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

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.

• Authors: J David Smeijer, Donald E Kohan, Peter Rossing, Ricardo Correa-Rotter, Adrian Liew, Sydney C W Tang, Dick de Zeeuw, Ron T Gansevoort, Wenjun Ju, Hiddo J Lambers Heerspink
• Journal: Cardiovascular diabetology (Cardiovasc Diabetol) Vol. 22 Issue 1 Pg. 251 (09 16 2023) ISSN: 1475-2840 [Electronic] England
• PMID: 37716952 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. BioMed Central Ltd., part of Springer Nature.

Chemical References

• Atrasentan
• Endothelin Receptor Antagonists

Topics

• Humans
• Atrasentan (adverse effects)
• Diabetes Mellitus, Type 2 (diagnosis, drug therapy, epidemiology)
• Insulin Resistance
• Kidney
• Renal Insufficiency, Chronic (diagnosis, drug therapy, epidemiology)
• Endothelin Receptor Antagonists (adverse effects)