Long-term proton pump inhibitors use and risk of gastric cancer: a meta-analysis of 926 386 participants

Wan, Qianyi; Wu, Xiaoting; Li, Ni; Li, Du; Zhou, Yong

doi:10.1136/gutjnl-2018-316416

Cited by 37 publications

(50 citation statements)

References 7 publications

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“…Therefore, it is difficult to distinguish between prevalent and incident PPI users, although we assume that many of those exposed in 2005 were already users prior to enrolment in the present study. We defined long-term use as an accumulated use of 6 months of more, which was considerably stricter than other studies looking at PPI use and the risk of gastric cancer (defined as current use, or minimally 1-2 prescriptions) [20],and pancreatic cancer, all defining PPI use as C 1 prescription [27][28][29][30][31][32][33]. Long-term use ([ 6 months has only been approved by the Food and Drug Administration for pathological hypersecretory conditions such as the Zollinger-Ellison syndrome; and erosive esophagitis (based on study data \ 12 months) [42].…”

Section: Discussionmentioning

confidence: 99%

“…An increasing number of studies have also investigated the risk of cancer with most evidence existing for gastric, colorectal and pancreatic cancer. The two metaanalyses on gastric cancer (in total including 8 different studies) concluded that there may be an increased risk in particular when used over longer periods of time [20,21]. Yet, the two meta-analyses evaluating colorectal cancer (including 5 different studies) did not find strong support for an association [22,23], although 2 more studies have been published since showing a significantly increased risks [24,25].…”

Section: Introductionmentioning

confidence: 99%

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Long-term proton pump inhibitor usage and the association with pancreatic cancer in Sweden

2019

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Background The long-term safety of proton pump inhibitors (PPIs) is increasingly questioned. The aim of our study was to assess the risk of pancreatic cancer among longterm PPI users in Sweden. Methods This population-based nationwide Swedish cohort study including 796,492 adult long-term PPI users has been used to calculate the standardized incidence rate ratios (SIRs) and 95% confidence intervals (CI) for pancreatic cancer, stratifying by indications of use, age, sex, and duration of use. The risk among all 20,210 long-term H2-receptor antagonist users was assessed as comparison.Results Pancreatic cancer was found in 1733 long-term PPI users, and 25 H2-receptor antagonist users. For PPI users, the risk of pancreatic cancer was increased overall (SIRs = 2.22; 95% CI 2.12-2.32) and in all subgroup analyses, with the highest risk among PPI-users younger than 40 years (SIR = 8.90,, and among individuals with a history of Helicobacter pylori (SIR = 2.99, 95% CI 2.54-3.49). After the first year after enrolment (during which PPI use may be because of early symptoms of pancreatic cancer), the risk remained increased over time, with SIR = 1.57 (95% CI 1.38-1.76) after 5 years. No associations were found for H2-receptor antagonists (SIR = 1.02, 95% CI 0.66-1.51). Conclusions This large study showed an increased risk of pancreatic cancer in long-term users of PPIs in Sweden, in particular among the youngest users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Long-term proton pump inhibitor usage and the association with pancreatic cancer in Sweden

2019

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“…Systematic review of 10 studies including three RCTs 104 Gastric cancer 2a Increased gastric cancer risk among long-term PPI users in large observational cohort studies and one meta-analysis (pooled OR 2.10, 95% CI 1.10-3.09). Probable confounding [16][17][18][19][20] Gastrointestinal infections and microbiome alterations…”

Section: Level Of Evidence Key Findings Referencesmentioning

confidence: 99%

“…PPIs can induce bacterial overgrowth of the stomach and longterm PPI use has been associated with increased risk for gastric cancer in observational studies of large patients cohorts. [16][17][18][19][20] Indeed, gastric microbes are believed to contribute to gastric carcinogenesis: Non-H pylori bacterial overgrowth and H pylori were shown to independently and synergistically accelerate the development of atrophic gastritis 92 and in the H pylori INS-GAS mouse model, the gastric commensal microbiota were shown to contribute to carcinogenesis. 93,94 Two human populations with high and low gastric cancer risk in Colombia showed marked differences in gastric microbiota compositions.…”

Section: Gastric Cancermentioning

confidence: 99%

“…Two population‐based case–control studies from Taiwan demonstrated increased odds for any‐site gastric cancer in patients who were treated at least two times for gastro‐oesophageal reflux disease between 1996 and 2011 (OR 2.48, 95% CI 1.92‐3.20) and in subjects with a cumulative duration of PPI treatment of >6 months for unknown indications between 2000 and 2013 (OR 2.00, 95% CI 1.36‐2.95), each compared with those who never used PPIs . A recent meta‐analysis including >900 000 individuals confirmed this association with a pooled OR of 2.10 (95% CI 1.10‐3.09) and the previously reported duration–response relationship (Table , Figure ). To date, the possible biological mechanisms underlying this association are unclear.…”

Section: Introduction: Gastric Acid Inhibition and Adverse Effects Ofmentioning

confidence: 99%

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Systematic review: the effects of proton pump inhibitors on the microbiome of the digestive tract—evidence from next‐generation sequencing studies

Macke

Schulz

Koletzko

et al. 2020

Aliment Pharmacol Ther

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Background: Proton pump inhibitors (PPI) are widely used to treat acid-related disorders of the upper gastrointestinal tract. However, large observational studies have raised concerns about PPI-associated adverse events. In recent years, data from next-generation sequencing studies suggested that PPIs affect the composition of the intestinal microbiota, while a balanced gut microbiome is essential for maintaining health.Aim: To review the available evidence from next-generation sequencing studies on the effect of PPIs on the intestinal microbiome and to discuss possible implications of PPI-induced dysbiosis in health and disease.Methods: A systematic review was conducted following the recommendations of the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. A PubMed query yielded 197 results. 19 publications met the prespecified eligibility criteria.Results: Twelve observational study cohorts with 708 PPI users and 11 interventional cohorts with 180 PPI users were included in the review. In most studies, PPI treatment did not affect microbiological richness and diversity, but was associated with distinct taxonomic alterations: In the upper gastrointestinal tract, PPI users showed overgrowth of orally derived bacteria, mostly Streptococcaceae (findings based on six independent cohorts with 126 PPI users). In faecal samples, PPIs increased multiple taxa from the orders Bacillales (eg, Staphylococcaceae), Lactobacillales (eg, Enterococcaceae, Lactobacillaceae, Streptococcaceae) and Actinomycetales (eg, Actinomycetaceae, Micrococcaceae), the families Pasteurellaceae and Enterobacteriaceae and the genus Veillonella. Taxa decreased by PPIs include Bifidobacteriaceae, Ruminococcaceae, Lachnospiraceae and Mollicutes (findings in faecal samples based on 19 independent cohorts with 790 PPI users). Conclusion: PPI use is associated with moderate alterations to upper and distal gut microbiota. The available data suggest that PPI-induced hypochlorhydria facilitates colonization of more distal parts of the digestive tract by upper gastrointestinal microbiota. MACKE Et Al 1 | INTRODUC TI ON: G A S TRI C ACID INHIB ITI ON AND ADVER S E EFFEC TS OF PPIS Gastric acid eliminates microorganisms, promotes the digestive process and facilitates the absorption of iron, calcium and vitamin B12. However, gastric acid also contributes to the development of mild and severe gastroduodenal pathologies. Proton pump inhibitor (PPIs) are the most effective therapy of acid-related diseases and are among the most commonly used drugs. 1 While generally considered a safe therapy, PPIs have been associated with numerous adverse effects in population-based observational studies conducted in recent years. These include cardiovascular and kidney disease, micronutrient deficiencies and osteoporosis, cognitive impairment and death. 2Most studies are retrospective and not hypothesis-driven in design, might be subject to significant confound and thus they cannot establish causality. 2,3 This is also the case for a recent study on ...

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Sex and smoking differences in the association between gastroesophageal reflux and risk of esophageal squamous cell carcinoma in a high‐incidence area: Golestan Cohort Study

Soroush

Roshandel

Khoshnia

et al. 2022

Intl Journal of Cancer

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Prior studies have conflicting findings regarding the association between gastroesophageal reflux disease (GERD) and esophageal squamous cell carcinoma (ESCC). We examined this relationship in a prospective cohort in a region of high ESCC incidence. Baseline exposure data were collected from 50 045 individuals using in‐person interviews at the time of cohort entry. Participants were followed until they developed cancer, died, or were lost to follow up. Participants with GERD symptoms were categorized into any GERD (heartburn or regurgitation), mixed symptoms, or heartburn alone. Multivariable Cox regression was used to assess the relationship between GERD symptom group and histologically confirmed ESCC. The model was adjusted for known risk factors for GERD and ESCC. 49 559 individuals were included in this study, of which 9005 had GERD symptoms. Over 13.0 years of median follow up, 290 individuals were diagnosed with ESCC. We found no association between any GERD and risk of ESCC (aHR 0.90, 95% CI: 0.66‐1.24, P = .54). Similar findings were observed for the GERD symptom subtypes. Significant interactions between any GERD and sex (P = .013) as well as tobacco smoking (P = .028) were observed. In post‐hoc analyses, GERD was associated with a decreased risk of ESCC in men (aHR 0.51, 95% CI: 0.27‐0.98 P = .04) and in smokers (aHR 0.26, 95% CI: 0.08‐0.83 P = .02). While there was little evidence for an overall association between GERD symptoms and ESCC risk, significant interactions with sex and smoking were observed. Men and smokers with GERD symptoms had a lower risk of ESCC development.

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Long-term proton pump inhibitors use and risk of gastric cancer: a meta-analysis of 926 386 participants

Cited by 37 publications

References 7 publications

Long-term proton pump inhibitor usage and the association with pancreatic cancer in Sweden

Long-term proton pump inhibitor usage and the association with pancreatic cancer in Sweden

Systematic review: the effects of proton pump inhibitors on the microbiome of the digestive tract—evidence from next‐generation sequencing studies

Sex and smoking differences in the association between gastroesophageal reflux and risk of esophageal squamous cell carcinoma in a high‐incidence area: Golestan Cohort Study

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