Adverse event reporting signals for SGLT-2 inhibitor-metformin combination therapy: a disproportionality analysis of the FAERS database
Abstract
Objective: This study aimed to evaluate the real-world safety profile of combination therapy with a sodium-glucose cotransporter-2 inhibitor (SGLT-2i) and metformin relative to monotherapy, utilizing the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database.
Methods: We extracted adverse event (AE) reports from the FAERS database from the first quarter (Q1) of 2013 to the fourth quarter (Q4) of 2025 in which the combined regimen (ertugliflozin, dapagliflozin, empagliflozin, or canagliflozin plus metformin) was designated as the primary suspect. Disproportionality analyses were performed using the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS) algorithms. Additionally, we examined the time-to-onset distribution and the clinical outcomes of the documented AEs.
Results: A total of 23,407 combination-therapy reports were included. At the System Organ Class (SOC) level, ROR-based signal detection identified pronounced disproportionalities in metabolism and nutrition disorders (ROR = 9.00), renal and urinary disorders (ROR = 3.91), reproductive system and breast disorders (ROR = 2.59), and infections and infestations (ROR = 2.49). At the Preferred Term (PT) level, the five most frequently reported events cross-validated by all four algorithms were diabetic ketoacidosis (n = 3,522), weight decreased (n = 1,294), blood glucose increased (n…
How strong is the evidence?
Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 3,522 participants or records.
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