The Association Between Proton Pump Inhibitors and COVID-19 is Confounded by Hyperglycemia in a Population-Based Study

{ 'indexed': {'date-parts': [[2024, 7, 18]], 'date-time': '2024-07-18T09:46:26Z', 'timestamp': 1721295986427}, 'reference-count': 50, 'publisher': 'Frontiers Media SA', 'license': [ { 'start': { 'date-parts': [[2022, 2, 4]], 'date-time': '2022-02-04T00:00:00Z', 'timestamp': 1643932800000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0/'}], 'content-domain': {'domain': ['frontiersin.org'], 'crossmark-restriction': True}, 'abstract': '<jats:p><jats:bold>Background and Aims:</jats:bold> There is conflicting evidence regarding ' 'the association between proton pump inhibitors (PPI) and the risk of acquisition and severity ' 'of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ' 'infection.</jats:p><jats:p><jats:bold>Aim:</jats:bold> To evaluate the association between ' 'PPI exposure and infection and development of severe disease in patients infected with ' 'SARS-CoV2in a large population-based historical ' 'cohort.</jats:p><jats:p><jats:bold>Methods:</jats:bold> Data were extracted from a health ' 'maintenance organization database in Israel that insures over 1,200,000 individuals from ' 'across the country. All patients who underwent SARS-CoV-2 testing between March and November ' '2020 were included. Logistic regression and matched analyses were used to compare patients ' 'prescribed and exposed to PPIs to those not prescribed PPIs regarding SARS-CoV-2 positivity. ' 'In addition, among SARS-CoV-2 positive patients (n = 44,397) the likelihood of developing ' 'severe disease, defined by a composite endpoint of death, ICU admission and prolonged ' 'hospitalization, was compared in those exposed and not exposed to ' 'PPIs.</jats:p><jats:p><jats:bold>Results:</jats:bold> Among 255,355 adult patients who ' 'underwent SARS-CoV-2 testing by PCR, 44,397 (17.4%) were positive for SARS-CoV-2 and 12,066 ' '(4.7%) patients were prescribed PPIs in the 3\xa0months before testing. In a multivariable ' 'logistic regression model controlling for age, gender, smoking status, BMI, diabetes ' 'mellitus, hypertension, COPD, history of ischemic heart disease and fasting blood glucose ' '(FBG) levels, no significant association was found between PPIs and SARS-CoV-2 positivity ' '(<jats:italic>p</jats:italic> = 0.09 aOR 0.94, 95% CI – 0.88–1.01). Among SARS-CoV-2 positive ' 'patients, 910 (2%) had a severe infection. Multivariate logistic regression controlling for ' 'the abovementioned confounders, showed no such association between PPIs and severe COVID-19 ' '(<jats:italic>p</jats:italic> = 0.28). Elevated FBG levels were significantly associated with ' 'both PPI exposure (<jats:italic>p</jats:italic> &amp;lt; 0.001) and severe COVID-19 infection ' '(<jats:italic>p</jats:italic> &amp;lt; 0.001). These results were reinforced by a matched ' 'analysis (n = 655 pairs).</jats:p><jats:p><jats:bold>Conclusion:</jats:bold> PPIs are ' 'spuriously associated with severe COVID-19 due to the presence of elevated FBG as a ' 'confounder. Our study accounted for the FBG levels of patients and known risk factors for ' 'severe COVID-19 infection, which may be the reason for the discrepancy in prior studies. ' 'These results may aid in understanding potential confounders when evaluating potential ' 'associations of PPIs with other respiratory or viral diseases.</jats:p>', 'DOI': '10.3389/fphar.2022.791074', 'type': 'journal-article', 'created': {'date-parts': [[2022, 2, 4]], 'date-time': '2022-02-04T05:50:38Z', 'timestamp': 1643953838000}, 'update-policy': 'http://dx.doi.org/10.3389/crossmark-policy', 'source': 'Crossref', 'is-referenced-by-count': 8, 'title': 'The Association Between Proton Pump Inhibitors and COVID-19 is Confounded by Hyperglycemia in a ' 'Population-Based Study', 'prefix': '10.3389', 'volume': '13', 'author': [ {'given': 'Asher', 'family': 'Shafrir', 'sequence': 'first', 'affiliation': []}, {'given': 'Ariel A.', 'family': 'Benson', 'sequence': 'additional', 'affiliation': []}, {'given': 'Lior H.', 'family': 'Katz', 'sequence': 'additional', 'affiliation': []}, {'given': 'Tiberiu', 'family': 'Hershcovici', 'sequence': 'additional', 'affiliation': []}, {'given': 'Menachem', 'family': 'Bitan', 'sequence': 'additional', 'affiliation': []}, {'given': 'Ora', 'family': 'Paltiel', 'sequence': 'additional', 'affiliation': []}, {'given': 'Ronit', 'family': 'Calderon-Margalit', 'sequence': 'additional', 'affiliation': []}, {'given': 'Rifaat', 'family': 'Safadi', 'sequence': 'additional', 'affiliation': []}, {'given': 'Michal', 'family': 'Shauly-Aharonov', 'sequence': 'additional', 'affiliation': []}], 'member': '1965', 'published-online': {'date-parts': [[2022, 2, 4]]}, 'reference': [ { 'key': 'B1', 'doi-asserted-by': 'publisher', 'first-page': '1707', 'DOI': '10.14309/ajg.0000000000000993', 'article-title': 'Increased Risk of COVID-19 Among Users of Proton Pump Inhibitors', 'volume': '115', 'author': 'Almario', 'year': '2020', 'journal-title': 'Am. J. Gastroenterol.'}, { 'key': 'B2', 'doi-asserted-by': 'publisher', 'first-page': '150', 'DOI': '10.1002/pst.433', 'article-title': 'Optimal Caliper Widths for Propensity‐score Matching when Estimating ' 'Differences in Means and Differences in Proportions in Observational ' 'Studies', 'volume': '10', 'author': 'Austin', 'year': '2011', 'journal-title': 'Pharm. Stat.'}, { 'key': 'B3', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.cgh.2021.01.014', 'article-title': 'The Mortality Risk of Proton Pump Inhibitors in 1.9 Million US Seniors: ' 'an Extended Cox Survival Analysis', 'author': 'Baik', 'year': '2021', 'journal-title': 'Clin. Gastroenterol. Hepatol.'}, { 'key': 'B4', 'first-page': '980', 'article-title': 'Diabetes Mellitus: Management of Gastrointestinal Complications', 'volume': '94', 'author': 'Careyva', 'year': '2016', 'journal-title': 'Am. Fam. Physician'}, { 'key': 'B5', 'doi-asserted-by': 'publisher', 'first-page': 'e14649', 'DOI': '10.14814/phy2.14649', 'article-title': 'Might Proton Pump or Sodium-Hydrogen Exchanger Inhibitors Be of Value ' 'to Ameliorate SARs-CoV-2 Pathophysiology?', 'volume': '8', 'author': 'Conrad', 'year': '2021', 'journal-title': 'Physiol. Rep.'}, { 'key': 'B6', 'doi-asserted-by': 'publisher', 'first-page': 'P697', 'DOI': '10.1016/j.cmi.2021.01.008', 'article-title': 'Proton Pump Inhibitor Use and Risk for Recurrent Clostridioides ' 'Difficile Infection: A Systematic Review & Meta-Analysis', 'volume': '27', 'author': "D'Silva", 'year': '2021', 'journal-title': 'Clin. Microbiol. Infect.'}, { 'key': 'B7', 'doi-asserted-by': 'publisher', 'first-page': '1412', 'DOI': '10.1056/nejmoa2101765', 'article-title': 'BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting', 'volume': '384', 'author': 'Dagan', 'year': '2021', 'journal-title': 'New Engl. J. Med.'}, { 'key': 'B8', 'doi-asserted-by': 'publisher', 'first-page': '575', 'DOI': '10.3390/jcm9020575', 'article-title': 'Characteristics of and Public Health Responses to the Coronavirus ' 'Disease 2019 Outbreak in China', 'volume': '9', 'author': 'Deng', 'year': '2020', 'journal-title': 'J. Clin. Med.'}, { 'key': 'B9', 'doi-asserted-by': 'publisher', 'first-page': '693', 'DOI': '10.1056/NEJMoa2021436', 'article-title': 'Dexamethasone in Hospitalized Patients with Covid-19', 'volume': '384', 'year': '2020', 'journal-title': 'New Engl. J. Med.'}, { 'key': 'B10', 'doi-asserted-by': 'publisher', 'first-page': '15', 'DOI': '10.1016/j.jamda.2020.09.046', 'article-title': 'The Use and Misuse of Proton Pump Inhibitors: An Opportunity for ' 'Deprescribing', 'volume': '22', 'author': 'Dharmarajan', 'year': '2021', 'journal-title': 'J. Am. Med. Dir. Assoc.'}, { 'key': 'B11', 'doi-asserted-by': 'publisher', 'first-page': '627', 'DOI': '10.2337/dc17-1536', 'article-title': 'Gastrointestinal Symptoms in Diabetes: Prevalence, Assessment, ' 'Pathogenesis, and Management', 'volume': '41', 'author': 'Du', 'year': '2018', 'journal-title': 'Diabetes Care'}, { 'key': 'B12', 'doi-asserted-by': 'publisher', 'first-page': '106222', 'DOI': '10.1016/j.ijantimicag.2020.106222', 'article-title': 'Randomised Controlled Trials for COVID-19: Evaluation of Optimal ' 'Randomisation Methodologies-Need for Data Validation of the Completed ' 'Trials and to Improve Ongoing and Future Randomised Trial Designs', 'volume': '57', 'author': 'Emani', 'year': '2021', 'journal-title': 'Int. J. Antimicrob. Agents'}, { 'key': 'B13', 'doi-asserted-by': 'publisher', 'first-page': '573', 'DOI': '10.1152/physrev.00016.2019', 'article-title': 'The Physiology of the Gastric Parietal Cell', 'volume': '100', 'author': 'Engevik', 'year': '2020', 'journal-title': 'Physiol. Rev.'}, { 'key': 'B14', 'doi-asserted-by': 'publisher', 'first-page': '1443', 'DOI': '10.1053/j.gastro.2020.11.053', 'article-title': 'Potential Biases in Studies of Acid Suppressing Drugs and COVID-19 ' 'Infection', 'volume': '160', 'author': 'Etminan', 'year': '2020', 'journal-title': 'Gastroenterology'}, { 'key': 'B15', 'doi-asserted-by': 'publisher', 'first-page': '455', 'DOI': '10.1053/j.gastro.2020.09.028', 'article-title': 'Effect of Acid Suppressants on the Risk of COVID-19: A Propensity ' 'Score-Matched Study Using UK Biobank', 'volume': '160', 'author': 'Fan', 'year': '2021', 'journal-title': 'Gastroenterology'}, { 'key': 'B16', 'doi-asserted-by': 'publisher', 'first-page': 'e21', 'DOI': '10.1016/S2213-2600(20)30116-8', 'article-title': 'Are Patients with Hypertension and Diabetes Mellitus at Increased Risk ' 'for COVID-19 Infection?', 'volume': '8', 'author': 'Fang', 'year': '2020', 'journal-title': 'Lancet Respir. Med.'}, { 'key': 'B17', 'doi-asserted-by': 'publisher', 'first-page': '845', 'DOI': '10.1007/s11739-020-02457-2', 'article-title': 'Systematic Review of the Prevalence of Current Smoking Among ' 'Hospitalized COVID-19 Patients in China: Could Nicotine Be a ' 'Therapeutic Option?', 'volume': '15', 'author': 'Farsalinos', 'year': '2020', 'journal-title': 'Intern. Emerg. Med.'}, { 'key': 'B18', 'doi-asserted-by': 'publisher', 'first-page': '2', 'DOI': '10.1136/bmj.39406.449456.be', 'article-title': 'Overprescribing Proton Pump Inhibitors', 'volume': '336', 'author': 'Forgacs', 'year': '2008', 'journal-title': 'Br. Med. J. Publishing Group'}, { 'key': 'B19', 'doi-asserted-by': 'publisher', 'first-page': '1345', 'DOI': '10.1001/jamainternmed.2020.3539', 'article-title': 'Risk Factors Associated with Mortality Among Patients with COVID-19 in ' 'Intensive Care Units in Lombardy, Italy', 'volume': '180', 'author': 'Grasselli', 'year': '2020', 'journal-title': 'JAMA Intern. Med.'}, { 'key': 'B20', 'doi-asserted-by': 'publisher', 'first-page': '1410', 'DOI': '10.1016/j.dld.2020.10.001', 'article-title': 'Proton Pump Inhibitor Use Is Associated with Increased Risk of Severity ' 'and Mortality from Coronavirus Disease 2019 (COVID-19) Infection', 'volume': '52', 'author': 'Hariyanto', 'year': '2020', 'journal-title': 'Dig. Liver Dis.'}, { 'key': 'B21', 'first-page': '2286', 'article-title': 'No Associations between Regular Use of Proton Pump Inhibitors and Risk ' 'of All-Cause and Cause-specific Mortality: A Population-Based Cohort of ' '0.44 Million Participants', 'volume-title': 'Official J. Am. Coll. Gastroenterol.', 'author': 'He', 'year': ''}, { 'key': 'B22', 'doi-asserted-by': 'publisher', 'first-page': '1845', 'DOI': '10.1016/j.cgh.2021.05.011', 'article-title': 'Proton Pump Inhibitor Use Is Not Strongly Associated with SARS-CoV-2 ' 'Related Outcomes: A Nationwide Study and Meta-Analysis', 'volume': '19', 'author': 'Israelsen', 'year': '2013', 'journal-title': 'Clin. Gastroenterol. Hepatol.'}, { 'key': 'B23', 'doi-asserted-by': 'publisher', 'first-page': '308', 'DOI': '10.1038/ajg.2012.444', 'article-title': 'Guidelines for the Diagnosis and Management of Gastroesophageal Reflux ' 'Disease', 'volume': '108', 'author': 'Katz', 'year': '2013', 'journal-title': 'Am. J. Gastroenterol.'}, { 'key': 'B24', 'doi-asserted-by': 'publisher', 'first-page': '125', 'DOI': '10.1111/joim.13183', 'article-title': 'Use of Proton Pump Inhibitors and Risk of Adverse Clinical Outcomes ' 'from COVID-19: a Meta-Analysis', 'volume': '289', 'author': 'Kow', 'year': '2021', 'journal-title': 'J. Intern. Med.'}, { 'key': 'B25', 'doi-asserted-by': 'publisher', 'first-page': '76', 'DOI': '10.1136/gutjnl-2020-322248', 'article-title': 'Severe Clinical Outcomes of COVID-19 Associated with Proton Pump ' 'Inhibitors: a Nationwide Cohort Study with Propensity Score Matching', 'volume': '70', 'author': 'Lee', 'year': '2020', 'journal-title': 'Gut'}, { 'key': 'B26', 'doi-asserted-by': 'publisher', 'first-page': '2013', 'DOI': '10.1136/gutjnl-2020-323672', 'article-title': 'Proton Pump Inhibitors and the Risk of Severe COVID-19: a post-hoc ' 'Analysis from the Korean Nationwide Cohort', 'volume': '70', 'author': 'Lee', 'year': '2021', 'journal-title': 'Gut'}, { 'key': 'B27', 'doi-asserted-by': 'publisher', 'first-page': '1806', 'DOI': '10.1136/gutjnl-2020-323366', 'article-title': 'Do proton Pump Inhibitors Influence SARS-CoV-2 Related Outcomes? A ' 'Meta-Analysis', 'volume': '70', 'author': 'Li', 'year': '2020', 'journal-title': 'Gut'}, { 'key': 'B28', 'doi-asserted-by': 'publisher', 'first-page': '121', 'DOI': '10.1111/joim.13121', 'article-title': 'Treatment with Proton Pump Inhibitors Increases the Risk of Secondary ' 'Infections and ARDS in Hospitalized Patients with COVID-19: Coincidence ' 'or Underestimated Risk Factor?', 'volume': '289', 'author': 'Luxenburger', 'year': '2021', 'journal-title': 'J. Intern. Med.'}, { 'key': 'B29', 'doi-asserted-by': 'publisher', 'first-page': '2153', 'DOI': '10.14309/ajg.0000000000001407', 'article-title': 'Proton Pump Inhibitors and COVID-19: Confusing Status Quo', 'volume': '116', 'author': 'Lv', 'year': '2021', 'journal-title': 'Official J. Am. Coll. Gastroenterol.'}, { 'key': 'B30', 'first-page': '49', 'article-title': 'On the Generalized Distance in Statistics', 'volume-title': 'Proc. Natl. Inst. Sci.', 'author': 'Mahalanobis', 'year': '1936'}, { 'key': 'B31', 'doi-asserted-by': 'publisher', 'first-page': '29554', 'DOI': '10.3390/ijms161226190', 'article-title': 'COVID-19 Infection and Anti-aging Gene Inactivation', 'volume': '16', 'author': 'Martins', 'year': '2015', 'journal-title': 'Int. J. Mol. Sci.'}, { 'key': 'B32', 'doi-asserted-by': 'publisher', 'first-page': '82', 'DOI': '10.1016/s2213-8587(20)30405-8', 'article-title': 'Risks of and Risk Factors for COVID-19 Disease in People with Diabetes: ' 'a Cohort Study of the Total Population of Scotland', 'volume': '9', 'author': 'McGurnaghan', 'year': '2021', 'journal-title': 'Lancet Diabetes Endocrinol.'}, { 'key': 'B33', 'doi-asserted-by': 'publisher', 'first-page': '1467', 'DOI': '10.1053/j.gastro.2021.01.005', 'article-title': 'SARS-CoV-2 Infection in the Gastrointestinal Tract: Fecal-Oral Route of ' 'Transmission for COVID-19?', 'volume': '160', 'author': 'Meng', 'year': '2021', 'journal-title': 'Gastroenterol.'}, { 'key': 'B34', 'doi-asserted-by': 'publisher', 'first-page': '682', 'DOI': '10.1053/j.gastro.2019.05.056', 'article-title': 'Safety of Proton Pump Inhibitors Based on a Large, Multi-Year, ' 'Randomized Trial of Patients Receiving Rivaroxaban or Aspirin', 'volume': '157', 'author': 'Moayyedi', 'year': '2019', 'journal-title': 'Gastroenterology'}, { 'key': 'B35', 'doi-asserted-by': 'publisher', 'first-page': '317', 'DOI': '10.1097/MOG.0000000000000641', 'article-title': 'How to Advise Patients on the Risk of Chronic Proton Pump Inhibitor ' 'Therapy', 'volume': '36', 'author': 'Moayyedi', 'year': '2020', 'journal-title': 'Curr. Opin. Gastroenterol.'}, { 'key': 'B36', 'doi-asserted-by': 'publisher', 'first-page': '137', 'DOI': '10.1097/meg.0000000000002013', 'article-title': 'Pre-hospitalization Proton Pump Inhibitor Use and Clinical Outcomes in ' 'COVID-19', 'volume': '34', 'author': 'Ramachandran', 'year': '2020', 'journal-title': 'Eur. J. Gastroenterol. Hepatol.'}, { 'key': 'B37', 'doi-asserted-by': 'publisher', 'first-page': '484', 'DOI': '10.1055/a-1236-3041', 'article-title': 'The Potential Therapeutic Role of Proton Pump Inhibitors in COVID-19: ' 'Hypotheses Based on Existing Evidences', 'volume': '70', 'author': 'Ray', 'year': '2020', 'journal-title': 'Drug Res. (Stuttg)'}, { 'key': 'B38', 'doi-asserted-by': 'publisher', 'first-page': '1175', 'DOI': '10.1111/j.1572-0241.2000.02006.x', 'article-title': 'Proximal Gastric Compliance and Perception of Distension in Type 1 ' 'Diabetes Mellitus: Effects of Hyperglycemia', 'volume': '95', 'author': 'Rayner', 'year': '2000', 'journal-title': 'Am. J. Gastroenterol.'}, { 'key': 'B39', 'doi-asserted-by': 'publisher', 'first-page': '41', 'DOI': '10.1093/biomet/70.1.41', 'article-title': 'The central Role of the Propensity Score in Observational Studies for ' 'Causal Effects', 'volume': '70', 'author': 'Rosenbaum', 'year': '1983', 'journal-title': 'Biometrika'}, { 'key': 'B40', 'doi-asserted-by': 'publisher', 'first-page': '293', 'DOI': '10.2307/2529981', 'article-title': 'Bias Reduction Using Mahalanobis-Metric Matching', 'author': 'Rubin', 'year': '1980', 'journal-title': 'Biometrics'}, { 'key': 'B50', 'volume-title': 'R: A Language and Environment for Statistical Computing', 'year': '2019'}, { 'key': 'B41', 'doi-asserted-by': 'publisher', 'first-page': '323', 'DOI': '10.1016/j.jclinepi.2004.10.012', 'article-title': 'A Review of Uses of Health Care Utilization Databases for Epidemiologic ' 'Research on Therapeutics', 'volume': '58', 'author': 'Schneeweiss', 'year': '2005', 'journal-title': 'J. Clin. Epidemiol.'}, { 'key': 'B42', 'doi-asserted-by': 'publisher', 'first-page': 'e0254847', 'DOI': '10.1371/journal.pone.0254847', 'article-title': 'Both high and Low Pre-infection Glucose Levels Associated with ' 'Increased Risk for Severe COVID-19: New Insights from a ' 'Population-Based Study', 'volume': '16', 'author': 'Shauly-Aharonov', 'year': '2021', 'journal-title': 'PLOS ONE'}, { 'key': 'B43', 'doi-asserted-by': 'publisher', 'first-page': '725', 'DOI': '10.1016/j.dsx.2020.05.037', 'article-title': 'Does Poor Glucose Control Increase the Severity and Mortality in ' 'Patients with Diabetes and COVID-19?', 'volume': '14', 'author': 'Singh', 'year': '2020', 'journal-title': 'Diabetes Metab. Syndr.'}, { 'key': 'B44', 'doi-asserted-by': 'publisher', 'first-page': '15', 'DOI': '10.1007/s15010-020-01509-1', 'article-title': 'Risk Factors for Covid-19 Severity and Fatality: a Structured ' 'Literature Review', 'volume': '49', 'author': 'Wolff', 'year': '2021', 'journal-title': 'Infection'}, { 'key': 'B45', 'volume-title': 'Diagnostic Testing for SARS-CoV-2: Interim Guidance, 11 September 2020', 'author': 'World Health', 'year': '2020'}, { 'key': 'B46', 'doi-asserted-by': 'publisher', 'first-page': '567', 'DOI': '10.17219/acem/67961', 'article-title': 'Gastrointestinal Complications in Patients with Diabetes Mellitus', 'volume': '27', 'author': 'Zawada', 'year': '2018', 'journal-title': 'Adv. Clin. Exp. Med.'}, { 'key': 'B47', 'doi-asserted-by': 'publisher', 'first-page': '525', 'DOI': '10.3389/fendo.2020.00525', 'article-title': 'Impaired Fasting Glucose and Diabetes Are Related to Higher Risks of ' 'Complications and Mortality Among Patients with Coronavirus Disease ' '2019', 'volume': '11', 'author': 'Zhang', 'year': '2020', 'journal-title': 'Front. Endocrinol. 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