Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories: Findings From the CANVAS Program

Am J Kidney Dis. 2021 Jan;77(1):23-34.e1. doi: 10.1053/j.ajkd.2020.06.018. Epub 2020 Sep 21.

Abstract

Rationale & objective: Canagliflozin reduces the risk for cardiovascular and kidney outcomes in type 2 diabetes. This study aimed to assess the relative and absolute effects of canagliflozin on clinical outcomes across different KDIGO (Kidney Disease: Improving Global Outcomes) risk categories based on estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio.

Study design: Post hoc analysis of the CANagliflozin cardioVascular Assessment Study (CANVAS) Program.

Settings & participants: The CANVAS Program randomly assigned 10,142 participants with type 2 diabetes at high cardiovascular risk and with eGFR≥30mL/min/1.73m2 to treatment with canagliflozin or placebo.

Intervention(s): Canagliflozin or matching placebo.

Outcomes: The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with a set of other cardiovascular and kidney prespecified outcomes.

Results: Of 10,142 participants, 10,031 (98.9%) had available baseline eGFR and urinary albumin-creatinine ratio data. The proportion of participants in low-, moderate-, high-, and very high-risk KDIGO categories was 58.6%, 25.8%, 10.6%, and 5.0%, respectively. The relative effect of canagliflozin on the primary outcome (HR, 0.86; 95% CI, 0.75-0.97) was consistent across KDIGO risk categories (P trend=0.2), with similar results for other cardiovascular and kidney outcomes. Absolute reductions in the primary outcome were greater within higher KDIGO risk categories (P trend=0.03) with a similar pattern of effect for the composite of cardiovascular death or hospitalization for heart failure (P trend=0.06) and for chronic eGFR slope (P trend = 0.04).

Limitations: Predominantly a low kidney risk population, relatively few participants in higher KDIGO risk categories, and exclusion of individuals with eGFR<30mL/min/1.73m2.

Conclusions: Although the relative effects of canagliflozin are similar across KDIGO risk categories, absolute risk reductions are likely greater for individuals at higher KDIGO risk. The KDIGO classification system may be able to identify individuals who might derive greater benefits for end-organ protection from treatment with canagliflozin.

Funding: This post hoc analysis was not specifically funded. The original CANVAS Program trials were funded by Janssen Research & Development, LLC and were conducted as a collaboration between the funder, an academic steering committee, and an academic research organization, George Clinical.

Trial registration: The original trials of the CANVAS Program were registered at ClinicalTrials.gov with study numbers NCT01032629 and NCT01989754.

Keywords: CKD classification; Canagliflozin; KDIGO; SGLT2 inhibitor; adverse event; albuminuria; cardiovascular outcomes; chronic kidney disease (CKD); eGFR slope; estimated glomerular filtration rate (eGFR); kidney disease trajectory; kidney outcomes; renal function; risk stratification; urinary albumin-creatinine ratio (UACR).

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria* / diagnosis
  • Albuminuria* / etiology
  • Canagliflozin* / administration & dosage
  • Canagliflozin* / adverse effects
  • Cardiovascular Diseases* / epidemiology
  • Cardiovascular Diseases* / therapy
  • Creatinine / blood
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / drug therapy
  • Female
  • Glomerular Filtration Rate / drug effects
  • Hospitalization / statistics & numerical data
  • Humans
  • Male
  • Mortality
  • Renal Insufficiency, Chronic* / diagnosis
  • Renal Insufficiency, Chronic* / epidemiology
  • Renal Insufficiency, Chronic* / etiology
  • Renal Insufficiency, Chronic* / metabolism
  • Risk Adjustment / methods*
  • Risk Factors
  • Sodium-Glucose Transporter 2 Inhibitors / administration & dosage
  • Sodium-Glucose Transporter 2 Inhibitors / adverse effects

Substances

  • Sodium-Glucose Transporter 2 Inhibitors
  • Canagliflozin
  • Creatinine

Associated data

  • ClinicalTrials.gov/NCT01032629
  • ClinicalTrials.gov/NCT01989754