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Simvastatin's Benefits May Extend to Atherosclerotic Plaque Stabilisation in Diabetics: Presented at DALM

By Chris Berrie

VENICE, ITALY -- October 25, 2004 -- Simvastatin-dependent plaque stabilisation in patients with type 2 diabetes arises from the drug's ability to decrease expression of receptor for advanced glycation end products (RAGE), and thence to reduce metalloproteinase (MMP) activity and promote plaque stabilisation, according to a randomised study.

Dr. Francesco Cipollone, MD, associate director of the Clinical Research Centre of the Aging Research Centre, University of Chieti, and professor of internal medicine, University of Chieti "G. d'Annunzio" School of Medicine, Chieti, Italy, presented the findings here on October 24th at the XV International Symposium on Drugs Affecting Lipid Metabolism.

Dr. Cipollone and colleagues recently demonstrated increased expression of RAGE in human diabetic plaques that was associated with the accelerated progression of atherosclerosis in diabetes. In their current research, they therefore aimed to characterise the effect of simvastatin on inflammatory infiltration and on the expression of RAGE and RAGE-dependent culprit genes in human carotid plaques.

They randomised 70 patients with type 2 diabetes and asymptomatic carotid artery stenosis (> 70%) to 4 months of the American Heart Association step 1 diet alone (n = 35; mean age, 69 years) or step 2 diet with 40-mg/day of simvastatin (n = 35; mean age, 70 years). There were no significant differences in the starting patient characteristics across these 2 groups.

Following endarterectomy, the plaques from these patients were analysed for immunoreactivity to RAGE and a series of plaque-associated enzymes. Each patient was then classified for lipid, oxidised low-density lipoprotein (oxLDL), and collagen content, and for CD68+ macrophages, CD3+ T-lymphocytes, smooth muscle cells, and human leukocyte antigen (HLA)-DR positive inflammatory cells.

The plaques from the simvastatin group showed significantly less immunoreactivity for RAGE (9% vs 25%, P <.0001), cyclooxygenase 2 (11% vs 26%, P <.0001), prostaglandin E synthase-1 (5% vs 22%, P <.0001), MMP-2 (8% vs 244%, P <.0001), and MMP-9 (10% vs 266%, P <.0001). They also showed an increase in collagen content (P <.0001), and a reduction in myeloperoxidase expression, gelatinolytic activity, and advanced glycosylation end products, lipid and oxLDL content (P <.0001). This reduced expression of myeloperoxidase, RAGE, cyclooxygenase 2 (COX-2), and MMPs induced by simvastatin paralleled the lower levels seen previously in nondiabetic patients.

In terms of the cell type analysis, the plaques from the simvastatin group had fewer macrophages, T-lymphocytes and HLA-DR+ cells (P <.0001). Dr. Cipollone also noted that the RAGE inhibition by simvastatin was not only seen in the plaque-derived sections, but also in the plaque-derived macrophages.

In summarising this analysis and its relevance to simvastatin-dependent plaque stabilisation, Dr. Cipollone said, "Our data provide the first demonstration that simvastatin inhibits the COX-2 pathway in plaque macrophages by glucose-independent RAGE downregulation, and thus, this effect may contribute to the strong benefits observed in clinical trials with simvastatin in diabetes."

This study thus identifies a new strategy for plaque stabilisation in diabetics, he added.


[Presentation title: Suppression of RAGE as a Basis of Simvastatin-Dependent Plaque Stabilisation in Type 2 Diabetes. Abstract 451]

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