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Article: Insulin resistance, kidney outcomes and effects of the endothelin receptor antagonist atrasentan in patients with type 2 diabetes and chronic kidney disease

TitleInsulin resistance, kidney outcomes and effects of the endothelin receptor antagonist atrasentan in patients with type 2 diabetes and chronic kidney disease
Authors
KeywordsAtrasentan
Chronic kidney disease
Endothelin receptor antagonist
Insulin resistance
Type 2 diabetes
Issue Date16-Sep-2023
PublisherBioMed Central
Citation
Cardiovascular Diabetology, 2023, v. 22, n. 1 How to Cite?
Abstract

Background: Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes and associated with the presence of chronic kidney disease (CKD). Experimental studies suggest that endothelin-1 increases IR. We assessed the association between IR and cardio-renal outcomes and the effect of the selective endothelin receptor antagonist atrasentan on IR in patients with type 2 diabetes and CKD. Methods: We used data from the RADAR and SONAR trials that recruited participants with type 2 diabetes and CKD [eGFR 25–75 mL/min/1.73 m², urine albumin-to-creatinine ratio of 300–5000 mg/g]. IR was calculated using the homeostatic model assessment (HOMA-IR). The association between HOMA-IR and the pre-specified cardio-renal outcomes was assessed using multivariable Cox proportional hazards regression, and effects of atrasentan on HOMA-IR by a linear mixed effect model. Results: In the SONAR trial, each log-unit increase in HOMA-IR was associated with an increased risk of the composite cardio-renal outcome [hazard ratio 1.32 (95%CI 1.09,1.60; p = 0.004)], kidney outcome [hazard ratio 1.30 (95%CI 1.00,1.68; p-value = 0.048)], and the kidney or all-cause mortality outcome [hazard ratio 1.25 (95%CI 1.01,1.55; p-value = 0.037)]. After 12 weeks treatment in the RADAR trial (N = 123), atrasentan 0.75 mg/day and 1.25 mg/day compared to placebo reduced HOMA-IR by 19.1 (95%CI -17.4, 44.3) and 26.7% (95%CI -6.4, 49.5), respectively. In the SONAR trial (N = 1914), atrasentan 0.75 mg/day compared to placebo reduced HOMA-IR by 9.6% (95%CI 0.6, 17.9). Conclusions: More severe IR is associated with increased risk of cardio-renal outcomes. The endothelin receptor antagonist atrasentan reduced IR. Trial registration: RADAR trial (Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan): NCT01356849. SONAR trial (The Study Of Diabetic Nephropathy With AtRasentan) NCT01858532.


Persistent Identifierhttp://hdl.handle.net/10722/338818
ISSN
2023 Impact Factor: 8.5
2023 SCImago Journal Rankings: 2.621
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorSmeijer, JD-
dc.contributor.authorKohan, DE-
dc.contributor.authorRossing, P-
dc.contributor.authorCorrea-Rotter, R-
dc.contributor.authorLiew, A-
dc.contributor.authorTang, SCW-
dc.contributor.authorDe Zeeuw, D-
dc.contributor.authorGansevoort, RT-
dc.contributor.authorJu, W-
dc.contributor.authorLambers, Heerspink HJ-
dc.date.accessioned2024-03-11T10:31:47Z-
dc.date.available2024-03-11T10:31:47Z-
dc.date.issued2023-09-16-
dc.identifier.citationCardiovascular Diabetology, 2023, v. 22, n. 1-
dc.identifier.issn1475-2840-
dc.identifier.urihttp://hdl.handle.net/10722/338818-
dc.description.abstract<p>Background: Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes and associated with the presence of chronic kidney disease (CKD). Experimental studies suggest that endothelin-1 increases IR. We assessed the association between IR and cardio-renal outcomes and the effect of the selective endothelin receptor antagonist atrasentan on IR in patients with type 2 diabetes and CKD. Methods: We used data from the RADAR and SONAR trials that recruited participants with type 2 diabetes and CKD [eGFR 25–75 mL/min/1.73 m², urine albumin-to-creatinine ratio of 300–5000 mg/g]. IR was calculated using the homeostatic model assessment (HOMA-IR). The association between HOMA-IR and the pre-specified cardio-renal outcomes was assessed using multivariable Cox proportional hazards regression, and effects of atrasentan on HOMA-IR by a linear mixed effect model. Results: In the SONAR trial, each log-unit increase in HOMA-IR was associated with an increased risk of the composite cardio-renal outcome [hazard ratio 1.32 (95%CI 1.09,1.60; p = 0.004)], kidney outcome [hazard ratio 1.30 (95%CI 1.00,1.68; p-value = 0.048)], and the kidney or all-cause mortality outcome [hazard ratio 1.25 (95%CI 1.01,1.55; p-value = 0.037)]. After 12 weeks treatment in the RADAR trial (N = 123), atrasentan 0.75 mg/day and 1.25 mg/day compared to placebo reduced HOMA-IR by 19.1 (95%CI -17.4, 44.3) and 26.7% (95%CI -6.4, 49.5), respectively. In the SONAR trial (N = 1914), atrasentan 0.75 mg/day compared to placebo reduced HOMA-IR by 9.6% (95%CI 0.6, 17.9). Conclusions: More severe IR is associated with increased risk of cardio-renal outcomes. The endothelin receptor antagonist atrasentan reduced IR. Trial registration: RADAR trial (Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan): NCT01356849. SONAR trial (The Study Of Diabetic Nephropathy With AtRasentan) NCT01858532.</p>-
dc.languageeng-
dc.publisherBioMed Central-
dc.relation.ispartofCardiovascular Diabetology-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectAtrasentan-
dc.subjectChronic kidney disease-
dc.subjectEndothelin receptor antagonist-
dc.subjectInsulin resistance-
dc.subjectType 2 diabetes-
dc.titleInsulin resistance, kidney outcomes and effects of the endothelin receptor antagonist atrasentan in patients with type 2 diabetes and chronic kidney disease-
dc.typeArticle-
dc.identifier.doi10.1186/s12933-023-01964-8-
dc.identifier.scopuseid_2-s2.0-85171412146-
dc.identifier.volume22-
dc.identifier.issue1-
dc.identifier.eissn1475-2840-
dc.identifier.isiWOS:001067278000002-
dc.identifier.issnl1475-2840-

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