Mediators of the effects of canagliflozin on kidney protection in patients with type 2 diabetes

Vlado Perkovic,Richard Oh,Roger Simpson,Hiddo J.L. Heerspink,Clare Arnott,Brendon L. Neuen,Dick de Zeeuw,Kenneth W. Mahaffey,Bruce Neal,JingWei Li

doi:10.1016/j.kint.2020.04.051

Abstract

Canagliflozin reduced kidney disease progression in participants with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. This analysis explored potential mediators of the effects of canagliflozin on kidney outcomes. The percent mediating effect of 18 biomarkers indicative of disease was determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the average post-randomization level of each biomarker. Multivariable analyses assessed the joint effects of biomarkers that mediated most strongly in univariable analyses. The kidney outcome was defined as a composite of 40% estimated glomerular filtration rate decline, end-stage kidney disease, or death due to kidney disease. Nine biomarkers (systolic blood pressure [8.9% of effect explained], urinary albumin:creatinine ratio [UACR; 23.9%], gamma glutamyltransferase [4.1%], hematocrit [51.1%], hemoglobin [41.3%], serum albumin [19.5%], erythrocytes [56.7%], serum urate [35.4%], and urine pH [7.5%]) individually mediated the effect of canagliflozin on the kidney outcome. In a parsimonious multivariable model, erythrocyte concentration, serum urate, and systolic blood pressure maximized cumulative mediation (115%). Mediating effects of UACR, but not other mediators, were highly dependent upon the baseline level of UACR: UACR mediated 42% and 7% of the effect in those with baseline UACR 30 mg/g or more and under 30 mg/g, respectively. The identified mediators support existing hypothesized mechanisms for the prevention of kidney outcomes with sodium glucose co-transporter 2 inhibitors. Thus, the disparity in mediating effects across baseline UACR subgroups suggests that the mechanism for kidney protection with canagliflozin may vary across patient subgroups.

Highlights

The CANagliflozin cardioVascular Assessment Study (CANVAS) Program reported that the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin reduces the risk of clinically important kidney outcomes in patients with type 2 diabetes with established cardiovascular disease or those at high cardiovascular risk.[1]
The potential mediating effects of 21 biomarkers were assessed, 18 of which were available for the entire CANVAS Program and 3 of which were available for participants in the CANVAS trial but not in CANVAS-Renal
Effects of canagliflozin compared with placebo on potential mediators There were clear effects of canagliflozin, compared with placebo, on multiple potential mediators of effect (Table 19 and Supplementary Tables S2, S3, and S4): hemoglobin A1c, fasting plasma glucose, systolic blood pressure (SBP), diastolic blood pressure, weight, body mass index, urine pH, serum bicarbonate, serum urate, serum gamma glutamyltransferase (GGT), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, hematocrit, hemoglobin, erythrocyte concentration, serum albumin, ketonuria, and urinary albumin:creatinine ratio (UACR)

Summary

Introduction

The CANagliflozin cardioVascular Assessment Study (CANVAS) Program reported that the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin reduces the risk of clinically important kidney outcomes in patients with type 2 diabetes with established cardiovascular disease or those at high cardiovascular risk.[1]. To qualify as a potential mediator, a biomarker must be affected both by the drug under investigation and associated with the outcome of interest. Even when these criteria are met, the change in the biomarker does not always infer a causal association.[8]. A recent mediation analysis of the effects of canagliflozin suggested that uric acid, albuminuria, and markers of plasma volume and hematopoiesis were the most important mediators for effects on heart failure.[9] Whether the same or other mediators underlie the long-term kidney protective effects of Kidney International (2020) 98, 769–777 clinical trial.

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