Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial.
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.


RESULTS
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).


CONCLUSIONS
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.
Bots
Michiel L
ML
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands. Electronic address: M.L.Bots@umcutrecht.nl.
Visseren
Frank L
FL
Department of Vascular Medicine, University Medical Centre Utrecht, Utrecht, Netherlands.
Evans
Gregory W
GW
Wake Forest University, Winston-Salem, NC, USA.
Riley
Ward A
WA
Wake Forest University, Winston-Salem, NC, USA.
Revkin
James H
JH
Pfizer, New London, CT, USA.
Tegeler
Charles H
CH
Wake Forest University, Winston-Salem, NC, USA.
Shear
Charles L
CL
Pfizer, New London, CT, USA.
Duggan
William T
WT
Pfizer, New London, CT, USA.
Vicari
Ralph M
RM
MIMA Century Research Associates, Melbourne, FL, USA.
Grobbee
Diederick E
DE
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands.
Kastelein
John J
JJ
Academic Medical Centre, Amsterdam, Netherlands.
D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000069059:Atorvastatin; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects; D002784:Cholesterol / Q000097:blood*; D004311:Double-Blind Method; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy*; D005260:Female; D006538:Heptanoic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D011804:Quinolines / Q000009:adverse effects / Q000627:therapeutic use*; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D011758:Pyrroles; D011804:Quinolines; C483909:torcetrapib; D002784:Cholesterol; D000069059:Atorvastatin