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)的作用,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不明确。
方法:2602名来自Canagliflozin和糖尿病合并肾病的肾脏事件临床评估试验的糖尿病肾病(DKD)患者随机接受canagliflozin或安慰剂,并随访偶然的心肾结果。PlGF,sFLT-1和VEGF-A在基线测量,第一年和第三年。主要结果是终末期肾病的复合结果,血清肌酐加倍,或肾/心血管死亡。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。
结果:在基线时,与PlGF水平较低的个体相比,PlGF水平较高的个体患心血管疾病更为普遍.canagliflozin治疗并没有显著改变PlGF,sFLT-1和VEGF-A在第1年和第3年的浓度。在多变量模型中,基线对数PlGF增加1个单位(危险比[HR]:1.76,95%置信区间[CI]:1.23,2.54,p值=0.002),sFLT-1(HR:3.34,[95%CI:1.71,6.52],p值<0.001),和PlGF/sFLT-1比率(HR:4.83,[95%CI:0.86,27.01],p值=0.07)与主要复合结局相关,而logVEGF-A增加1个单位并不增加主要结局的风险(HR:0.96[95CI:0.81,1.07]).还评估了每个生物标志物1年的变化:主要复合结局的HR(95%CI)为2.45(1.70,3.54),1年logPlGF浓度增加1个单位,对数sFLT-11年浓度增加1个单位为4.19(2.18,8.03),对数PlGF/sFLT-11年浓度增加1个单位为21.08(3.79,117.4)。1年VEGF-A对数浓度的增加与主要复合结局无关(HR:1.08,[95%CI:0.93,1.24],p值=0.30)。
结论:T2D和DKD患者PlGF水平升高,sFLT-1和PlGF/sFLT-1比值发生心肾事件的风险较高。Canagliflozin没有显著降低PlGF的浓度,sFLT-1和VEGF-A。
背景:信用,https://clinicaltrials.gov/ct2/show/NCT02065791.
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.
METHODS: 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.
BACKGROUND: CREDENCE, https://clinicaltrials.gov/ct2/show/NCT02065791.