Role of glycosuria in SGLT2 inhibitor-induced cardio-renal protection: a mechanistic analysis of the CREDENCE trial.
Abstract SGLT2 inhibitors have been shown to provide pronounced reductions in cardio-renal outcomes, including cardiovascular death, heart failure, and renal failure. The mechanisms underlying these benefits remain uncertain. We hypothesized that the effects could be attributed to the elevated glycosuria induced by these drugs. Urine concentrations of glucose, creatinine, and ketones were measured at baseline and after 1-year treatment with either placebo or canagliflozin 100mg/day in ~2600 individuals from the CREDENCE trial (enrolling patients with type 2 diabetes, chronic kidney disease, and albuminuria). Associations between glycosuria and the primary composite endpoint from CREDENCE and secondary outcomes were assessed using Cox proportional hazards models. Canagliflozin treatment increased fractional urinary glucose excretion from 3±9% at baseline to 30±26% at year 1 (vs 5±19% with placebo, p<0.001). Subjects on canagliflozin and in the top quartile of urine glucose/creatinine ratio at year 1 were significantly protected for the primary endpoint (HR=0.42 [95% C.I.:0.30–0.61]); similar results were seen for hospitalized heart failure (HR=0.45 [0.27–0.73]) and all-cause death (HR=0.56 [0.39–0.80]). These associations persisted on adjustments for multiple conventional risk factors. In patients with T2D and CKD treated with canagliflozin, individuals with the highest amount of glycosuria showed the strongest protection against multiple cardio-renal outcomes. Article Highlights § In cardiovascular outcome trials, SGLT2 inhibitors have been shown to provide marked protection against both cardiovascular morbidity and progression of kidney disease. The mechanisms underlying these effects remain imperfectly understood. § By using urine samples from patients with type 2 diabetes and kidney disease treated with canagliflozin, we asked the question of the relationship of glycosuria – the readout of SGLT2 engagement – with cardio-renal outcomes. § Individuals with the highest amount of glycosuria showed the strongest protection against multiple cardio-renal outcomes. § Glycosuria is mechanistically linked with several effects underlying cardio-renal benefit.