EXPERT REVIEW OF CARDIOVASCULAR THERAPY 2020, VOL. 18, NO. 3, 127–130 https://doi.org/10.1080/14779072.2020.1745633 EDITORIAL The mystery of evacetrapib - why are CETP inhibitors failing? Stephen J. Nichollsa and Kristen Bubba,b aMonash Cardiovascular Research Centre, Monash University, Melbourne, Australia; bBiomedical Discovery Institute, Monash University, Melbourne, Australia ARTICLE HISTORY Received 23 January 2020; Accepted 18 March 2020 KEYWORDS Atherosclerosis; lipids; risk factors; CETP; prevention Cholesteryl ester transfer protein (CETP) plays a pivotal role in raise blood pressure [11,18,19]. The finding that these effects lipoprotein metabolism, primarily by virtue of its ability to facilitate occurred in rodents which do not express CETP suggested transfer of esterified cholesterol from high-density lipoproteins a potential off-target toxicity of the molecule [20]. While the (HDL) to very low-density lipoproteins (VLDL) and low-density specific mechanism underlying the clinical toxicity remains lipoprotein (LDL) [1]. There has been considerable interest in uncertain, these findings did suggest that the ability to develop pharmacological approaches to CETP inhibition on the basis of a CETP inhibitor, without such toxicity, might still prove bene- observations from both population studies [2] and cohorts with ficial for patients with cardiovascular disease. genetic polymorphisms [1,3,4] demonstrating low CETP activity to Dalcetrapib is a modest CETP inhibitor, raising HDL choles- associate with high levels of HDL cholesterol and low rates of terol by up to 30% and with no discernible impact on LDL cardiovascular disease. A range of CETP inhibitory strategies cholesterol levels. Small clinical trials established no increase including small molecule inhibitors, antisense oligonucleotides, in vascular inflammation or presence of endothelial dysfunc- and vaccination have proven to be atheroprotective in rabbit tion with dalcetrapib, suggesting a lack of torcetrapib like models [5–8]. Accordingly, CETP inhibition attracted considerable toxicity [21,22]. A large clinical outcomes trial was stopped interest as a pharmacological approach to raising HDL cholesterol due to clinical futility [12]. A post hoc pharmacogenomic and potentially reducing cardiovascular risk. analysis of this trial revealed that patients carrying the AA However, multiple clinical development programs of CETP rs1967309 polymorphism of adenylate cyclase 9 on chromo- inhibitors have produced disappointing results. This has posi- some 16 demonstrated less cardiovascular events in the dal- tioned CETP inhibition in the growing pile of promising phar- cetrapib group, associated with greater increases in ex vivo macological targets that have failed to convincingly reduce cholesterol efflux capacity and a lack of increase in inflamma- cardiovascular risk [9–13]. Many pundits have opined that tory markers, compared with dalcetrapib treated patients CETP inhibitors have failed and the field should move on to without this polymorphism [23]. This has led to a new cardi- alternative approaches in order to reduce the residual clinical ovascular outcomes trial performed exclusively in patients risk observed in patients treated with established medical with this polymorphism [24]. therapies. Careful interrogation, however, of the totality of Evacetrapib is a more potent CETP inhibitor, raising HDL data generated from these development programs, combined cholesterol by more 125% and lowering LDL cholesterol by with emerging insights from genomic analyses suggests more than 30%, when administered either as monotherapy or potential new avenues for the pursuit of CETP inhibitor devel- in addition to statin therapy [25]. In a similar fashion to pre- opment in clinical practice. vious CETP inhibitors, the clinical outcomes trial was stopped Torcetrapib was the first CETP inhibitor to achieve an prematurely for clinical futility with no evidence of event curve advanced phase of clinical development. Early studies demon- separation after a median treatment period of 26 months [13]. strated HDL cholesterol raising by more than 60% and incre- While subsequent lipid studies revealed that the HDL choles- mental lowering of LDL cholesterol by up to 20% on top of terol increase with evacetrapib was accompanied by eleva- statin therapy [2,14]. However, a large clinical outcomes trial tions in levels of both apolipoproteins E and C-III [26], there was terminated prematurely due to the finding of a 25% is currently no evidence that this has a deleterious effect at the increase in the primary endpoint and 58% increase in mortality level of the artery wall. Accordingly, the mechanism under- in torcetrapib treated patients [11]. Parallel vascular imaging lying the lack of clinical benefit, despite incremental LDL studies demonstrated that similar lipid effects failed to favor- cholesterol lowering and raising of HDL cholesterol remained ably modulate the progression of either coronary atherosclero- uncertain. sis or carotid intima-medial thickness [15–17]. Subsequent Anacetrapib is an additional potent CETP inhibitor, raising analyses revealed that torcetrapib resulted in excessive adrenal HDL cholesterol by more than 130% and lowering LDL cho- production of aldosterone and cortisol and arterial wall expres- lesterol by more than 30% [27]. These findings were observed sion of endothelin, in addition to its well-established ability to in patients with both high cardiovascular risk and also in those CONTACT Stephen J. Nicholls [email protected] Monash Cardiovascular Research Centre, Monash University, 246 Clayton Road, Clayton, VIC 3168, Australia © 2020 Informa UK Limited, trading as Taylor & Francis Group 128 S. J. NICHOLLS AND K. BUBB with familial hypercholesterolemia [28]. An early safety study cholesterol from HDL to VLDL and LDL in the setting of normal performed in more than 1600 high vascular risk patients not CETP function. In addition to reduced cholesterol content of LDL only demonstrated a lack of torcetrapib like toxicity, but also particles, kinetic studies have demonstrated an increase in the reported a reduction in cardiovascular events, primarily due to fractional catabolic rate of LDL particles, which may be enhanced a lower need for coronary revascularization [27]. The largest in the setting of accelerated removal of triglyceride-rich LDL parti- CETP inhibitor clinical outcomes trial performed to date cles, which would be more prevalent in the setting of CETP inhibi- demonstrated a statistically significant 9% reduction in cardi- tion [36]. This has been reaffirmed by observations that the more ovascular events in patients treated with anacetrapib for potent CETP inhibitors do reduce levels of both LDL and non-HDL a median of 4.1 years [29]. Analysis of this trial demonstrated cholesterol. Overall, this suggests that efforts to reduce risk via a direct association between non-HDL cholesterol levels and CETP inhibition might be better served by focusing on its ability to cardiovascular events. A subsequent report of longer-term lower atherogenic lipoproteins as opposed to prior efforts that follow-up, after the trial, demonstrated a greater reduction in have been driven by the interest in raising HDL cholesterol. cardiovascular events in the anacetrapib treated patients [29]. Additional genetic analyses demonstrated that the poten- While this finding provided ultimate evidence that the admin- tial benefit of less CETP is observed in the presence, but not istration of a CETP inhibitor could reduce cardiovascular risk, absence, of hydroxy-methyl-glutaryl coenzyme A reductase there were lingering concerns regarding adipose tissue accu- [35]. This provides genetic evidence to suggest that the mulation of the drug [30] and ultimately clinical development administration of CETP inhibitors might be more likely to did not proceed to the regulatory approval stage. work in the absence of statin therapy. The biochemical plau- One additional potent CETP inhibitor, TA-8995, was evalu- sibility for this concept lies in the fact that removal of LDL ated in early clinical trials with evidence of more effective HDL from the systemic circulation with both statins and CETP cholesterol raising and LDL cholesterol lowering than other inhibitors involve the LDL receptor. This introduces the poten- agents, when administered at much lower doses [31]. To date, tial for saturation of LDL uptake by the liver and may support this agent has not proceeded to the setting of a large cardi- greater LDL cholesterol and potentially greater event reduc- ovascular outcomes trial. tion with CETP inhibitors administered in the absence of sta- For more than a decade considerable resources were tins. Whether this will lead to efficacy of CETP inhibition, or focused on the potential for CETP inhibition to reduce cardi- other novel lipid lowering agents, in patients with statin intol- ovascular risk. However, despite all of the optimism, four large erance remains to be tested in clinical trials. outcomes trial demonstrated a combination of toxicity, clinical A parallel observation from these large clinical outcomes futility, and modest clinical benefit after prolonged treatment. trials has been the potential impact of CETP inhibitors on the The question that remains is how best to conclude the totality subsequent development of type 2 diabetes. In each of these of data with regard to this class of pharmacological agents? studies, regardless of the ultimate impact on cardiovascular Has CETP