Cardiovascular Outcomes Across the Sodium-Glucose Cotransporter (SGLT) Selectivity Spectrum in Type 2 Diabetes and Chronic Kidney Disease: A Systematic Review of Heart Failure, Myocardial Infarction, and Stroke

Adults with type 2 diabetes (T2D) mellitus and chronic kidney disease (CKD) face substantial risks of heart failure and atherothrombotic cardiovascular events.Although sodium-glucose cotransporter (SGLT) inhibitors are commonly considered a single therapeutic class, differences in SGLT2 and SGLT1 selectivity may influence their cardiovascular outcome profiles.This systematic review examined whether protection against myocardial infarction, stroke, and heart failure varied across highly selective SGLT2 inhibitors, relatively less selective canagliflozin, and dual SGLT1/2 inhibition with sotagliflozin.MEDLINE through PubMed, Embase, Cochrane CENTRAL, and the Web of Science Core Collection were searched from inception to July 1, 2026, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement.Randomized, placebo-controlled trials enrolling adults with T2D and CKD, or providing separately extractable results for this population, were eligible.Seven parent trials, represented by 16 linked reports, were included.Their overall populations collectively comprised 61,857 participants, although eligible evidence was derived from either complete trial populations or extractable T2D-CKD subgroups.Narrative synthesis was undertaken because of heterogeneity in CKD definitions, baseline cardiovascular risk, outcome reporting, and subgroup availability.Protection against heart failure-related outcomes was observed consistently across the pharmacological spectrum.In SCORED, sotagliflozin provided the clearest concurrent signal for reductions in total major adverse cardiovascular events, myocardial infarction, and stroke.Canagliflozin reduced major cardiovascular events and hospitalization for heart failure, but its effects on individual myocardial infarction and stroke outcomes were statistically inconclusive.Highly selective SGLT2 inhibitors predominantly demonstrated heart failure and cardiorenal benefits, while CKD-specific estimates for individual atherothrombotic outcomes were frequently unavailable or inconclusive.No parent trial was judged to have a high overall risk of bias, although reliance on secondary and post hoc analyses introduced some concerns.Greater SGLT1 engagement may plausibly broaden cardiovascular protection beyond the established heart failure benefit of SGLT inhibition; however, receptor selectivity was not randomized, and cross-trial differences may reflect variation in populations, kidney phenotypes, endpoints, follow-up, and statistical power.Direct comparative or individualparticipant-data analyses are required before differential cardiovascular effects can be attributed to pharmacological selectivity.