Another CETP Inhibitor Fails to Show Cardiovascular Benefit, Despite Reducing LDL Cholesterol and Raising HDL Cholesterol: Implications of the ACCELERATE Trial
By Kevin C Maki, PhD
Cholesteryl ester transfer protein (CETP) is an enzyme that modulates the transfer of cholesterol esters from high-density lipoprotein (HDL) particles to apolipoprotein (apo)-B containing particles, including very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles. CETP inhibitor drugs, by blocking this action, raise the level of HDL cholesterol (HDL-C) and lower the level of LDL cholesterol (LDL-C).
Previous outcomes trials with two CETP inhibitors, torcetrapib and dalcetrapib, failed to show cardiovascular disease (CVD) event risk reduction.1 Torcetrapib use was associated with increased CVD event risk, which was believed to be secondary to off-target effects, including raising blood pressure and aldosterone levels and lowering serum potassium concentration. Whereas torcetrapib raised HDL-C by 70% and lowered LDL-C by 25%, dalcetrapib was a weak CETP inhibitor and raised HDL-C by only 30%, while having no effect on LDL-C. A CVD outcomes trial with dalcetrapib was stopped for futility, showing no evidence of benefit or harm regarding CVD event risk.
The ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial evaluated the effects of evacetrapib 130 mg/d vs. placebo, when added to standard therapies in ~12,000 men and women with high CVD risk secondary to having clinical atherosclerotic CVD with a history of a recent acute coronary syndrome, cerebrovascular atherosclerosis, peripheral atherosclerosis, or diabetes mellitus with known coronary disease).2
After randomization, the effects of evacetrapib compared to placebo on mean or median changes from baseline to the 3-month timepoint in lipoprotein-related parameters were as follows (all p < 0.001):
- HDL-C: +134.8%;
- LDL-C: -37.1%;
- Triglycerides (TG): -6.0%;
- Apo B: -19.3%;
- Lipoprotein (a): -22.3%.
There were also small changes (all p < 0.01), relative to placebo, in systolic/diastolic blood pressure (+1.2/+0.5 mm Hg) and C-reactive protein (8.6%).
Despite substantial changes in potentially favorable directions in lipoprotein-related variables, no difference was present for the primary efficacy outcome of the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina: hazard ratio (HR) 1.01, 95% confidence interval (CI) 0.91 to 1.11, p = 0.91. After an interim analysis with 82% of the final projected number of events, the trial was stopped early for futility. No significant benefits were present for any of the individual components of the primary outcome, nor for a secondary composite that excluded hospitalization for unstable angina.
Comment. The third failure of a CETP inhibitor to show CVD event risk reduction may sound the death knell for this class of lipid-altering agents. The reasons for the lack of benefit in ACCELERATE are unclear. Although HDL-C concentration is a strong inverse predictor for CVD event risk, the mechanisms responsible for this consistent finding are uncertain. There are numerous ways that the HDL-C level can be raised, some of which could be beneficial, while others may be only cosmetic.
More disturbing than the lack of benefit associated with a rise in HDL-C, is the fact that LDL-C, TG, apo B and lipoprotein (a) were all lowered, yet this did not reduce CVD event risk. Reduced CVD event risk has been observed with other agents that lower apo B-containing lipoproteins such statins, ezetimibe and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, so why did changes in these values with evacetrapib fail to lower risk?
Niacin lowers apo B-containing lipoproteins and lipoprotein (a), while also raising HDL-C, and it failed to demonstrate CVD event risk reduction in both the HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) study (co-administered with laropiprant) and in the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial .3 However, there were issues in both trials regarding whether the subjects enrolled were appropriate candidates for niacin therapy.3 For example, more than two-thirds of the subjects in HPS2-THRIVE had baseline non-HDL-C of less than 100 mg/dL. Such individuals would not be likely to have been prescribed niacin in clinical practice.
Interventions that lower LDL-C and apo B-containing lipoproteins through mechanisms that involve inducing an upregulation in hepatic LDL receptor activity, including statins, ezetimibe and PCSK9 inhibitors have all been shown to reduce CVD event risk. Lowering LDL-C and apo B-containing lipoproteins with evacetrapib had no effect on risk. Should we infer from these results that lowering LDL-C and apo B-containing lipoproteins through mechanisms that do not upregulate hepatic LDL receptor activity will not reduce CVD risk? Alternatively, is it the case that evacetrapib had some off-target effect(s) that offset the benefits of LDL-C and apo B-containing lipoprotein reduction, as has been hypothesized for torcetrapib? Evacetrapib did produce modest increases in blood pressure and C-reactive protein. These changes were small enough that they are unlikely to have been sufficient to directly offset the expected CVD benefits from reductions in LDL-C and apo B-containing lipoproteins. However, they could be indicators of other adverse neuroendocrine and/or inflammatory effects. At present, it is not possible to determine whether the explanation for the lack of benefit with evacetrapib was attributable to one of these, or perhaps some other explanation.
- Barter PJ, Rye KA. Targeting high-density lipoproteins to reduce cardiovascular risk: what is the evidence? Clin Ther. 2015;37:2716-2731.
- Lincoff AM, Nicholls SJ, Riesmeyer JS, et al.; ACCELERATE Investigators. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med. 2017;376:1933-1942.
- Mani P, Rohatgi A. Niacin therapy, HDL cholesterol, and cardiovascular disease: is the HDL hypothesis defunct? Curr Atheroscler Rep. 2015;17:521.