HDL and CETP Inhibition
The association between elevated concentrations of HDL and reduced cardiovascular outcomes has long been recognized. It has been uncertain whether there is a causal relationship between HDL and outcomes, or whether this is purely an association. Further, whether lifestyle or pharmacologic interventions to elevate HDL concentration are cardioprotective is unknown. Therapies for LDL demonstrate a linear relationship between LDL reduction and lower rates of cardiovascular events even for patients with low baseline levels. The evidence to suggest pharmacological increases in HDL levels reduce cardiovascular events however is minimal. Niacin has been prescribed for this purpose but the most recent trial has called this practice into question.(1)
Current understanding of HDL suggests this class of lipoproteins has many functions in human biology, some of which are not well understood. Its role in reverse cholesterol transport has been well-studied is generally held as the primary reason for its atheroprotective effects. The process of reverse cholesterol tranport involves transfer of free cholesterol and phospholipids from atherosclerotic plaque foam cells to apoA-1 particles (nascent HDL) and mature HDL particles. During this process, free cholesterol is esterified to cholesterol esters (CEs) and transported to the liver for elimination. Cholesterol ester transfer protein (CETP) is a plasma glycoprotein in humans which transfers CEs from HDL to triglyceride-rich particles (e.g. LDL and VLDL) (Figure 1).(2)
Initial attempts at raising HDL pharmacoligically have had mixed results. The AIM-HIGH study had very modest elevations of HDL (25% increase in treatment arm vs. 12% in placebo arm) and a relatively small sample size of 3414 for assessing clinical outcomes- especially considering the high utilization of guideline-based background therapy and a baseline LDL of 76mg/dl. The trial was stopped 18 months early for futility and also a small numerical increase in the rate of stroke (1.6% vs. 0.9%), (Figure 2). The primary endpoint event rate in AIM-HIGH was 16.4% vs. 16.2% (p=NS) for the niacin and placebo arms respectively. AIM-HIGH failed to address either whether niacin can reduce cardiovascular events or to provide insight into the benefits of therapeutically targeting HDL.(1) A much larger study, the HPS2-THRIVE (NCT00461630) trial, has enrolled 25,000 patients to provide adequate power to test whether niacin is cardioprotective.(3)
AIM-HIGH Trial Summary(1)
Inhibition of CETP was first recognized as a therapeutic target when individuals with homozygous deficiency (i.e. no CETP activity) were found to have mean HDL levels of approximately 160mg/dL and mean LDL levels of approximately 80mg/dl. Individuals with heterozygous deficiency had moderately elevated HDL without any difference in LDL.(4) A subsequent meta-analysis of common single nucleotide polymorphisms (SNPs) in the CETP gene demonstrated that these variants which result in moderate reductions in CETP activity are associated with reduced cardiovascular risk.(5)
The CETP inhibitor torcetrapib was the first to reach advanced-stage clinical trials. Early data from rabbit models appeared promising(6) and the lipid-modification effects were significant in humans(Table 1).(7) The phase III study, ILLUMINATE, compared torcetrapib vs. placebo on a background of atorvastatin therapy. The torcetrapib arm had a relative 72.1% HDL increase and 24.9% LDL decrease. To the great surprise of many in the cardiology community, the trial was stopped early due to an increase in major cardiovascular events (Figure 3).(8)
ILLUMINATE Trial Summary(8)
In ILLUMINATE, the torcetrapib arm had a mean 5.4mmHg systolic blood pressure elevation compared to the placebo arm. Although this blood pressure effect had been seen previously, the signal was not as strong and was thought to be of little clinical significance. Rigorous review of the data revealed that this BP effect was most likely due to "off-target" effects of torcetrapib on the adrenal gland, including an elevation in aldosterone levels and corticosterone- not due to CETP inhibition.(9) While it is unknown whether this effect entirely explains the increase in cardiovascular events, it did lead to further scrutiny and testing of other CETP inhibitors.
The results of three concurrent imaging studies evaluating torcetrapib, one using IVUS (ILLUSTRATE)(10) and two carotid ultrasound (RADIANCE I and II)(11,12) were also reported in 2007. All three trials failed to meet their primary endpoints, but a post-hoc analysis of the IVUS trial, ILLUSTRATE, suggested that those patients achieving the highest HDL levels (Figure 4) had plaque regression, supporting the concept of reverse cholesterol transport with CETP inhibitors.(13) This report along with more recent evidence suggests that the HDL produced by CETP is functional(14), providing reassurance that if CETP inhibition could be accomplished without off-target effects – "clean" CETP inhibiition - this may still be a valid therapeutic target.
ILLUSTRATE Trial Summary (10)
RADIANCE1 Trial Summary (11)
RADIANCE2 Trial Summary (12)
The CETP inhibitor dalcetrapib, was the next CETP inhibitor to proceed to clinical studies. The phase III program, dal-OUTCOMES (NCT00658515) was launched in 2008 and is expected to end in 2013.(15) Dal-OUTCOMES will randomize 15,600 patients with a recent acute coronary syndrome to dalcetrapib or placebo. Two additional studies, part of the large umbrella dal-HEART Program, dal-VESSEL and dal-PLAQUE were presented at the European Society of Cardiology Meeting in 2011. Secondary to the concerns raised by ILLUMINATE, dal-VESSEL was designed to evaluate the blood pressure and endothelial effects of dalcetrapib. The primary end point of the study was the change from baseline in brachial FMD after 12 weeks, and the primary safety end point was 24-hour ambulatory blood-pressure monitoring assessed at four weeks. No changes were observed between the groups for either endpoint.(16) dal-PLAQUE was designed to evaluate the effects of dalcetrapib on carotid plaque inflammation and structure. The co-primary endpoints were magnetic resonance imaging (MRI) at two years and positron-emission tomography/computed tomography (PET/CT) at six months. No deleterious effects on carotid plaque structure or increase in inflammation were found.(17)
dal-VESSEL Trial Summary (18)
dal-PLAQUE Trial Summary (17)
Anacetrapib was the third agent in the class to undergo testing, including a large phase II study designed to exclude a torcetrapib-like effect. In 2010, the results of this phase II study, DEFINE were published. Anacetrapib is distinguished from dalcetrapib by a more similar structure to torcetrapib as well as very potent CETP inhibition effects. In DEFINE, an additional LDL reduction of 39.8% and an HDL increase of 138.1% were observed compared to statin monotherapy. Importantly, DEFINE demonstrated none of the safety concerns found with torcetrapib and through a Bayesian analysis provided 94% confidence that anacetrapib did not have a similar hazard to torectrapib- in fact anacetrapib treated patients tended to have fewer cardiovascular events.(19) The phase III study, REVEAL HPS3-TIMI 55 (NCT01252953), began enrollment in 2011 and is expected to end in 2017. REVEAL will randomize 30,000 patients with stable atherosclerotic disease to placebo or anacetrapib (Figure 5).
At the 2011 AHA Scientific Sessions, initial phase II results of a fourth CETP inhibitor, evacetrapib, were presented and subsequently published. Similar to both dalcetrapib and anacetrapib, evacetrapib did not result in either blood pressure elevation or signs of effects on the adrenal gland, providing further reassurance that the results of ILLUMINATE do not reflect a CETP "class effect". The lipid-modifying effects evacetrapib were evaluated both as monotherapy and on background statin therapy (Table 1).(20) The phase III program for evacetrapib has yet to be announced.(20)
Evacetrapib Dose Ranging Study(20)
Lipid-modification beyond statins with CETP inhibition has the potential to significantly lower the risk of future adverse events in patients with coronary artery disease. Early studies with torcetrapib, did not demostrate improved outcomes, but the drug had major off-target toxicities. "Clean" CETP inhibiton with drugs such as dalcetrapib, anacetrapib, and evacetrapib, has generated tremendous excitement in the cardiovascular community not only because of its unique target, but also because of the dramatic LDL and HDL effects that occur with very potent CETP inhibition. Whether this class of medications proves to be the next "homerun" or not, their study should add greatly to our understanding of the biology of atherosclerosis and lipoprotein metabolism.
- AIM-HIGH Investigators, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365:2255-2267.
- Tall, A. R. Functions of cholesterol ester transfer protein and relationship to coronary artery disease risk. Journal of clinical lipidology 2010; 4:389-393.
- Armitage, J., et al. Treatment of HDL to Reduce the Incidence of Vascular Events HPS2-THRIVE. 2010 [cited February 1 2012]. Available from http://clinicaltrials.gov/ct2/show/NCT00461630.
- Inazu, A., et al. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med 1990; 323: 1234-1238.
- Thompson, A., et al. Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. JAMA 2008; 299:2777-2788.
- Okamoto, H., et al. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature 2000; 406:203-207.
- McKenney, J. M., M. H. Davidson, C. L. Shear, and J. H. Revkin. Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels on a background of atorvastatin. J Amer Coll Cardiol 2006; 48:1782-1790.
- Barter, P. J., et al. 2007. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357:2109-2122.
- Forrest, M. J., et al. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol 2008; 154:1465-1473.
- Nissen, S. E., et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007; 356:1304-1316.
- Kastelein, J. J., et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 2007; 356:1620-1630.
- Bots, M. L., et al. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet 2007; 370:153-160.
- Nicholls, S. J., et al. Cholesteryl ester transfer protein inhibition, high-density lipoprotein raising, and progression of coronary atherosclerosis: insights from ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation). Circulation 2008; 118::2506-2514.
- Castro-Perez, J., et al. Anacetrapib promotes reverse cholesterol transport and bulk cholesterol excretion in Syrian golden hamsters. Journal of Lipid Research 2011; 52:1965-1973.
- Schwartz, G. G., et al. 2009. Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J 2009; 158:896-901.e3.
- Luscher, T. F. Effects of dalcetrapib on vascular function: results of phase IIb dal-VESSEL study . 2011 [cited Feb 1 2012]. Available from http://www.escardio.org/about/press/press-releases/esc11-paris/Pages/HL1-dal-VESSEL.aspx.
- Fayad, Z. A., et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet 2011; 378:1547-1559.
- Kastelein, J. J., et al. Rationale and design of dal-VESSEL: a study to assess the safety and efficacy of dalcetrapib on endothelial function using brachial artery flow-mediated vasodilatation. Current Med Res Opinion 2011; 27:141-150.
- Cannon, C. P., et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010; 363:2406-2415.
- Nicholls, S. J., et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA 2011; 306:2099-2109.
- Learning lessons from Pfizer's $800 million failure. Nature Reviews. Drug Discovery 2011; 10:163-164.
- Cao, G., et al. Evacetrapib is a novel, potent, and selective inhibitor of cholesteryl ester transfer protein that elevates HDL cholesterol without inducing aldosterone or increasing blood pressure. Journal of Lipid Research 2011; 52:2169-2176.
- Gordon, T., et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977; 62:707-714.
- Lee, J. M., et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study. J Amer Coll Cardiol 2009. 54:1787-1794.
- Tall, A. R. The effects of cholesterol ester transfer protein inhibition on cholesterol efflux. Am J Cardiol 2009; 104 Suppl:39E-45E.
- Yvan-Charvet, L., et al. Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib. Arteriosclerosis, Thrombosis, and Vascular Biology 2010; 30:1430-1438.
- Yvan-Charvet, L., et al. Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL. Arteriosclerosis, Thrombosis, and Vascular Biology 2007; 27:1132-1138.
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