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

Autor: Smeijer JD; Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Kohan DE; Division of Nephrology, University of Utah Health, Salt Lake City, UT, USA., Rossing P; Steno Diabetes Center Copenhagen, Herlev, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark., Correa-Rotter R; National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico., Liew A; Mount Elizabeth Novena Hospital, Singapore, Singapore.; George Institute for Global Health, Newtown, Australia., Tang SCW; Division of Nephrology, Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong., de Zeeuw D; Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Gansevoort RT; Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Ju W; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA., Lambers Heerspink HJ; Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. h.j.lambers.heerspink@umcg.nl.; George Institute for Global Health, Newtown, Australia. h.j.lambers.heerspink@umcg.nl.
Jazyk: angličtina
Zdroj: Cardiovascular diabetology [Cardiovasc Diabetol] 2023 Sep 16; Vol. 22 (1), pp. 251. Date of Electronic Publication: 2023 Sep 16.
DOI: 10.1186/s12933-023-01964-8
Abstrakt: 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.
(© 2023. BioMed Central Ltd., part of Springer Nature.)
Databáze: MEDLINE
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