OBJECTIVES: The US Food and Drug Administration issued guidance in 2008 regarding the cardiovascular safety of antidiabetic medications, after which several studies with new classes of glucose-lowering drugs have shown cardiovascular benefits. We aimed to study the heterogeneity in the definition of composite renal endpoint in cardiovascular outcome trials conducted in T2D patients.

METHODS: We conducted a review to examine the definitions of the composite renal endpoint from the randomized controlled trials (RCTs) conducted in T2D patients assessing the cardiovascular safety of SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 receptor agonists.

RESULTS: Twelve RCTs were included in the review, of which seven provided definitions for a renal composite outcome. The LEADER trial provided the most comprehensive definition including, onset of macroalbuminuria, doubling of serum creatinine, renal replacement therapy, and death from renal cause. The SAVOR-TIMI, EMPA-REG OUTCOME, CANVAS trials included doubling of serum creatinine, renal replacement therapy, and death from renal cause. The CARMELINA and DECLARE-TIMI trials included renal replacement therapy, death from renal cause, and decrease of ≥40% in eGFR from baseline. The EXSCEL trial also reported a comprehensive definition of renal composite including, onset of macroalbuminuria, doubling of serum creatinine, renal replacement therapy, decrease of ≥40% in eGFR from baseline, and death from renal cause. The HARMONY OUTCOMES trial included renal endpoints under the composite of a microvascular event.

CONCLUSIONS: Although all RCTs reporting on the renal composite outcome definition included renal replacement therapy and death from renal causes in their definition, the inclusion of onset of macroalbuminuria, % decrease in eGFR, and doubling of serum creatinine was variable in the trials studied, suggesting heterogeneity in the definitions used, and thus, rendering it challenging to indirectly compare renal outcomes. More standardized renal outcome definitions and reporting could lead to better evidence-based guidance for diabetic kidney disease and improving clinical care for T2D patients.