Aims/hypothesis

Higher plasma concentrations of tumour necrosis factor receptor (TNFR)-1, TNFR-2 and kidney injury molecule-1 (KIM-1) have been found to be associated with higher risk of kidney failure in individuals with type 2 diabetes in previous studies. Whether drugs can reduce these biomarkers is not well established. We measured these biomarkers in samples of the CANVAS study and examined the effect of the sodium–glucose cotransporter 2 inhibitor canagliflozin on these biomarkers and assessed whether the early change in these biomarkers predict cardiovascular and kidney outcomes in individuals with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS).

Methods

Biomarkers were measured with immunoassays (proprietary multiplex assay performed by RenalytixAI, New York, NY, USA) at baseline and years 1, 3 and 6. Mixed-effects models for repeated measures assessed the effect of canagliflozin vs placebo on the biomarkers. Associations of baseline levels and the early change (baseline to year 1) for each biomarker with the kidney outcome were assessed using multivariable-adjusted Cox regression.

Results

In total, 3523/4330 (81.4%) of the CANVAS participants had available samples at baseline. Each doubling in baseline TNFR-1, TNFR-2 and KIM-1 was associated with a higher risk of kidney outcomes, with corresponding HRs of 3.7 (95% CI 2.3, 6.1; p < 0.01), 2.7 (95% CI 2.0, 3.6; p < 0.01) and 1.5 (95% CI 1.2, 1.8; p < 0.01), respectively. Canagliflozin reduced the level of the plasma biomarkers with differences in TNFR-1, TNFR-2 and KIM-1 between canagliflozin and placebo during follow-up of 2.8% (95% CI 3.4%, 1.3%; p < 0.01), 1.9% (95% CI 3.5%, 0.2%; p = 0.03) and 26.7% (95% CI 30.7%, 22.7%; p < 0.01), respectively. Within the canagliflozin treatment group, each 10% reduction in TNFR-1 and TNFR-2 at year 1 was associated with a lower risk of the kidney outcome (HR 0.8 [95% CI 0.7, 1.0; p = 0.02] and 0.9 [95% CI 0.9, 1.0; p < 0.01] respectively), independent of other patient characteristics. The baseline and 1 year change in biomarkers did not associate with cardiovascular or heart failure outcomes.

Conclusions/interpretation

Canagliflozin decreased KIM-1 and modestly reduced TNFR-1 and TNFR-2 compared with placebo in individuals with type 2 diabetes in CANVAS. Early decreases in TNFR-1 and TNFR-2 during canagliflozin treatment were independently associated with a lower risk of kidney disease progression, suggesting that TNFR-1 and TNFR-2 have the potential to be pharmacodynamic markers of response to canagliflozin.

Graphical abstract

中文翻译：

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CANVAS试验中SGLT2抑制剂卡格列净对血浆生物标志物TNFR-1、TNFR-2和KIM-1的影响

目标/假设

在先前的研究中，已发现较高血浆浓度的肿瘤坏死因子受体 (TNFR)-1、TNFR-2 和肾损伤分子-1 (KIM-1) 与 2 型糖尿病患者的肾衰竭风险较高有关。药物是否可以减少这些生物标志物尚不明确。我们在 CANVAS 研究的样本中测量了这些生物标志物，并检查了钠-葡萄糖协同转运蛋白 2 抑制剂卡格列净对这些生物标志物的影响，并评估了这些生物标志物的早期变化是否可以预测 2 型糖尿病患者的心血管和肾脏结局。评估研究 (CANVAS)。

方法

在基线和第 1 年、第 3 年和第 6 年用免疫测定法（由美国纽约州纽约市 RenalytixAI 进行的专有多重测定法）测量生物标志物。重复测量的混合效应模型评估了卡格列净与安慰剂对生物标志物的影响。使用多变量调整的 Cox 回归评估每种生物标志物的基线水平和早期变化（基线至第 1 年）与肾脏结果的关联。

结果

总共有 3523/4330 (81.4%) 的 CANVAS 参与者在基线时有可用的样本。基线 TNFR-1、TNFR-2 和 KIM-1 的每一次翻倍与更高的肾脏结局风险相关，相应的 HR 为 3.7（95% CI 2.3，6.1；p  < 0.01）、2.7（95% CI 2.0， 3.6; p  < 0.01) 和 1.5 (95% CI 1.2, 1.8; p  < 0.01)。卡格列净降低血浆生物标志物水平，在随访期间卡格列净和安慰剂之间的 TNFR-1、TNFR-2 和 KIM-1 差异为 2.8%（95% CI 3.4%，1.3%；p  < 0.01），1.9% (95% CI 3.5%, 0.2%; p  = 0.03) 和 26.7% (95% CI 30.7%, 22.7%; p < 0.01)，分别。在卡格列净治疗组中，第 1 年 TNFR-1 和 TNFR-2 每降低 10% 与较低的肾脏结局风险相关（HR 0.8 [95% CI 0.7, 1.0; p  = 0.02] 和 0.9 [95 % CI 0.9, 1.0；p  < 0.01]），与其他患者特征无关。生物标志物的基线和 1 年变化与心血管或心力衰竭结果无关。

结论/解释

在 CANVAS 中，与安慰剂相比，卡格列净降低了 KIM-1 并适度降低了 TNFR-1 和 TNFR-2。坎格列净治疗期间 TNFR-1 和 TNFR-2 的早期降低与肾病进展风险降低独立相关，这表明 TNFR-1 和 TNFR-2 有可能成为对坎格列净反应的药效学标志物。

图形概要