Distinct pattern of reported adverse event with SGLT2 inhibitors in heart failure: A pharmacovigilance study using VigiBase data

BACKGROUND AND AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT-2i), developed for type 2 diabetes mellitus (T2DM), have been approved in symptomatic heart failure (HF). Comparison of their safety profiles between T2DM and HF remain scarce. Using international pharmacovigilance data, reported adverse events (AEs) with SGLT-2i were compared between T2DM and HF indications. METHODS: Individual case safety reports (ICSRs) involving dapagliflozin or empagliflozin, both approved for T2DM and HF, were collected from the World Health Organization's pharmacovigilance database up to September 30, 2024. Five AEs of interest were specifically investigated including ketoacidosis, genitourinary infection, Fournier's gangrene, amputation and kidney failure. Reporting odds ratio (ROR) and 95% confidence interval (CI) were calculated to compare reported AEs between T2DM and HF indication. RESULTS: Of the 47,804 ICSRs selected, only 10.0% involved HF patients. Serious AEs accounted for 41.0% of cases in T2DM patients and 44.2% in HF patients. As expected, ketoacidosis (14.6% vs 4.1%), Fournier's gangrene (2.3% vs 1.8%), and amputation (0.5% vs 0.3%) were significantly more reported in T2DM and kidney failure was more reported in HF (6.1% vs 3.8% in T2DM). The differences were illustrated by significant ROR. However, no difference was evidenced for genitourinary tract infections between the two indications. Median time to onset of AEs was shorter in HF (111.5 days±198.7 vs 264.9±664.9 in T2DM, p<0.001) and AEs leading to death were more frequently reported in this subgroup. CONCLUSION: SGLT2 inhibitor safety profiles differ across indications, shaped in part by patient characteristics. In heart failure, the reporting of unexpected serious events, such as ketoacidosis, and a higher proportion of fatal outcomes sharply reinforces the need for intensified safety surveillance.