FGF-23, hsCRP, Cardiovascular Events, and the Benefit of Canagliflozin in the CANVAS Trial

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BACKGROUND: The CANVAS (Canagliflozin Cardiovascular Assessment Study) trial provided the opportunity to determine the utility of measuring cardiorenal biomarkers, such as fibroblast growth factor 23 (FGF-23) and high-sensitivity C-reactive protein (hsCRP) levels for determining risk prediction and treatment response to sodium glucose co-transporter 2 inhibitor therapy in patients with type 2 diabetes mellitus. OBJECTIVES: The prognostic value of these biomarkers for predicting adverse cardiovascular (CV) outcomes and treatment response was assessed. METHODS: Of 4,330, 3,188 (73.6%) participants had available longitudinal biomarker samples. The association between FGF-23 and hsCRP with composite CV death or hospitalization for heart failure (HHF), HHF, CV death, and major adverse CV events were assessed using multivariable Cox proportional hazard models adjusted for clinical risk factors, and markers of cardiac and renal injury. Event rates by randomized treatment assignment were calculated for FGF-23 and hsCRP after assignment to a "low-risk" (quartiles [Q] 1-3) or "high-risk" (Q4) group. Multimarker risk assessment was done by stratifying participants by both FGF-23 and hsCRP quartiles to create 4 risk groups. RESULTS: When compared with Q1, FGF-23 levels in Q4 were significantly associated with CV death/HHF (HR: 1.65; 95% CI: 1.15-2.40; P = 0.008) and HHF (HR: 1.96; 95% CI: 1.04-3.69; P = 0.037) whereas hsCRP levels in Q4 were significantly associated with CV death (HR: 1.78; 95% CI: 1.16-2.73; P = 0.008) and major adverse CV events (HR: 1.35; 95% CI: 1.02-1.78; P = 0.038) in adjusted analyses. There was consistent effect of canagliflozin vs placebo across high- and low-risk groups (P-interactions ≥0.30). CONCLUSIONS: FGF-23 and hsCRP are biomarkers associated with increased CV risk, but these markers did not identify participants who preferentially benefited from treatment with canagliflozin.

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