Clinical Research
Cardiometabolic Risk
Genetic Inhibition of CETP, Ischemic Vascular Disease and Mortality, and Possible Adverse Effects

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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.

Key Words

cardiovascular diseases
genetics
lipids
lipoproteins

Abbreviations and Acronyms

CETP
cholesteryl ester transfer protein
CI
confidence interval
HDL
high-density lipoprotein
HR
hazard ratio
ICVD
ischemic cerebrovascular disease
IHD
ischemic heart disease
IS
ischemic stroke
LDL
low-density lipoprotein
MI
myocardial infarction
SNP
single nucleotide polymorphism

Cited by (0)

This work was supported by a Specific Targeted Research Project grant from the European Union, Sixth Framework Programme Priority (FP-2005-LIFESCIHEALTH-6) contract no. 037631; the Danish Medical Research Council; the Research Fund at Rigshospitalet, Copenhagen University Hospital; Chief Physician Johan Boserup and Lise Boserup's Fund; Ingeborg and Leo Dannin's Grant; Henry Hansen's and Wife's Grant; William Nielsen's Fund; and a grant from the Odd Fellow Order. Dr. Nordestgaard has received lecture and/or consultancy honoraria from AstraZeneca, Merck & Co., Inc., Pfizer Inc., Karo Bio, Omthera Pharmaceuticals, Inc., Abbott, Sanofi-Aventis, and Regeneron. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.