CETP inhibitor increases HDL-C significantly but does not reduce CV outcomes
In the ACCELERATE study, treatment with evacetrapib compared with placebo was associated with an increase in the HDL-C and a reduction in LDL-C, but not with a reduction of cardiovascular outcomes.
Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular DiseaseLiterature - Lincoff MA, Nicholls SJ, Riesmeyer JS, et al. - N Engl J Med 2017;376:1933-42
Background
There is an inverse association between HDL-C and cardiovascular (CV) outcomes, but raising HDL-C with cholesteryl ester transfer protein (CETP) inhibitors through modulating the transfer of esterified cholesterol from HDL particles to apoB-containing lipoproteins, has not translated into reduced CV risk so far [1-3]. Torcetrapib, one of the CETP inhibitors, in combination with atorvastatin was associated with higher rates of death and CV events compared with atorvastatin alone, although it increased HDL-C by approximately 70% [4]. Similarly, dalcetrapib did not result in a lower rate of CV events compared with placebo in patients with a recent acute coronary syndrome, although it increased HDL-C by 30% [5].
In this analysis of the ACCELERATE study, the impact on the risk of CV complications or death of adding evacetrapib, another CETP inhibitor, to standard-of-care was evaluated and compared with placebo, in 12,092 patients with high-risk vascular disease.
Main results
- After 3 months of therapy with evacetrapib, there was a mean percent increase from baseline in HDL-C of 133.2%, as compared with a mean percent increase of 1.6% in the placebo group (between-group difference 131.6%, 95% CI 130.0-133.1, P<0.001).
- The mean LDL-C decreased by 31.1% in the evacetrapib group and increased by 6.0% in the placebo group (between-group difference −37.1%, 95% CI −38.1 to −36.1, P<0.001).
- The primary efficacy endpoint of the composite CV death, myocardial infarction (MI), stroke, coronary revascularization or hospitalization for unstable angina occurred in 12.9% of patients in the evacetrapib group and in 12.8% of patients in the placebo group (HR 1.01, 95% CI 0.91-1.11, P=0.91).
- The secondary endpoint event of the composite CV death, MI or stroke occurred in 7.2% of patients in the evacetrapib group and in 7.5% of patients in the placebo group (HR 0.97, 95% CI 0.85-1.10, P=0.59).
- The unadjusted incidence of death from any cause was significantly lower with evacetrapib compared with placebo (P=0.04).
- Hypertension was reported as adverse event in a significantly higher percentage of patients in the evacetrapib group compared with the placebo group (11.4% vs. 10.1%; P=0.02).
- The median percent increase from baseline in high-sensitivity C-reactive protein (CRP) was greater in the evacetrapib group compared with the placebo group: 8.6% (IQR: −27.0 to 63.3) vs. 0% (IQR: −32.1 to 52.4); P<0.001.
- A lower percentage of patients in the evacetrapib group had a creatine kinase increase of 3 or more times the upper limit of the normal range compared with the placebo group (2.4% vs. 3.1%).
Conclusion
In the ACCELERATE study, treatment with evacetrapib compared with placebo was associated with an increase in the HDL-C and a reduction in LDL-C, but not with a reduction of CV outcomes.
References
1. Assmann G, Schulte H, von Eckardstein A, et al. High-density lipoprotein cholesterol as a predictor of coronary heart disease risk: the PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis 1996; 124: Suppl: S11-S20.
2. Castelli WP, Garrison RJ, Wilson PW, et al. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Study. JAMA 1986; 256: 2835-8.
3. Sharrett AR, Ballantyne CM, Coady SA, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001; 104: 1108-13.
4 Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357: 2109-22.
5. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012; 367: 2089-99.