Effects of the SGLT2 inhibitor canagliflozin on plasma biomarkers TNFR-1, TNFR-2 and KIM-1 in the CANVAS trial.
Effects of the SGLT2 inhibitor canagliflozin on plasma biomarkers TNFR-1, TNFR-2 and KIM-1 in the CANVAS trial.
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DOI：
10.1007/s00125-021-05512-5
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发表时间：
2021-10
期刊：
影响因子：
8.2
通讯作者：
Heerspink HJL
中科院分区：
文献类型：
--
作者：
Sen T;Li J;Neuen BL;Neal B;Arnott C;Parikh CR;Coca SG;Perkovic V;Mahaffey KW;Yavin Y;Rosenthal N;Hansen MK;Heerspink HJL
在先前的研究中，已发现较高的肿瘤坏死因子受体（TNFR）-1，TNFR-2和肾损伤分子-1（KIM-1）血浆浓度与2型糖尿病患者发生肾衰竭的风险较高相关。药物是否可以减少这些生物标志物还没有得到很好的确定。我们测量了CANVAS研究样本中的这些生物标志物，并检查了钠-葡萄糖协同转运蛋白2抑制剂canagliflozin对这些生物标志物的影响，并评估了CANagliflozin心血管评估研究（CANVAS）中这些生物标志物的早期变化是否可预测2型糖尿病患者的心血管和肾脏结局。在基线和第1、3和6年，使用免疫测定法（由RenalytixAI，纽约，NY，USA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。使用多变量校正的考克斯回归评估了每种生物标志物的基线水平和早期变化（基线至第1年）与肾脏结局的相关性。总共有3523/4330（81.4%）例CANVAS参与者在基线时有可用样本。基线TNFR-1、TNFR-2和KIM-1每增加一倍，肾脏结局风险就更高，相应的HR分别为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）。卡格列净降低了血浆生物标志物的水平，随访期间卡格列净与安慰剂之间TNFR-1、TNFR-2和KIM-1的差异为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）。在卡格列净治疗组中，第1年TNFR-1和TNFR-2每降低10%与肾脏结局风险降低相关（HR分别为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局无关。在CANVAS研究中，与安慰剂相比，卡格列净降低了2型糖尿病患者的KIM-1，并适度降低了TNFR-1和TNFR-2。卡格列净治疗期间TNFR-1和TNFR-2的早期降低与肾脏疾病进展风险降低独立相关，表明TNFR-1和TNFR-2有可能成为卡格列净应答的药效学标志物。在线版本包含同行评审但未经编辑的补充材料，可通过10.1007/s 00125 -021-05512-5获得。
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). 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. 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. 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. The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-021-05512-5.
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影响因子：
5.3
作者：
Park M;Maristany D;Huang D;Shlipak MG;Whooley M
通讯作者：
Whooley M
影响因子：
19.6
作者：
通讯作者：
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DOI：
10.1111/dom.13301
发表时间：
2018-08
期刊：
Diabetes, obesity & metabolism
影响因子：
--
作者：
Dekkers CCJ;Petrykiv S;Laverman GD;Cherney DZ;Gansevoort RT;Heerspink HJL
通讯作者：
Heerspink HJL
影响因子：
13.6
作者：
Niewczas, Monika A.;Gohda, Tomohito;Krolewski, Andrzej S.
通讯作者：
Krolewski, Andrzej S.
影响因子：
82.9
作者：
Niewczas, Monika A.;Pavkov, Meda E.;Krolewski, Andrzej S.
通讯作者：
Krolewski, Andrzej S.