BackgroundStudies have suggested that sodium glucose co‐transporter 2 inhibitors exert anti‐inflammatory effects. We examined the association of baseline growth differentiation factor‐15 (GDF‐15), a marker of inflammation and cellular injury, with cardiovascular events, hospitalization for heart failure (HF), and kidney outcomes in patients with type 2 diabetes in the CANVAS (Canagliflozin Cardiovascular Assessment Study) and determined the effect of the sodium glucose co‐transporter 2 inhibitor canagliflozin on circulating GDF‐15.Methods and ResultsThe CANVAS trial randomized 4330 people with type 2 diabetes at high cardiovascular risk to canagliflozin or placebo. The association between baseline GDF‐15 and cardiovascular (non‐fatal myocardial infarction, non‐fatal stroke, cardiovascular death), HF, and kidney (40% estimated glomerular filtration rate decline, end‐stage kidney disease, renal death) outcomes was assessed using multivariable adjusted Cox regression models. During median follow‐up of 6.1 years (N=3549 participants with available samples), 555 cardiovascular, 129 HF, and 137 kidney outcomes occurred. Each doubling in baseline GDF‐15 was significantly associated with a higher risk of cardiovascular (hazard ratio [HR], 1.2; 95% CI, 1.0‒1.3), HF (HR, 1.5; 95% CI, 1.2‒2.0) and kidney (HR, 1.5; 95% CI, 1.2‒2.0) outcomes. Baseline GDF‐15 did not modify canagliflozin’s effect on cardiovascular, HF, and kidney outcomes. Canaglifozin treatment modestly lowered GDF‐15 compared with placebo; however, GDF‐15 did not mediate the protective effect of canagliflozin on cardiovascular, HF, or kidney outcomes.ConclusionsIn patients with type 2 diabetes at high cardiovascular risk, higher GDF‐15 levels were associated with a higher risk of cardiovascular, HF, and kidney outcomes. Canagliflozin modestly lowered GDF‐15, but GDF‐15 reduction did not mediate the protective effect of canagliflozin.

中文翻译：

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循环 GDF-15 与心肾结果和卡格列净效果之间的关联：CANVAS 试验的结果

背景研究表明，钠葡萄糖协同转运蛋白 2 抑制剂具有抗炎作用。我们在 CANVAS 中检查了基线生长分化因子-15 (GDF-15)（炎症和细胞损伤的标志物）与心血管事件、心力衰竭 (HF) 住院和肾脏结局之间的关系。 Canagliflozin 心血管评估研究）并确定了钠葡萄糖协同转运蛋白 2 抑制剂 canagliflozin 对循环 GDF-15 的影响。方法和结果 CANVAS 试验将 4330 名心血管高风险的 2 型糖尿病患者随机分配到 canagliflozin 或安慰剂组。基线 GDF-15 与心血管（非致死性心肌梗死、非致死性卒中、心血管死亡）、HF、和肾脏（估计肾小球滤过率下降 40%、终末期肾病、肾死亡）结果使用多变量调整 Cox 回归模型进行评估。在 6.1 年的中位随访期间（N=3549 名有可用样本的参与者），发生了 555 例心血管、129 例心衰和 137 例肾脏结局。基线 GDF-15 每次翻倍与心血管风险（风险比 [HR]，1.2；95% CI，1.0-1.3）、HF（HR，1.5；95% CI，1.2-2.0）和肾脏风险显着相关（HR，1.5；95% CI，1.2-2.0）结果。基线 GDF-15 并未改变卡格列净对心血管、HF 和肾脏结局的影响。与安慰剂相比，卡格列净治疗适度降低了 GDF-15；然而，GDF-15 并未介导卡格列净对心血管、HF 或肾脏结局的保护作用。结论在心血管风险高的 2 型糖尿病患者中，较高的 GDF-15 水平与较高的心血管、HF 和肾脏结局风险相关。Canagliflozin 适度降低 GDF-15，但 GDF-15 降低并未介导 canagliflozin 的保护作用。