Smeijer Johannes David, Gomez Maria F, Rossing Peter, Heerspink Hiddo J L
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden.
Diabetes Obes Metab. 2025 Feb;27(2):511-518. doi: 10.1111/dom.16041. Epub 2024 Nov 6.
Type 2 diabetes (T2D) patients with a clinical phenotype characterized by a high degree of insulin resistance are at increased risk of chronic kidney disease (CKD). We previously demonstrated that the endothelin receptor antagonist (ERA) atrasentan reduced insulin resistance in T2D. In this study, we compared the effect of atrasentan on insulin resistance across different phenotypic clusters of patients with T2D.
We performed a post hoc analysis of the SONAR trial, a randomized, placebo-controlled trial of the ERA atrasentan in patients with T2D and CKD. Patients were stratified into four previously identified phenotypic clusters: severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD) and mild age-related diabetes (MARD). Changes in insulin resistance, assessed by HOMA-IR, were compared between the phenotypic clusters using a mixed effects model.
In total, 931 patients were included in the analysis. In the overall population, atrasentan compared to placebo reduced HOMA-IR by 12.9% [95%CI 3.5,21.4]. This effect of atrasentan was more pronounced in clusters characterized by insulin resistance or deficiency: (SIRD cluster 26.2% [95% CI 3.8,43.3] and SIDD cluster 18.5% [95%CI -3.8,35.9]), although the latter did not reach statistical significance. The effect of atrasentan compared to placebo was less pronounced in the other two clusters (MARD 12.2% [95% CI -1.7,24.12] and MOD -5.3% [95% CI -28.9,13.9]).
Atrasentan significantly improved insulin sensitivity in patients with T2D and CKD, especially in those characterized by high insulin resistance (SIRD cluster). Further studies are warranted to investigate the long-term clinical outcomes of atrasentan treatment in these distinct phenotypic clusters.
具有高度胰岛素抵抗临床表型的2型糖尿病（T2D）患者患慢性肾脏病（CKD）的风险增加。我们之前证明内皮素受体拮抗剂（ERA）阿曲生坦可降低T2D患者的胰岛素抵抗。在本研究中，我们比较了阿曲生坦对不同表型簇的T2D患者胰岛素抵抗的影响。
我们对SONAR试验进行了事后分析，这是一项关于ERA阿曲生坦在T2D和CKD患者中进行的随机、安慰剂对照试验。患者被分为四个先前确定的表型簇：严重胰岛素缺乏型糖尿病（SIDD）、严重胰岛素抵抗型糖尿病（SIRD）、轻度肥胖相关糖尿病（MOD）和轻度年龄相关糖尿病（MARD）。使用混合效应模型比较各表型簇之间通过稳态模型评估的胰岛素抵抗（HOMA-IR）变化。
总共931名患者纳入分析。在总体人群中，与安慰剂相比，阿曲生坦使HOMA-IR降低了12.9%[95%置信区间3.5,21.4]。阿曲生坦的这种作用在以胰岛素抵抗或缺乏为特征的簇中更为明显：（SIRD簇为26.2%[95%置信区间3.8,43.3]，SIDD簇为18.5%[95%置信区间-3.8,35.9]），尽管后者未达到统计学显著性。与安慰剂相比，阿曲生坦在其他两个簇中的作用不太明显（MARD为12.2%[95%置信区间-1.7,24.12]，MOD为-5.3%[95%置信区间-28.9,13.9]）。
阿曲生坦显著改善了T2D和CKD患者的胰岛素敏感性，尤其是在那些具有高胰岛素抵抗特征的患者（SIRD簇）中。有必要进一步研究阿曲生坦治疗这些不同表型簇患者的长期临床结局。
