血管内皮生长因子与心肾事件风险：来自 CREDENCE 试验的结果。
Vascular endothelial growth factors and risk of cardio-renal events: Results from the CREDENCE trial.
机构信息
Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Heart Failure and Biomarker Trials, Baim Institute for Clinical Research, Boston, MA.
Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
出版信息
Am Heart J. 2024 May;271:38-47. doi: 10.1016/j.ahj.2024.02.016. Epub 2024 Feb 22.
BACKGROUND
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.
METHOD
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.
RESULTS
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, P-value = .002), sFLT-1 (HR: 3.34, [95% CI: 1.71, 6.52], P-value < .001), and PlGF/sFLT-1 ratio (HR: 4.83, [95% CI: 0.86, 27.01], P-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], P-value = .30).
CONCLUSIONS
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.
CLINICAL TRIAL
背景
血管内皮生长因子（VEGF）家族成员的循环浓度在 2 型糖尿病（T2D）中可能异常升高。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 的心脏-肾脏并发症中的作用尚未确定。
方法
来自卡格列净和已确诊肾病的糖尿病患者中的肾脏事件及心血管预后的临床评估试验（Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial）的 2602 名患有糖尿病肾病（DKD）的患者被随机分配接受卡格列净或安慰剂治疗，并随访心脏-肾脏不良结局。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、血清肌酐加倍或肾脏/心血管死亡的复合结局。使用 Cox 比例风险回归分析生物标志物与不良临床事件的关系。
结果
在基线时，PlGF 水平较高的个体与 PlGF 值较低的个体相比，心血管疾病的患病率更高。第 1 年和第 3 年时，卡格列净治疗并未明显改变 PlGF、sFLT-1 和 VEGF-A 浓度。在多变量模型中，基线 log PlGF 增加 1 单位（危险比 [HR]：1.76，95%置信区间 [CI]：1.23，2.54，P 值 =.002）、sFLT-1（HR：3.34，[95% CI：1.71，6.52]，P 值 <.001）和 PlGF/sFLT-1 比值（HR：4.83，[95% CI：0.86，27.01]，P 值 =.07）与主要复合结局相关，而 log VEGF-A 增加 1 单位不会增加主要结局的风险（HR：0.96 [95% CI：0.81，1.07]）。还评估了每种生物标志物在 1 年内的变化：log PlGF 浓度增加 1 年的主要复合结局 HR（95% CI）为 2.45（1.70，3.54），log sFLT-1 浓度增加 1 年为 4.19（2.18，8.03），log PlGF/sFLT-1 浓度增加 1 年为 21.08（3.79，117.4）。log VEGF-A 浓度增加 1 年与主要复合结局无显著相关性（HR：1.08，[95% CI：0.93，1.24]，P 值 =.30）。
结论
T2D 和 DKD 患者 PlGF、sFLT-1 和 PlGF/sFLT-1 比值升高，心脏-肾脏事件风险更高。卡格列净并未显著降低 PlGF、sFLT-1 和 VEGF-A 浓度。
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