Role of Glycosuria in SGLT2 Inhibitor-Induced Cardiorenal Protection: A Mechanistic Analysis of the CREDENCE Trial

Abstract

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.

Figure 1

Box plots of baseline urinary glucose excretion ratio (G/Cr; n = 2,598) by eGFR category (A) and year 1 G/Cr (n = 2,714) by eGFR category (B). Green segments are mean category values; P values were determined by Wilcoxon signed rank test. The red dotted line is the mean value of the highest eGFR category. For both distributions, note the wide dispersion of G/Cr values despite the log scale.

Figure 2

Box plots of baseline UACR (n = 2,543) by eGFR category (A) and year 1 UACR (n = 2,328) by eGFR category (B). For both UACR distributions, note the wide dispersion of values despite the log scale, baseline hematocrit (n = 2,335) by eGFR category (C), and year 1 hematocrit (n = 2,248) (D) by eGFR category. Green segments are mean category values; P values were determined by Wilcoxon signed rank test.

Figure 3

Kaplan-Meier plots of the primary composite end point by G/Cr quartile (quart.; top quartile vs. lower quartiles) in the canagliflozin and placebo arm.

Figure 4

Kaplan-Meier plots of renal composite end point, hHF, or CV death, hHF, and all-cause death by G/Cr quartile (top quartile vs. lower quartiles).

Figure 5

Multivariate Cox regression of the primary composite end point and all-cause death (canagliflozin arm). Dots are odds ratios, lines are 95% CIs calculated for 1 SD of continuous variables, and 1 log unit for UACR. Quart., quartile; SBP, systolic blood pressure.