The effect of the endothelin receptor antagonist atrasentan on insulin resistance in phenotypic clusters of patients with type 2 diabetes and chronic kidney disease
Smeijer, Johannes David ; Gomez, Maria F. LU
; Rossing, Peter
and Heerspink, Hiddo J.L.
(2025)
In Diabetes, Obesity and Metabolism
27(2).
p.511-518
- 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... (More)
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.
(Less)
- author
- Smeijer, Johannes David
; Gomez, Maria F.
LU
; Rossing, Peter
and Heerspink, Hiddo J.L.
- organization
- publishing date
- 2025
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- clinical trial, diabetic nephropathy, drug mechanism, insulin resistance
- in
- Diabetes, Obesity and Metabolism
- volume
- 27
- issue
- 2
- pages
- 8 pages
- publisher
- John Wiley & Sons Inc.
- external identifiers
-
- pmid:39503150
- scopus:85208427899
- ISSN
- 1462-8902
- DOI
- 10.1111/dom.16041
- language
- English
- LU publication?
- yes
- id
- f79a01e9-d9e4-4a6b-9049-63c7154fcc78
- date added to LUP
- 2025-02-17 15:00:37
- date last changed
- 2025-07-08 02:41:12
@article{f79a01e9-d9e4-4a6b-9049-63c7154fcc78,
abstract = {{<p>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.</p>}},
author = {{Smeijer, Johannes David and Gomez, Maria F. and Rossing, Peter and Heerspink, Hiddo J.L.}},
issn = {{1462-8902}},
keywords = {{clinical trial; diabetic nephropathy; drug mechanism; insulin resistance}},
language = {{eng}},
number = {{2}},
pages = {{511--518}},
publisher = {{John Wiley & Sons Inc.}},
series = {{Diabetes, Obesity and Metabolism}},
title = {{The effect of the endothelin receptor antagonist atrasentan on insulin resistance in phenotypic clusters of patients with type 2 diabetes and chronic kidney disease}},
url = {{http://dx.doi.org/10.1111/dom.16041}},
doi = {{10.1111/dom.16041}},
volume = {{27}},
year = {{2025}},
}