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Role of Simvastatin as an Immunomodulator in Type 2 Diabetes

¹ Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
² Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina
³ Department of Biometry and Epidemiology, Medical University of South Carolina, Charleston, South Carolina
⁴ Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina

Address correspondence and reprint requests to Maria F. Lopes-Virella, MD, PhD, Professor of Medicine and Pathology, Ralph H. Johnson VA Medical Center, Medical University of South Carolina, Strom Thurmond Research Building, 114 Doughty St., Room 529, Charleston, SC 29425. E-mail: virellam{at}musc.edu

OBJECTIVE—To test the hypothesis that simvastatin reduces the levels of circulating immune complexes (ICs) containing modified lipoproteins (mLDLs; mLDL-ICs), which may represent an additional mechanism for the reduced incidence of cardiovascular events in patients treated with simvastatin.

RESEARCH DESIGN AND METHODS—A total of 26 patients with type 2 diabetes and triglyceride levels <400 mg/dl who were not receiving lipid-lowering medications or CYP 3A4 inhibitors were enrolled in the study. After 2 weeks on a lipid-lowering diet and exercise, the patients were started on simvastatin 20 mg/day. The dose of simvastatin was adjusted until the levels of LDL cholesterol were 100 mg/dl. Blood was collected at baseline, 3 and 6 months after LDL cholesterol levels reached target, and 3 months after stopping simvastatin to measure advanced glycation end product LDL and oxidized LDL antibodies, mLDL-IC, intracellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), E-selectin, metalloproteinase-1 (MMP-1), lipid profile, liver function tests, creatinine kinase, glucose, and HbA_1c.

RESULTS—Twenty-one patients completed the study. Their HbA_1c remained within 1% of baseline levels. There was a highly significant decrease in mLDL-IC levels after 3 and 6 months of treatment with simvastatin, with a return to near baseline levels after discontinuation.

CONCLUSIONS—Simvastatin significantly reduced the concentration of mLDL-IC, probably as a consequence of both a decrease in the formation of mLDL and to a reduction in the titers of mLDL antibodies. This effect is likely to have a beneficial impact in the inflammatory reaction associated with atherosclerosis.

Abbreviations: AGE, advanced glycation end product • apoB, apolipoprotein B • CHD, coronary heart disease • IC, immune complex • ICAM-1, intracellular adhesion molecule-1 • MHC-II, major histocompatibility complex II • mLDL, modified lipoprotein • MMP-1, metalloproteinase-1 • VCAM-1, vascular adhesion molecule-1

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				M. Petrou, M. Gregoriades, and V. Vassiliou Role of Simvastatin as an Immunomodulator in Type 2 Diabetes: Response to Lopes-Virella et al. Diabetes Care, August 1, 2004; 27(8): 2093 - 2094. [Full Text] [PDF]