Use of Proton Pump Inhibitors Correlates with Increased Risk of Pancreatic Cancer: A Case-Control Study in Taiwan

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1 44 KUWAIT MEDICAL JOURNAL Original Article Use of Proton Pump Inhibitors Correlates with Increased Risk of Pancreatic Cancer: A CaseControl Study in Taiwan ShihWei Lai FungChang Sung 3,4, ChengLi Lin 3,4, KuanFu Liao 5,6 School of Medicine, and Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan 6 ABSTRACT Objective: To investigate whether use of proton pump inhibitors (PPIs) enhances the risk of pancreatic cancer Design: Retrospective case control study University, Taiwan Subjects: with newly diagnosed pancreatic cancer as the case group subjects without pancreatic cancer selected from the same Intervention: Use of Proton pump inhibitors Main Outcome Measure: History of using PPIs and other comorbidities were compared between cases and controls Results: After adjustment for confounders, multivariable logistic regression analysis showed that pancreatic cancer Conclusions: Taking PPIs correlates with increased risk INTRODUCTION Pancreatic cancer is an important global burden cancer related deaths, it is the eighth most common worldwide, the fourth in the US and the eighth in Taiwan medications and pancreatitis as factors associated with this disease et al in an European international cohort study found that the incidence ratio of pancreatic cancer in patients with pancreatitis found the risk of pancreatic cancer increased in patients with gastric ulcer Proton pump inhibitors (PPIs), a class of drugs that reduce gastric acid secretion, are commonly prescribed omeprazole treatment may lead to hypergastrinemia and profound hypochlorhydria in response to the reduced gastric acid secretion be associated with digestive tract malignancies gastrin receptors in human pancreatic cancer cells, and gastrin can stimulate the growth of human pancreatic cancer cells in culture that use of PPIs may lead to hypergastrinemia, which might correlate with increased risk of pancreatic we conducted a casecontrol study to explore whether there is an association between PPIs use and pancreatic MATERIALS AND METHODS Study population This casecontrol study used the claims data of the Address correspondence to: KuanFu Liao, Department of Internal Medicine, Taichung Tzu Chi General Hospital, No.66, Sec. 1, Fongsing Road, Tanzi District, Taichung City, 427, Taiwan, Phone: , Fax: , kuanfuliao@yahoo.com.tw

2 KUWAIT MEDICAL JOURNAL 45 has been detailed in previous studies universal insurance program has a coverage rate of being established by the Taiwan National Health on insured demographic status, ambulatory care and th RevisionClinical Inclusion criteria aged 20 years or older who had newly diagnosed cancer case, four subjects without pancreatic cancer from the same database were randomly selected as groups were matched by gender, age (per 5 years) Patients with earlyundiagnosed pancreatic cancer initially presenting with abdominal symptoms within two years before the index date were excluded of medications on pancreatic cancer risk, histamine2 receptor antagonists, statins, nonstatin lipidlowering drugs, and cyclooxygenase2 inhibitors before index Comorbidities potentially associated with pancreatic cancer risk Comorbidities before index date potentially associated with pancreatic cancer risk were as follows: acute pancreatitis, chronic pancreatitis, diabetes Table 1: Characteristics between pancreatic cancer cases and control subjects Pancreatic cancer pvalue Characteristics of subjects No N = 3908 Yes N = 977 n n % Gender Men Women Age group (years) 4064 Comorbidities before index date Acute pancreatitis Chronic pancreatitis Gallstones Hepatitis C Medications (ever used) Proton pump inhibitors Histamine2 receptor antagonists Statins Nonstatin lipidlowering drugs Aspirin and cyclooxygenase2 inhibitors Aspirin only Cyclooxygenase2 inhibitors only Both of above with and without pancreatic cancer

3 46 Table 2: Variables Crude Adjusted Age (per one year) Acute pancreatitis Chronic pancreatitis Gallstones Hepatitis C Medications Proton pump inhibitors Histamine2 receptor antagonists Statins Nonstatin lipidlowering drugs aspirin and nonuse of cyclooxygenase2 inhibitors) Aspirin only Cyclooxygenase2 inhibitors only Both of above OR (95%) CI OR (95%) CI Adjusted for acute pancreatitis, chronic pancreatitis, diabetes mellitus, obesity, and histamine2 receptor antagonists, statins, nonstatin Statistical analysis controls for distribution of demographic status, square test and ttest were used to examine the crude analysis were further included in multivariable The risk of the cancer was estimated by individual PPI with the adjustment of acute pancreatitis, chronic pancreatitis, diabetes mellitus, obesity, histamine2 receptor antagonists, statins, nonstatin lipidlowering drugs, and both of aspirin and cyclooxygenase2 RESULTS Characteristics of the study population proportions of acute pancreatitis, chronic pancreatitis, diabetes mellitus, obesity, PPIs use, histamine2 receptor antagonists use, statins use, nonstatin lipidlowering drugs use, and cyclooxygenase2 inhibitors subjects in both groups had used other nonsteroidal Association between comorbidities, medications and pancreatic cancer risk After adjustment for multiple confounders that were logistic regression analysis showed that the adjusted Subanalysis of association between individual proton pump inhibitors and pancreatic cancer risk

4 KUWAIT MEDICAL JOURNAL 47 Table 3: Risk of pancreatic cancer associated with individual proton pump inhibitors Nonuse of PPIs as a reference Case/N 358/3745 Crude odds ratio (95% CI) Adjusted odds ratio (95% CI) Pantoprazole Lansoprazole Rabeprazole Esomeprazole Adjusted for acute pancreatitis, chronic pancreatitis, diabetes mellitus, obesity, histamine2 receptor antagonists, statins, nonstatin lipidlowering drugs, and both of aspirin and cyclooxygenase2 inhibitors DISCUSSION So far, only one observational study with large sample size from UK general practice research been earlyundiagnosed pancreatic cancer who initially presented with abdominal symptoms and received subjects who have used PPIs only within two years before index date were excluded from this present risk of pancreatic cancer might be increased up to explanation about the strong discrepancies of the linking hypergastrinemia and pancreatic cancer is that there are gastrin receptors in human pancreatic cancer cells, and gastrin can stimulate the growth of human pancreatic cancer cells in culture bacterial overgrowth and generation of nitrosamines secondary to gastric acid suppression may also contribute to human pancreatic carcinogenesis in vitro the prior hypothesis that use of PPIs might cause hypergastrinemia and gastric acid suppression, which might correlate with increased risk of pancreatic Because of the lag time between diagnosing date of pancreatic cancer and onset of pancreatic cancer, we could not make sure whether PPIs use was before or after onset of pancreatic cancer, even though subjects who have used PPIs only within two years before index PPIs use is really causality for pancreatic cancer risk or only a coincidence for treating abdominal symptoms of earlyundiagnosed pancreatic cancer cannot be was no record of body mass index due to inherited is no other study supporting such an association between PPIs use and pancreatic cancer, interpretation CONCLUSION We conclude that although residual confounding with a markedly increased risk of pancreatic cancer in ACKNOWLEDGEMENTS The authors thank the National Health Research Institute in Taiwan for providing the insurance claims The authors disclose Funding: This study was supported in part by Taiwan China Medical University Hospital (Grant number study design, data collection and analysis, decision to REFERENCES et al

5 et al age of onset, and survival in patients with pancreatic et al omeprazole therapy on serum gastrin in patients acid suppression and risk of oesophageal and gastric of gastrin as a growth peptide in human pancreatic acute pancreatitis in type 2 diabetes and risk reduction on antidiabetic drugs: a populationbased cohort study correlates with increased risk of pancreatic cancer: Proton pump inhibitors and histamine2receptor antagonists and pancreatic cancer risk: a nested case

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