SGLT2 inhibitors as foundational cardiorenal therapy: trial heterogeneity, evidence gaps, and practical sequencing in heart failure and chronic kidney disease

Background Sodium-glucose cotransporter-2 (SGLT2) inhibitors were developed as glucose-lowering therapies for type 2 diabetes mellitus but are now used as disease-modifying treatment in heart failure and chronic kidney disease. Their benefits are well established, but the major trials differ substantially in cardiovascular risk, heart failure phenotype, kidney function, albuminuria, background therapy, and endpoint selection. Methods This structured narrative review was based on searches of PubMed/MEDLINE, Scopus, and Google Scholar from January 2015 through September 5, 2026. Randomized cardiovascular, heart failure, and kidney outcome trials were prioritized, together with secondary analyses, major meta-analyses, guidelines and consensus documents, selected combination-therapy studies, and observational evidence relevant to real-world effectiveness. Earlier historical and regulatory sources were included when necessary to contextualize the cardiovascular outcomes trial era. Main body Across the SGLT2 inhibitor trial program, the most consistent effects are fewer worsening heart failure events and slower progression of chronic kidney disease. Effects on major adverse cardiovascular events and cardiovascular mortality are less uniform across individual agents and populations. Kidney outcome trials have expanded the evidence from albuminuric diabetic CKD in CREDENCE to diabetic and non-diabetic CKD in DAPA-CKD and a broader range of kidney function and albuminuria in EMPA-KIDNEY. Heart failure trials support benefit across the ejection-fraction spectrum. SGLT2 inhibitors can also be integrated with established heart failure therapy and renin-angiotensin system blockade. In albuminuric CKD with type 2 diabetes, combined empagliflozin and finerenone produces greater albuminuria reduction than either therapy alone, although superiority for long-term cardiovascular or kidney events has not been established. Real-world studies support external validity but do not replace randomized evidence for causal or drug-to-drug comparisons. Evidence gaps remain in maintenance dialysis, kidney transplantation, polycystic kidney disease, selected immune-mediated kidney diseases, and optimal sequencing of multidrug therapy. Conclusion SGLT2 inhibitors are a central component of contemporary cardiorenal therapy, but their use should be guided by the populations, endpoints, and background treatments studied rather than by assuming identical benefit across all agents and settings. Clinical integration is best informed by the dominant cardiorenal phenotype, kidney function, albuminuria, volume status, blood pressure, concomitant therapy, and the remaining limits of the evidence.