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

<p>  </p> <p><strong>Objective</strong> 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.</p> <p><strong>Research Design and Methods </strong> 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.  </p> <p><strong>Results</strong> 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. </p> <p><strong>Conclusions</strong> 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. </p>