Fasting substrate concentrations predict cardiovascular outcomes in the CANagliflozin cardioVascular Assessment Study (CANVAS)

Objective To examine whether the circulating substrate mix may be related to the incidence of heart failure (HF) and cardiovascular (CV) mortality and how it is altered by canagliflozin treatment.

Research Design and Methods  We measured fasting glucose, free fatty acids (FFA), glycerol, β-hydroxybutyrate, acetoacetate, lactate, and pyruvate concentrations in 3,581 samples from the CANVAS trial at baseline and at 1 and 2 years after randomization. Results were analyzed by univariate and multivariate Cox proportional hazards models.  

Results Patients in the lowest baseline FFA tertile were more often men with a longer duration of T2D, higher urinary albumin excretion and lower HDL-cholesterol levels, higher history of CVD, and higher use of statins and insulin. Using all 7 metabolites as predictors, FFA were inversely associated with incident hospitalized HHF (0.33 [0.21–0.55]), while glycerol was a positive predictor (2.21 [1.45–3.35]). In a model further adjusted for 16 potential confounders (including prior HF and CV disease and pharmacologic therapies), FFA remained a significant negative predictor. FFA and glycerol also predicted CV mortality (0.53 [0.35–0.81] and 1.81 [1.26–2.58], respectively) and all-cause death (0.50 [0.36–0.70] and 1.64 [1.22–2.18]). When added to these models, background insulin therapy was an independent positive predictor of risk of death. Canagliflozin treatment significantly increased plasma FFA and β-hydroxybutyrate regardless of background antihyperglycemic therapy. 

Conclusions A constitutive metabolic setup consisting of higher lipolysis may be beneficial in delaying or preventing HHF; a further stimulation of lipolysis by canagliflozin may reinforce this influence.