my personal edition > cholesterol/lipid disorders > news


  E-Mail this DGDispatch to a colleague

DGDispatch

Inhibition of Intestinal Cholesterol Absorption and Hepatic Cholesterol Production by Ezetimibe/Simvastatin Therapy Reduces Dramatically Plasma LDL-C: Presented at DALM

By Crina Frincu-Mallos, PhD

NEW YORK, N.Y. -- October 12, 2007 -- Changes in cholesterol metabolism accompany significant reductions in low-density lipoprotein cholesterol (LDL-C), and the inhibition of both intestinal absorption and hepatic production results in more than 50% reduction in plasma LDL-C concentration, according to a study presented here at the XVI International Symposium on Drugs Affecting Lipid Metabolism (DALM).

Investigator William Taggart, MD, Merck Research Laboratories, Rahway, New Jersey, United States, said that the two agents used to perturb the balance of cholesterol in this study -- ezetimibe and simvastatin -- are usually prescribed in patients needing plasma cholesterol reduction.

This was a randomised, double-blind, placebo-controlled, four-period, crossover study, where the effects of ezetimibe 10 mg in combination with simvastatin 20 mg were compared with ezetimibe or simvastatin monotherapy, and also with placebo.

Forty-one subjects were enrolled in the study, mean age 36.9 years old (range, 23-55 years old), with mean body mass index of 25.5 kg/m² (range, 21.1-30.4 kg/m²), mean LDL-C levels of 152 mg/dL (range, 130-180 mg/dL), and triglycerides <250 mg/dL.

Fractional cholesterol absorption was measured during the 7th week of each treatment period using the continuous feeding dual-isotope method, while cholesterol production was evaluated based on plasma concentration of lathosterol and by estimates of foecal sterol mass balance, Dr. Taggart said on October 5.

The therapies were all well tolerated, with the exception of one case of creatine phosphokinase elevation >=10 ULN on simvastatin that resolved without changing treatment, the researchers said.

Percent decrease in plasma LDL-C levels were 55.0% for ezetimibe in combination with simvastatin (P <.001), 20.0% for ezetimibe monotherapy (P <.001), 38.1% for simvastatin monotherapy (P <.001). Levels increased by 2.6% in the placebo group.

"Coadministration therapy was significantly superior to the monotherapy groups in lowering LDL-C," said Dr. Taggart.

Looking at the geometric mean ratio, ezetimibe in combination with simvastatin versus simvastatin alone was 0.39 (90% CI: 0.35, 0.44), indicating a 61% reduction in the fraction of cholesterol absorbed (P <.001).

Cholesterol synthesis rates were 1591 mg/day for ezetimibe plus simvastatin, 787 mg/day for simvastatin alone, 1851 mg/day for ezetimibe alone, and 884 mg/day for placebo.

"When the two drugs are used concomitantly, they retain their individual efficacies," explained Dr. Taggart.

The investigators concluded that the combination of ezetimibe and simvastatin resulted in "nearly additive reductions in LDL-C, in the presence of decreases in net cholesterol absorption, decreases in plasma cholesterol precursors, and increased foecal sterols."

Funding for this study was provided by Merck Schering Plough Joint Venture, North Wales, Pennsylvania, United States.


[Presentation title: Inhibition of Intestinal Cholesterol Absorption and Endogenous Cholesterol Production by Ezetimibe/Simvastatin in Man. Abstract 265]

E-Mail this DGDispatch to a colleague

To print, use this version