Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia
John J P Kastelein1, Sander I van Leuven, Leslie Burgess
1Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. j.j.kastelein@amc.uva.nl
Insights
Torcetrapib combined with atorvastatin did not reduce atherosclerosis progression in familial hypercholesterolemia patients, despite increasing HDL cholesterol. The combination therapy was associated with disease progression in the common carotid artery segment.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Medical Research
Background:
- Torcetrapib, a cholesteryl ester transfer protein inhibitor, was investigated for its potential to reduce atherosclerotic vascular disease by elevating high-density lipoprotein (HDL) cholesterol.
- Familial hypercholesterolemia is a genetic condition characterized by high cholesterol levels, increasing the risk of atherosclerosis.
Purpose of the Study:
- To evaluate the efficacy of torcetrapib in combination with atorvastatin compared to atorvastatin monotherapy in patients with heterozygous familial hypercholesterolemia.
- To assess the impact of torcetrapib on the progression of atherosclerosis, measured by changes in carotid intima-media thickness.
Main Methods:
- 850 patients with heterozygous familial hypercholesterolemia underwent B-mode ultrasonography at baseline and follow-up.
- Patients received atorvastatin monotherapy or a combination of atorvastatin and 60 mg torcetrapib for 2 years after an atorvastatin run-in period.
- Carotid intima-media thickness was measured to assess changes in atherosclerosis progression.
Main Results:
- The torcetrapib-atorvastatin group showed significantly higher HDL cholesterol (81.5 mg/dL vs. 52.4 mg/dL) and lower LDL cholesterol (115.1 mg/dL vs. 143.2 mg/dL) compared to the atorvastatin-only group.
- No significant difference in the primary efficacy measure (maximum carotid intima-media thickness increase) was observed between the groups (P=0.87).
- However, the torcetrapib-atorvastatin group showed an increase in mean carotid intima-media thickness in the common carotid artery segment, unlike the atorvastatin-only group (P=0.005).
Conclusions:
- Torcetrapib combined with atorvastatin did not reduce atherosclerosis progression as assessed by carotid arterial-wall thickness in familial hypercholesterolemia patients.
- The combination therapy was associated with disease progression in the common carotid artery segment, despite favorable changes in HDL and LDL cholesterol levels.
- The study highlights potential risks associated with CETP inhibitors like torcetrapib, even when achieving desired lipid profile changes.
Background:
Torcetrapib, an inhibitor of cholesteryl ester transfer protein, may reduce atherosclerotic vascular disease by increasing levels of high-density lipoprotein (HDL) cholesterol.
Methods:
A total of 850 patients with heterozygous familial hypercholesterolemia underwent B-mode ultrasonography at baseline and at follow-up to measure changes in carotid intima-media thickness. The patients completed an atorvastatin run-in period and were subsequently randomly assigned to receive either atorvastatin monotherapy or atorvastatin combined with 60 mg of torcetrapib for 2 years.
Results:
After 24 months, in the atorvastatin-only group, the mean (+/-SD) HDL cholesterol level was 52.4+/-13.5 mg per deciliter and the mean low-density lipoprotein (LDL) cholesterol level was 143.2+/-42.2 mg per deciliter, as compared with 81.5+/-22.6 mg per deciliter and 115.1+/-48.5 mg per deciliter, respectively, in the torcetrapib-atorvastatin group. During the study, average systolic blood pressure increased by 2.8 mm Hg in the torcetrapib-atorvastatin group, as compared with the atorvastatin-only group. The increase in maximum carotid intima-media thickness, the primary measure of efficacy, was 0.0053+/-0.0028 mm per year in the atorvastatin-only group and 0.0047+/-0.0028 mm per year in the torcetrapib-atorvastatin group (P=0.87). The secondary efficacy measure, annualized change in mean carotid intima-media thickness for the common carotid artery, indicated a decrease of 0.0014 mm per year in the atorvastatin-only group, as compared with an increase of 0.0038 mm per year in the torcetrapib-atorvastatin group (P=0.005).
Conclusions:
In patients with familial hypercholesterolemia, the use of torcetrapib with atorvastatin, as compared with atorvastatin alone, did not result in further reduction of progression of atherosclerosis, as assessed by a combined measure of carotid arterial-wall thickness, and was associated with progression of disease in the common carotid segment. These effects occurred despite a large increase in HDL cholesterol levels and a substantial decrease in levels of LDL cholesterol and triglycerides. (ClinicalTrials.gov number, NCT00136981 [ClinicalTrials.gov].).
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