Liver function markers predict cardiovascular and renal outcomes in the CANVAS Program

• Cardiorenal outcomes and multiple metabolic abnormalities have been associated with raised liver function tests (LFTs)  

• This study aims to methodically test the association between LFT levels and major cardiorenal outcomes in a large clinical trial in type 2 diabetes, and the influence of placebo-controlled canagliflozin treatment 

• The findings suggest that higher gamma-glutamyl transferase (γGT) levels are top LFT markers of risk of hospitalised heart failure (HHF) and death in patients with diabetes and high cardiovascular (CV) risk. In addition, canagliflozin reduces the risk of HHF and renal damage separately of LFTs and potential confounders 

The CANVAS Program combined two trials, CANVAS and CANVAS-R. This involved a total of 10,142 participants with type 2 diabetes and high CV risk. Participants in CANVAS were randomly assigned in a 1:1:1 ratio to receive canagliflozin (300 mg), canagliflozin (100 mg), or matching placebo, and participants in CANVAS-R were randomly assigned in a 1:1 ratio to receive canagliflozin (initial dose of 100 mg daily, with an optional increase to 300 mg starting from week 13) or matching placebo. 

• Composite of CV outcomes 

  • HF hospitalisations 

  • MACE 

  • HF/CV death

• Composite of renal outcomes

  • Decline in eGFR

  • Renal replacement 

  • Renal Death

• All cause death

• Median follow up of the entire cohort was 2.4 (4.1) years 

• Alkaline phosphatase (ALP) was positively predictive across all endpoints 

• Alanine aminotransferase (ALT) was reciprocally predictive across all endpoints 

• γGT was directly associated with CV outcomes, but not renal outcomes 

• Bilirubin was inversely related to renal outcomes 

• There was a significant reduction in ALT, ALP and γGT, with canagliflozin treatment over 2 years 

• Canagliflozin demonstrated a significant reduction in HHF and renal risk 

Greater baseline and post-randomisation γGT levels were demonstrated to be predictive of the risk of death. Independent of LFTs and possible confounders, canagliflozin protected against HF hospitalisation and renal damage. 

• Post-hoc investigation 

• Baseline LFTs were within normal range for all trial participants 

• The exact distribution of weights among LFTs may be unstable 

• It is possible that additional significant confounders were not accounted for 

• The biomarker domains identified in CANVAS (e.g. hematocrit, urate, hemoglobin, NTproBNP) were not included in this analysis