Elsevier

The Lancet

Volume 370, Issue 9582, 14–20 July 2007, Pages 153-160
The Lancet

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

https://doi.org/10.1016/S0140-6736(07)61088-5Get rights and content

Summary

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.

Introduction

Mixed dyslipidaemia is often seen as part of a cluster of vascular risk factors, closely related to insulin resistance and abdominal obesity, known as metabolic syndrome.1 Patients with metabolic syndrome are at increased risk of future cardiovascular events.2, 3, 4 The pandemic of obesity has caused a noticeable increase in the rate of the metabolic syndrome and type 2 diabetes.2 These disorders are typically associated with an atherogenic dyslipidaemia characterised by hypertriglyceridaemia, reduced high density lipoprotein (HDL) cholesterol, a preponderance of small, dense low-density lipoprotein (LDL) cholesterol particles and high concentrations of cholesterol-rich remnant particles.2, 5, 6 Atherogenic dyslipidaemia is linked with an increased risk of atherosclerotic vascular disease.3, 4 Lifestyle modification and lowering of blood pressure and LDL cholesterol can reduce risk.7 Treatments to increase low HDL cholesterol could further reduce risk.8

Several lines of evidence suggest that HDL cholesterol has a role in cardiovascular risk. A low HDL cholesterol concentration is an established vascular risk factor.3, 4, 9 Drugs such as nicotinic acid and fibrates increase HDL cholesterol by 10–25%8 and augmentation of HDL cholesterol could contribute to reduction of vascular risk10, 11, 12 and attenuate progression of atherosclerosis.12, 13, 14

The cholesteryl ester transfer protein (CETP) regulates plasma HDL cholesterol concentration. CETP can transfer cholesterol esters from HDL particles to lipoproteins that contain apolipoprotein B (apoB), such as very low density lipoprotein and LDL, in exchange for triglycerides.8, 15 People who have a genetically low expression of CETP have high concentrations of HDL cholesterol.16 Conversely, patients with mixed dyslipidaemia have high CETP concentrations and activity, and low HDL cholesterol.17, 18 The net transfer of cholesterol esters from HDL cholesterol to lipoproteins containing apo B is much higher in patients with mixed dyslipidaemia than in normolipidaemic individuals.19 Since an increased transfer of cholesteryl esters out of HDL particles will cause low HDL cholesterol, inhibition of CETP could potentially raise HDL cholesterol concentrations and thereby protect against atherosclerosis.7, 20, 21 Indeed, studies with CETP inhibitors have shown that they raised HDL cholesterol by 60% or more.22, 23 In studies of cholesterol-fed rabbits, CETP inhibition was profoundly antiatherogenic,24 but this effect has not been shown in people.

We aimed to assess the effect of torcetrapib, a CETP inhibitor, on the progression of atherosclerosis in patients with mixed dyslipidaemia, by measuring the thickening of carotid intima-media, a marker of atherosclerosis. This study should, however, be viewed in the context of a randomised controlled trial25 of the clinical effect of combined treatment with torcetrapib and atorvastatin on morbidity and mortality. That study was prematurely terminated because of an excess of all-cause mortality in patients given torcetrapib.26

Section snippets

Participants

64 recruitment and imaging centres in North America and Europe participated in a randomised, multicentre, parallel group trial, from Dec 1, 2003, to Dec 27, 2006.27 Institutional review boards of all participating centres approved the protocol. 2918 patients aged 18–70 years were screened (figure 1). Eligibility criteria were triglycerides of greater than 1·7 mmol/L and a concurrent LDL cholesterol concentration that was high enough to qualify for statin treatment according to the guidelines of

Results

Figure 1 shows the trial profile and table 1 shows demographic characteristics and medication at baseline. All torcetrapib–atorvastatin clinical trials were stopped on Dec 2, 2006, when an independent data safety and monitoring board for another study of torcetrapib and atorvastatin recommended that it be terminated because of an increase in deaths in the treatment group.26 48 participants who were still receiving treatment on that date were asked to discontinue treatment immediately and to

Discussion

Our results showed that the torcetrapib-induced inhibition of CETP was associated with raised HDL cholesterol and lowered LDL cholesterol, changes that would have been expected to be antiatherogenic. However, no significant attenuation of atherosclerosis progression could be identified by measurement of the thickness of carotid intima-media. What is the reason for this discrepancy? Randomised trials of the effects of lipid lowering regimens on thickness of carotid intima media have consistently

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