Long-term proton pump inhibitor (PPI) use and the development of gastric pre-malignant lesions

Song, Huan; Zhu, Jianwei; Lu, DongHao

doi:10.1002/14651858.cd010623.pub2

Cited by 132Helicobacter pylori-related gastroenterology studiesGastroesophageal reflux and treatmentsGastric Cancer Management and Outcomes

Long-term proton pump inhibitor (PPI) use and the development of gastric pre-malignant lesions

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Song, Huan, Zhu, Jianwei, Lu, DongHao·2014·Cochrane Database of Systematic Reviews

DOI 10.1002/14651858.cd010623.pub2PMC PMC10843246

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Abstract

BACKGROUND: Proton pump inhibitors (PPIs) are the most effective drugs to reduce gastric acid secretion. PPIs are one of the most commonly prescribed classes of medications worldwide. Apart from short-term application, maintenance therapy with PPIs is recommended and increasingly used in certain diseases, such as Zollinger-Ellison syndrome and gastro-oesophageal reflux disease, especially for people with erosive oesophagitis or Barrett's oesophagus. Although PPIs are generally safe, their efficacy and safety of long-term use remains unclear. The question of whether the long-term use of PPIs could promote the development of gastric pre-malignant lesions has been widely investigated, but results are inconsistent. Limited insight on this problem leads to a dilemma in decision making for long-term PPI prescription. OBJECTIVES: To compare the development or progression of gastric pre-malignant lesions, such as atrophic gastritis, intestinal metaplasia, enterochromaffin-like (ECL) cell hyperplasia, and dysplasia, in people taking long-term (six months or greater) PPI maintenance therapy. SEARCH METHODS: We searched the following databases (from inception to 6 August 2013): the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL. In addition, we searched the reference lists of included trials and contacted experts in the field. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) in adults (aged 18 years or greater) concerning the effects of long-term (six months or greater) PPI use on gastric mucosa changes, confirmed by endoscopy or biopsy sampling (or both). DATA COLLECTION AND ANALYSIS: Two review authors independently performed selection of eligible trials, assessment of trial quality, and data extraction. We calculated odds ratios (OR) for analysis of dichotomous data and mean differences for continuous data, with 95% confidence intervals (CI). MAIN RESULTS: We included seven trials (1789 participants). Four studies had high risk of bias and the risk of bias in the other three trials was unclear. In addition, it was difficult to assess possible reporting bias. We pooled 1070 participants from four RCTs to evaluate corporal atrophy development revealing an insignificantly increased OR of 1.50 (95% CI 0.59 to 3.80; P value = 0.39; low-quality evidence) for long-term PPI users relative to non-PPI users. In five eligible trials, corporal intestinal metaplasia was assessed among 1408 participants, also with uncertain results (OR 1.46; 95% CI 0.43 to 5.03; P value = 0.55; low-quality evidence). However, by pooling data of 1705 participants from six RCTs, our meta-analysis showed that participants with PPI maintenance treatment were more likely to experience either diffuse (simple) (OR 5.01; 95% CI 1.54 to 16.26; P value = 0.007; very-low-quality evidence) or linear/micronodular (focal) ECL hyperplasia (OR 3.98; 95% CI 1.31 to 12.16; P value = 0.02; low-quality evidence) than controls. No participant showed any dysplastic or neoplastic change in any included studies. AUTHORS' CONCLUSIONS: There is presently no clear evidence that the long-term use of PPIs can cause or accelerate the progression of corpus gastric atrophy or intestinal metaplasia, although results were imprecise. People with PPI maintenance treatment may have a higher possibility of experiencing either diffuse (simple) or linear/micronodular (focal) ECL cell hyperplasia. However, the clinical importance of this outcome is currently uncertain.

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Other meta-analyses do not confirm an increased risk of GC in long-term PPI users.
“and other meta-analyses not confirming such a risk[65,66]”
From Proton pump inhibitors and dysbiosis: current knowledge and aspects to be clarified (2019) · cites this paper as [65]

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Self-citation
[Does long-term use of proton pump inhibitors promote premalignant lesions of the gastric mucosa?].
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Authors: Song, H., Zhu, J., & Lu, D.
Affiliations: Karolinska Institutet (SE)
Shandong University (CN)
ORCID: Song, Huan
Zhu, Jianwei
Lu, DongHao
Venue: Cochrane Database of Systematic Reviews
Publisher: Wiley
Published: 2014-12-02
Volume: 2014
Issue: 12
Pages: CD010623-CD010623
ISSN: 1361-6137 (ISSN-L)
1465-1858
DOI: 10.1002/14651858.cd010623.pub2
PMC: PMC10843246
OpenAlex: W1496904506
Cited by: 132
References: 83
Citations by year: 2026: 6 · 2025: 6 · 2024: 14 · 2023: 15 · 2022: 12 · 2021: 12 · 2020: 13 · 2019: 17 · 2018: 13 · 2017: 13 · 2016: 6 · 2015: 5
FWCI: 1.51
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Cochrane Database of Systematic Reviews (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Surgery › Helicobacter pylori-related gastroenterology studies
Health Sciences › Medicine › Gastroenterology › Gastroesophageal reflux and treatments
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
Keywords: proton pump inhibitors, long-term PPI use, atrophic gastritis, intestinal metaplasia, enterochromaffin-like cell hyperplasia, gastric dysplasia, gastric mucosa, drug safety, maintenance therapy, erosive esophagitis, Barrett's esophagus, Zollinger-Ellison syndrome, gastroesophageal reflux disease
MeSH terms: Gastritis, Atrophic, Humans, Hyperplasia, Intestines, Metaplasia, Precancerous Conditions, Stomach Neoplasms, Time Factors, Randomized Controlled Trials as Topic, Enterochromaffin-like Cells, Proton Pump Inhibitors, Maintenance Chemotherapy

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Long-term proton pump inhibitor (PPI) use and the development of gastric pre-malignant lesions

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