Role of Simvastatin as an Immunomodulator in Type 2 Diabetes

  1. Maria F. Lopes-Virella, MD, PHD12,
  2. Marina Mironova, MD, PHD1,
  3. Elias Stephan, MD1,
  4. Ramon Durazo-Arvizu, PHD3 and
  5. Gabriel Virella, MD, PHD4
  1. 1Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
  2. 2Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina
  3. 3Department of Biometry and Epidemiology, Medical University of South Carolina, Charleston, South Carolina
  4. 4Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
  1. 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

Abstract

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 HbA1c.

RESULTS—Twenty-one patients completed the study. Their HbA1c 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.

Footnotes

  • M.F.L.-V. has received a small university grant from Merck and is part of an advisory board for Merck.

    • Accepted December 23, 2003.
    • Received June 26, 2003.
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  1. doi: 10.2337/diacare.27.4.908 Diabetes Care April 2004 vol. 27 no. 4 908-913
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