A 34-year genetic study finds CETP-lowering variants cut ischemic heart disease risk by 24 percent with no adverse effects seen with torcetrapib (J Am Coll Cardiol 2012)

Original title: Genetic inhibition of CETP, ischemic vascular disease and mortality, and possible adverse effects

J Am Coll Cardiol · 17 October 2012 · 10

Johannsen TH, Frikke-Schmidt R, Schou J, Nordestgaard BG, Tybjærg-Hansen A

This study tested whether genetic variation in the CETP gene supports a protective effect of CETP inhibition on ischemic events and mortality, without the adverse effects reported for torcetrapib. In the Copenhagen City Heart Study, a prospective cohort of 10,261 individuals followed for up to 34 years (1976 to 2010), two common CETP variants that reduce CETP activity were used to mimic pharmacological CETP inhibition. Carrying 4 versus 0 HDL-raising alleles was associated with up to 14% higher HDL cholesterol and lower triglycerides, LDL cholesterol, and non-HDL cholesterol. Corresponding hazard ratios were 0.76 for any ischemic vascular event, 0.74 for ischemic heart disease, 0.65 for myocardial infarction, 0.77 for ischemic cerebrovascular disease, 0.71 for ischemic stroke, and 0.88 for total mortality, with no association between CETP genotype and the side-effect markers previously reported for torcetrapib, establishing genetic CETP inhibition as protective against ischemic vascular disease and death without the off-target harms seen with torcetrapib.

Original abstract

Objectives: This study tested whether genetic variation in the CETP gene is consistent with a protective effect of cholesteryl ester transfer protein (CETP) inhibition on risk of ischemic events and on total mortality, without the adverse effects reported for torcetrapib.

Background: Torcetrapib, an inhibitor of CETP, increased risk of death and ischemic cardiovascular disease of those randomized to the drug, despite improving the lipid profile.

Methods: The Copenhagen City Heart Study is a prospective cohort study of 10,261 individuals, aged 20 to 93 years, who were followed for up to 34 years (1976 to 2010). Of these, 2,087 developed ischemic heart disease, 1,064 developed ischemic cerebrovascular disease, and 3,807 died during follow-up. We selected 2 common genetic variants in CETP previously associated with reductions in CETP activity, thus mimicking the effect of pharmacological CETP inhibition.

Results: In individuals carrying 4 versus 0 high-density lipoprotein cholesterol-increasing alleles, there was an increase in levels of high-density lipoprotein cholesterol of up to 14% (0.2 mmol/l), and concomitant decreases in triglycerides, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol of, respectively, 6% (0.1 mmol/l), 3% (0.1 mmol/l), and 4% (0.2 mmol/l) (p for trend 0.004 to <0.001). Corresponding hazard ratios were 0.76 (95% confidence interval [CI]: 0.68 to 0.85) for any ischemic vascular event, 0.74 (95% CI: 0.65 to 0.85) for ischemic heart disease, 0.65 (95% CI: 0.54 to 0.79) for myocardial infarction, 0.77 (95% CI: 0.65 to 0.93) for ischemic cerebrovascular disease, 0.71 (95% CI: 0.58 to 0.88) for ischemic stroke, and 0.88 (95% CI: 0.80 to 0.97) for total mortality. CETP genotypes did not associate with variation in markers of possible side effects previously reported for torcetrapib.

Conclusions: Genetic CETP inhibition associates with reductions in risk of ischemic heart disease, myocardial infarction, ischemic cerebrovascular disease, and ischemic stroke, with a corresponding antiatherogenic lipid profile, and with increased longevity, without adverse effects.

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