Effects of the CETP Inhibitor Evacetrapib Administered as Monotherapy or in Combination With Statins on HDL and LDL Cholesterol

Nicholls, Stephen J.; Brewer, H. Bryan; Kastelein, John J.P.; Krueger, Kathryn A.; Wang, Ming Dauh; Shao, Mingyuan; Hu, Bo; McErlean, Ellen; Nissen, Steven E.

doi:10.1001/jama.2011.1649

Cited by 390 publications

(239 citation statements)

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“…Evacetrapib, an investigational CETP inhibitor, has not demonstrated the off‐target liabilities associated with torcetrapib, has been well tolerated and has demonstrated clinically relevant pharmacodynamic (PD) efficacy in early phase development 9. In patients with dyslipidaemia, evacetrapib by itself or in combination with statins increased HDL‐C concentrations and decreased LDL‐C concentrations without producing significant changes in blood pressure, aldosterone, cortisol or electrolytes.…”

Section: Introductionmentioning

confidence: 99%

CYP‐mediated drug–drug interactions with evacetrapib, an investigational CETP inhibitor: in vitro prediction and clinical outcome

Cannady

Suico

Wang

et al. 2015

Brit J Clinical Pharma

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AimsEvacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor under development for reducing cardiovascular events in patients with high risk vascular disease. CETP inhibitors are likely to be utilized as ‘add‐on’ therapy to statins in patients receiving concomitant medications, so the potential for evacetrapib to cause clinically important drug–drug interactions (DDIs) with cytochromes P450 (CYP) was evaluated.MethodsThe DDI potential of evacetrapib was investigated in vitro, followed by predictions to determine clinical relevance. Potential DDIs with possible clinical implications were then investigated in the clinic.Results In vitro, evacetrapib inhibited all of the major CYPs, with inhibition constants (K i) ranging from 0.57 µm (CYP2C9) to 7.6 µm (CYP2C19). Evacetrapib was a time‐dependent inhibitor and inducer of CYP3A. The effects of evacetrapib on CYP3A and CYP2C9 were assessed in a phase 1 study using midazolam and tolbutamide as probe substrates, respectively. After 14 days of daily dosing with evacetrapib (100 or 300 mg), midazolam exposures (AUC) changed by factors (95% CI) of 1.19 (1.06, 1.33) and 1.44 (1.28, 1.62), respectively. Tolbutamide exposures (AUC) changed by factors of 0.85 (0.77, 0.94) and 1.06 (0.95, 1.18), respectively. In a phase 2 study, evacetrapib 100 mg had minimal impact on AUC of co‐administered simvastatin vs. simvastatin alone with a ratio of 1.25 (1.03, 1.53) at steady‐state, with no differences in reported hepatic or muscular adverse events.ConclusionsTaken together, the extent of CYP‐mediated DDI with the potential clinical dose of evacetrapib is weak and clinically important DDIs are not expected to occur in patients taking concomitant medications.

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Section: Introductionmentioning

confidence: 99%

CYP‐mediated drug–drug interactions with evacetrapib, an investigational CETP inhibitor: in vitro prediction and clinical outcome

Cannady

Suico

Wang

et al. 2015

Brit J Clinical Pharma

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“…Preclinical animal model studies have further substantiated these findings by showing an elevated level of HDL in mice with non-expressing CETP (14 -16). Since then, the inhibition of CETP activity by small molecule inhibitors has been pursued as an active approach to prevent atherosclerosis with varying levels of success at clinical trial phases (17)(18)(19)(20). Given the complexity of lipid metabolism and the pivotal role of CETP in the process, understanding CETP structure, CETP inhibition, and the mechanism by which CETP transfers neutral lipids is of prime importance.…”

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confidence: 99%

Structural Plasticity of Cholesteryl Ester Transfer Protein Assists the Lipid Transfer Activity

Chirasani

Revanasiddappa

Senapati

2016

Journal of Biological Chemistry

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Coronary heart disease (CHD)2 is one of the prime causes of an increase in the mortality rate worldwide. Over the past few years, various epidemiological studies have provided ample evidence that increased levels of HDL, by transporting cholesterol from atherosclerotic plaques to liver for excretion, can arrest the progression of CHD (1, 2). Subsequent preclinical studies on overexpression of apolipoprotein A-I (apoA-I), the major protein constituent of HDL, have reported significant reduction in CHD risk (3, 4). Although raising HDL levels is a longstanding strategy for mitigating CHD risk, the current lipidtargeted therapies, including the usage of statins, fibrates, and niacin, have shown reduced therapeutic potential (5-7). Hence, there is a continuous requirement for new strategies that can elevate HDL levels to halt the progression of CHD.Cholesteryl ester transfer protein (CETP), a plasma glycoprotein with 476 residues, has been found to mediate the transfer of cholesteryl esters (CEs) from HDL to LDL and VLDL as well as the reciprocal transfer of triglycerides (TGs) from LDL and VLDL to HDL (8, 9). The identification of deficient CETP gene levels and correlated high HDL levels in a Japanese population (10 -13) brought CETP into focus as a therapeutic target for controlling HDL levels. Preclinical animal model studies have further substantiated these findings by showing an elevated level of HDL in mice with non-expressing CETP (14 -16). Since then, the inhibition of CETP activity by small molecule inhibitors has been pursued as an active approach to prevent atherosclerosis with varying levels of success at clinical trial phases (17)(18)(19)(20). Given the complexity of lipid metabolism and the pivotal role of CETP in the process, understanding CETP structure, CETP inhibition, and the mechanism by which CETP transfers neutral lipids is of prime importance. The last decade, therefore, has seen the employment of sophisticated techniques, like cryo-EM (21, 22), x-ray (23, 24), and MD simulations (25-28) on this front. Nevertheless, the story of CETP remains far from complete.The crystal structure of CETP (Protein Data Bank entry 2OBD) has been solved with four bound lipid molecules (23). The structure shows two ␤-barrel domains at the N and C termini, each with a twisted ␤-sheet and a long ␣-helix; a central ␤-sheet between the two ␤-barrels; a C-terminal ␣-helix; and a 60-Å-long hydrophobic tunnel occupied by two CE molecules. Additionally, there were two plug-in dioleoylphosphatidylcholine molecules with polar headgroups exposed to plasma and acyl chains buried in the hydrophobic tunnel of CETP. Interestingly, one of the CEs in the hydrophobic tunnel was in the bent conformation, whereas the second CE molecule was in the linear conformation. Recent cryopositive staining EM and optimized negative-staining electron microscopy (OpNS-EM) protocols combined with CETP C terminus-specific polyclonal antibody studies have suggested that CETP penetrates its C-terminal ␤-barrel domain into LDL or VLDL and its N-termi...

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“…Evacetrapib, the last of the CETP inhibitors being discussed, has been found to be safe and well tolerated either as monotherapy or in combination with statins in patients with either high LDL-C or low HDL-C [Nicholls et al 2011]. The drug was considered efficacious, raising HDL-C by up to 129%, lowering LDL-C by as much as 36%, and reducing TGs by up to 11%.…”

Section: Current Therapiesmentioning

confidence: 99%

Reducing residual risk: modern pharmacochemistry meets old-fashioned lifestyle and adherence improvement

Kones¹

2013

Therapeutic Advances in Cardiovascular Disease

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Despite remarkable advances in identifying and managing coronary heart disease, the global burden of cardiovascular (CV) risk and levels of undetected, subclinical heart disease remain enormous. Substantial numbers of patients do not reach their therapeutic goals, others are unable to tolerate the treatments, half may fail to adhere to their programs, and in those who do attain their targets, major cardiovascular events may continue. Wellknown risk factors, such as obesity and diabetes, have now gained the upper hand, with no evidence-based remedy capable of reversing this trend. All told, less than 1% of American adults and adolescents qualify for ideal CV health; world-wide, the growing prevalence of CV risk factors in children is imposing. A number of novel emerging drug therapies are in development, some recently approved for use in patients with familial hypercholesterolemia.Hopefully, they will contribute significantly to the current therapeutic armamentarium. However, for meaningful improvement in total and residual CV risk, an optimal mix of all available modalities will likely be necessary, including earlier and more effective prevention, aggressive medical care, revascularization and device implantation, judicious use of novel agents, and reengineering of the environment.

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Effects of the CETP Inhibitor Evacetrapib Administered as Monotherapy or in Combination With Statins on HDL and LDL Cholesterol

Abstract: clinicaltrials.gov Identifier: NCT01105975.

Cited by 390 publications

References 30 publications

CYP‐mediated drug–drug interactions with evacetrapib, an investigational CETP inhibitor: in vitro prediction and clinical outcome

CYP‐mediated drug–drug interactions with evacetrapib, an investigational CETP inhibitor: in vitro prediction and clinical outcome

Structural Plasticity of Cholesteryl Ester Transfer Protein Assists the Lipid Transfer Activity

Reducing residual risk: modern pharmacochemistry meets old-fashioned lifestyle and adherence improvement

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