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Relationship between atorvastatin dose and the harm caused by torcetrapib

Philip J Barter1, Kerry-Anne Rye, Mohan S Beltangady

  • 1The Heart Research Institute, Sydney, Australia. barterp@hri.org.au

Journal of Lipid Research
|September 4, 2012
PubMed

Insights

The cholesteryl ester transfer protein (CETP) inhibitor torcetrapib caused harm, specifically increased mortality and cardiovascular events, but only in patients taking a low dose (10 mg) of atorvastatin. Higher atorvastatin doses appeared to mitigate these risks.

Area of Science:

  • Cardiovascular Pharmacology
  • Clinical Trial Analysis
  • Drug Safety Evaluation

Background:

  • Development of cholesteryl ester transfer protein (CETP) inhibitor torcetrapib was halted due to safety concerns.
  • The ILLUMINATE trial indicated increased all-cause mortality (ACM) and major cardiovascular events (MCVEs) with torcetrapib use.

Purpose of the Study:

  • To investigate the specific patient subgroup experiencing harm from torcetrapib.
  • To determine if the dose of atorvastatin influenced torcetrapib-associated risks.

Main Methods:

  • Subgroup analysis of the ILLUMINATE trial data.
  • Statistical analysis of ACM and MCVEs in relation to torcetrapib and atorvastatin dosage.
  • Multivariable regression to adjust for clinical risk factors.

Main Results:

  • Torcetrapib-associated harm (ACM and MCVEs) was confined to the 10 mg atorvastatin subgroup.
  • No increased risk was observed when torcetrapib was coadministered with higher doses of atorvastatin.
  • Adjusting for baseline risk factors did not alter the observed harm in the 10 mg atorvastatin subgroup.

Conclusions:

  • The adverse effects of torcetrapib were specifically linked to coadministration with low-dose atorvastatin (10 mg).
  • Higher doses of atorvastatin may offer a protective effect against torcetrapib-induced harm.
  • The mechanism of harm is independent of lipid changes, blood pressure, or electrolytes.

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