CETP Inhibitors and the HDL-C Hypothesis

Question

What happened to this once-promising class of drugs?

Response from Nancy H. Goodbar, PharmD
Assistant Dean, Professional and Student Affairs; Associate Professor of Pharmacy Practice, Presbyterian College School of Pharmacy, Clinton, South Carolina
Anderson J. Isaac, PharmD Candidate
Presbyterian College School of Pharmacy, Clinton, South Carolina
Katelyn E. Thomasson, PharmD Candidate
Presbyterian College School of Pharmacy, Clinton, South Carolina
Adrienne M. Wright, PharmD Candidate
Presbyterian College School of Pharmacy, Clinton, South Carolina

Endeavors to develop medications that increase high-density lipoprotein cholesterol (HDL-C) levels are rooted in the HDL-C hypothesis. Originating in 1951 from the research of Barr and colleagues and later supported by clinical evidence, such as the Framingham study, this hypothesis suggests that as HDL-C increases or is sustained at or above recommended levels, the development of atherosclerosis is reduced and subsequent cardiovascular risk decreases.^[1]

Because low levels of HDL-C and high levels of low-density lipoprotein cholesterol (LDL-C) have been correlated with increased cardiovascular risks, various pharmacological products have been developed with the hope of reducing mortality associated with LDL-C and HDL-C levels that are not within the normal limits. Currently, HMG-CoA reductase inhibitors (statins), fibrates, and thiazolidinediones are used in patients with low HDL-C levels. While these pharmacological products provide moderate increases in HDL-C levels, they are not without limitations; thus pharmaceutical pursuits to develop products superior to these approaches are ongoing.^[2]

Within the past few years, a class of drugs known as cholesteryl ester transfer protein (CETP) inhibitors have been under investigation for their potential to increase HDL-C levels and, in effect, reduce cardiovascular risk.

CETP is a glycoprotein that aids in the transfer of cholesteryl ester and triglycerides from HDL-C to apolipoprotein B-containing lipoprotein, very-low-density lipoprotein, and LDL-C. With the inhibition of CETP, HDL-C levels are likely to increase while LDL-C levels decrease.

Since the discovery of CETP inhibitors, clinical studies have been conducted to evaluate their safety and efficacy.^[2]

Evacetrapib, torcetrapib, and dalcetrapib are all CETP inhibitors that once sought approval from the US Food and Drug Administration (FDA) for patients at risk for cardiovascular events and low HDL-C, but their development was halted after clinical research showed an increased mortality risk, a cardiovascular event risk equivalence to placebo, and/or a lack of clinically meaningful results.^[3,4,5]

Despite the failure of earlier CETP inhibitors to come to market, the trajectory of anacetrapib, a CETP inhibitor developed by Merck, was initially more promising. Early research on anacetrapib showed significant increases in HDL-C levels of 95% to 118% and significant decreases in LDL-C levels of 29% to 37% compared with placebo. Additionally, anacetrapib was well tolerated overall, with no significant differences in adverse effects when compared with placebo.^[6,7] However, these initial studies were not designed to assess the impact of anacetrapib on patient-oriented cardiovascular events such as myocardial infarction (MI), stroke, or death due to cardiovascular causes. The REVEAL trial, which enrolled over 30,000 patients with atherosclerotic vascular disease, was designed to evaluate the potential for anacetrapib to improve cardiovascular outcomes. Over a median follow-up time of 4.1 years, researchers found that, in addition to significantly increasing HDL-C and decreasing LDL-C, anacetrapib reduced the risk for a first major coronary event by 9% and reduced the risk for coronary death or MI by 11% compared with placebo.^[8] Despite positive results, Merck ultimately halted its pursuit of approval by the FDA for anacetrapib. While statistically significant, the cardiovascular risk reduction reported in the REVEAL trial is modest at best and, as suggested by the REVEAL trial researchers, likely explained by a reduction in LDL-C rather than an increase in HDL-C. A lack of clinically significant improvements in secondary outcomes, potential safety issues, and the cost of bringing the drug to market also may have contributed to Merck's decision not to seek regulatory approval.

End of the Road?

Does this mean the end of CETP inhibitors as a class? Perhaps.

Currently, two CETP inhibitors remain under investigation. Dalcetrapid, which lacked positive results in previous studies, is now being investigated for cardiovascular risk reduction in a phase 3 trial of patients with the AA genotype at SNP rs1967309.^[9,10] Pharmacogenomic screening of patients in previous studies of this CETP inhibitor showed a positive association between this genotype and reduced cardiovascular events.^[10] CKD-519, another CETP inhibitor, is under early development by a Korean pharmaceutical company.^[2,10,11]

Though some hope for CETP inhibitors remains, perhaps the bigger question is whether HDL-C levels alone should be a target of drug therapy.

While CETP inhibitors have produced extremely large increases in HDL-C levels, this has not resulted in clinically meaningful outcomes. Additionally, some research suggests that extremely high levels of HDL-C are associated with an increased risk for mortality.^[12] Finally, while research shows that HDL-C levels of > 40 mg/dL in men and > 50 mg/dL in women are desirable, most clinical practice guidelines recommend against specifically targeting low HDL-C levels with pharmacotherapy, especially if patients have no other risk factors.^[13,14,15]

Taken together, all of this suggests that clinical research on the remaining CETP inhibitors or any other intervention that aims to increase HDL-C will need to clearly establish a clinically significant reduction in cardiovascular events and/or mortality and a favorable long-term safety profile before drugs targeting HDL-C are considered useful tools for the management of dyslipidemia and cardiovascular disease.

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