Pooled RADIANCE trial data link the carotid-thickening harm of torcetrapib to a mineralocorticoid effect, not to its HDL-raising action (Circulation 2008)

Original title: Cholesteryl ester transfer protein inhibitor torcetrapib and off-target toxicity: a pooled analysis of the rating atherosclerotic disease change by imaging with a new CETP inhibitor (RADIANCE) trials

Circulation · 24 November 2008 · 8

Vergeer M, Bots ML, van Leuven SI, Basart DC, Sijbrands EJ, Evans GW, Grobbee DE, Visseren FL, Stalenhoef AF, Stroes ES, Kastelein JJ

To explore why torcetrapib raised cardiovascular events despite raising HDL cholesterol, researchers pooled data from the RADIANCE 1 and 2 trials, which measured carotid intima-media thickness (cIMT) in 904 subjects with familial hypercholesterolemia and 752 subjects with mixed dyslipidemia randomized to atorvastatin alone or torcetrapib plus atorvastatin. Mean common cIMT progression was greater with torcetrapib plus atorvastatin than atorvastatin alone (0.0076 plus or minus 0.0011 versus 0.0025 plus or minus 0.0011 mm per year, p = 0.0014). Torcetrapib-treated subjects showed higher blood pressure, sodium, and bicarbonate and lower potassium after randomization, with the potassium fall linked to the blood pressure rise, an effect worsened by renin-angiotensin-aldosterone system inhibitor use. Subjects with the greatest LDL cholesterol reduction had the least cIMT progression, and those with the greatest blood pressure rise had the most, while HDL cholesterol change showed no relationship to cIMT change, supporting mineralocorticoid-mediated off-target toxicity, not HDL-C elevation, as the likely driver of harm with torcetrapib.

Original abstract

Background: Torcetrapib, an inhibitor of cholesteryl ester transfer protein, has been shown to increase the cardiovascular event rate despite conferring a significant high-density lipoprotein cholesterol increase. Using data from the Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor [corrected] (RADIANCE) trials, which assessed the impact of torcetrapib on carotid intima-media thickness (cIMT), we sought to explore potential mechanisms underlying this adverse outcome.

Methods And Results: Data from the RADIANCE 1 and 2 studies, which examined cIMT in 904 subjects with familial hypercholesterolemia and in 752 subjects with mixed dyslipidemia, were pooled. Subjects were randomized to either atorvastatin or torcetrapib combined with atorvastatin. Mean common cIMT progression was increased in subjects receiving torcetrapib plus atorvastatin compared with subjects receiving atorvastatin alone (0.0076+/-0.0011 versus 0.0025+/-0.0011 mm/y; P=0.0014). Subjects treated with torcetrapib plus atorvastatin displayed higher postrandomization systolic blood pressure and plasma sodium and bicarbonate levels in conjunction with lower potassium levels. The decrease in potassium levels was associated with the blood pressure increase. Markedly, the use of renin-angiotensin-aldosterone system inhibitors tended to aggravate the blood pressure increase. Subjects receiving torcetrapib plus atorvastatin with the strongest low-density lipoprotein cholesterol reduction showed the smallest cIMT progression, whereas subjects with the highest systolic blood pressure increase showed the largest cIMT progression. High-density lipoprotein cholesterol increase was not associated with cIMT change.

Conclusions: These analyses support mineralocorticoid-mediated off-target toxicity in patients receiving torcetrapib as a contributing factor to an adverse outcome. The absence of an inverse relationship between high-density lipoprotein cholesterol change and cIMT progression suggests that torcetrapib-induced high-density lipoprotein cholesterol increase does not mediate atheroprotection. Future studies with cholesteryl ester transfer protein inhibitors without off-target toxicity are needed to settle this issue.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.