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Kidney Week

Abstract: FR-PO232

How Does Canagliflozin Confer Renoprotection? Results From a Mediation Analysis of the CANVAS Program

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Li, Jingwei, The George Institute for Global Health, UNSW Sydney, Sydney, New South Wales, Australia
  • Neal, Bruce, The George Institute for Global Health, UNSW Sydney, Sydney, Australia
  • Perkovic, Vlado, The George Institute for Global Health, UNSW Sydney, Sydney, New South Wales, Australia
  • de Zeeuw, Dick, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
  • Simpson, Roger, Janssen Research & Development, LLC, Raritan, New Jersey, United States
  • Oh, Richard, Janssen Research & Development, LLC, Raritan, New Jersey, United States
  • Mahaffey, Kenneth W., Stanford University School of Medicine, Stanford, California, United States
  • L Heerspink, Hiddo Jan, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
Background

Canagliflozin reduced renal risk in patients with type 2 diabetes participating in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. This study explored potential mediators of the beneficial effects of canagliflozin on renal outcomes.

Methods

The percent mediating effect of 18 biomarkers, hypothesized to be likely changed by canagliflozin treatment and associated with renal risk, was determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the biomarker of interest. Multivariable analyses assessed the joint effects of biomarkers that mediated most strongly in univariable analyses. The renal outcome was a composite of 40% eGFR decline, end-stage kidney disease, or renal death.

Results

Early changes after randomization in levels of 7 biomarkers (systolic blood pressure (9.5% of effect explained), urinary albumin:creatinine ratio [UACR] (18.2%), gamma glutamyltransferase (9.3%), hematocrit (40.7%), hemoglobin (29.1%), erythrocytes (40.5%), and serum urate (19.0%) were identified as individually mediating the effect of canagliflozin on the renal outcome. The same biomarkers and serum albumin were identified as significant mediators based on average post-randomization levels. In a parsimonious multivariable model, erythrocyte concentration, serum urate and systolic blood pressure were the three biomarkers that maximized cumulative mediation (115% [95%CI 72.96 to 203.66]). Mediating effects of UACR, but not other mediators, were highly dependent upon the baseline level of the mediator; UACR mediated 42% of the effect in those with baseline UACR >30 mg/g but only 8% in those with baseline UACR <30 mg/g.

Conclusion

The identified mediators support existing hypothesized mechanisms for the prevention of renal outcomes with SGLT2 inhibitors. The disparity in mediating effects across subgroups defined by baseline UACR suggests mechanisms of protection may vary in importance across patient subsets.

Funding

  • Commercial Support