Endothelial-vasoprotective effects of HDL are impaired in patients with type-2 diabetes , but are improved after extended-release niacin therapy Sorrentino – Endothelial effects of HDL in diabetes

BACKGROUND: High-density lipoprotein (HDL)-raising therapies are currently under intense evaluation, but the effects of HDL may be highly heterogeneous. We therefore compared the endothelial effects of HDL from healthy subjects and from patients with type 2 diabetes mellitus and low HDL (meeting the criteria for metabolic syndrome), who are frequently considered for HDL-raising therapies. Moreover, in diabetic patients, we examined the impact of extended-release (ER) niacin therapy on the endothelial effects of HDL. METHODS AND RESULTS: HDL was isolated from healthy subjects (n=10) and patients with type 2 diabetes (n=33) by sequential ultracentrifugation. Effects of HDL on endothelial nitric oxide and superoxide production were characterized by electron spin resonance spectroscopy analysis. Effects of HDL on endothelium-dependent vasodilation and early endothelial progenitor cell-mediated endothelial repair were examined. Patients with diabetes were randomized to a 3-month therapy with ER niacin (1500 mg/d) or placebo, and endothelial effects of HDL were characterized. HDL from healthy subjects stimulated endothelial nitric oxide production, reduced endothelial oxidant stress, and improved endothelium-dependent vasodilation and early endothelial progenitor cell-mediated endothelial repair. In contrast, these beneficial endothelial effects of HDL were not observed in HDL from diabetic patients, which suggests markedly impaired endothelial-protective properties of HDL. ER niacin therapy improved the capacity of HDL to stimulate endothelial nitric oxide, to reduce superoxide production, and to promote endothelial progenitor cell-mediated endothelial repair. Further measurements suggested increased lipid oxidation of HDL in diabetic patients, and a reduction after ER niacin therapy. CONCLUSIONS: HDL from patients with type 2 diabetes mellitus and metabolic syndrome has substantially impaired endothelial-protective effects compared with HDL from healthy subjects. ER niacin therapy not only increases HDL plasma levels but markedly improves endothelial-protective functions of HDL in these patients, which is potentially more important. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov. Identifier: NCT00346970. Endothelial-vasoprotective effects of HDL are impaired in patients with type-2 diabetes, but are improved after extended-release niacin therapy Sorrentino – Endothelial effects of HDL in diabetes Sajoscha A. Sorrentino, MD, Christian Besler, MD, Lucia Rohrer, PhD, Martin Meyer, MD, Kathrin Heinrich, BS Ferdinand H. Bahlmann, MD,PhD, Maja Mueller,BS, Tibor Horváth, BS, Carola Doerries, DVM, Mariko Heinemann, BS, Stella Flemmer, BS, Andrea Markowski, BS, Costantina Manes, MD, Matthias J. Bahr, MD, Hermann Haller,MD, Arnold von Eckardstein, MD, Helmut Drexler, MD, Ulf Landmesser, MD Klinik für Kardiologie und Angiologie, Klinik für Nierenund Hochdruckerkrankungen, and Klinik für Gastroenterologie, Hepatologie and Endokrinologie; Medizinische Hochschule Hannover, Hannover, Germany; Cardiovascular Center, University Hospital Zurich, Switzerland; Institute of Clinical Chemistry, and Zurich Center of Integrated Human Physiology, University of Zurich, Switzerland *Both authors contributed equally Total word count: 5,874 Address for correspondence: Ulf Landmesser, MD Cardiovascular Center University Hospital Zürich Rämistr 100 (C-Hof 111) 8091 Zürich Switzerland Tel.: +41-(0)44-255-9595 Fax: +41-(0)44-255-4401 E-mail: Ulf.Landmesser@usz.ch Subject codes: [95] Endothelium/vascular type/nitric oxide; [91] Oxidant stress