title: Relationship between atorvastatin dose and the harm caused by torcetrapib.
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 confined 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 significantly 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 confined 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.
authors.affiliation: The Heart Research Institute, Sydney, Australia. barterp@hri.org.au
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Barter
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
authors.forename: Mohan S
authors.initials: MS
authors.lastname: Beltangady
authors.forename: William C
authors.initials: WC
authors.lastname: Ports
authors.forename: William T
authors.initials: WT
authors.lastname: Duggan
authors.forename: S Matthijs
authors.initials: SM
authors.lastname: Boekholdt
authors.forename: David A
authors.initials: DA
authors.lastname: DeMicco
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Charles L
authors.initials: CL
authors.lastname: Shear
mesh_terms: D000368:Aged; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use; D000069059:Atorvastatin; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D011804:Quinolines; C483909:torcetrapib; D000069059:Atorvastatin