SGLT2 inhibitors have been shown to provide pronounced reductions in cardiorenal 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 of treatment with either placebo or canagliflozin 100 mg/day, in approximately 2,600 individuals from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial (enrolling patients with type 2 diabetes, chronic kidney disease (CKD), and albuminuria). Associations between glycosuria and the primary composite end point from CREDENCE, and secondary outcomes were assessed using Cox proportional hazards models. Canagliflozin treatment increased fractional urinary glucose excretion (± SD) from 3 ± 9% at baseline to 30 ± 26% at year 1 (vs. 5 ± 19% with placebo; P < 0.001). Patients in the canagliflozin arm and in the top quartile of urine glucose to creatinine ratio at year 1 were significantly protected for the primary end point (hazard ratio [HR] 0.42; 95% CI 0.30–0.61); similar results were seen for cases of hospitalized heart failure (HR 0.45; 95% CI 0.27–0.73) and all-cause death (HR 0.56; 95% CI 0.39–0.80). These associations persisted when adjustments were made for multiple conventional risk factors. Among patients with type 2 diabetes and CKD treated with canagliflozin, individuals with the highest glycosuria levels had the strongest protection against multiple cardiorenal 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 investigated the relationship of glycosuria (i.e., the readout of SGLT2 engagement) with cardiorenal outcomes.
- Individuals with the highest glycosuria levels had the strongest protection against multiple cardiorenal outcomes.
- Glycosuria is mechanistically linked with several effects underlying cardiorenal benefit.
