The endothelin receptor antagonist bosentan improves peripheral endothelial function in patients with type 2 diabetes mellitus and microalbuminuria: A randomised trial

Abstract

Aims/hypothesis: Endothelial dysfunction is important in the development of vascular complications in diabetes. Patients with type 2 diabetes have increased production of the vasoconstrictor and pro-inflammatory peptide, endothelin-1. Short-term intra-arterial administration of endothelin antagonists improves endothelium-dependent vasodilatation in patients with type 2 diabetes. We tested the hypothesis that oral administration of the dual endothelin receptor antagonist, bosentan, improves peripheral endothelial function in patients with type 2 diabetes and microalbuminuria. Methods: This placebo-controlled and double-blind study was performed on 46 patients with type 2 diabetes and microalbuminuria (urine albumin/creatinine ratio >3 mg/mmol) at a medical university department. Patients were randomised to bosentan, 125 mg two times per day (n=28), or placebo (n=28) for 4 weeks. The computer-generated randomisation code was kept in sealed envelopes. Patients and people doing examinations or assessing outcomes were blinded. The primary endpoint was change in microvascular endothelium-dependent vasodilatation, based on change in digital reactive hyperaemia index. The secondary endpoint was change in brachial artery flow-mediated vasodilatation. Results: Reactive hyperaemia index increased from 1.73±0.43 (mean±SD) at baseline to 2.08±0.59 at follow-up (p<0.05) in the bosentan group (n=22), but did not change in the placebo group (1.84±0.49 to 1.87±0.47; n=24). The change in reactive hyperaemia index from baseline was greater in the bosentan group than in the placebo group (p<0.05). Nitroglycerine-induced digital hyperaemia was not affected. Brachial artery flow-mediated vasodilatation and blood pressure did not change during treatment. Conclusions/interpretation: Oral treatment of 4 weeks duration with the dual endothelin receptor antagonist, bosentan, improves peripheral endothelial function in patients with type 2 diabetes and microalbuminuria. Trial Registration:: ClinicalTrial.gov NCT01357109; Karolinska Clinical Trial Registration Identifier CT20090017 (see www.kctr.se ) Funding:: Research Council of Sweden, Swedish Heart and Lung Foundation, Novo Nordisk Foundation, Karolinska Institutet/Stockholm County Council Strategic Cardiovascular Programme, Gustav V and Queen Victoria Foundation, the Family Erling Persson Foundation, Actelion Pharmaceuticals and Actelion Research Award. © 2011 Springer-Verlag.