HDL-raising therapies have discordant effects on atherosclerosis

March 26, 2007

Apparently, not all therapies that increase levels of high-density lipoprotein (HDL) cholesterol are created equal. Imaging studies released at the American College of Cardiology's 56th annual scientific session show no effect of the cholesterol ester transfer protein (CETP) torcetrapib on atherosclerosis, despite unprecedented increases in HDL cholesterol, and a potentially useful effect of infused reconstituted HDL.

Apparently, not all therapies that increase levels of high-density lipoprotein (HDL) cholesterol are created equal. Imaging studies released at the American College of Cardiology's 56th annual scientific session show no effect of the cholesterol ester transfer protein (CETP) torcetrapib on atherosclerosis, despite unprecedented increases in HDL cholesterol, and a potentially useful effect of infused reconstituted HDL.

Development of torcetrapib was halted late last year when this compound was associated with an increased risk of death in a large clinical trial that was terminated early for this reason. The data presented here by Steven E. Nissen, MD, and John P. Kastelein, MD, PhD, were findings from intravascular ultrasound (IVUS) of coronary arteries and B-mode ultrasound of carotid arteries.

In 1,188 patients with symptomatic coronary artery disease (CAD) and at least one stenosis with at least 20% narrowing on angiography, Dr. Nissen compared the effects of atorvastatin alone with the combination of torcetrapib and atorvastatin on atheroma volume. The group randomized to torcetrapib and atorvastatin had an increase in HDL cholesterol of 59%, compared with the group assigned to atorvastatin monotherapy. Surprisingly, the level of low-density lipoprotein (LDL) cholesterol fell by 20% in the torcetrapib recipients, according to the investigators.

Despite these favorable changes in lipids, torcetrapib did not slow the progression of coronary atherosclerosis. Furthermore, although the study was not powered to detect differences in adverse clinical events, there were more such events in the torcetrapib group, a difference that did not reach statistical significance.

Dr. Kastelein studied the same molecule in two groups of patients-one with heterozygous familial hypercholesterolemia and another with mixed dyslipidemia. As in previous studies, the patients were randomized to torcetrapib plus atorvastatin or atorvastatin alone. Instead of IVUS, he used ultrasound of the carotid artery to measure carotid intima media thickness (CIMT).

Again, despite a large reduction in HDL cholesterol and a significant reduction in LDL cholesterol compared with atorvastatin alone, the torcetrapib group did not slow progression of atherosclerosis. Maximum CIMT was not different between the two groups, and the mean common CIMT was actually significantly worse with torcetrapib, said Dr. Kastelein, chairman, department of vascular medicine, University of Amsterdam, The Netherlands.

According to Dr. Nissen, the 4.6-mm Hg increase in systolic blood pressure seen in his study "may have counterbalanced any effects on lipids." Other potential explanations are that CETP inhibition may not generate HDL particles that function normally to facilitate reverse cholesterol transport or a generalized toxicity of torcetrapib on the vessel wall.

The findings "don't rule out this class of medicines but we need a clean CETP inhibitor that does not raise blood pressure, and then do small imaging trials prior to doing large morbidity and mortality trials," Dr. Nissen said.

Another strategy for increasing HDL is the use of intravenous reconstituted HDL (CSL-111) made from Apo A-1 isolated from human plasma. When mixed with phosphatidylcholine derived from soybeans and reconstituted, it chemically and biologically resembles native HDL.

Results of the Effect of Reconstituted High-Density Lipoprotein on Atherosclerosis-Safety and Efficacy trial (ERASE) were presented by Jean-Claude Tardif, MD, Montreal Heart Institute, Quebec, Canada. "Short-term infusions of CSL-111 resulted in no significant reduction in change in atheroma volume compared with placebo, but did result in statistically significant improvement in the plaque characterization index and atherosclerosis score on quantitative coronary angiography," he said.

ERASE included 183 acute coronary syndrome (ACS) patients who were randomized within 2 weeks after an ACS to receive weekly infusions of either 40 or 80 mg/kg CSL-111 or infusions of placebo for 4 weeks. The higher CSL-111 dose was discontinued after the first 12 patients randomized experienced elevated liver enzymes.

IVUS examinations of the designated target coronary artery were conducted at baseline and between 2 to 3 weeks after the last infusion. Dr. Tardif reported that IVUS detected no significant difference between the CSL-111 and placebo patients in terms of the primary endpoint-coronary atheroma volume. Atheroma volume decreased by 3.4% in the CSL-111 group and 1.6% in the placebo group. However, Dr. Tardif said that when compared to baseline, CSL-111 did produce a statistically significant decrease (p

CSL-111 did produce statistically significant improvements in the secondary endpoints of plaque characteristics and coronary score on quantitative coronary angiography. "Coronary angiography results signal rapid favorable effects of the drug," Dr. Tardif said. The differing characteristics of plaque indexes between the treatment groups suggest that CSL-111 does have effects on plaque and vascular biology that are different from placebo.

Dr. Kastelein speculated that the mature HDL particle that tocetrapib produced may act differently from the "baby form of HDL" produced by infusions of reconstituted HDL that has not yet acquired a large load of cholesterol ester. The results observed with only four weekly infusions of the reconstituted HDL "are significant enough to move to the next stage of clinical trials with this agent," he said.