Circulating concentrations of vascular endothelial growth factor (VEGF) family members may be abnormally elevated in type 2 diabetes (T2D). The roles of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFLT-1), and VEGF-A in cardio-renal complications of T2D are not established. The 2602 individuals with diabetic kidney disease (DKD) from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial were randomized to receive canagliflozin or placebo and followed for incident cardio-renal outcomes. PlGF, sFLT-1, and VEGF-A were measured at baseline, year 1, and year 3. Primary outcome was a composite of end-stage kidney disease, doubling of the serum creatinine, or renal/cardiovascular death. Cox proportional hazard regression was used to investigate the association between biomarkers with adverse clinical events. At baseline, individuals with higher PlGF levels had more prevalent cardiovascular disease compared to those with lower values. Treatment with canagliflozin did not meaningfully change PlGF, sFLT-1, and VEGF-A concentrations at years 1 and 3. In a multivariable model, 1 unit increases in baseline log PlGF (hazard ratio [HR]: 1.76, 95% confidence interval [CI]: 1.23, 2.54, -value = .002), sFLT-1 (HR: 3.34, [95% CI: 1.71, 6.52], -value < .001), and PlGF/sFLT-1 ratio (HR: 4.83, [95% CI: 0.86, 27.01], -value = .07) were associated with primary composite outcome, while 1 unit increase in log VEGF-A did not increase the risk of primary outcome (HR: 0.96 [95% CI: 0.81, 1.07]). Change by 1 year of each biomarker was also assessed: HR (95% CI) of primary composite outcome was 2.45 (1.70, 3.54) for 1 unit increase in 1-year concentration of log PlGF, 4.19 (2.18, 8.03) for 1 unit increase in 1-year concentration of log sFLT-1, and 21.08 (3.79, 117.4) for 1 unit increase in 1-year concentration of log PlGF/sFLT-1. Increase in 1-year concentrations of log VEGF-A was not associated with primary composite outcome (HR: 1.08, [95% CI: 0.93, 1.24], -value = .30). People with T2D and DKD with elevated levels of PlGF, sFLT-1, and PlGF/sFLT-1 ratio were at a higher risk for cardiorenal events. Canagliflozin did not meaningfully decrease concentrations of PlGF, sFLT-1, and VEGF-A. CREDENCE, .

中文翻译：

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血管内皮生长因子和心肾事件风险：CREDENCE 试验的结果

2 型糖尿病 (T2D) 中血管内皮生长因子 (VEGF) 家族成员的循环浓度可能异常升高。胎盘生长因子 (PlGF)、可溶性 fms 样酪氨酸激酶 1 (sFLT-1) 和 VEGF-A 在 T2D 心肾并发症中的作用尚未确定。来自 Canagliflozin 和糖尿病肾病肾脏事件临床评估试验的 2602 名糖尿病肾病 (DKD) 患者被随机分配接受坎格列净或安慰剂治疗，并随访心肾结局。在基线、第 1 年和第 3 年测量 PlGF、sFLT-1 和 VEGF-A。主要结局是终末期肾病、血清肌酐加倍或肾/心血管死亡的复合结果。 Cox比例风险回归用于研究生物标志物与不良临床事件之间的关联。在基线时，PlGF 水平较高的个体与 PlGF 水平较低的个体相比，心血管疾病的患病率更高。卡格列净治疗在第 1 年和第 3 年并未显着改变 PlGF、sFLT-1 和 VEGF-A 浓度。在多变量模型中，基线 Log PlGF 增加 1 个单位（风险比 [HR]：1.76，95% 置信区间 [ CI]: 1.23, 2.54, 值 = .002), sFLT-1 (HR: 3.34, [95% CI: 1.71, 6.52], 值 < .001) 和 PlGF/sFLT-1 比率 (HR: 4.83 , [95% CI: 0.86, 27.01], -值 = .07) 与主要复合结局相关，而 log VEGF-A 增加 1 个单位并不会增加主要结局的风险 (HR: 0.96 [95% CI: 0.81，1.07]）。还评估了每个生物标志物一年内的变化：log PlGF 1 年浓度每增加 1 个单位，主要复合结果的 HR (95% CI) 为 2.45 (1.70, 3.54)，1 个单位则为 4.19 (2.18, 8.03) log sFLT-1 的 1 年浓度增加，log PlGF/sFLT-1 的 1 年浓度每增加 1 个单位，增加 21.08 (3.79, 117.4)。 1 年 VEGF-A 浓度对数的增加与主要复合结局无关（HR：1.08，[95% CI：0.93，1.24]，-值 = 0.30）。 PlGF、sFLT-1 和 PlGF/sFLT-1 比率水平升高的 T2D 和 DKD 患者发生心肾事件的风险较高。卡格列净没有显着降低 PlGF、sFLT-1 和 VEGF-A 的浓度。克莱登斯，.