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 CANagliflozin cardioVascular Assessment Study (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 type 2 diabetes (T2D), higher urinary albumin excretion, lower HDL-cholesterol levels, higher history of CV disease (CVD), and higher use of statins and insulin. When all seven metabolites were used as predictors, FFA were inversely associated with incident hospitalized HF (hazard ratio [HR] 0.33 [95% CI 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 CVD and pharmacologic therapies, FFA remained a significant negative predictor. FFA and glycerol also predicted CV mortality (HR 0.53 [95% CI 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 hospitalized HF; a further stimulation of lipolysis by canagliflozin may reinforce this influence.

中文翻译：

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空腹底物浓度可预测 CANagliflozin 心血管评估研究 (CANVAS) 中的心血管结果

目的检查循环底物混合物是否可能与心力衰竭 (HF) 和心血管 (CV) 死亡率的发生率相关，以及卡格列净治疗如何改变它。研究设随机化后。通过单变量和多变量 Cox 比例风险模型分析结果。结果 处于最低基线 FFA 三分位数的患者通常是男性，其 2 型糖尿病 (T2D) 病程较长、尿白蛋白排泄量较高、HDL-胆固醇水平较低、心血管疾病 (CVD) 病史较高以及他汀类药物和药物的使用较多。胰岛素。当所有七种代谢物都用作预测因子时，FFA 与住院 HF 事件呈负相关（风险比 [HR] 0.33 [95% CI 0.21–0.55]），而甘油是阳性预测因子（2.21 [1.45–3.35]）。在针对 16 个潜在混杂因素（包括先前的 HF 和 CVD 以及药物治疗）进一步调整的模型中，FFA 仍然是一个重要的负预测因子。FFA 和甘油还可以预测 CV 死亡率（分别为 HR 0.53 [95% CI 0.35–0.81] 和 1.81 [1.26–2.58]）和全因死亡（0.50 [0.36–0.70] 和 1.64 [1.22–2.18]）。当添加到这些模型中时，背景胰岛素治疗是死亡风险的独立阳性预测因子。无论背景降糖治疗如何，卡格列净治疗显着增加血浆 FFA 和 β-羟基丁酸。结论 由较高脂肪分解组成的组成性代谢设置可能有助于延迟或预防住院 HF。卡格列净进一步刺激脂肪分解可能会加强这种影响。