Safety of Concomitant Metformin and Proton Pump Inhibitor Use: A Population Retrospective Cohort Study

Purpose: The purpose of this study was to investigate the effect of concomitant use on important clinical outcomes. Methods: In this retrospective cohort study, a cohort of new metformin users was identified between 2004 and 2010 and followed up until termination of insurance coverage, December 31, 2010, or the outcomes were reached. The primary outcome was a composite of time to all-cause mortality or hospitalization; our secondary outcome was time to cardiovascular hospitalization. Exposures to metformin, a proton pump inhibitor (PPI), and/or a histamine(2) receptor antagonist (H2RA) were compared with a Cox proportional hazards model after adjustment. Findings: Relative to metformin-only users, metformin and PPI users were at increased risk of the primary outcome (adjusted hazard ratio [HR] = 1.55; 95% CI, 1.46-1.64); metformin and H2RA users also had an elevated risk (adjusted HR = 1.29; 95% CI, 0.97-1.70). Similar patterns were seen with cardiovascular-specific hospitalization. Compared with no drug use, metformin users had an increased risk of the primary outcome, but risk was substantially elevated when patients were taking PPIs or H2RAs, alone or in combination with metformin. Implications: Concomitant use of metformin and a PPI or metformin and an H2RA were associated with an increased risk of death or hospitalization. This fmding suggests that the harm observed may not be due to a specific drug interaction but uncontrolled confounding secondary to an increased risk in those patients using a PPI or H2RA. (C) 2016 Elsevier HS Journals, Inc. All rights reserved.