J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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Originally published In Press as doi:10.1194/jlr.M500387-JLR200 on October 28, 2005

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Journal of Lipid Research, Vol. 47, 193-200, January 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

The effect of high-dose simvastatin on triglyceride-rich lipoprotein metabolism in patients with type 2 diabetes mellitus

William L. Isley1,*, John M. Miles*, Bruce W. Patterson{dagger} and William S. Harris§

* Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, MN
{dagger} Center for Human Nutrition and Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
§ St. Luke's Lipid and Diabetes Research Center, Mid-America Heart Institute, Kansas City, MO

Published, JLR Papers in Press, October 28, 2005.

1 To whom correspondence should be addressed. e-mail: isley.william{at}mayo.edu

Statins decrease triglycerides (TGs) in addition to decreasing low density lipoprotein-cholesterol. Although the mechanism for the latter effect is well understood, it is still unclear how TG decrease is achieved with statin therapy. Because hypertriglyceridemia is common in obese patients with type 2 diabetes mellitus, we studied triglyceride-rich lipoprotein triglyceride (TRL-TG) turnover in 12 such subjects using stable isotopically labeled glycerol. The diabetic subjects were studied after 12 weeks of placebo and after a similar course of therapy with simvastatin (80 mg daily) in a single-blind design. The results were compared with those from six nonobese nondiabetic control subjects. Simvastatin therapy reduced serum TGs by 35% in the diabetic subjects. Compared with the control subjects, TRL-TG secretion was almost 2-fold higher in the diabetic subjects (45.4 ± 4.9 vs. 24.4 ± 1.9 µmol/min; P < 0.002) and was unaffected by simvastatin therapy. However, TRL-TG clearance was significantly increased in the diabetic subjects during simvastatin treatment compared with placebo (0.25 ± 0.03 vs. 0.16 ± 0.02 pools/h; P < 0.002). This change was accompanied by a 49% increase in preheparin plasma lipase activity (P < 0.03) and a 21% increase in postheparin LPL activity (P < 0.01). Together, these findings provide strong evidence that the effect of statins on serum TGs is related to an increase in LPL activity, resulting in accelerated delipidation of TRL particles. The effect of high-dose simvastatin on triglyceride-rich lipoprotein metabolism in patients with type 2 diabetes mellitus.

Supplementary key words very low density lipoprotein • lipoprotein kinetics • statin


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