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Efficacy and Safety of the Cholesteryl Ester Transfer Protein Inhibitor

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Efficacy and Safety of the Cholesteryl Ester Transfer Protein Inhibitor Circ J 2018; 82: 183 – 191 ORIGINAL ARTICLE doi: 10.1253/circj.CJ-16-1324 Ischemic Heart Disease Efficacy and Safety of the Cholesteryl Ester Transfer Protein Inhibitor Evacetrapib in Combination With Atorvastatin in Japanese Patients With Primary Hypercholesterolemia Tamio Teramoto, MD, PhD; Arihiro Kiyosue, MD, PhD; Takeshi Iimura, MD; Yasushi Takita; Jeffrey S. Riesmeyer, MD; Masahiro Murakami, MD, PhD Background: Inhibition of cholesteryl ester transfer protein by evacetrapib when added to atorvastatin may provide an additional treatment option for patients who do not reach their low-density lipoprotein cholesterol (LDL-C) goal. Methods and Results: This multicenter, randomized, 12-week, double-blind, parallel-group, placebo-controlled, outpatient, phase 3 study evaluated the efficacy of evacetrapib with atorvastatin in reducing LDL-C in 149 Japanese patients (evacetrapib/atorvastatin, n=53; ezetimibe/atorvastatin, n=50; placebo/atorvastatin, n=46) with primary hypercholesterolemia. The primary efficacy measure was percent change from baseline to week 12 in LDL-C (β quantification). Treatment with evacetrapib 130 mg daily for 12 weeks resulted in a statistically significant treatment difference of −25.70% compared with placebo in percentage decrease in LDL-C (95% CI: −34.73 to −16.68; P<0.001). Treatment with evacetrapib 130 mg also resulted in a statistically significant difference of 126.39% in the change in high-density lipoprotein cholesterol (HDL-C) compared with placebo (95% CI: 113.54–139.24; P<0.001). No deaths or serious adverse events were reported. Four patients (3 in the evacetrapib group and 1 in the ezetimibe group) discontinued due to adverse events. Conclusions: Evacetrapib daily in combination with atorvastatin was superior to placebo in lowering LDL-C after 12 weeks, and resulted in a statistically significant increase of HDL-C compared with placebo. Also, no new safety risks were identified. Key Words: Cholesteryl ester transfer protein inhibitor; Evacetrapib; High-density lipoprotein; Hypercholesterolemia; Low-density lipoprotein he use of 3-hydroxy-3-methyl-glutaryl-coenzyme A the hazard ratio for total CAD increases 1.4-, 1.7-, 2.2-, and reductase inhibitors (statins) to reduce low-density 2.8-fold when LDL-C is 2.06–2.57, 2.58–3.09, 3.10–3.61, lipoprotein cholesterol (LDL-C) has resulted in and ≥3.62 mmol/L, respectively, compared with LDL-C T 5 relative reductions in cardiovascular events of 20–30%. As <2.06 mmol/L. a result, current guidelines for dyslipidemia management Cholesteryl ester transfer protein (CETP) is a plasma and prevention of atherosclerotic cardiovascular diseases glycoprotein secreted primarily by the liver that mediates recommend reducing LDL-C.1–3 the transfer of cholesteryl ester (CE) from high-density Although LDL-C management has provided significant lipoprotein (HDL) to apolipoprotein (apo)B-rich lipopro- clinical benefits, atherosclerosis remains a major health teins (Lp; i.e., very-low-density lipoprotein [VLDL] and burden in Japan, where the relative risk of coronary artery LDL) in exchange for their triglycerides, as well as the disease (CAD) has been confirmed by epidemiological transfer of triglycerides/CE between apo-B-rich lipopro- studies to increase in tandem with LDL-C and total teins. Inhibition of CETP represents a potent mechanism cholesterol (TC). The NIPPON DATA 80 study showed for increasing HDL cholesterol (HDL-C) and lowering that the relative risk of death due to CAD increases 1.4-, LDL-C. There is evidence that CETP inhibition prevents 1.7-, 1.8-, and 3.8-fold when TC is 5.18–5.68, 5.69–6.20, transfer of CE from HDL-C to apoB-containing lipopro- 6.21–6.70, and ≥6.71 mmol/L, respectively, compared with teins and may increase cholesterol efflux.6–8 The majority of TC 4.14–4.65 mmol/L, for men and women combined.4 A animal model data indicate that CETP is proatherogenic, more recent Japanese epidemiological study reported that supporting an anti-atherogenic effect of CETP inhibitors.8,9 Received January 9, 2017; revised manuscript received May 1, 2017; accepted June 21, 2017; released online August 3, 2017 Time for primary review: 31 days Teikyo Academic Research Center, Teikyo University, Tokyo (T.T.); Tokyo-Eki Center-building Clinic, Tokyo (A.K.); Department of Cardiovascular Medicine, University of Tokyo Hospital, Tokyo (A.K.); Eli Lilly Japan, Kobe (T.I., Y.T.), Japan; and Eli Lilly and Company, Indianapolis, IN (J.S.R., M.M.), USA Present address: Elsevier Japan, Tokyo, Japan (T.I.). Mailing address: Masahiro Murakami, MD, PhD, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. E-mail: [email protected] ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Journal Vol.82, January 2018 184 TERAMOTO T et al. Evacetrapib is a potent and selective CETP inhibitor. vascular disease,20 be terminated due to futility. The decision The effect of evacetrapib on LDL-C reduction has been was not based on safety concerns. As a consequence of evaluated in 2 phase 2 studies. A phase 2 study conducted these results, all ongoing studies of evacetrapib, including outside Japan noted a 22.3% decrease in LDL-C in patients this study, were terminated by the sponsor.21 treated with evacetrapib 100 mg alone, and a 47.6% decrease when evacetrapib 100 mg was used with 20 mg atorvas- Methods tatin.10 Similarly, a phase 2 study in Japanese patients noted a 22% reduction in LDL-C in patients treated with This was a multicenter, randomized, 12-week double- evacetrapib 100 mg alone, and a 52% decrease when blind, parallel-group, placebo-controlled, phase 3 study evacetrapib 100 mg was used with 10 mg atorvastatin. The (ClinicalTrials.gov: NCT02260648), with 3 consecutive safety data on evacetrapib 30, 100, and 500 mg demon- periods (screening period; diet lead-in and washout period; strated that evacetrapib was safe and well tolerated.11 and a 12-week, double-blind treatment period). Drugs that are added to statin therapy for the treatment The study was performed in accordance with the Inter- of hypercholesterolemia and prevention of atherosclerotic national Conference on Harmonisation guidelines for cardiovascular disease include fibrates, resins (anion Good Clinical Practice, all applicable laws, rules, and exchange resin), ezetimibe, and proprotein convertase regulations. The protocol was approved by the ethics review subtilisin kexin type 9 (PCSK9) monoclonal antibodies. board of each participating study center, and all patients Statin use is accompanied by an increase in PCSK9, leading provided written informed consent. to lysosomal degradation of the LDL receptor. This may Study treatment included evacetrapib 130 mg QD, ezeti- explain the observation that doubling the statin dose results mibe 10 mg QD, and placebo added to background therapy in only a 6% additional reduction in LDL-C.12 Ezetimibe of atorvastatin 10 mg. Before screening, patients were is often used as a first-line drug for statin-intolerant asked to fast for at least 8 h before laboratory samples were patients. In patients requiring a more vigorous reduction collected for central measurement and other screening in LDL-C, ezetimibe is frequently used. The reduction of assessments were performed. All eligible patients were LDL-C with ezetimibe 10 mg in patients with hypercholes- asked to begin the diet lead-in and washout period within terolemia is approximately 18%.13,14 With regard to the 2 weeks of the screening visit. Patients taking lipid- effect of ezetimibe in combination with statins, a post- modifying medication such as ezetimibe, bile acid seques- marketing clinical study in Japan showed that after treat- trant, eicosapentaenoic acid, and docosahexaenoic acid ment with ezetimibe 10 mg in patients who were receiving (except for atorvastatin 10 mg) were instructed to discon- atorvastatin 10 mg, LDL-C decreased by approximately tinue lipid-modifying medication during the washout period 26%.15 The IMPROVE-IT study showed that the addition for 4 weeks before their first treatment visit. Patients were of ezetimibe to simvastatin 40 mg resulted in an additional also instructed to start a diet therapy in accordance with 6% reduction in the relative risk of major adverse cardiac Japan Atherosclerosis Society (JAS) guidelines3 during the events.16 We have chosen to use ezetimibe as a reference washout period in order to evaluate lipid levels under the drug in this study to better characterize the clinical posi- diet therapy, and to minimize the effect of diet on lipid tioning of evacetrapib as an LDL-C-lowering drug. values throughout the study period. Diet therapy was to Atorvastatin is one of the statins most commonly used continue throughout the study. around the world, with a wealth of evidence on reducing Patients who completed the diet lead-in and washout the risk of cardiovascular events.17,18 A systematic review period and met all enrollment criteria were randomized to and meta-analysis showed that LDL-C decreased by 28.9– a treatment group (evacetrapib 130 mg QD, ezetimibe 42.0% with atorvastatin 10 mg once daily (QD).18 For 10 mg QD, or placebo) in a 1:1:1 ratio. Randomization was Japanese patients with hypercholesterolemia, atorvastatin performed at each investigative site using an interactive 10 mg QD is a standard dosage regimen.19 A phase 2 study Web response system. Once treatment began during the in Japanese patients showed an additive reduction in 12-week double-blind treatment
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