心脏肾生物标志物、卡格列净与糖尿病肾病结局：CREDENCE 试验。

Cardiorenal Biomarkers, Canagliflozin, and Outcomes in Diabetic Kidney Disease: The CREDENCE Trial.

机构信息

Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston (J.L.J., R.M., Y.L.).

Heart Failure and Biomarker Trials, Baim Institute for Clinical Research, Boston, MA (J.L.J.).

出版信息

Circulation. 2023 Aug 22;148(8):651-660. doi: 10.1161/CIRCULATIONAHA.123.065251. Epub 2023 Aug 21.

DOI:10.1161/CIRCULATIONAHA.123.065251

PMID:37603600

Abstract

BACKGROUND

People with type 2 diabetes and albuminuria are at an elevated risk for cardiac and renal events. The optimal biomarkers to aid disease prediction and to understand the benefits of sodium-glucose cotransporter-2 inhibition remain unclear.

METHODS

Among 2627 study participants in the CREDENCE trial (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), concentrations of NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T, growth differentiation factor-15, and IGFBP7 (insulin-like growth factor binding protein 7) were measured. The effect of canagliflozin on biomarker concentrations was evaluated. The prognostic potential of each biomarker on the primary outcome (a composite of end-stage kidney disease [dialysis, transplantation, or a sustained estimated glomerular filtration rate of <15 mL·min·1.73 m], doubling of the serum creatinine level, or renal death or cardiovascular death) was assessed.

RESULTS

The median (quartiles 1 and 3) concentration of each biomarker was generally elevated: NT-proBNP, 180 ng/L (82, 442 ng/L); high-sensitivity cardiac troponin T, 19 ng/L (12, 29 ng/L); growth differentiation factor-15, 2595 ng/L (1852, 3775 ng/L); and IGFBP7, 121.8 ng/mL (105.4, 141.5 ng/mL). At 1 year, the biomarkers all rose by 6% to 29% in the placebo arm but only by 3% to 10% in the canagliflozin arm (all <0.01 in multivariable linear mixed-effect models). Baseline concentrations of each biomarker were strongly predictive of cardiac and renal outcomes. When the biomarkers were analyzed together in a multimarker panel, individuals with high risk scores (hazard ratio [HR], 4.01 [95% CI, 2.52-6.35]) and moderate risk scores (HR, 2.39 [95% CI, 1.48-3.87]) showed a higher risk for the primary outcome compared with those with low risk scores. By 1 year, a 50% increase in NT-proBNP (HR, 1.11 [95% CI, 1.08-1.15]), high-sensitivity cardiac troponin T (HR, 1.86 [95% CI, 1.64-2.10]), growth differentiation factor-15 (HR, 1.45 [95% CI, 1.24-1.70]), and IGFBP7 (HR, 3.76 [95% CI, 2.54-5.56]) was associated with risk of the primary outcome.

CONCLUSIONS

Multiple cardiorenal stress biomarkers are strongly prognostic in people with type 2 diabetes and albuminuria. Canagliflozin modestly reduced the longitudinal trajectory of rise in each biomarker. Change in the biomarker level in addition to the baseline level augments the primary outcome prediction.

REGISTRATION

URL: https://www.

CLINICALTRIALS

gov; Unique identifier: NCT02065791.

摘要

背景

2 型糖尿病合并白蛋白尿患者发生心脏和肾脏事件的风险增加。用于辅助疾病预测和了解钠-葡萄糖共转运蛋白 2 抑制剂益处的最佳生物标志物仍不清楚。

方法

在 CREDENCE 试验（卡格列净和已确诊肾病的 2 型糖尿病患者中的肾脏事件临床评估）的 2627 名研究参与者中，测量了 N-末端脑钠肽前体（NT-proBNP）、高敏心肌肌钙蛋白 T、生长分化因子 15 和胰岛素样生长因子结合蛋白 7（IGFBP7）的浓度。评估了卡格列净对生物标志物浓度的影响。评估了每种生物标志物对主要结局（终末期肾病[透析、移植或持续估计肾小球滤过率<15mL·min·1.73m]、血清肌酐水平加倍、肾死亡或心血管死亡的复合）的预测潜力。

结果

每个生物标志物的中位数（四分位数 1 和 3）浓度通常升高：NT-proBNP，180ng/L（82，442ng/L）；高敏心肌肌钙蛋白 T，19ng/L（12，29ng/L）；生长分化因子 15，2595ng/L（1852，3775ng/L）；和 IGFBP7，121.8ng/mL（105.4，141.5ng/mL）。在 1 年时，安慰剂组的生物标志物均升高 6%至 29%，而卡格列净组仅升高 3%至 10%（所有<0.01 在多变量线性混合效应模型中）。每个生物标志物的基线浓度强烈预测心脏和肾脏结局。当在多标志物面板中分析这些生物标志物时，高风险评分（HR，4.01[95%CI，2.52-6.35]）和中度风险评分（HR，2.39[95%CI，1.48-3.87]）个体的主要结局风险高于低风险评分个体。到 1 年时，NT-proBNP 增加 50%（HR，1.11[95%CI，1.08-1.15]）、高敏心肌肌钙蛋白 T（HR，1.86[95%CI，1.64-2.10]）、生长分化因子 15（HR，1.45[95%CI，1.24-1.70]）和 IGFBP7（HR，3.76[95%CI，2.54-5.56]）与主要结局风险相关。