-1405. doi:10.1097/MEG.0000000000001198
6. Katz PO, Dunbar KB, Schnoll-Sussman FH, Greer KB, Yadlapati R, Spechler SJ. ACG clinical guideline for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2022;117(1):27-56.doi:10.14309/ajg.0000000000001538
7. Targownik LE, Fisher DA, Saini SD. AGA Clinical Practice Update on De-Prescribing of Proton Pump Inhibitors: Expert Review. Gastroenterology. 2022;162(4):1334-1342. doi:10.1053/j.gastro.2021.12.247
8. Yadlapati R, Gyawali CP, Pandolfino JE; CGIT GERD Consensus Conference Participants. AGA clinical practice update on the personalized approach to the evaluation and management of GERD: Expert review. Clin Gastroenterol Hepatol. 2022;20(5):984-994.e1. doi:10.1016/j.cgh.2022.01.025
9. Laine L, Ahnen D, McClain C, Solcia E, Walsh JH. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors.Aliment Pharmacol Ther. 2000;14(6):651-668. doi:10.1046/j.1365-2036.2000.00768.x
10. Gao H, Li L, Geng K, et al. Use of proton pump inhibitors for the risk of gastric cancer. Medicine (Baltimore). 2022;101(49):e32228. doi:10.1097/MD.0000000000032228
11. Shang YS, Zhong PY, Ma Y, Bai N, Niu Y, Wang ZL. Efficacy and safety of proton pump inhibitors in patients with coronary artery diseases receiving oral antiplatelet agents and/or anticoagulants: A systematic review and meta-analysis. J Cardiovasc Pharmacol. 2022;80(1):1-12. doi:10.1097/FJC.0000000000001284
12. Nolde M, Ahn N, Dreischulte T, et al. Proton pump inhibitors and the risk of cardiovascular events and cardiovascular mortality: A systematic review and meta-analysis of observational studies. Eur J Intern Med. 2022;106:80-89. doi:10.1016/j.ejim.2022.09.021
13. Ahn N, Nolde M, Krause E, et al. Do proton pump inhibitors increase the risk of dementia? A systematic review, meta-analysis and bias analysis. Br J Clin Pharmacol. 2023;89(2):602-616. doi:10.1111/bcp.15583
14. Mohammadi K, Yaribash S, Razi B, Dashti-Khavidaki S. Comparing safety of proton-pump inhibitors versus H2-receptor antagonists in kidney transplant recipients: A systematic review and meta-analysis. J Clin Pharm Ther. 2022;47(5):567-574. doi:10.1111/jcpt.13589
15. Wehmeyer MH, Horvatits T, Buchholz A, et al. Stop of proton-pump inhibitor treatment in patients with liver cirrhosis (STOPPIT): study protocol for a prospective, multicentre, controlled, randomized, double-blind trial. Trials. 2022;23(1):302. Published 2022 Apr 12. doi:10.1186/s13063-022-06232-w

Prepared by:
Alijia Neal, PharmD Candidate Class of 2023
University of Illinois at Chicago College of Pharmacy

Reviewed and Edited by:
Christie Denton, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

June 2023

The information presented is current as of April 7, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.