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Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind
Michiel L Bots1, Frank L Visseren2, Gregory W Evans3
1Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands.
Insights
Torcetrapib did not slow carotid atherosclerosis progression in patients with mixed dyslipidaemia, despite raising HDL cholesterol and lowering LDL cholesterol. The drug increased blood pressure and showed no clinical benefit, leading to its discontinuation.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Clinical Trials
Background:
- Mixed dyslipidaemia is characterized by high triglycerides, low HDL, and high LDL cholesterol.
- Inhibiting cholesteryl ester transfer protein (CETP) to increase HDL cholesterol may benefit these patients.
- Torcetrapib is a CETP inhibitor investigated for its effects on atherosclerosis.
Purpose of the Study:
- To evaluate the effect of the CETP inhibitor torcetrapib on carotid atherosclerosis progression in patients with mixed dyslipidaemia.
- To assess the impact of torcetrapib, in combination with atorvastatin, versus atorvastatin alone on intima-media thickness.
Main Methods:
- A randomized, double-blind trial involving 752 patients with mixed dyslipidaemia.
- Participants received atorvastatin with either torcetrapib (n=377) or placebo (n=375) for 24 months.
- Carotid ultrasound measured intima-media thickness changes at 6-month intervals.
Main Results:
- Torcetrapib significantly increased HDL cholesterol by 63.4% and decreased LDL cholesterol by 17.7%.
- No significant difference in the rate of carotid intima-media thickness progression was observed between groups (-0.005 mm/year, p=0.46).
- Torcetrapib significantly increased systolic blood pressure by 5.4 mm Hg compared to placebo (p<0.0001).
Conclusions:
- Torcetrapib effectively altered lipid profiles but did not reduce carotid atherosclerosis progression.
- The drug's adverse effect on blood pressure and lack of clinical benefit led to its discontinuation.
- Torcetrapib demonstrated no clinical utility in managing mixed dyslipidaemia and atherosclerosis.
Background:
Patients with mixed dyslipidaemia have raised triglycerides, low high-density lipoprotein (HDL) cholesterol, and high low-density lipoprotein (LDL) cholesterol. Augmentation of HDL cholesterol by inhibition of the cholesteryl ester transfer protein (CETP) could benefit these patients. We aimed to investigate the effect of the CETP inhibitor, torcetrapib, on carotid atherosclerosis progression in patients with mixed dyslipidaemia.
Methods:
We did a randomised double-blind trial at 64 centres in North America and Europe. 752 eligible participants completed an atorvastatin-only run-in period for dose titration, after which they all continued to receive atorvastatin at the titrated dose. 377 of these patients were randomly assigned to receive 60 mg of torcetrapib per day and 375 to placebo. We made carotid ultrasound images at baseline and at 6-month intervals for 24 months. The primary endpoint was the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Analysis was restricted to 683 patients who had at least one dose of treatment and had at least one follow-up carotid intima-media measurement; they were analysed as randomised. Mean follow-up for these patients was 22 (SD 4.8) months. This trial is registered with ClinicalTrials.gov, number NCT00134238.
Findings:
The change in maximum carotid intima-media thickness was 0.025 (SD 0.005) mm per year in patients given torcetrapib with atorvastatin and 0.030 (0.005) mm per year in those given atorvastatin alone (difference -0.005 mm per year, 95% CI -0.018 to 0.008, p=0.46). Patients in the combined-treatment group had a 63.4% relative increase in HDL cholesterol (p<0.0001) and an 17.7% relative decrease in LDL cholesterol (p<0.0001), compared with controls. Systolic blood pressure increased by 6.6 mm Hg in the combined-treatment group and 1.5 mm Hg in the atorvastatin-only group (difference 5.4 mm Hg, 95% CI 4.3-6.4, p<0.0001).
Interpretation:
Although torcetrapib substantially raised HDL cholesterol and lowered LDL cholesterol, it also increased systolic blood pressure, and did not affect the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further.
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