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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Diabetes, Obesity and Metabolism |
| Vol/bind | 27 |
| Udgave nummer | 2 |
| Sider (fra-til) | 511-518 |
| Antal sider | 8 |
| ISSN | 1462-8902 |
| DOI | |
| Status | Udgivet - 2025 |
Bibliografisk note
Funding Information:This study has received funding from the Innovative Health Initiative under grant agreement no. 115974. The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA and JDRF. Any dissemination of results reflects only the author's view; the JU is not responsible for any use that may be made of the information it contains.
Funding Information:
P.R. reports grants and payment of honoraria for lectures, educational events and steering group participation from AstraZeneca, Bayer and Novo Nordisk (all to the Steno Diabetes Center Copenhagen); payment of honoraria for lectures and participation in advisory boards from Boehringer Ingelheim, Sanofi, Gilead and Astellas (all to the Steno Diabetes Center Copenhagen); and receipt of study drugs for free for investigator\u2010initiated studies from Bayer, Novo Nordisk and Lexicon. H. J. L. Heerspink is a consultant for AstraZeneca, Alexion, Bayer, Boehringer Ingelheim, CSL\u2010Behring, DIMERIX, Eli Lilly, Gilead, Janssen, Novartis, Novo Nordisk, Roche, Travere Pharmaceuticals and VIFOR Pharma. He received research support through his institution from AstraZeneca, Boehringer Ingelheim, Janssen and Novo Nordisk. He received lecture fees from AstraZeneca, Bayer and Novo Nordisk. M.F.G. received support from the Swedish Heart\u2010Lung Foundation (20190470), Swedish Research Council (EXODIAB, 2009\u20101039; 2018\u201002837) and Swedish Foundation for Strategic Research (LUDC\u2010IRC, 15\u20100067).
Publisher Copyright:
© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.