1. Rational approach to the treatment for heterozygous familial hypercholesterolemia in childhood and adolescence: A review
L. Iughetti, B. Predieri, F. Balli, and S. Calandra. J. Endocrinol. Invest. 30: 700-719, 2007
Cholesterol esterification is believed to promote the transformation of macrophages into foam cells, which may predispose to both endothelial dysfunction and inflammatory processes, characteristic of atherosclerotic lesions. Acyl coenzyme A-cholesterol acyltransferase (ACAT) is the enzyme responsible for the acylation of intracellular free cholesterol to form cholesterol ester. Inhibiting ACAT may favorably affect overall lipid profiles by decreasing plasma levels of LDL-C, TC, and triglycerides. Avasimibe, an orally active acylsulfamate-phenyl ester, is believed to be an inhibitor of both ACAT isoenzymes presenting beneficial effects on plasma lipids and direct anti-atherosclerotic activity in various animal models of hypercholesterolemia. Recently, a study evaluated the effects of avasimibe on lipids and lipoproteins in children and adults with HoFH. Twenty-seven subjects were enrolled in an 18-week, double-blind, randomized, 3-sequence crossover trial of atorvastatin (80 mg/day), avasimibe (750 mg/day), and the combined therapy of atorvastatin and avasimibe. There were no significant lipid changes resulting from the administration of avasimibe monotherapy. Avasimibe in combination with atorvastatin resulted in a significantly better reduction of TC as compared with statin alone (–22% and –18%, respectively), while all other lipid changes were not statistically significant for combination therapy compared to atorvastatin monotherapy, although a greater reduction in triglycerides, LDL-C, and HDL-C was demonstrated. The results obtained in this study suggested that the mechanisms of ACAT inhibition and HMG-CoA reductase inhibition were synergistic in certain settings by either inhibiting the production or enhancing the clearance of certain lipid fractions. Moreover, this trial demonstrated the safety of avasimibe and tolerability in HoFH patients when administered over a short treatment period either as monotherapy or in combination with statin. In fact, relatively few serious adverse events occurred during the study and steroid hormone levels, evaluated in subjects younger than 18 yr of age, were within normal range.
2. Inhibition of Acyl Coenzyme A-cholesterol Acyltransferase: A Possible Treatment of Atherosclerosis?
Therese M. Heinonen. Current Atherosclerosis Reports 2002, 4:65–70
In humans, the role of ACAT in the hepatocyte is less well defined, although there have been studies supporting the relationship between hepatic ACAT activity and VLDL production. The potential for ACAT inhibitors to modify the production of cholesterol has led to activity within the pharmaceutical industry evaluating agents based on this mechanism. However, the activity here has been disappointing. Most ACAT inhibitors that have significantly decreased plasma cholesterol and triglyceride levels in hypercholesterolemic animal models have failed to demonstrate similar effects in humans. Interestingly though, a recently completed clinical trial assessing the effects of the ACAT inhibitor, avasimibe (CI-1011), in patients with combined hyperlipidemia has demonstrated a decrease in plasma VLDL cholesterol and triglyceride concentrations of up to 30% over a 2- to 8-week period. In this trial, total cholesterol, LDL cholesterol, and high-density lipoprotein (HDL) cholesterol levels were not altered [19•]. The exact mechanism by which VLDL is lowered is not yet known, but a hepatic mechanism for this effect is supported by findings of decreased cellular cholesteryl ester mass, apolipoprotein (apo) B secretion, and enhanced intracellular degradation of apoB in cell culture and animal studies of avasimibe.
3. New Targets for Medical Treatment of Lipid Disorders
Margaret E. Brousseau, and Ernst J. Schaefer. Current Atherosclerosis Reports 2002, 4:343–349
The study consisted of an 8-week baseline phase of dietary and single-blind, placebo treatment followed by an 8-week phase of double-blind, randomized, parallel-treatment with placebo or avasimibe. Avasimibe was given at one of four doses (50, 125, 250, and 500 mg) to five equal-sized groups of patients. The authors state that all doses of avasimibe were well tolerated, with no significant abnormalities noted in biochemical or clinical parameters. Upon entry into the 8-week placebo phase, all patients were counseled to follow an NCEP Step 1 diet throughout the study. Relative to placebo, no statistically significant changes were detected in concentrations of total cholesterol, LDL, HDL, or apoB among the treatment groups. In contrast, plasma levels of very low-density lipoprotein (VLDL) cholesterol and triglycerides were significantly reduced by avasimibe therapy.