2023 Volume 30 Issue 11 Pages 1580-1600
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).
In Japan, the hazard ratios for coronary artery disease (CAD) and death have been found to increase with elevated low-density lipoprotein cholesterol (LDL-C)1-3), similar to the observations of many epidemiological studies conducted in the United States and Europe. Therefore, the prevention of atherosclerotic cardiovascular disease (ASCVD) is critical for which LDL-C management is key. Various guidelines such as those in Europe4), the United States5), and Japan6) set the management target values for LDL-C according to the risk of patients. Diet and exercise therapy are prioritized first for managing LDL-C, but if LDL-C does not reach the target levels, then drug therapy should be considered. Statin therapy is the first-line treatment that is recommended for lowering LDL-C, as supported by the most established evidence. Meta-analyses of large-scale clinical trials showed that the administration of statin at a higher dose, which leads to a greater LDL-C reduction, can suppress more cardiovascular events7, 8). In line with the meta-analyses, compared with 1 mg/day, 4 mg/day of pitavastatin led to a 19% relative risk reduction in cardiovascular events (hazard ratio, 0.81; 95% confidence interval (CI), 0.69–0.95) in the REAL-CAD trial conducted in Japanese patients with CAD9).
However, looking at the status of LDL-C management in Japan, many patients cannot achieve the LDL-C management target with statins alone10). As stated in the 2022 edition of the Japan Arteriosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases (JAS 2022), when LDL-C cannot be adequately managed by statin alone, combination therapy with ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitor, and eicosapentaenoic acid is effective in preventing ASCVD6).
Statins inhibit HMG-CoA reductase, which is the rate-limiting enzyme for cholesterol synthesis in the liver, thus suppressing cholesterol synthesis. However, this is followed by a compensatory increase in cholesterol absorption from the small intestine11). On the other hand, ezetimibe inhibits Niemann-Pick C1-Like 1 (NPC1L1), which is a cholesterol transporter in the small intestine, thus suppressing cholesterol absorption. This in turn is followed by a compensatory increase in cholesterol synthesis in the liver. Therefore, the statins/ezetimibe combination therapy is pharmacologically ideal for reducing plasma cholesterol. Indeed, combination therapy reduced LDL-C levels more effectively than an increased dose of statin12, 13). Furthermore, a fixed-dose combination drug improves medication adherence14), leading to a better outcome in the reduction of all-cause mortality15) and cardiovascular risk16).
Pitavastatin, which is a component of the fixed-dose combination drug examined in this trial, is hardly metabolized by cytochrome P450 (CYP) and may have a lower risk of drug–drug interactions mediated by CYP than statins that are metabolized by CYP (e.g., atorvastatin, simvastatin)17). A randomized controlled trial that directly compared pitavastatin, atorvastatin, and rosuvastatin showed that hemoglobin A1c (HbA1c) levels significantly increased from baseline in the atorvastatin and rosuvastatin groups but not in the pitavastatin group18). Furthermore, a meta-analysis of clinical trials of pitavastatin showed no significant adverse effects on blood glucose levels19), which is a concern with intensive statin treatment. Therefore, pitavastatin is effective and well-tolerated20).
In the present study, we compared the efficacy and safety of the pitavastatin/ezetimibe fixed-dose combination with those of pitavastatin monotherapy. The doses for the fixed-dose combination drugs were determined as 2 mg or 4 mg for pitavastatin and 10 mg for ezetimibe because of the following reasons: various guidelines such as those in Europe4), the United States5), and Japan6, 21) recommend the use of ezetimibe as an add-on to statin therapy for patients with acute coronary syndrome (ACS) and familial hypercholesterolemia (FH) if LDL-C targets are not achieved at the maximally tolerated dose of statin. The highest dose of pitavastatin, 4 mg/day, is more effective than the low dose of 1 mg/day to reduce cardiovascular events9). A dose of 2 mg pitavastatin was also selected because it is the most frequently prescribed dose in combination with ezetimibe in Japan, and 10 mg ezetimibe is the only approved dose.
To compare the efficacy and safety of a 12-week treatment with 2 mg pitavastatin/10 mg ezetimibe (K-924 LD) and 4 mg pitavastatin/10 mg ezetimibe (K-924 HD) with 2 mg and 4 mg pitavastatin (PS 2 mg and PS 4 mg, respectively), in patients with hypercholesterolemia.
This phase III, multicenter, active-controlled, randomized, double-blind, parallel-group comparative trial was conducted at three centers in Japan in compliance with the latest version of the Declaration of Helsinki and the Good Clinical Practice. Ethical approval was obtained from the Medical Corporation Heishinkai OPHAC Hospital institutional review board, and all patients provided written informed consent.
PatientsThe inclusion criteria were as follows: (i) patients with hypercholesterolemia aged ≥ 20 years; (ii) patients who had been receiving either or both constant diet and exercise therapy for at least 12 weeks before the screening; and (iii) patients with primary prevention whose LDL-C (Friedewald formula) at screening met one of the following criteria according to the management category based on JAS 2017 22): 160 mg/dL ≤ LDL-C ＜220 mg/dL for low risk; 140 mg/dL ≤ LDL-C ＜190 mg/dL for moderate risk; or 120 mg/dL ≤ LDL-C ＜160 mg/dL for high risk. JAS 2017 was the latest version during patient registration. The main exclusion criteria were as follows: (i) a history of pitavastatin- or ezetimibe-associated myopathy or rhabdomyolysis; (ii) creatine kinase (CK) ≥ 3× the upper limit of the normal range (ULN); (iii) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≥ 3× ULN; (iv) receiving LDL apheresis; or (v) fasting triglyceride (TG) ≥ 400 mg/dL. The full exclusion criteria are provided in Supplementary Table 1.
| 1. History of pitavastatin- or ezetimibe-associated myopathy or rhabdomyolysis. |
| 2. History of hypersensitivity to pitavastatin or ezetimibe. |
| 3. Severe hepatic impairment (Child-Pugh classification of B or C) or biliary obstruction. |
| 4. Women who were or might become pregnant or who were breastfeeding. |
| 5. CK ≥ 3×ULN at the screening. |
| 6. ALT and AST ≥ 3×ULN at the screening. |
| 7. Type 1 diabetes or poorly controlled type 2 diabetes (HbA1c ≥ 8.0%) at the screening. |
| 8. Poorly controlled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg) at the screening. |
| 9. eGFR ＜30 mL/min/1.73 m2 at the screening or receiving dialysis. |
| 10. New York Heart Association Functional Classification Class III or IV. |
| 11. Poorly controlled arrhythmia. |
| 12. Poorly controlled endocrine and metabolic diseases. |
| 13. History of coronary artery disease or familial hypercholesterolemia. |
| 14. Presence or a high risk of recurrence after remission of malignant tumors. |
| 15. Blood donation of 200 mL or more within 4 weeks prior to the screening visit; 400 mL or more within 12 weeks for men or 16 weeks for women prior to the screening; or plasma and platelet donation within 2 weeks prior to the screening. |
| 16. History of serious drug hypersensitivity (anaphylactic shock etc.). |
| 17. Patients who needed administration of prohibited concomitant medications after informed consent during the study period. |
| 18. Fasting triglycerides ≥ 400 mg/dL at the screening. |
| 19. Receiving LDL apheresis. |
| 20. Malabsorption, history of malabsorption, or history of surgical treatment of gastrointestinal tract that can affect absorptive function (excluding appendectomy or that for hernia). |
| 21. Alcoholism or drug dependence. |
| 22. Participation in any interventional clinical trial with the administration of investigational study drug other than placebo within 16 weeks prior to this trial or participation in any clinical trial at the same time with this trial. |
| 23. History of administration of K-924 |
| 24. Other ineligibility determined by an investigator. |
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; K-924, pitavastatin ezetimibe fixed-dose combination; LDL, low-density lipoproteins; ULN, upper limit of normal range.
Eligible patients were randomly assigned to the PS 2 mg, PS 4 mg, K-924 LD, and K-924 HD groups in a 1:1:1:1 ratio (Fig.1). Patient allocation was performed by a third party who was independent of the principal investigator, sub-investigator, and trial sponsor according to a dynamically determined allocation probability using age, gender, and risk category based on JAS 2017 22) as allocation factors.
＊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.
Masking of the study medication was performed using K-924 LD tablets (containing 2 mg pitavastatin and 10 mg ezetimibe), K-924 LD placebo tablets (2 mg pitavastatin only), K-924 HD tablets (4 mg pitavastatin and 10 mg ezetimibe), and K-924 HD placebo tablets (4 mg pitavastatin only), which had the same appearance and were indistinguishable. The randomized patients were orally administered one tablet of the assigned trial drug once daily after meals for 12 weeks. Patients, investigators, and sponsors had been masked until all data were fixed.
Physiological tests and fasting blood and urine collections were performed at screening visits and at 0, 4, 8, and 12 weeks.
Endpoints and AssessmentsThe primary efficacy endpoint was the percentage change in LDL-C from baseline at 12 weeks of treatment. LDL-C was calculated using the Friedewald formula (LDL-C=TC−(HDL-C＋TG/5)) if TG was ＜400 mg/dL, and a direct measurement method was used instead if TG was ≥ 400 mg/dL.
The secondary efficacy endpoints included the percentage changes from baseline to the end of treatment in other parameters, including non-high-density lipoprotein cholesterol (non-HDL-C), HDL-C, total cholesterol (TC), TG, apolipoprotein AI (ApoAI), ApoAII, ApoB, ApoB48, ApoCII, ApoCIII, ApoE, lipoprotein (a) (Lp(a)), lathosterol, beta-sitosterol, campesterol, remnant-like particle cholesterol (RLP-C) using MetaboLead, and lipoprotein fraction analysis using high-performance liquid chromatography (HPLC). Another secondary efficacy endpoint was the achievement rate of the LDL-C management target recommended in JAS 2017 22) as follows: (1) ＜160 mg/dL if low risk; (2) ＜140 mg/dL if moderate risk; and (3) ＜120 mg/dL if high risk.
The main safety endpoints included: (1) the incidence of adverse events (AEs) and adverse drug reactions (ADRs); (2) changes from baseline in clinical laboratory values, including AST, ALT, γ-GT, CK, serum creatinine, eGFR, fasting blood glucose, insulin, HOMA-R, glycoalbumin, and HbA1c; and (3) the number of patients whose AST, ALT, or CK values exceeded the cutoff level (for AST and ALT, ≥ 3× ULN on consecutive visits, ≥ 5× ULN, and ≥ 10× ULN; and for CK, ≥ 10× ULN alone and ≥ 10× ULN with muscular symptoms). An AE was defined as any untoward medical occurrence in a study participant who received the study drug administration regardless of the causal relationship with the study drug. An AE was considered an ADR when the causal relationship between the event and the studied drug could not be ruled out.
HPLC measurements were performed by Immuno-Biological Laboratories Co, Ltd. (Fujioka, Gunma, Japan). All the other biochemical analyses were performed by LSI Medience Corporation (Chiyoda-ku, Tokyo, Japan).
Statistical AnalysisThe efficacy analysis set included all patients who were randomly assigned, took the trial drug at least once, and had baseline and post-baseline efficacy measurements. The safety analysis set included all patients who took the trial drug at least once.
The primary efficacy endpoints were analyzed using the mixed model for repeated measurements (MMRM) that included the treatment group, time point, the interaction term of the treatment group by time point, and risk category based on JAS 2017 22) as fixed effects and LDL-C baseline value as a covariate. An unstructured covariance structure was used to model within-subject errors, and the Kenward–Roger method was used to estimate degrees of freedom.
The primary efficacy analysis was performed to investigate whether all of the following three hypotheses were confirmed in terms of the above primary efficacy endpoint: (1) K-924 HD was superior to PS 4 mg; (2) K-924 LD was superior to PS 2 mg, and (3) a decrease in LDL-C was greater in K-924 HD than in K-924 LD in the point estimate of the percentage change.
The secondary efficacy endpoints of percentage change from baseline at week 12 in the lipid parameters such as non-HDL-C, HDL-C, TC, and TG were analyzed in the same manner as the primary efficacy endpoint. The remaining lipid parameters were evaluated using analysis of covariance (ANCOVA) with the treatment group and risk category according to JAS 2017 22) as fixed effects and the baseline value as a covariate. The percentage changes from baseline at each time point were analyzed using a one-sample t-test. The achievement rate of the LDL-C management target at week 12 was calculated with a 95% CI for each group, which was compared between the K-924 LD and PS 2 mg groups and between the K-924 HD and PS 4 mg groups. Additionally, sub-population analyses of the percentage change from baseline to 12 weeks were performed by age category, presence or absence of diabetes, presence or absence of hypertension, and risk category according to JAS 2017 22).
For the analysis of safety endpoints, Fisher’s exact test was performed to compare the incidence of AEs and ADRs between the K-924 LD group and PS 2 mg group, and between the K-924 HD group and PS 4 mg group. In the tabulation and analysis of AEs, the names of AEs were read according to MedDRA/J Ver 24.0. Wilcoxon signed-rank test was performed for the changes from baseline in laboratory values. The number of patients with elevated AST, ALT, or CK meeting the prespecified cutoff criteria during the treatment period was calculated for each group, except for those who already had such levels of the parameters before the start of the study treatment.
The significance level was set at two-sided 5%, and the confidence coefficient was set at two-sided 95%. SAS ver.9.4 (SAS Institute, Inc., Cary, North Carolina, USA) was used for analyses. All efficacy safety endpoint analyses were based on a predetermined statistical analysis plan.
Sample SizeThe sample size was calculated with the assumptions based on the phase III double-blind comparative trial of pitavastatin23) and phase III trials of ezetimibe in combination with atorvastatin24) or rosuvastatin25), assuming 10.1% point of difference in the percentage changes in LDL-C between the K-924 HD and PS 4 mg groups and between the K-924 LD and PS 2 mg groups in each comparison at 4, 8, and 12 weeks, 140 of inter-subject variance, and 79.1 of intra-subject variance. We also assumed a 3.6% point of difference in the percentage changes in LDL-C between the K-924 HD and K-924 LD groups in each comparison at 4, 8, and 12 weeks and 2.1% of discontinuation rates. The significance level was set at a two-sided 5%. The allocation ratio was set at 1:1:1:1.
The number of patients was 288, 72 in each group, required to meet the primary efficacy analysis with a probability of ≥ 90% in the Monte Carlo simulation performed with the above conditions.
This clinical trial was conducted between April 2, 2020, and November 21, 2020. Written informed consent was obtained from 483 patients, 293 of whom were deemed eligible as a result of screening tests and were randomly allocated to one of the four treatment groups (73, 73, 73, and 74 patients in the PS 2 mg, PS 4 mg, K-924 LD, and K-924 HD groups, respectively). Of these, five patients discontinued their participation prior to the administration of the trial drug, and 288 patients were administered the trial drug (72 patients each in the PS 2 mg, PS 4 mg, K-924 LD, and K-924 HD groups). Two patients in the K-924 HD group discontinued their participation after the administration of the trial drug due to the occurrence of AEs, and 286 patients completed the clinical trial (Fig.2). The 288 patients who were administered the trial drug were set as the efficacy and safety analysis set. There were no large differences in the baseline characteristics between the groups (Table 1). As a whole, the average age was 56.1±9.0 years, 47.9% were men, baseline LDL-C was 166.1±20.2 mg/dL, and the proportion of patients by risk category based on JAS 2017 22) was 47.9% for low risk, 28.8% for moderate risk, and 23.3% for high risk.
＊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”.
| Pitavastatin | K-924 | Total | |||
|---|---|---|---|---|---|
| 2 mg | 4 mg | LD | HD | ||
| n=72 | n=72 | n=72 | n=72 | n=288 | |
| Age, year | 56.4±9.5 | 55.7±8.5 | 55.5±9.5 | 56.8±8.7 | 56.1±9.0 |
| Male, n (%) | 34 (47.2) | 34 (47.2) | 35 (48.6) | 35 (48.6) | 138 (47.9) |
| BMI, kg/m2 | 23.2±3.4 | 23.3±3.7 | 23.7±3.6 | 23.5±4.1 | 23.4±3.7 |
| Type 2 diabetes, n (%) | 7 (9.7) | 9 (12.5) | 10 (13.9) | 6 (8.3) | 32(11.1) |
| Hypertension, n (%) | 11 (15.3) | 9 (12.5) | 16 (22.2) | 17 (23.6) | 53 (18.4) |
| Risk Category of Atherosclerosis, n (%) | |||||
| Low Risk | 34 (47.2) | 35 (48.6) | 35 (48.6) | 34 (47.2) | 138 (47.9) |
| Intermediate Risk | 22 (30.6) | 20 (27.8) | 21 (29.2) | 20 (27.8) | 83 (28.8) |
| High Risk | 16 (22.2) | 17 (23.6) | 16 (22.2) | 18 (25.0) | 67 (23.3) |
| LDL-C, mg/dLa | 166.2±19.1 | 162.1±21.9 | 168.9±19.9 | 167.0±19.5 | 166.1±20.2 |
| Non-HDL-C, mg/dL | 189.6±22.1 | 185.8±23.6 | 197.5±22.0 | 191.3±19.9 | 191.1±22.2 |
| Cholesterol, mg/dL | 246.9±26.1 | 244.6±26.0 | 255.2±23.2 | 251.0±24.8 | 249.4±25.2 |
| Triglycerides, mg/dL | 103.3 (75.0, 144.0) | 106.5 (72.8, 153.8) | 121.8 (90.8, 176.0) | 106.0 (79.0, 144.0) | 110.3 (79.5, 155.0) |
Data are presented as mean±SD or median (interquartile range) for continuous parameters and as the number (%) of patients for categorical parameters.
BMI, body mass index; HD, high dose; K-924, pitavastatin ezetimibe fixed-dose combination; LD, low dose; LDL-C, low-density lipoprotein cholesterol; Non-HDL-C, non-high-density lipoprotein cholesterol; SD, standard deviation.
a: Friedewald formula
Fig.3 shows the primary endpoint results. Least-squares means of the percentage change in LDL-C from baseline at week 12 were −39.5%, −45.2%, −51.4%, and −57.8% in the PS 2 mg, PS 4 mg, K-924 LD, and K-924 HD groups, respectively, all of which were statistically significant. The primary efficacy analysis showed that the differences were −11.9% (95% CI, −15.2% to −8.7%; p=0.000) between the K-924 LD and PS 2 mg groups and −12.7% (95% CI, −15.9% to −9.4%; p=0.000) between the K-924 HD and PS 4 mg groups, showing that the fixed-dose combination drugs were superior to each corresponding dose of pitavastatin monotherapy. Furthermore, the K-924 HD group had a greater decrease in the point estimate of the percentage change in LDL-C than the K-924 LD group with a difference of −6.4%, which was statistically significant with the 95% CI of −9.6% to −3.2% and a p-value of ≤ 0.001 shown by a secondary analysis. The reductions in LDL-C were significant and stable throughout the treatment periods of 4, 8, and 12 weeks (Fig.4, Supplementary Table 2).
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
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
| Baseline | Week 4 | Week 8 | Week 12 | ||
|---|---|---|---|---|---|
| Pitavastatin 2 mg | Value (n) | 166.2±19.1 (72) | 102.5±16.4 (72) | 101.4±17.9 (72) | 100.2±15.6 (72) |
| % Change from BL | - | -38.2±7.9＊＊ | -38.9±8.3＊＊ | -39.5±8.3＊＊ | |
| Pitavastatin 4 mg | Value (n) | 162.1±21.9 (72) | 91.3±17.5 (72) | 88.3±16.7 (72) | 88.7±16.9 (72) |
| % Change from BL | - | -43.4±9.2＊＊ | -45.0±11.0＊＊ | -44.8±10.8＊＊ | |
| K-924 LD | Value (n) | 168.9±19.9 (72) | 81.5±16.7 (72) | 83.1±21.3 (72) | 81.5±21.2 (72) |
| % Change from BL | - | -51.6±8.7＊＊ | -50.6±11.7＊＊ | -51.7±11.3＊＊ | |
| K-924 HD | Value (n) | 167.0±19.5 (72) | 70.6±13.9 (72) | 71.5±13.7 (72) | 70.0±14.2 (70) |
| % Change from BL | - | -57.4±8.6＊＊ | -56.9±9.1＊＊ | -57.7±9.5 |
Data are presented as mean±SD. ＊＊: P＜0.01 vs. baseline by one sample t-test
LDL-C, low-density lipoprotein cholesterol; K-924, pitavastatin ezetimibe fixed-does combination; HD, high dose; LD, low dose; BL, baseline; SD, standard deviation
The percentage changes from baseline to week 12 in various efficacy parameters of the secondary endpoints are shown in Table 2 for non-HDL-C, HDL-C, TC, and TG; Supplementary Table 3 for RLP-C, ApoAI, ApoAII, ApoB, ApoB48, ApoCII, ApoCIII, ApoE, and Lp(a); and Fig.5 for lathosterol, beta-sitosterol, and campesterol. Non-HDL-C, TC, HDL-C, and TG showed a statistically significant improvement from baseline in all groups. The reductions in non-HDL-C and TC were significantly higher in the K-924 LD group than in the PS 2 mg group, in the K-924 HD group than in the PS 4 mg group, and the K-924 HD group than in the K-924 LD group. The percentage change in HDL-C did not significantly differ between the K-924 LD and PS 2 mg groups and between the K-924 HD and PS 4 mg groups. The K-924 LD group was superior to the PS 2 mg group in TG reduction, whereas there were no statistically significant differences between the K-924 HD and PS 4 mg groups and between the K-924 LD and K-924 HD groups. Parameters in which absolute values of the percentage change that were larger in the K-924 LD group than in the PS 2 mg group were RLP-C, ApoAII, ApoB, ApoB48, ApoCII, and ApoCIII. Parameters in which absolute values of the percentage change that were larger in the K-924 HD group than in the PS 4 mg group were RLP-C, ApoB, ApoB48, and ApoCII (Supplementary Table 3). The reductions in beta-sitosterol and campesterol in the K-924 LD and K-924 HD groups were significantly larger than those in the PS 2 mg and PS 4 mg groups, respectively. In contrast, the reductions in lathosterol in the fixed-dose combination groups were smaller than in those of the pitavastatin monotherapy groups (Fig.5). Subgroup analysis of the percentage change in LDL-C is shown in Supplementary Table 4.
| Pitavastatin | K-924 | ||||
|---|---|---|---|---|---|
| 2 mg | 4 mg | LD | HD | ||
| Non-HDL-C, | Baseline | 189.6±22.1 | 185.8±23.6 | 197.5±22.0 | 191.3±19.9 |
| mg/dL | Week 12 | 119.4±19.6 | 106.6±19.6 | 101.8±21.6 | 87.1±17.6 |
| %Change | -37.0±1.1＊＊ | -42.3±1.1＊＊ | -48.1±1.1＊＊ | -54.5±1.1＊＊ | |
| P vs. K-924 LD | 0.000‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| HDL-C, | Baseline | 57.3±17.2 | 58.8±15.5 | 57.7±14.5 | 59.7±15.6 |
| mg/dL | Week 12 | 60.7±16.9 | 61.4±16.3 | 62.2±14.3 | 62.7±15.1 |
| %Change | 6.6±1.2＊＊ | 5.0±1.2＊＊ | 8.9±1.2＊＊ | 6.4±1.3＊＊ | |
| P vs. K-924 LD | 0.202 | ||||
| P vs. K-924 HD | 0.435 | ||||
| P vs. K-924 HD | 0.163 | ||||
| TC, mg/dL | Baseline | 246.9±26.1 | 244.6±26.0 | 255.2±23.2 | 251.0±24.8 |
| Week 12 | 180.1±22.2 | 168.0±20.9 | 164.0±24.7 | 149.8±20.8 | |
| %Change | -27.1±0.9＊＊ | -31.2±0.9＊＊ | -35.3±0.9＊＊ | -40.3±0.9＊＊ | |
| P vs. K-924 LD | 0.000‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| TG, mg/dL | Baseline | 119.3±71.2 | 118.6±57.5 | 144.4±75.3 | 122.9±63.1 |
| Week 12 | 95.4±44.9 | 89.4±41.9 | 103.1±61.4 | 85.8±41.5 | |
| %Change | -15.4±2.7＊＊ | -21.9±2.7＊＊ | -23.2±2.7＊＊ | -26.0±2.7＊＊ | |
| P vs. K-924 LD | 0.043† | ||||
| P vs. K-924 HD | 0.283 | ||||
| P vs. K-924 HD | 0.474 | ||||
Data are presented as mean±SD for values at baseline and week 12 and LS mean±SE for %Changes at week 12.
%Changes during the 12 weeks were estimated using the mixed model for repeated measurements (MMRM) with the treatment group, time point, interaction between the treatment group and time point, and risk category of JAS 2017 as fixed effects and baseline value of the lipid parameter 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.
＊＊: P＜0.01 vs. baseline by one-sample t-test for LS Means with MMRM.
‡: P ≤ 0.01, †: P ≤ 0.05 Pitavastatin 2 mg vs. K-924 LD, Pitavastatin 4 mg vs. K-924 HD, K-924 LD vs. K-924 HD by MMRM.
HD, high dose; HDL-C, high-density lipoprotein cholesterol; JAS 2017, Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017; K-924, pitavastatin ezetimibe fixed-dose combination; LD, low dose; LS, least squares; MMRM, mixed model for repeated measurements; Non-HDL-C, non-high-density lipoprotein cholesterol; SD, standard deviation; SE, standard error; TC, total cholesterol; TG, triglyceride
| Pitavastatin | K-924 | ||||
|---|---|---|---|---|---|
| 2 mg | 4 mg | LD | HD | ||
| RLP-C, | Baseline | 7.6±6.4 (n= 72) | 7.3±3.8 (n= 72) | 9.0±5.1 (n= 72) | 7.9±4.4 (n= 72) |
| mg/dL | Week 12 | 3.3±2.0 (n= 72) | 2.8±1.7 (n= 72) | 3.4±3.0 (n= 72) | 2.4±2.0 (n= 70) |
| %Change | -51.1±2.8＊＊ | -58.2±2.8＊＊ | -59.5±2.8＊＊ | -70.2±2.8＊＊ | |
| P vs. K-924 LD | 0.033† | ||||
| P vs. K-924 HD | 0.002‡ | ||||
| P vs. K-924 HD | 0.007† | ||||
| ApoAI, | Baseline | 144.2±25.7 (n= 71) | 145.8±20.2 (n= 72) | 148.3±21.2 (n= 72) | 148.6±21.6 (n= 72) |
| mg/dL | Week 12 | 147.3±23.8 (n= 71) | 147.1±22.1 (n= 72) | 151.8±21.3 (n= 72) | 149.2±20.2 (n= 70) |
| % Change | 2.4±0.9＊ | 0.9±0.9 | 2.9±0.9＊＊ | 1.1±0.9 | |
| P vs. K-924 LD | 0.715 | ||||
| P vs. K-924 HD | 0.866 | ||||
| P vs. K-924 HD | 0.172 | ||||
| ApoAII, | Baseline | 32.8±6.0 (n= 71) | 33.3±5.4 (n= 72) | 34.8±6.2 (n= 72) | 33.7±6.2 (n= 72) |
| mg/dL | Week 12 | 34.8±7.0 (n= 71) | 34.9±6.9 (n= 72) | 35.0±7.0 (n= 72) | 34.8±6.2 (n= 70) |
| %Change | 6.2±1.5＊＊ | 4.8±1.5＊＊ | 1.4±1.5 | 3.7±1.5＊ | |
| P vs. K-924 LD | 0.024† | ||||
| P vs. K-924 HD | 0.617 | ||||
| P vs. K-924 HD | 0.274 | ||||
| ApoB, | Baseline | 107.6±12.7 (n= 71) | 106.0±13.5 (n= 72) | 111.7±12.2 (n= 72) | 107.7±10.5 (n= 72) |
| mg/dL | Week 12 | 77.2±11.7 (n= 71) | 70.5±12.6 (n= 72) | 68.5±12.4 (n= 72) | 60.3±11.1 (n= 70) |
| %Change | -28.1±1.2＊＊ | -33.5±1.2＊＊ | -37.9±1.2＊＊ | -44.1±1.2＊＊ | |
| P vs. K-924 LD | 0.000‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| ApoB48, | Baseline | 7.9±6.1 (n= 71) | 8.2±6.2 (n= 68) | 9.6±7.6 (n= 67) | 8.1±5.4 (n= 68) |
| mg/L | Week 12 | 8.5±7.3 (n= 70) | 7.3±6.2 (n= 68) | 7.5±5.8 (n= 66) | 5.8±5.1 (n= 65) |
| %Change | 11.4±6.0 | -0.2±6.0 | -9.1±6.1 | -18.5±6.2＊＊ | |
| P vs. K-924 LD | 0.018† | ||||
| P vs. K-924 HD | 0.034† | ||||
| P vs. K-924 HD | 0.282 | ||||
| ApoCII, | Baseline | 5.3±2.0 (n= 71) | 5.5±2.1 (n= 72) | 6.4±3.1 (n= 72) | 5.7±1.8 (n= 72) |
| mg/dL | Week 12 | 4.4±1.6 (n= 71) | 4.5±1.8 (n= 72) | 4.4±1.6 (n= 72) | 4.0±1.5 (n= 70) |
| %Change | -15.2±2.1＊＊ | -16.1±2.1＊＊ | -26.4±2.1＊＊ | -29.5±2.1＊＊ | |
| P vs. K-924 LD | 0.000‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| P vs. K-924 HD | 0.292 | ||||
| ApoCIII, | Baseline | 11.2±3.6 (n= 71) | 11.3±3.4 (n= 72) | 12.6±4.4 (n= 72) | 11.7±2.9 (n= 72) |
| mg/dL | Week 12 | 9.8±2.8 (n= 71) | 9.6±3.0 (n= 72) | 9.9±3.1 (n= 72) | 9.5±2.6 (n= 70) |
| %Change | -11.5±2.0＊＊ | -14.1±1.9＊＊ | -19.1±2.0＊＊ | -18.0±2.0＊＊ | |
| P vs. K-924 LD | 0.006‡ | ||||
| P vs. K-924 HD | 0.161 | ||||
| P vs. K-924 HD | 0.693 | ||||
| ApoE, | Baseline | 3.1±0.9 (n= 71) | 3.1±0.8 (n= 72) | 3.4±1.0 (n= 72) | 3.1±0.9 (n= 72) |
| mg/dL | Week 12 | 2.2±0.6 (n= 71) | 2.2±0.7 (n= 72) | 2.2±0.7 (n= 72) | 2.0±0.7 (n= 70) |
| %Change | -28.1±1.7＊＊ | -30.7±1.7＊＊ | -32.3±1.7＊＊ | -34.9±1.8＊＊ | |
| P vs. K-924 LD | 0.089 | ||||
| P vs. K-924 HD | 0.095 | ||||
| P vs. K-924 HD | 0.305 | ||||
| Lp(a), | Baseline | 18.5±21.2 (n= 71) | 17.4±14.3 (n= 72) | 18.8±16.7 (n= 72) | 17.8±18.3 (n= 72) |
| mg/dL | Week 12 | 17.2±22.3 (n= 71) | 16.1±15.5 (n= 72) | 17.4±19.1 (n= 72) | 17.9±20.5 (n= 70) |
| %Change | -15.3±3.7＊＊ | -13.9±3.7＊＊ | -16.6±3.7＊＊ | -8.4±3.7＊ | |
| P vs. K-924 LD | 0.811 | ||||
| P vs. K-924 HD | 0.291 | ||||
| P vs. K-924 HD | 0.115 | ||||
Data are presented as mean±SD for values at baseline and week 12 and LS mean±SE for %Change at week 12.
n; Number of patients included in ANCOVA
%Changes at week 12 were estimated by ANCOVA with the treatment group and risk category according to JAS 2017 as fixed effects and the baseline value of the lipid parameter as a covariate.
＊＊: P＜0.01, ＊: P＜0.05 vs. baseline by one-sample t-test for LS Means with ANCOVA.
‡: P ≤ 0.01, †: P ≤ 0.05 Pitavastatin 2 mg vs. K-924 LD, Pitavastatin 4 mg vs. K-924 HD, K-924 LD vs. K-924 HD by ANCOVA.
ANCOVA, analysis of covariance; Apo, apolipoprotein; HD, high dose; JAS 2017, Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017; K-924, pitavastatin ezetimibe fixed-dose combination; LD, low dose; Lp(a), lipoprotein (a); LS, least squares; RLP-C, remnant like particle cholesterol; SD, standard deviation; SE, standard error
(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
| Pitavastatin | K-924 | ||||
|---|---|---|---|---|---|
| 2 mg | 4 mg | LD | HD | ||
| Age, years | |||||
| ＜65 | %Change | -39.0±1.3＊＊ (n= 57) | -44.6±1.3＊＊ (n= 57) | -51.1±1.3＊＊ (n= 57) | -58.9±1.3＊＊ (n= 58) |
| P vs. K-924 LD | 0.000‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| ≥ 65 | %Change | -41.2±2.4＊＊ (n= 15) | -47.2±2.4＊＊ (n= 15) | -52.6±2.4＊＊ (n= 15) | -54.0±2.5＊＊ (n= 14) |
| P vs. K-924 LD | 0.002‡ | ||||
| P vs. K-924 HD | 0.055 | ||||
| P vs. K-924 HD | 0.684 | ||||
| Type 2 diabetes | |||||
| No | %Change | -39.2±1.2＊＊ (n= 65) | -45.0±1.2 ＊＊ (n= 63) | -50.1±1.2＊＊ (n= 62) | -58.9±1.2＊＊ (n= 66) |
| P vs. K-924 LD | 0.000‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| Yes | %Change | -42.0±3.3＊＊ (n= 7) | -46.0±3.0＊＊ (n= 9) | -58.7±2.7＊＊ (n= 10) | -48.3±3.5 ＊＊ (n= 6) |
| P vs. K-924 LD | 0.001‡ | ||||
| P vs. K-924 HD | 0.631 | ||||
| P vs. K-924 HD | 0.027† | ||||
| Hypertension | |||||
| No | %Change | -39.9±1.2 ＊＊ (n= 61) | -45.3±1.2 ＊＊ (n= 63) | -50.8±1.3 ＊＊ (n= 56) | -59.4±1.3＊＊ (n= 55) |
| P vs. K-924 LD | 0.000‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| Yes | %Change | -37.4±3.2＊＊ (n= 11) | -44.3±3.6＊＊ (n= 9) | -53.7±2.7＊＊ (n= 16) | -52.6±2.5＊＊ (n= 17) |
| P vs. K-924 LD | 0.000‡ | ||||
| P vs. K-924 HD | 0.062 | ||||
| P vs. K-924 HD | 0.769 | ||||
| Risk Category based on JAS 2017 | |||||
| Low Risk | %Change | -40.0±1.5＊＊ (n= 34) | -48.2±1.5 ＊＊ (n= 35) | -51.3±1.5＊＊ (n= 35) | -61.6±1.6＊＊ (n= 34) |
| P vs. K-924 LD | 0.000‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| Moderate Risk | %Change | -39.2±1.9 ＊＊ (n= 22) | -41.8±2.0＊＊ (n= 20) | -49.0±2.0＊＊ (n= 21) | -57.9±2.0＊＊ (n= 20) |
| P vs. K-924 LD | 0.001‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| P vs. K-924 HD | 0.002‡ | ||||
| High Risk | %Change | -38.8±2.9 ＊＊ (n= 16) | -43.3±2.8＊＊ (n= 17) | -54.8±2.9 ＊＊ (n= 16) | -50.4±2.7＊＊ (n= 18) |
| P vs. K-924 LD | 0.000‡ | ||||
| P vs. K-924 HD | 0.080 | ||||
| P vs. K-924 HD | 0.260 | ||||
Data are presented as LS mean±SE for %Change. n: Number of patients included in MMRM analysis model. MMRM: an analysis model with treatment group, time point, the interaction between the treatment group and time point, and Risk Category of Atherosclerosis JAS 2017 as fixed effects and LDL-C baseline value as the covariate.
＊＊: P＜0.01 vs. baseline by one-sample t-test for LS Means with MMRM.
‡: P ≤ 0.01, †: P ≤ 0.05 Pitavastatin 2 mg vs. K-924 LD, Pitavastatin 4 mg vs. K-924 HD, K-924 LD vs. K-924 HD by MMRM.
HD, high dose; K-924, pitavastatin ezetimibe fixed-dose combination; JAS 2017, Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017; LD, low dose; LDL-C, low-density lipoprotein cholesterol; LS, least squares; MMRM, mixed model for repeated measurements; SE, standard error.
The LDL-C target achievement rates at week 12 were 100%, 98.6%, 97.2%, and 100% for the PS 2 mg, PS 4 mg, K-924 LD, and K-924 HD groups, respectively, with no significant difference between the K-924 LD and PS 2 mg groups and between the K-924 HD and PS 4 mg groups. The achievement rates in high-risk patients whose LDL-C should be ＜120 mg/dL were 100%, 94.1%, 100%, and 100% in the PS 2 mg, PS 4 mg, K-924 LD, and K-924 HD groups, respectively.
The percentage changes from baseline to week 12 in cholesterol, TG, and particle numbers of lipoprotein fractions measured by HPLC are shown in Supplementary Table 5. Cholesterol in the CM fraction did not significantly change in any group. Cholesterol in the VLDL and LDL fractions significantly decreased in all groups with significantly larger reductions in the K-924 LD and K-924 HD groups than in the PS 2 mg and PS 4 mg groups, respectively. Cholesterol for each of LDL subclass by particle size, that is large LDL, medium LDL, small LDL, and very small LDL were significantly reduced (Supplementary Table 6). The percentage changes in cholesterol in the HDL fraction were similar to those in HDL-C by the direct method as mentioned above.
| Pitavastatin | K-924 | ||||
|---|---|---|---|---|---|
| 2 mg | 4 mg | LD | HD | ||
| cholesterol (mg/dL) | |||||
| CM | %Change | 2.0±24.4 (n= 29) | 17.8±24.0 (n= 30) | 1.3±23.9 (n= 31) | -47.5±25.1 (n= 28) |
| P vs. K-924 LD | 0.984 | ||||
| P vs. K-924 HD | 0.062 | ||||
| P vs. K-924 HD | 0.165 | ||||
| VLDL | %Change | -39.8±3.2＊＊ (n= 29) | -45.3±3.1＊＊ (n= 30) | -53.4±3.1＊＊ (n= 31) | -60.7±3.2＊＊ (n= 28) |
| P vs. K-924 LD | 0.003‡ | ||||
| P vs. K-924 HD | 0.001‡ | ||||
| P vs. K-924 HD | 0.106 | ||||
| LDL | %Change | -34.2±1.9＊＊ (n= 29) | -40.5±1.9＊＊ (n= 30) | -48.7±1.8＊＊ (n= 31) | -53.0±2.0＊＊ (n= 28) |
| P vs. K-924 LD | 0.000‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| P vs. K-924 HD | 0.115 | ||||
| HDL | %Change | 5.2±2.0＊ (n= 29) | 4.2±2.0＊ (n= 30) | 8.3±1.9＊＊ (n= 31) | 5.1±2.0＊ (n= 28) |
| P vs. K-924 LD | 0.275 | ||||
| P vs. K-924 HD | 0.761 | ||||
| P vs. K-924 HD | 0.266 | ||||
| TG (mg/dL) | |||||
| CM | %Change | 37.4±26.9 (n= 29) | 25.3±26.4 (n= 30) | -7.3±26.2 (n= 31) | -31.5±27.5 (n= 28) |
| P vs. K-924 LD | 0.236 | ||||
| P vs. K-924 HD | 0.140 | ||||
| P vs. K-924 HD | 0.530 | ||||
| VLDL | %Change | -17.5±6.2＊＊ (n= 29) | -16.9±6.1＊＊ (n= 30) | -19.0±6.1＊＊ (n= 31) | -33.2±6.3＊＊ (n= 28) |
| P vs. K-924 LD | 0.860 | ||||
| P vs. K-924 HD | 0.066 | ||||
| P vs. K-924 HD | 0.110 | ||||
| LDL | %Change | -14.7±2.0＊＊ (n= 29) | -15.0±1.9＊＊ (n= 30) | -15.1±1.9＊＊ (n= 31) | -13.7±2.0＊＊ (n= 28) |
| P vs. K-924 LD | 0.911 | ||||
| P vs. K-924 HD | 0.635 | ||||
| P vs. K-924 HD | 0.628 | ||||
| HDL | %Change | 0.45±4.2 (n= 29) | -2.6±4.1 (n= 30) | -5.4±4.1 (n= 31) | -13.1±4.3＊＊ (n= 28) |
| P vs. K-924 LD | 0.320 | ||||
| P vs. K-924 HD | 0.081 | ||||
| P vs. K-924 HD | 0.200 | ||||
| Particle number (nM) | |||||
| CM | %Change | 24.4±24.4 (n= 29) | 23.5±24.0 (n= 30) | -4.6±23.8 (n= 31) | -35.0±25.1 (n= 28) |
| P vs. K-924 LD | 0.397 | ||||
| P vs. K-924 HD | 0.095 | ||||
| P vs. K-924 HD | 0.386 | ||||
| VLDL | %Change | -30.3±3.3＊＊ (n= 29) | -33.3±3.2＊＊ (n= 30) | -39.9±3.2＊＊ (n= 31) | -46.8±3.3＊＊ (n= 28) |
| P vs. K-924 LD | 0.038† | ||||
| P vs. K-924 HD | 0.004‡ | ||||
| P vs. K-924 HD | 0.137 | ||||
| LDL | %Change | -32.1±1.8＊＊ (n= 29) | -37.5±1.8＊＊ (n= 30) | -44.9±1.8＊＊ (n= 31) | -48.9±1.9＊＊ (n= 28) |
| P vs. K-924 LD | 0.000‡ | ||||
| P vs. K-924 HD | 0.000‡ | ||||
| P vs. K-924 HD | 0.126 | ||||
| HDL | %Change | 3.2±1.5＊ (n= 29) | 1.9±1.5 (n= 30) | 2.9±1.5 (n= 31) | -0.9±1.5 (n= 28) |
| P vs. K-924 LD | 0.886 | ||||
| P vs. K-924 HD | 0.200 | ||||
| P vs. K-924 HD | 0.079 | ||||
Data are presented as LS mean±SE for %Change.
n: Number of patients included in ANCOVA
%Changes at week 12 were estimated by ANCOVA with the treatment group and risk category according to JAS 2017 as fixed effects and the baseline value of the lipid parameter as the covariate.
＊＊: P＜0.01, ＊: P＜0.05 vs. baseline by one-sample t-test for LS Means with ANCOVA.
‡: P ≤ 0.01, †: P ≤ 0.05 Pitavastatin 2 mg vs. K-924 LD, Pitavastatin 4 mg vs. K-924 HD, K-924 LD vs. K-924 HD by ANCOVA.
ANCOVA, analysis of covariance; CM, chylomicrons; HDL, high-density lipoproteins; HPLC, High Performance Liquid Chromatography; JAS 2017, Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017; HD, high dose; HPLC, high- performance liquid chromatography; K-924, pitavastatin ezetimibe fixed-dose combination; LD, low dose; LDL, low-density lipoproteins; LS, least squares; SE, standard error; TG, triglycerides; VLDL, very low-density lipoproteins.
| Pitavastatin | K-924 | ||||
|---|---|---|---|---|---|
| 2 mg | 4 mg | LD | HD | ||
| n= 29 | n= 30 | n= 31 | n= 28 | ||
| Large LDL | Baseline | 34.8±8.5 | 35.8±9.9 | 33.7±8.2 | 37.3±7.4 |
| cholesterol, mg /dL | Week 12 | 22.3±5.1 | 20.1±4.2 | 16.6±3.4 | 16.4±4.3 |
| %Change | -35.2±10.0＊＊ | -41.2±14.6＊＊ | -48.8±13.0＊＊ | -54.8±12.6＊＊ | |
| Medium LDL | Baseline | 62.0±8.8 | 60.1±9.7 | 61.5±10.9 | 63.9±8.8 |
| cholesterol, mg /dL | Week 12 | 40.4±6.5 | 35.8±6.3 | 31.1±6.4 | 28.8±7.7 |
| %Change | -34.3±10.2＊＊ | -39.4±12.2＊＊ | -48.5±11.1＊＊ | -54.4±13.9＊＊ | |
| Small LDL | Baseline | 28.7±7.5 | 26.1±5.9 | 28.7±7.0 | 27.5±6.2 |
| cholesterol, mg /dL | Week 12 | 18.8±5.6 | 16.1±3.8 | 14.8±4.4 | 12.9±4.2 |
| %Change | -33.9±11.6＊＊ | -37.0±13.3＊＊ | -47.6±11.8＊＊ | -51.5±19.9＊＊ | |
| Very small LDL | Baseline | 11.0±2.6 | 10.1±2.1 | 11.0±2.6 | 10.6±2.2 |
| cholesterol, mg /dL | Week 12 | 7.4±2.0 | 6.4±1.3 | 6.0±1.6 | 5.3±1.3 |
| %Change | -32.5±11.0＊＊ | -35.2±11.9＊＊ | -45.2±11.3＊＊ | -48.8±17.7＊＊ | |
Data are presented as mean±SD.
n: The number of subjects who had both baseline and post baseline measurements.
＊＊: P＜0.01 vs. baseline by one sample t-test.
HD, high dose; HPLC, high-performance liquid chromatography; K-924, pitavastatin ezetimibe fixed-dose combination; LD, low dose; LDL, low- density lipoproteins; SD, standard deviation.
AEs in the PS 2 mg, PS 4 mg, K-924 LD, and K-924 HD groups were observed in 12 (16.7%), 19 (26.4%), 18 (25.0%), and 14 (19.4%) patients, respectively, and ADRs were in two (2.8%), five (6.9%), four (5.6%), and five (6.9%) patients, respectively (Table 3). There were no statistically significant differences in the incidence of AEs and ADRs between the K-924 LD and PS 2 mg groups as well as between the K-924 HD and PS 4 mg groups. Serious AEs included two cases in two patients in the PS 4 mg group (2.8%) (urinary calculus and prostate cancer), but a causal relationship with the trial drug was ruled out. AEs that resulted in discontinuation of the trial drug administration included two cases in two patients in the K-924 HD group (2.8%) (palmoplantar pustulosis and elevated ALT); for the latter, a causal relationship with the trial drug was not ruled out. This patient recovered after discontinuation of the trial drug administration. Palmoplantar pustulosis did not improve even after the discontinuation of the trial drug administration, or rather worsened; thus, a causal relationship was ruled out.
| Pitavastatin | K-924 | |||
|---|---|---|---|---|
|
2 mg n= 72 |
4 mg n= 72 |
LD n= 72 |
HD n= 72 |
|
| Adverse events, n (%) | 12 (16.7) | 19 (26.4) | 18 (25.0) | 14 (19.4) |
| P vs. K-924 LD | 0.305 | |||
| P vs. K-924 HD | 0.428 | |||
| Serious, n (%) | 0 | 2 (2.8) | 0 | 0 |
| Discontinuation, n (%) | 0 | 0 | 0 | 2 (2.8) |
| Incidence ≥ 2 patients in any group | ||||
| Nasopharyngitis | 2 (2.8) | 0 | 1 (1.4) | 0 |
| Alanine aminotransferase increased | 0 | 4 (5.6) | 2 (2.8) | 4 (5.6) |
| Aspartate aminotransferase increased | 0 | 0 | 1 (1.4) | 2 (2.8) |
| Blood creatine phosphokinase increased | 2 (2.8) | 3 (4.2) | 1 (1.4) | 0 |
| Gamma-glutamyltransferase increased | 0 | 2 (2.8) | 1 (1.4) | 0 |
| Platelet count decreased | 2 (2.8) | 0 | 0 | 0 |
| Urinary occult blood positive | 0 | 3 (4.2) | 1 (1.4) | 1 (1.4) |
| Back pain | 3 (4.2) | 0 | 0 | 0 |
| Rash | 2 (2.8) | 0 | 0 | 0 |
| Adverse drug reactions, n (%) | 2 (2.8) | 5 (6.9) | 4 (5.6) | 5 (6.9) |
| P vs. K-924 LD | 0.681 | |||
| P vs. K-924 HD | 1.000 | |||
| Serious, n (%) | 0 | 0 | 0 | 0 |
| Discontinuation, n (%) | 0 | 0 | 0 | 1 (1.4) |
Data are presented as the number (n) (%) of patients.
P value, Fisher’s exact test
K-924, pitavastatin ezetimibe fixed-dose combination; HD, high dose; LD, low dose
No patients had increased AST, ALT, or CK levels meeting the prespecified cutoff criteria (data not shown).
The changes in AST, ALT, γ-GT, CK, serum creatinine, eGFR, fasting blood glucose, insulin, HOMA-R, glycoalbumin, and HbA1c from baseline at week 12 are shown in Supplementary Table 7. The mean levels of liver function-related parameters, AST, ALT, and γ-GT, and muscle-related marker, CK, were significantly elevated but did not exceed the upper limit of the reference range in all groups except for the case of CK in PS 2 mg. The renal function parameters, creatinine and eGFR, and most glucose metabolism-related parameters did not change, whereas fasting blood glucose in the PS 4 mg group and HbA1c in all groups, except for PS 2 mg, were elevated. The mean value of HbA1c was within the reference range.
| Pitavastatin | K-924 | ||||
|---|---|---|---|---|---|
| 2 mg | 4 mg | LD | HD | ||
| n= 72 | n= 72 | n= 72 | n= 70 | ||
| AST, U/L | Baseline | 19.5±5.5 | 20.4±5.7 | 21.0±6.8 | 21.2±6.5 |
| Week 12 | 22.3±7.7 | 24.4±9.4 | 26.3±9.2 | 27.8±8.1 | |
| Change | 2.8±4.3＊＊ | 4.0±5.7＊＊ | 5.3±6.8＊＊ | 6.6±6.0＊＊ | |
| ALT, U/L | Baseline | 18.8±11.2 | 20.6±12.9 | 19.3±9.2 | 21.1±14.0 |
| Week 12 | 23.2±13.6 | 27.3±18.4 | 28.2±17.0 | 32.8±18.1 | |
| Change | 4.3±7.0＊＊ | 6.7±8.9＊＊ | 8.9±13.2＊＊ | 11.7±12.1＊＊ | |
| γ-GT, U/L | Baseline | 23.7±17.9 | 26.9±21.5 | 36.4±43.0 | 33.6±30.5 |
| Week 12 | 27.4±25.6 | 32.6±30.7 | 39.2±40.8 | 38.7±37.0 | |
| Change | 3.7±10.1＊＊ | 5.7±14.6＊＊ | 2.7±31.6＊ | 5.1±12.6＊＊ | |
| CK, U/L | Baseline | 114.0±62.9 | 112.4±51.7 | 114.3±55.0 | 114.7±59.3 |
| Week 12 | 128.9±79.5 | 163.2±249.6 | 133.8±78.6 | 136.7±72.4 | |
| Change | 14.9±64.6 | 50.9±247.7＊＊ | 19.6±48.2＊＊ | 22.0±50.5＊＊ | |
| Creatinine, mg/dL | Baseline | 0.79±0.18 | 0.76±0.13 | 0.78±0.17 | 0.79±0.17 |
| Week 12 | 0.79±0.19 | 0.76±0.13 | 0.78±0.15 | 0.79±0.17 | |
| Change | 0.00±0.07 | -0.00±0.05 | -0.00±0.08 | 0.01±0.04 | |
| eGFR, | Baseline | 70.0±11.2 | 72.4±9.6 | 71.5±11.4 | 70.7±11.3 |
| mL/min/1.73m² | Week 12 | 69.8±10.6 | 72.8±10.8 | 71.4±12.2 | 70.4±11.8 |
| Change | -0.2±6.4 | 0.4±4.8 | -0.1±6.2 | -0.4±4.8 | |
| Glucose, mg/dL | Baseline | 103.3±16.1 | 103.2±12.7 | 105.3±16.9 | 102.3±11.0 |
| Week 12 | 103.9±14.9 | 104.6±15.1 | 106.7±16.6 | 103.1±14.5 | |
| Change | 0.6±7.0 | 1.4±5.3＊ | 1.3±9.5 | 0.9±8.0 | |
| Insulin, mU/L | Baseline | 5.7±3.3 | 5.3±2.5 | 5.5±3.0 | 5.2±2.6 |
| Week 12 | 5.8±3.6 | 5.3±2.6 | 5.5±3.5 | 5.2±3.2 | |
| Change | 0.1±2.1 | 0.0±1.4 | 0.0±2.6 | 0.0±1.4 | |
| HOMA-R | Baseline | 1.5±1.0 | 1.4±0.7 | 1.5±0.9 | 1.3±0.7 |
| Week 12 | 1.5±1.0 | 1.4±0.8 | 1.5±1.1 | 1.4±0.9 | |
| Change | 0.01±0.60 | 0.04±0.40 | 0.05±0.90 | 0.02±0.40 | |
| GA, % | Baseline | 14.9±1.7 | 14.8±1.8 | 14.7±1.9 | 14.9±1.4 |
| Week 12 | 14.9±1.8 | 14.8±2.0 | 14.7±2.0 | 14.9±1.6 | |
| Change | 0.02±0.77 | 0.03±0.78 | -0.04±0.62 | 0.02±0.73 | |
| HbA1c, % | Baseline | 5.8±0.5 | 5.8±0.5 | 5.8±0.5 | 5.7±0.5 |
| Week 12 | 5.8±0.5 | 5.9±0.6 | 5.8±0.5 | 5.9±0.5 | |
| Change | 0.02±0.19 | 0.06±0.18＊＊ | 0.04±0.19＊＊ | 0.11±0.18＊＊ | |
Data are presented as mean±SD.
＊P＜0.05, ＊＊P＜0.01 vs. baseline by Wilcoxon signed-rank test.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; eGFR, estimated glomerular filtration rate; γ-GT, gamma glutamyl transpeptidase; GA, Glycoalbumin; HD, high dose; HbA1c, hemoglobin A1c; HOMA-R, homeostasis model assessment for insulin resistance; K-924, pitavastatin ezetimibe fixed-dose combination; LD, low dose.
The combination therapy with pitavastatin and ezetimibe, the components of the fixed-dose combination drugs used in the present trial, has been investigated in multiple clinical trials and shows greater reductions in LDL-C compared with pitavastatin monotherapy26-30). The efficacy and safety of the two formulations of the pitavastatin/ezetimibe fixed-dose combination over 12 weeks were confirmed in the present phase III, multicenter, active-controlled, randomized, double-blind, parallel-group comparative trial conducted under the Good Clinical Practice guidelines. In addition, markers of cholesterol synthesis and absorption were measured to investigate the pharmacological effects of each component, which has, to the best of our knowledge, not been done in previous studies. The percentage reductions in LDL-C in both formulations of the fixed-dose combination exceeded 50%, and the efficacy was superior to that of pitavastatin monotherapy. In a recent article from Taiwan, another formulation of a 2 mg pitavastatin/10 mg ezetimibe fixed-dose combination provided a 51% reduction in LDL-C from baseline to week 12 31), which is similar to that provided by a K-924 LD treatment in the current study.
A variety of evidence has established that the lower the LDL-C, the better the secondary prevention of CAD7). This concept is supported by coronary plaque imaging, whereby a positive relationship between LDL-C lowering and coronary plaque regression has been demonstrated32). In the JAS 2022 Guidelines, an LDL-C target level of ＜70 mg/dL should be considered for secondary prevention in patients with FH, ACS, diabetes, CAD, or atherothrombotic stroke (including other types of ischemic strokes complicated with established atheroma)6). Similarly, in the 2018 AHA/ACC/Multi-Society Guideline, the LDL-C target level is also ＜70 mg/dL aimed with maximally tolerated doses of statins in patients at very high risk for ASCVD including those with a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions, where the major ASCVD events are recent ACS, myocardial infarction, ischemic stroke, and symptomatic peripheral arterial disease. The high-risk conditions include age ≥ 65 years, FH, diabetes, hypertension, and CKD5). More strictly in the 2019 ESC/EAS Guidelines, the LDL-C target is to achieve both the reduction from baseline by ≥ 50% and ＜55 mg/dL in patients at very high risk, including those with ACS, FH complicated by ASCVD, and diabetes complicated by target organ damage and a reduction by ≥ 50% and ＜70 mg/dL in patients at high risk, including those with diabetes without target organ damage4). Thus, strict LDL-C targets are set for very high risk and high-risk patients in Europe, the United States, and Japan, and additional administration of ezetimibe to statins is recommended as the next step if LDL-C targets are not achieved. The IMPROVE-IT trial, which investigated the benefit of the additional administration of ezetimibe to simvastatin in patients with ACS, showed that adding ezetimibe further suppressed cardiovascular events33). The achieved LDL-C levels were approximately 70 and 50 mg/dL in the simvastatin and simvastatin/ezetimibe combination groups, respectively. Therefore, the benefit of additional administration of ezetimibe was confirmed at least in patients with ACS even when LDL-C was controlled at the level of 70 mg/dL with statins. Furthermore, the PRECISE-IVUS trial confirmed that further plaque regression was achieved by the addition of ezetimibe to statins34), suggesting beneficial effects for suppressing CAD. In the present trial, K-924 was confirmed to have a more potent LDL-C lowering effect than pitavastatin monotherapy, which should allow more patients, including those at high risk of ASCVD, to achieve the LDL-C management target.
Statins, by inhibiting the cholesterol synthesis pathway, decrease lathosterol, a cholesterol synthesis marker. However, this results in a compensatory increase in the cholesterol absorption markers, sitosterol and campesterol. This increase may be dose-dependent11, 35). Meanwhile, among the relatively potent statins, atorvastatin increases but rosuvastatin decreases sitosterol, and campesterol levels36), and atorvastatin increases NPC1L1 expression in the small intestine37). Hence, not only the dose but also the characteristics of the compound may modulate the effects of statins on cholesterol absorption. In the present trial, the levels of sitosterol and campesterol were not significantly changed in the pitavastatin monotherapy groups, suggesting that pitavastatin may be a statin that does not markedly increase the absorption markers. Pitavastatin induced the expression of LDL-receptor mRNA in HepG2 cells more efficiently than other lipophilic statins at the condition where cholesterol synthesis was inhibited to the same degree38). Therefore, different statins may provide different degrees of feedback in the liver and intestines in response to the inhibition of cholesterol synthesis. Pitavastatin is less likely to promote cholesterol absorption and does not compete with the inhibitory effect of ezetimibe on cholesterol absorption, thereby it is considered a reasonable partner of fixed-dose combination with ezetimibe.
Meanwhile, ezetimibe, with its inhibitory effect on cholesterol absorption, decreases sitosterol and campesterol but in compensation increases lathosterol39). The present trial showed that the combination of ezetimibe in the K-924 groups caused significant reductions in sitosterol and campesterol by approximately 50% and 60%, respectively. Although there were no statistically significant differences, those reductions were suggested to be greater in the K-924 HD group than in the K-924 LD group, which were similar to the results of a previous study showing that ezetimibe combination provided greater reductions in cholesterol absorption markers with high-intensity statins40). Cholesterol synthesis inhibition was slightly attenuated by K-924 compared with pitavastatin monotherapy; however, lathosterol decreased by 34.2% and 46.7% in the K-924 LD and HD groups, respectively.
The clinical significance of cholesterol absorption markers is not clear; however, high levels of cholesterol absorption markers were associated with the risk of CAD in several studies41-43). Furthermore, subgroup analyses of 4S42) and PROSPER44) suggested that the prevention of cardiovascular disease with statins may be attenuated in patients whose cholesterol uptake in the small intestine is enhanced. Therefore, the combined use of ezetimibe with statins is highly beneficial for patients with enhanced cholesterol absorption. The HIJ-PROPER trial of pitavastatin and ezetimibe combination in patients with ACS did not show a significant reduction in the primary endpoint composed of cardiovascular events but suggested a significant reduction in the high-sitosterol subgroup compared with pitavastatin monotherapy26, 45).
The population for whom treatment with K-924 may be considered at first should be those at higher risk who have difficulty in managing LDL-C sufficiently with statins alone such as patients with diabetes, patients with FH, and secondary prevention patients. The presence of diabetes is associated with an increased risk for atherosclerotic disease, and ACS patients with diabetes benefited more from the combined use of a statin and ezetimibe in preventing cardiovascular events than those without diabetes in the IMPROVE-IT trial46). A sub-analysis of PRECISE-IVUS showed a correlation between the percentage change in LDL-C and the change in atheroma volume in ACS patients with diabetes, suggesting the importance of intensive lipid-lowering therapies with a combination of statins and ezetimibe47). A meta-analysis that included IMPROVE-IT and PRECISE-IVUS showed greater benefit from the combined therapy of ezetimibe and statins in the prevention of major adverse cardiovascular events in patients with diabetes than those without diabetes48). When considering the prevention of cardiovascular disease through combination therapy in patients with diabetes, K-924 may provide a treatment option worth considering because of the component, pitavastatin, which has been shown to have neutral effects on glycemic control19). Furthermore, in the present trial, K-924 showed significant improvement in RLP-C as well as HDL-C and TG, which also help in the management of atherogenic lipoproteins and residual risk that are commonly observed abnormalities in patients with diabetes.
Regarding safety, there were no statistically significant differences in the incidence of AEs and ADRs between the PS 2 mg and K-924 LD groups or between the PS 4 mg and K-924 HD groups. A recent publication from Taiwan31) also reported no difference in the incidence of AEs between 2 mg pitavastatin and the 2 mg pitavastatin/10 mg ezetimibe fixed-dose combination. AEs such as muscular, hepatic, and renal disorders that are frequently associated with statins were also similar in the pitavastatin and K-924 groups and the mean changes in the markers for those AEs were within the reference range and showed no clinical significance.
The patients enrolled in the present trial were those for primary prevention. The efficacy and safety of K-924 in patients for secondary prevention, who require stricter LDL-C management, are to be confirmed. Furthermore, because hypercholesterolemia is treated over long periods, the long-term efficacy and safety of K-924 need to be confirmed. However, the safety and efficacy of the pitavastatin and ezetimibe combination therapy have been well established in the real-world setting during the past 15 years after both agents became clinically available. Those should be the same in the case of K-924 with a treatment adherence that is expected to be better than the combination therapy of these two drugs.
The pitavastatin/ezetimibe fixed-dose combination showed superior LDL-C-lowering effects than pitavastatin monotherapy due to the complementary pharmacological actions of the individual components. The safety profile was similar to that of pitavastatin monotherapy.
The authors would like to acknowledge the investigators and patients who participated in this study. This study was conducted at Medical Corporation Heishinkai OPHAC Hospital (Yasuko Owada), Medical Corporation Heishinkai OCROM Clinic (Satoshi Inoue), and Medical Corporation Heishinkai ToCROM Clinic (Osamu Matsuoka). This work was supported by Kowa Company, Ltd. The funder had a role in the study design, data collection, data analysis, and data interpretation in addition to the preparation, review, and approval of this manuscript. We would like to thank Editage (www.editage.com) for English language editing.
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.
