Disproportionate reporting of euglycaemic and diabetic ketoacidosis with SGLT-2 inhibitors across expanding cardiorenal indications: a cross-database study of FAERS and JADER

SGLT-2 inhibitors are now used beyond type 2 diabetes (T2DM) in heart failure (HF) and chronic kidney disease (CKD), where glucose is monitored less routinely. Whether their established ketoacidosis signal—particularly euglycaemic diabetic ketoacidosis (euDKA)—is maintained as the indications expand, and whether it reproduces across independent reporting systems, is untested. We analysed the US FAERS (2020Q1–2026Q1) and Japanese JADER using one pipeline. Signals required consensus across four methods (ROR, PRR, IC, EBGM/EB05). Analyses were run overall, within report-level indication strata [T2DM, HF, CKD, off-label type 1 diabetes (T1DM)] and against an active comparator (DPP-4 inhibitors), with two pre-specified negative controls, time-to-onset modelling and sensitivity analyses. The DKA signal met four-method consensus within every indication stratum, including HF and CKD, and was highest in off-label T1DM; it was therefore maintained, not diluted, as indications expanded. Overall RORs were 67.4 (95% CI 65.7–69.2) in FAERS and 112.3 (104.8–120.3) in JADER. SGLT-2 inhibitors accounted for 85.8% (FAERS) and 91.7% (JADER) of all euDKA reports, though euDKA was only 4.1% and 7.8% of SGLT-2 inhibitor reports. Both negative controls were null in both databases. Median time-to-onset was 60 days (Weibull β=0.48, 95% CI 0.46–0.50). Across two independent reporting systems, the SGLT-2 inhibitor ketoacidosis signal was maintained across the expanding cardiorenal indications, with euDKA concentrated within this class and early onset. Ketone-based assessment is warranted when ketoacidosis is suspected, particularly soon after initiation. As a disproportionality analysis, these are hypothesis-generating signals that cannot establish incidence, relative risk, or causality.