New Treatments Dramatically Raise HDL Cholesterol
May 15, 2004 3 minutes read
Abstract & Commentary
Synopsis: Drugs that inhibit Cholesterol Ester Transfer Protein (CETP) markedly increase levels of HDL cholesterol.
Source: Brousseau ME, et al. N Engl J Med. 2004;350:1505-1515.
Despite the favorable effect of statins on the risk of coronary heart disease, many patients still experience significant morbidity and mortality. As Brousseau and colleagues note, "the most common abnormality in patients with coronary heart disease is low levels of HDL cholesterol." In approximately half of these patients it is the primary abnormality. Currently available therapies such as fibrates and niacin raise the levels of HDL Cholesterol (HDL-C) but rarely raise the HDL levels more than 25%.
Brousseau et al conducted a single-blind, placebo-controlled study to examine the effects of torcetrapib, a potent inhibitor of Cholesterol ester transfer protein (CETP), on plasma lipoproteins levels in 19 subjects with low levels of HDL-C (< 40 mg per deciliter), 9 of whom were also treated with 120 mg of atorvastin daily. All subjects received placebo for 4 weeks and then received 120 mg of torcetrapib daily for the following 4 weeks. Six of the subjects who did not receive atrovastatin also participated in a third phase, in which they received 120 mg of torcetrapib twice daily for 4 weeks.
Treatment with 120 mg of torcetrapib daily increased plasma concentrations of HDL-C by 61% (P < 0.001). Treatment with 120 mg twice daily increased the HDL-C 106% (P < 0.001). Trocetrapib also reduced the low density lipoprotein (LDL) cholesterol levels by 17 % in the group that also received atrovastatin. Finally torcetrapib significantly increased the particle size of HDL and LDL in each of the cohorts.
Comment by Ralph R. Hall MD, FACP
This appears to have been a phase I study of Torcetrapib and, despite the small numbers of patients, the dramatic increase in HDL warranted publication.
Focusing on CETP inhibitions is a relatively new approach to the management of atherosclerotic vessel disease. Since there has been so much publicity in the newspapers about these and other studies1 which reversed atherosclerosis in a few weeks, patients with coronary heart disease are aware of these new options. It will behoove us to understand the pathophysiology and status of these studies.
Recent studies have emphasized the role of HDL in protecting against atherosclerosis.2 As Brewer notes in his editorial in the same issue of the New England Journal of Medicine3 increasing the HDL level by 1mg may reduce the risk of cardiovascular disease by 2-3%. HDL acts in several ways. It protects low-density proteins (LDL) from oxidation and may decrease the production of endothelial cell adhesion molecules that facilitate the uptake of cells into the vessel wall. Its primary mode of action is the transport of cholesterol back to the liver for excretion into the bile.
One of the pathways for cholesterol transport is by the transfer of cholesterol ester in HDL by cholesterol ester transfer protein (CETP) to very low density lipoproteins (VLDL ) and LDL which are then returned to the liver for excretion into the bile. In a recent study the infusion into humans of apolipoprotein A-I and phosphospholipids which results in short term increases in HDL (and perhaps increases the effectiveness of HDL) decreased the volume of atheroma by 4.2 % in six weeks.1
There were 14 mild and 3 minor side effects with Torcetrapib. No patient dropped out of the study due to side effects. Despite these favorable results the study was small and of very short duration. The dramatic changes in lipid levels and constituency of the lipids give one concern about what other changes in metabolism might occur over a longer period of time.
It will take larger and longer studies to verify the safety and efficacy of these new treatments. However, this is an important an hopeful new approach
Dr. Hall, Emeritus Professor of Medicine University of Missouri-Kansas City School of Medicine, is Associate Editor of Internal Medicine Alert.
References
1. Nissen SE et al. JAMA. 2003;290:2292-2300.
2. Brewer HB. Arterscler Thromb Vasc Biol. 2004;24: 397-391.
3. Brewer HB. N Engl J Med. 2004;350:1491-4149.
Drugs that inhibit Cholesterol Ester Transfer Protein markedly increase levels of HDL cholesterol.
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