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A more recent version of this article appeared on January 1, 2006

Papers In Press, published online ahead of print October 28, 2005
J. Lipid Res., doi:10.1194/jlr.M500387-JLR200
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Submitted on August 26, 2005
Revised on October 27, 2005
Accepted on October 27, 2005

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

William L. Isley, John M. Miles, Bruce W. Patterson, and William S. Harris

Division of Endocrinology, Mayo Foundation, Rochester, MN 55905

Corresponding Author: isley.william{at}mayo.edu

Statins decrease triglycerides in addition to lowering low-density lipoprotein cholesterol. While the mechanism for the latter effect is well understood, it is still unclear how triglyceride lowering is achieved with statin therapy. Since hypertriglyceridemia is common in obese patients with type 2 diabetes mellitus, we studied triglyceride rich lipoprotein triglyceride (TRL-TG) turnover in twelve such subjects using stable isotopically-labeled glycerol. The diabetic subjects were studied after twelve weeks of placebo and after a similar course of therapy with simvastatin 80 mg daily in a single blind design. The results were compared to those from six non-obese non-diabetic control subjects. Simvastatin therapy reduced serum triglycerides by 35% in the diabetic subjects. Compared to the control subjects, TRL-TG secretion was almost two-fold higher in the diabetic subjects (45.4plusmn 4.9 vs 24.4plusmn 1.9 mu mol/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 to placebo (0.25plusmn 0.03 vs 0.16plusmn 0.02 pools/hr, p<0.002). This change was accompanied by a 49% increase in pre-heparin plasma lipase activity (p<0.03) and a 21% increase in post-heparin lipoprotein lipase (LPL) activity (p<0.01). Taken together, these findings provide strong evidence that the effect of statins on serum triglycerides is related to an increase in LPL activity, resulting in accelerated delipidation of TRL particles.


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