Key result
Genetic CETP inhibition linked to ~24% lower risk of ischemic vascular events.
Why the study?
This study tested whether genetic variation in CETP is consistent with a protective effect of CETP inhibition on ischemic events and mortality without the adverse effects seen with torcetrapib.
Does genetic inhibition of CETP reduce the risk of ischemic vascular disease and mortality in adults?
Cohort (n=10,261)
Does genetic inhibition of CETP reduce the risk of ischemic vascular disease and mortality in adults?
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“HDL levels are inversely associated with CVD and many preclinical studies have demonstrated vasculoprotective effects of HDL, suggesting that raising HDL should lead to protection from CVD. However, recent trials with CETP inhibitors that markedly raise HDL, and niacin that modestly raises HDL, have paradoxically shown adverse effects or no benefit toward vascular endpoints. These results, in addition to some mendelian randomization studies, have raised doubts regarding the direct role of HDL in atheroprotection. This genetic association study, however, indicates that there still may be benefits to raising HDL via CETP inhibition. Results from ongoing clinical trials with other CETP inhibitors devoid of off-target blood pressure effects should be illuminating.”
“individuals with genetic variants for CETP, resulting in lifelong exposure to raised high-density lipoprotein (HDL)-cholesterol and decreases in triglycerides, LDL-cholesterol, and non-HDL cholesterol, had a reduced risk of CVD”
Genetic CETP inhibition is associated with a reduced risk of ischemic cardiovascular events and increased longevity without the adverse effects seen with torcetrapib, supporting the potential of CETP inhibitors as a therapeutic class.
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.
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Johannsen et al. (2012) conducted a cohort in Ischemic vascular disease and mortality (n=10,261). Genetic variation in the CETP gene (4 vs 0 HDL-increasing alleles) vs. 0 HDL-increasing alleles was evaluated on Any ischemic vascular event (HR 0.76, 95% CI 0.68-0.85). Genetic CETP inhibition (4 vs 0 HDL-increasing alleles) was associated with a reduced risk of any ischemic vascular event (HR 0.76; 95% CI 0.68-0.85) and total mortality without adverse effects.
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