Torcetrapib Does Not Reduce Atherosclerosis Beyond Atorvastatin and Induces More Proinflammatory Lesions Than Atorvastatin

Haan, Willeke de; Weij, Jitske de Vries-van der; Hoorn, José W.A. van der; Gautier, Thomas; Hoogt, Caroline C. van der; Westerterp, Marit; Romijn, Johannes A.; Jukema, J. Wouter; Havekes, Louis M.; Princen, H.M.G.; Rensen, Patrick C.N.

doi:10.1161/circulationaha.107.761965

Cited by 90 publications

(74 citation statements)

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“…Nevertheless, the apparent trend of decreasing risk with increasing atorvastatin dose for both endpoints, combined with a lack of imbalance in other predictors that would explain the result, is consistent with the proposition that higher doses of atorvastatin may have protected against the adverse effects of torcetrapib via properties of the drug unrelated to the lowering of LDL-C ( 5 ). These results do not support the proposition, suggested by others ( 6 ), that addition of higher doses of atorvastatin may have interacted adversely with torcetrapib, because in this case, the opposite relationship with atorvastatin dose would have been observed. Nor does the analysis support the proposition that the adverse effects of torcetrapib were the consequence of the observed changes in blood pressure, concentrations of plasma lipoproteins, electrolytes, or CRP.…”

Section: Discussioncontrasting

confidence: 93%

Relationship between atorvastatin dose and the harm caused by torcetrapib

Barter

Rye

Beltangady

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org heart disease or risk equivalents ( 1 ). Quite unexpectedly, the trial was terminated prematurely for safety reasons. The primary results have been described previously ( 1 ). Briefl y, torcetrapib 60 mg/day on a background of atorvastatin 10, 20, 40, or 80 mg/day, raised HDL-cholesterol (HDL-C) and lowered LDL-cholesterol (LDL-C), but also resulted in a signifi cantly increased risk of both all-cause mortality (ACM) [hazard ratio (HR) = 1.58, 95% CI (1.14, 2.19), P = 0.006] and major cardiovascular events (MCVEs) [HR = 1.25, 95% CI (1.09, 1.44), P = 0.001].Observed adverse effects of torcetrapib included an increase in both systolic blood pressure (SBP) and diastolic blood pressure (DBP), an increase in the levels of sodium, bicarbonate, and aldosterone, and a decrease in the level of potassium ( 1 ). Subsequent preclinical studies have shown that torcetrapib increases the synthesis and secretion of aldosterone and cortisol from cultured adrenal cortical cells ( 2, 3 ), has an adverse effect on endothelial function, and increases expression of endothelin-1 in the artery wall ( 4 ). These adverse effects of torcetrapib have been shown to be unrelated to inhibition of CETP activity ( 2, 3 ).We now report a post hoc exploratory analysis of the ILLUMINATE trial in an attempt to determine potential predictors of ACM and the occurrence of MCVEs. METHODSILLUMINATE was a prospective, randomized, multi-center, double-blind clinical trial as previously described ( 1 ). Briefl y, Abstract Development of the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib, was halted after the ILLUMINATE trial revealed an increase in both all-cause mortality (ACM) and major cardiovascular events (MCVEs) associated with its use. We now report that the harm caused by torcetrapib was confi ned to those in the 10 mg atorvastatin subgroup for both ACM [hazard ratio (HR) = 2.68, 95% CI (1.58, 4.54), P < 0.0001] and MCVEs [HR = 1.41, 95% CI (1.14, 1.74), P = 0.002], with no evidence of harm when torcetrapib was coadministered with higher doses of atorvastatin. In the atorvastatin 10 mg subgroup, age, prior heart failure and stroke were signifi cantly associated with ACM, independent of torcetrapib treatment, whereas low apoA-I, smoking, hypertension, heart failure, myocardial infarction, and stroke were independently associated with MCVEs. After adjusting for these factors, the HR associated with torcetrapib treatment in the 10 mg atorvastatin subgroup remained elevated for both ACM [HR = 2.67, 95% CI (1.57, 4.54), P < 0.001] and MCVE [HR = 1.36, 95% CI (1.10, 1.69), P = 0.005]. Thus, the harm caused by torcetrapib was confi ned to individuals taking atorvastatin 10 mg. The harm could not be explained by torcetrapib-induced changes in lipid levels, blood pressure, or electrolytes. It is conceivable that higher doses of atorvastatin protected against the harm caused by torcetrapib . The Investigation of Lipid Level management to Understand its iMpact IN ATherosclerotic Events ...

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Section: Discussioncontrasting

confidence: 93%

Relationship between atorvastatin dose and the harm caused by torcetrapib

Barter

Rye

Beltangady

et al. 2012

Journal of Lipid Research

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“…However, APOE*3Leiden mice (like WT mice) do not possess a CETP gene, and therefore these mice do not respond to HDL-modulating interventions. By crossbreeding the APOE*3Leiden mice to mice expressing the human CETP gene ( 75 ), APOE*3Leiden.CETP mice were obtained that respond to both lipid-lowering as well as HDL-raising interventions (50)(51)(52)(53)76 ). In the current study, we found signifi cant lowering effects of anti-PCSK9 antibodies on TC and TG levels in APOE*3Leiden.CETP mice, but HDL-C was not affected (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…The APOE*3Leiden.CETP mice are a well-established mouse model for familial dysbetalipoproteinemia with human-like lipoprotein metabolism and atherosclerosis development, which respond in a human-like manner to both lipid lowering as well as HDLraising drugs (like statins, fi brates, niacin, etc.) used in the treatment of CVD (49)(50)(51)(52).…”

Section: In Vivomentioning

confidence: 99%

PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE

Ason

Hoorn²,

Chan

et al. 2014

Journal of Lipid Research

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“…However, although the HDL elevating effect of statins is marginal on the average, statins may be benefi cial for improvement of HDL in a subset of women with high score LDL + HDL. Such an effect could be important, considering that a higher HDL level after 3 months of statin treatment has been shown be associated with protection from major cardiovascular events ( 50 ) and since novel therapies developed to increase HDL did not lead to an overall benefi t on endpoints (51)(52)(53)(54).…”

Section: Power Calculationsmentioning

confidence: 99%