Efficacy and Safety of Pitavastatin/Ezetimibe Fixed-Dose Combination vs. Pitavastatin: Phase III, Double-Blind, Randomized Controlled Trial

Kenichi Tsujita, Koutaro Yokote, Junya Ako, Ryohei Tanigawa, Sachiko Tajima, Hideki Suganami, Kenichi Tsujita, Koutaro Yokote, Junya Ako, Ryohei Tanigawa, Sachiko Tajima, Hideki Suganami

Abstract

Aim: We compared the efficacy and safety of pitavastatin/ezetimibe fixed-dose combination with those of pitavastatin monotherapy in patients with hypercholesterolemia.

Methods: This trial was a multicenter, randomized, double-blind, active-controlled, parallel-group trial. A total of 293 patients were randomly assigned into four groups receiving 2 mg pitavastatin, 4 mg pitavastatin, 2 mg pitavastatin/10 mg ezetimibe (K-924 LD), and 4 mg pitavastatin/10 mg ezetimibe (K-924 HD) once daily for 12 weeks.

Results: The percentage changes in low-density lipoprotein cholesterol (LDL-C), the primary endpoint, were -39.5% for 2 mg pitavastatin, -45.2% for 4 mg pitavastatin, -51.4% for K-924 LD, and -57.8% for K-924 HD. Compared with pitavastatin monotherapy, the pitavastatin/ezetimibe fixed-dose combination significantly reduced LDL-C, total cholesterol, and non-high-density lipoprotein cholesterol. Meanwhile, the cholesterol synthesis marker, lathosterol, was significantly decreased with pitavastatin monotherapy and the pitavastatin/ezetimibe fixed-dose combination, although the decrease was attenuated in the latter. On the other hand, the cholesterol absorption markers, beta-sitosterol and campesterol, were reduced with the fixed-dose combination but not with pitavastatin monotherapy. The incidence of adverse events and adverse drug reactions was not significantly different between the two groups receiving the fixed-dose combination and monotherapy. The mean values of laboratory tests that are related to liver function and myopathy increased but remained within the reference range in all groups.

Conclusions: The pitavastatin/ezetimibe fixed-dose combination showed an excellent LDL-C-reducing effect by the complementary pharmacological action of each component, and its safety profile was similar to that of pitavastatin monotherapy (ClinicalTrials.gov Identifier: NCT04289649).

Keywords: Ezetimibe; Fixed-dose combination; Hypercholesterolemia; Pitavastatin.

Conflict of interest statement

K.T. has received grants from PPD-Shin Nippon Biomedical Laboratories, Alexion Pharmaceuticals, Abbott Medical, Bayer Yakuhin, Boehringer Ingelheim, Daiichi Sankyo, ITI, Ono Pharmaceutical, Otsuka Pharmaceutical, and Takeda Pharmaceutical, and personal fees from Abbott Medical, Amgen, AstraZeneca, Bayer Yakuhin, Daiichi Sankyo, Medtoronic Japan, Kowa, Novartis Pharma, Otsuka Pharmaceutical, Pfizer Japan, and Janssen Pharmaceutical; and has been holding an endowed chair by funding from Abbott Japan, Boston Scientific Japan, Fides-one, GM Medical, ITI, Kaneka Medix, NIPRO, Terumo, Abbott Medical, Cardinal Health Japan, Fukuda Denshi, Japan Lifeline, Medical Appliance, and Medtoronic Japan. K.Y. has received grants from Taisho Pharmaceutical, Takeda Pharmaceutical, Shionogi, MSD, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Bayer Yakuhin, Sumitomo Pharma, Boehringer Ingelheim, Teijin Pharma, Astellas Pharma, Ono Pharmaceutical, Novo Nordisk Pharma, Kowa, and Abbott Japan, and personal fees from MSD, Mitsubishi Tanabe Pharma, Novo Nordisk Pharma, Takeda Pharmaceutical, Astellas Pharma, Sumitomo Pharma, Ono Pharmaceutical, AstraZeneca, Novartis Pharma, Kowa, Daiichi Sankyo, Boehringer Ingelheim, Taisho Pharmaceutical, and Pfizer. J.A. has received grants from Boehringer Ingelheim, and personal fees from Kowa, Otsuka Pharmaceutical, Bayer Yakuhin, Ono Pharmaceutical, AstraZeneca, Eli Lilly Japan, Daiichi Sankyo, Boehringer Ingelheim, Novartis Pharma, Bristol-Myers Squibb, MSD, and Abbott Medical. R.T., S.T., and H.S. are employees of Kowa.

Figures

Fig.1. Study design
Fig.1. Study design
＊To enroll patients who were taking drugs that might affect the evaluation of lipids, discontinuation of the applicable drug administration was required at the time of consent acquisition at least four weeks before the screening test; however, patients who were taking drugs that affects serum lipids for a longer period of time (e.g., probucol) were prohibited to undergo wash-out and participate in the study.
Fig.2. Disposition of patients
Fig.2. Disposition of patients
＊1: Seven out of 173 met the exclusion criteria. ＊2: The seven individuals who met the exclusion criteria and did not meet the selection criteria were counted as “Not meeting a selection criterion”.
Fig.3. Percent change from baseline in LDL-C…
Fig.3. Percent change from baseline in LDL-C level at week 12
Data are presented as LS mean±SE. a: estimated using the mixed model for repeated measurements (MMRM) model with the treatment group, time point, interaction between the treatment group and time point, and risk category according to JAS 2017 as fixed effects and LDL-C baseline value as a covariate. Data from 72 patients at weeks 4, 8, and 12 were included in the analyses except for the data in the K-924 HD group at week 12 whose number was 70. b: primary analysis c: exploratory analysis ＊＊: p＜0.01 vs. baseline by one-sample t-test for LS Means with MMRM. ‡: p ≤ 0.01 2 mg pitavastatin vs. K-924 LD, 4 mg pitavastatin vs. K-924 HD, K-924 LD vs. K-924 HD by MMRM. K-924, pitavastatin ezetimibe fixed-dose combination; HD, high dose; LD, low dose; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation; LS, least squares; SE, standard error; MMRM, mixed model for repeated measurements
Fig.4. Time course of the LDL-C levels
Fig.4. Time course of the LDL-C levels
Data are presented as mean±SD., ( ): number LDL-C, low-density lipoprotein cholesterol; K-924, pitavastatin ezetimibe fixed-dose combination; HD, high dose; LD, low dose
Fig.5. Percent change from baseline in lathosterol,…
Fig.5. Percent change from baseline in lathosterol, beta-sitosterol, campesterol level at week 12
(A) Lathosterol, (B) Beta-sitosterol, (C) Campesterol Data are presented as LS mean±SE %Changes at week 12 were estimated using the ANCOVA model with the treatment group and risk category according to JAS 2017 as fixed effects and baseline value of the lipid parameter as a covariate. ＊＊: p＜0.01 vs. baseline by one-sample t-test for LS Means with ANCOVA. ‡: p ≤ 0.01 2 mg pitavastatin vs. K-924 LD, 4 mg pitavastatin vs. K-924 HD, LD vs. K-924 HD by ANCOVA. K-924, pitavastatin ezetimibe fixed-dose combination; HD, high dose; LD, low dose; SD, standard deviation; LS, least squares; SE, standard error; ANCOVA, analysis of covariance

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