Niacin restores vasoprotective effects of HDL in type 2 diabetes

High-density lipoprotein (HDL) from patients with type 2 diabetes has impaired vasoprotective effects, compared with HDL in healthy individuals, according to the results of a new study published in Circulation.  However, treatment with extended-release niacin substantially restores the beneficial vasoprotective effects of HDL. These data highlight the need to take account of HDL functionality, as well as plasma HDL cholesterol levels, when assessing the potential of HDL- targeted treatments.

 The data were reviewed by HDL Forum Editor Professor Philip Barter, Heart Research Institute, Sydney, Australia.

 Sorrentino SA, Besler C, Rohrer L et al. Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation published online Dec 21, 2009; DOI: 10.1161/CIRCULATIONAHA.108.836346

 Normally, HDL exert a range of potent biological activities that provide protection against atherosclerosis. These actions include a key role in mediating cholesterol efflux from plaque macrophages and foam cells, and from peripheral tissues, with transport to the liver for excretion via the process of reverse cholesterol transport., as well as anti-oxidant, anti-inflammatory, anti-apoptotic, antithrombotic, anti-infectious and vasodilatory properties (1) (Fig 1).

 

This new study adds to evidence showing that the atheroprotective effects of HDL In individuals with type 2 diabetes are impaired (2,3). Of special interest, the study shows that treatment with ER niacin can help to restore the functional properties of HDL in type 2 diabetes.

 Researchers at Hannover Medical School, Germany and the Cardiovascular Center, University Hospital Zurich isolated HDL from 10 healthy subjects and 33 individuals with type 2 diabetes with reduced HDL cholesterol levels consistent with the metabolic syndrome (mean HDL cholesterol 36 mg/dL). All diabetic patients were receiving a statin concurrently. The effects of each type of HDL on endothelial nitric oxide (NO) production, superoxide production, endothelium-dependent vasodilation and early endothelial progenitor cell-mediated endothelial repair, essential vasoprotective effects of HDL, were evaluated.

HDL from healthy subjects, but not from those with type 2 diabetes, markedly stimulated endothelial NO production, reduced endothelial oxidant stress and promoted in vivo endothelial repair capacity. In contrast, there was increased lipid peroxidation of HDL from patients with type 2 diabetes compared with HDL from healthy subjects (Fig 2.). These findings suggest marked impairment of beneficial vasoprotective activities of HDL in patients with type 2 diabetes.

 

In the second part of the study, type 2 diabetic patients were randomized to treatment with extended-release niacin (target dose 1500 mg/day) or placebo for 3 months.

 Treatment with niacin not only improved HDL cholesterol levels (by 14%) but also markedly improved the beneficial effects of HDL on the endothelium by:

- improving the capacity of HDL to stimulate endothelial cell NO production

- increasing the endothelial antioxidant effects of HDL

- improving endothelial-protective effects of HDL

- promoting endothelial repair

- inhibiting endothelial cell oxidant stress.

 While the mechanisms by which niacin achieves these effects have yet to be established, evidence that niacin reduces lipid oxidation of HDL suggests a possible pathway. The findings from this study also provide novel explanation for the beneficial effects of niacin on progression of atherosclerosis, as observed in recent studies including ARBITER-6 HALTS (4,5).

 The authors concluded that the results of the study highlight the need to take account of indexes of HDL functionality, as well as circulating HDL cholesterol levels when assessing the clinical potential of HDL-targeted therapies.

 References

1. Assmann G, Nofer JR. Atheroprotective effects of high-density lipoproteins. Ann Rev Med 2003;54:321-341.

2. Nobecourt E, Jacqueminet S, Hansel B et al. Defective antioxidative activity of small, dense HDL particles in type 2 diabetes: relationship to oxidative stress and hyperglycaemia. Diabetologia 2005;48:529-38.

3. Kontush A, de Faria EC, Chantepie S et al. A normotriglyceridemic, low HDL-cholesterol phenotype is characterised by elevated oxidative stress and HDL particles with attenuated antioxidative activity. Atherosclerosis 2005;182:277-85.

4. Lee JMS, Robson MD, Yu L-M et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function. J Am Coll Cardiol 2009;54:1787-94

5. Taylor AJ, Villines TC, Stanek EJ et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. New Engl J Med. Published on-line November 15, 2009. DOI 10.1056/NEJMoa0907569.

 


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