The effect of the endothelin receptor antagonist atrasentan on insulin resistance in phenotypic clusters of patients with type 2 diabetes and chronic kidney disease.

IF 5.4 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Diabetes, Obesity & Metabolism Pub Date : 2024-11-06 DOI:10.1111/dom.16041
Johannes David Smeijer, Maria F Gomez, Peter Rossing, Hiddo J L Heerspink
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Abstract

Aims: 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.

Materials and methods: 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.

Results: 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]).

Conclusions: 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.

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内皮素受体拮抗剂阿曲生坦对 2 型糖尿病和慢性肾脏病患者表型群胰岛素抵抗的影响。
目的:临床表型以高度胰岛素抵抗为特征的 2 型糖尿病(T2D)患者罹患慢性肾病(CKD)的风险增加。我们曾证实,内皮素受体拮抗剂(ERA)阿曲生坦能减轻 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,该试验是 ERA 阿曲生坦治疗 T2D 和 CKD 患者的随机安慰剂对照试验。患者被分为四个先前确定的表型群:严重胰岛素缺乏性糖尿病(SIDD)、严重胰岛素抵抗性糖尿病(SIRD)、轻度肥胖相关性糖尿病(MOD)和轻度年龄相关性糖尿病(MARD)。使用混合效应模型比较了不同表型组之间通过 HOMA-IR 评估的胰岛素抵抗的变化:共有 931 名患者参与了分析。在总体人群中,与安慰剂相比,阿曲生坦可将 HOMA-IR 降低 12.9% [95%CI 3.5,21.4]。阿曲生坦的这一效果在以胰岛素抵抗或缺乏为特征的群组中更为明显:(SIRD 群组 26.2% [95%CI 3.8,43.3],SIDD 群组 18.5% [95%CI -3.8,35.9]),尽管后者未达到统计学意义。与安慰剂相比,阿曲生坦在其他两个群组(MARD 12.2% [95%CI -1.7,24.12] 和 MOD -5.3% [95%CI -28.9,13.9])中的效果并不明显:结论:阿曲生坦能明显改善 T2D 和 CKD 患者的胰岛素敏感性,尤其是那些具有高胰岛素抵抗特征的患者(SIRD 组)。有必要进一步研究阿曲生坦治疗在这些不同表型群组中的长期临床效果。
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来源期刊
Diabetes, Obesity & Metabolism
Diabetes, Obesity & Metabolism 医学-内分泌学与代谢
CiteScore
10.90
自引率
6.90%
发文量
319
审稿时长
3-8 weeks
期刊介绍: Diabetes, Obesity and Metabolism is primarily a journal of clinical and experimental pharmacology and therapeutics covering the interrelated areas of diabetes, obesity and metabolism. The journal prioritises high-quality original research that reports on the effects of new or existing therapies, including dietary, exercise and lifestyle (non-pharmacological) interventions, in any aspect of metabolic and endocrine disease, either in humans or animal and cellular systems. ‘Metabolism’ may relate to lipids, bone and drug metabolism, or broader aspects of endocrine dysfunction. Preclinical pharmacology, pharmacokinetic studies, meta-analyses and those addressing drug safety and tolerability are also highly suitable for publication in this journal. Original research may be published as a main paper or as a research letter.
期刊最新文献
The cellular and molecular mechanisms mediating the protective effects of sodium-glucose linked transporter 2 inhibitors against metabolic dysfunction-associated fatty liver disease. Association and mediation pathways of maternal hyperglycaemia and liability to gestational diabetes with neonatal outcomes: A two-sample Mendelian randomization study. The effect of the endothelin receptor antagonist atrasentan on insulin resistance in phenotypic clusters of patients with type 2 diabetes and chronic kidney disease. Benefits of combining SGLT2 inhibitors and pioglitazone on risk of MASH in type 2 diabetes-A real-world study. Non-clinical and first-in-human characterization of ECC5004/AZD5004, a novel once-daily, oral small-molecule GLP-1 receptor agonist.
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