2024 Volume 31 Issue 3 Pages 288-305
Aim: Ezetimibe administration with ongoing statin therapy is an effective option for further lowering low-density lipoprotein cholesterol (LDL-C) levels. Thus, we investigated the long-term efficacy and safety of fixed-dose combination of pitavastatin/ezetimibe (K-924 LD: 2 mg/10 mg; K-924 HD: 4 mg/10 mg).
Methods: We conducted a phase III, multicenter, open-label trial involving patients with hypercholesterolemia receiving pitavastatin (2 or 4 mg) who had not achieved their LDL-C management target. Patients were enrolled into the K-924 LD and HD groups based on whether they had received pitavastatin 2 and 4 mg, respectively, and treated for 52 weeks. K-924 was administered orally once daily. The primary objective was to examine the percent change in LDL-C from baseline at week 52 with last observation carried forward imputation (LOCF) in all patients.
Results: Of the 109 patients evaluated, 62 and 47 were assigned to the K-924 LD and HD groups, respectively. In all patients, LDL-C decreased by -30.3±14.3% (p＜0.001) from baseline (134.4±37.9 mg/dL). Consequently, 91.8% and 37.5% of the patients for primary and secondary prevention reached their LDL-C management target, respectively. These results were consistent in both the K-924 LD and HD groups. In the safety analysis, a single adverse drug reaction occurred in a patient in the K-924 HD group.
Conclusion: After replacing pitavastatin monotherapy, K-924 was found to be effective and well-tolerated over 52 weeks. Thus, K-924 can contribute to intensifying LDL-C-lowering therapy without increasing the number of medications.
ClinicalTrials.gov Identifier: NCT04289662
The reduction of low-density lipoprotein cholesterol (LDL-C) levels has been associated with improved rates of cardiovascular morbidity and mortality1, 2), as reflected in the widely accepted statement “the lower, the better”. Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are representative drugs for LDL-C-lowering therapy, and have been proven to be highly effective in high-doses3-5). Meanwhile, different drug targets can be found among other cholesterol-lowering agents, such as with ezetimibe, which reduces cholesterol absorption by inhibiting Niemann-Pick C1-Like 1. However, although a wide range of lipid-lowering drugs are currently available, not all patients achieve their LDL-C management targets6).
Combination therapy with pharmaceuticals of varying mechanisms is an aggressive strategy for LDL-C-lowering treatment. For example, combined administration of statin and ezetimibe has shown a stronger LDL-C-lowering effect than statin monotherapy7). Moreover, the effectiveness of this combination therapy has been demonstrated in its ability to reduce cardiovascular events in the IMPROVE-IT trial8) and regress coronary plaque volume in the PRECISE-IVUS trial9). Current guidelines, including the Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2022, recommend combination therapy with ezetimibe or a proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor when the maximum tolerated dose of statins fails to achieve acceptable effectiveness10-12). In such cases, the use of fixed-dose combination drugs may help reduce polypharmacy, thus improving medication adherence.
Pitavastatin is approved in many countries with a maximum dose of 4 mg/day and is classified as a moderate-intensity statin in the ACC/AHA/Multi-society Guideline 2018 10). It is hardly metabolized by cytochrome P450 (CYP) and thus has a lower risk of drug-drug interactions mediated by CYP13). In the REAL-CAD trial, it was revealed that high-dose (4 mg/day) pitavastatin therapy reduced cardiovascular events in Japanese patients with stable coronary artery disease (CAD) when compared with low-dose (1 mg/day) therapy4). The LDL-C-lowering effect and safety of pitavastatin/ezetimibe combination therapy have been reported, but only over a treatment duration of 20 weeks or less14, 15).
In our previous phase 3, double-blind, randomized controlled trial, we reported the superiority of K-924, a fixed-dose combination of pitavastatin/ezetimibe (K-924 LD:2 mg/10 mg, K-924 HD:4 mg/10 mg) over pitavastatin monotherapy in reducing LDL-C levels after 12 weeks of treatment16). In this study, we investigated the LDL-C-lowering effect and safety of the K-924 fixed-dose combination of pitavastatin/ezetimibe over a period of 52 weeks.
This study was a phase III, 52-week, multicenter, open-label clinical trial (registered at clinicaltrials.gov as NCT04289662). Patients with hypercholesterolemia receiving pitavastatin (either 2 or 4 mg) who had not achieved their LDL-C management target were considered for study enrollment. This study was conducted at 13 sites in Japan, in compliance with the latest version of the Declaration of Helsinki and Good Clinical Practice, and was approved by the institutional review board. Patients received complete information regarding the study protocol and written informed consent was obtained prior to study enrollment.
PatientsThe inclusion criteria were as follows: (1) patients with hypercholesterolemia aged ≥ 20 years; (2) who had been receiving constant diet and/or exercise therapy for at least 4 weeks before the screening; (3) receiving pitavastatin 2 or 4 mg/day at least 4 weeks prior to the screening; and (4) whose LDL-C calculated by the Friedewald formula at screening met any of the following criteria according to the management category based on the JAS Guideline 2017 17): (a) primary prevention (low-risk): LDL-C ≥ 160 mg/dL; (b) primary prevention (intermediate-risk): LDL-C ≥ 140 mg/dL; (c) primary prevention (high-risk): LDL-C ≥ 120 mg/dL; (d) secondary prevention in patients with a history of CAD: LDL-C ≥ 100 mg/dL; and (e) secondary prevention in patients with a history of CAD with concomitant familial hypercholesterolemia (FH), acute coronary syndrome (ACS), or diabetes mellitus complicated by other high risk conditions: LDL-C ≥ 70 mg/dL. The main exclusion criteria were as follows: (1) patients with a creatinine kinase level at least 3 times the upper limit of normal (ULN); (2) alanine aminotransferase and aspartate aminotransferase levels at least 2 times the ULN; (3) type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus (T2DM) with HbA1c ≥ 8% at the screening; (4) uncontrolled hypertension with systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg at the screening; (5) an estimated glomerular filtration rate ＜30 mL/min/1.73 m2 at the screening or on dialysis; and (6) ACS or stroke developed within 12 months before consent procedure. The complete inclusion and exclusion criteria are presented in Supplementary Table 1.
| Inclusion criteria: |
| Subjects must meet all of the following criteria to be included in this study: |
| (1) Subjects with hypercholesterolemia aged ≥ 20 years old upon the consent procedure |
| (2) Subjects on a certain diet therapy and/or exercise therapy for ≥ 4 weeks before the date of the screening test |
| (3) Subjects on pitavastatin 2 mg/day or pitavastatin 4 mg/day for ≥ 4 weeks before the date of the screening test |
| (4) Subjects with LDL-C (Friedewald formula) at the screening met any of the following criteria proposed by the Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017 |
| - Primary prevention (low-risk): LDL-C ≥ 160 mg/dl |
| - Primary prevention (intermediate-risk): LDL-C ≥ 140 mg/dl |
| - Primary prevention (high-risk): LDL-C ≥ 120 mg/dl |
| - Secondary prevention in subjects with a history of coronary artery disease: LDL-C ≥ 100 mg/dl |
| - Secondary prevention in subjects with a history of coronary artery disease, with concomitant familial hypercholesterolemia, acute coronary syndrome, or diabetes mellitus complicated by other high-risk conditions: LDL-C ≥ 70 mg/dl |
| Exclusion criteria: |
| Subjects meeting any of the following criteria were excluded from this study. |
| (1) Subjects with a history of myopathy or rhabdomyolysis associated with pitavastatin or ezetimibe |
| (2) Subjects with a history of hypersensitivity to pitavastatin or ezetimibe |
| (3) Subjects with severe liver impairment (Child Pugh classification: Grade B or higher) or biliary obstruction |
| (4) Pregnant women, breastfeeding women, women planning to become pregnant or to breastfeed during the study, or women of childbearing potential not using specified contraception |
| (5) Subjects with CK not less than three times the ULN at the screening test |
| (6) Subjects with ALT and AST not less than twice the ULN at the screening test |
| (7) Subjects with type 1 diabetes mellitus or with poorly-controlled type 2 diabetes mellitus with HbA1c ≥ 8% at the screening test |
| (8) Subjects with poorly-controlled hypertension with a systolic blood pressure of ≥ 160 mmHg or diastolic blood pressure of ≥ 100 mmHg at the screening test |
| (9) Dialysis subjects or subjects with eGFR of ＜ 30 mL/min/1.73 m2 at the screening test |
| (10) Subjects complicated with heart failure of ≥ Grade III according to the NYHA functional classification |
| (11) Subjects with poorly-controlled arrhythmia |
| (12) Subjects with a poorly-controlled metabolic or endocrine disease |
| (13) Subjects complicated with malignant tumor, or subjects considered highly likely to relapse after remission |
| (14) Subjects who developed acute coronary syndrome or stroke within 12 months before consent procedure |
| (15) Subjects underwent either of the following blood sampling: whole blood sampling of ≥ 200 mL within 4 weeks, whole blood sampling of ≥ 400 mL within 12 weeks (males) or within 16 weeks (females), or apheresis (plasma/platelet components) within 2 weeks prior to the screening test |
| (16) Subjects with a history of severe drug allergy (e.g. anaphylactic shock) |
| (17) Subjects requiring prohibited concomitant medication throughout the study after the consent procedure |
| (18) Subjects with TG of ≥ 400 mg/dl at the time of the screening test |
| (19) Subjects undergoing LDL apheresis |
| (20) Subjects with malabsorption or a history thereof, or with a history of any other surgical treatment for the gastrointestinal tract (except appendectomy and surgical treatment of hernias etc.) deemed to affect absorption |
| (21) Subjects with alcohol dependence or drug addiction |
| (22) Subjects who participated in another clinical study and took an investigational drug other than a placebo containing no active ingredient within 16 weeks before the administration of the study drug or who plan to parallelly participate in another clinical study during participation in this study |
| (23) Subjects who have experience of K-924 treatment |
| (24) Subjects determined by the principal investigator or a sub-investigator as inappropriate for the study |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; eGFR, estimated glomerular filtration rate; LDL-C, low-density lipoprotein cholesterol; NYHA, New York Heart Association; TG, triglyceride; ULN, upper limit of normal
After obtaining informed consent, patients were screened to assess their eligibility within 4 to 56 days prior to study drug administration (screening period). Subsequently, patients who were initially receiving pitavastatin 2 and 4 mg (once daily) were placed into the K-924 LD and HD groups, respectively, where the study drugs (pitavastatin/ezetimibe K-924 LD: 2 mg/10 mg, K-924 HD: 4 mg/10 mg) were administered once daily after meals for 52 weeks (Fig.1). On-site visits were conducted during the treatment period at weeks 0, 4, 12, 24, 32, 40, and 52. Remote consultations were allowed only at week 4. Patients treated with K-924 LD and K-924 HD were allowed to switch to K-924 HD and receive additional drugs for dyslipidemia, respectively, at or after week 24 if they did not achieve their LDL-C management target even after 12 or more weeks of treatment and presented no safety issues.
Patients treated with K-924 LD and K-924 HD were allowed to switch to K-924 HD and to receive additional drugs for dyslipidemia, respectively, at or after week 24, if they did not achieve their LDL-C management targets even after 12 or more weeks of treatment and present no safety issues.
Blood sampling was performed under fasting conditions, in which patients did not consume any food or drinks other than water for at least 10 h. The following lipid parameters were measured: total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), triglycerides (TG), remnant-like particle cholesterol (RLP-C) and several apolipoproteins. LDL-C was calculated using the Friedewald formula [LDL-C=TC−HDL-C−(TG/5)], applicable when the TG value was ＜400 mg/dL; otherwise, LDL-C measurement by the direct method was used. Non-HDL-C was calculated as TC−HDL-C. In addition, beta-sitosterol and campesterol, which are cholesterol absorption markers, and lathosterol, a cholesterol synthesis marker, were also measured. Safety parameters including adverse events (AEs), adverse drug reactions (ADRs), laboratory data, and vital signs were assessed throughout the treatment period.
The primary objective was to examine the percent change in LDL-C from baseline at week 52 with last observation carried forward imputation (LOCF) in all enrolled patients. Subgroup analyses of the abovementioned were performed according to the baseline LDL-C level, the baseline lathosterol, beta-sitosterol, and campesterol level, risk category of the JAS guideline 2017, and the presence or absence of T2DM and FH. Other efficacy measurements were as follows: (1) percent change from baseline in lipid-related parameters at week 40 or 52 (LOCF) or each time point, and (2) achievement rate of the LDL-C management target recommended in the JAS Guideline 2017. The safety objectives include evaluating (1) the incidence of AEs and ADRs and (2) changes in clinical laboratory values from baseline. AEs that occurred during the treatment period were collected regardless of causality to the study drug; drug-related AEs were defined as ADRs. These events were reported based on physician judgment. The names of AEs or ADRs were read using MedDRA ver. 24.0. All biochemical analyses were performed by the LSI Medience Corporation (Chiyoda-ku, Tokyo, Japan).
Statistical AnalysisAt the start of the trial, the sample size (n=110) was determined based on the guidelines of the International Council for Harmonisation-E1 (Population Exposure: The Extent of Population Exposure to Assess Clinical Safety). The efficacy analysis set included all patients who were administered K-924 at least once and had baseline and postbaseline efficacy measurements. The safety analysis set included all patients who received K-924 at least once. To evaluate the achievement rate of LDL-C management target as well as changes in lipid parameters, missing data at week 52 were imputed using the LOCF method. The term “week 52 (LOCF)” is used throughout the manuscript to distinguish between the imputed and non-imputed results. The efficacy and safety analyses were performed in all patients, and separately in the K-924 LD and HD groups. The patients who switched from K-924 LD to K-924 HD during the treatment period were still included in the K-924 LD group. Comparison of baseline and post-baseline data was performed using a one-sample t-test for efficacy parameters and the Wilcoxon signed-rank test for safety parameters. Continuous and dichotomous variables are presented as mean±standard deviation and the number of patients (percentage), respectively. The significance level was set at a two-sided p-value of 0.05. Statistical analysis system ver. 9.4 (SAS Institute, Inc., Cary, NC, USA) was used for all analyses.
Trial enrollment began in March 2020, and follow-up was completed in August 2021. Informed consent was obtained from 130 patients, of which 110 patients who fulfilled the eligibility criteria were enrolled in the trial. One patient assigned to the K-924 LD group was incorrectly administered a K-924 HD tablet. Therefore, the patient was assigned to the K-924 HD group. Another patient assigned to the K-924 LD group was excluded from the analyses according to the definition of the efficacy and safety analysis sets because of absence of clinical visit and unavailability of post-treatment information. Thus, 109 patients (62 and 47 in the K-924 LD and K-924 HD groups, respectively) were included in the efficacy and safety analysis sets (Supplementary Fig.1). During the treatment period, six patients in the K-924 LD group were switched to treatment with K-924 HD, and three patients in the K-924 HD group received additional medications for dyslipidemia because they did not reach their LDL-C management target.
One patient assigned to the K-924 LD group was incorrectly administered a K-924 HD tablet. Therefore, the patient was assigned to the K-924 HD group.
The baseline patients’ characteristics are presented in Table 1. In all patients, the mean age was 63.3 years and 67.9% of patients were men. Additionally, 46.8% of patients presented with T2DM. Seven patients with FH (6.4%) were included in this trial, which is an autosomal dominant inherited disease often caused by mutations in the LDL receptor gene. Of these, three were heterozygous FH and four were unknown. In total, 44% of patients were categorized into secondary prevention according to the JAS Guideline 2017. Mean LDL-C at baseline was 134.4, 133.3, and 135.9 mg/dL for the total patients, the K-924 LD group, and the HD group, respectively.
| Total (n = 109) | K-924 LD (n = 62) | K-924 HD (n = 47) | |
|---|---|---|---|
| Age, yr | 63.3±10.1 | 63.8±8.9 | 62.7±11.7 |
| Male | 74 (67.9) | 42 (67.7) | 32 (68.1) |
| Body mass index, kg/m2 | 24.9±3.4 | 24.6±3.5 | 25.3±3.4 |
| LDL-C, mg/dL | 134.4±37.9 | 133.3±33.2 | 135.9±43.7 |
| Total cholesterol, mg/dL | 214.6±43.1 | 212.9±38.6 | 216.9±48.9 |
| Non-HDL-C, mg/dL | 159.7±39.3 | 156.9±32.7 | 163.3±46.8 |
| HDL-C, mg/dL | 55.0±14.4 | 56.0±13.9 | 53.6±15.0 |
| Triglyceride, mg/dL | 127.2±57.0 | 118.1±52.6 | 139.1±60.8 |
| Type 2 diabetes mellitus | 51 (46.8) | 30 (48.4) | 21 (44.7) |
| Hypertension | 84 (77.1) | 47 (75.8) | 37 (78.7) |
| Familial hypercholesterolemia | 7 (6.4) | 2 (3.2) | 5 (10.6) |
| Risk category of JAS Guideline 2017 | |||
| Primary prevention (total) | 61 (56.0) | 40 (64.5) | 21 (44.7) |
| Low risk | 4 (3.7) | 1 (1.6) | 3 (6.4) |
| Intermediate risk | 8 (7.3) | 5 (8.1) | 3 (6.4) |
| High risk | 49 (45.0) | 34 (54.8) | 15 (31.9) |
| Secondary prevention (total) | 48 (44.0) | 22 (35.5) | 26 (55.3) |
| History of CAD | 7 (6.4) | 5 (8.1) | 2 (4.3) |
| History of CAD with high-risk conditions | 41 (37.6) | 17 (27.4) | 24 (51.1) |
Data are presented as mean±standard deviation or number of patients (%).
Abbreviations: CAD, coronary artery disease; HDL-C, high-density lipoprotein cholesterol; JAS, Japan Atherosclerosis Society; LDL-C, low-density lipoprotein cholesterol.
In all patients, mean percent change in LDL-C from baseline was -30.3±14.3% at week 52 (LOCF) (n=109, p＜0.001). This LDL-C reduction was sustained over 52 weeks (Supplementary Table 2). Additionally, mean percent changes in LDL-C at week 52 (LOCF) were -29.5±11.7% (n=62, p＜0.001) and -31.3±17.2% (n=47, p＜0.001) in the K-924 LD and HD groups, respectively (Fig.2, Table 2). For the six patients who underwent up-titration from K-924 LD to K-924 HD, the mean LDL-C levels at baseline, before up-titration, and post up-titration (week 52 [LOCF]) were 133.4±47.2, 96.3±12.6, and 83.6±19.3 mg/dL, respectively, showing a 13.8±11.4% further reduction with up-titration compared to before up-titration. After excluding these six patients in the K-924 LD group, the mean percent change in LDL-C was -28.9±11.8% (n=56, p＜0.001). Similarly, after excluding the three patients who received additional medications for dyslipidemia in the K-924 HD group, the mean percent change in LDL-C was -29.1±14.5% (n=44, p＜0.001).
| Baseline | Week 4 | Week 12 | Week 24 | Week 32 | Week 40 | Week 52 | Week 52 (LOCF) | ||
|---|---|---|---|---|---|---|---|---|---|
| LDL-C | |||||||||
| Total | n | 109 | 98 | 107 | 106 | 107 | 106 | 106 | 109 |
| Mean±SD | 134.4±37.9 | 97.5±34.0 | 95.5±38.3 | 96.4±35.2 | 95.4±25.2 | 92.2±26.3 | 90.8±23.9 | 91.3±23.8 | |
| % change | -29.0±13.1 | -28.6±14.1 | -27.4±14.4 | -26.7±15.5 | -29.6±14.2 | -30.4±14.5 | -30.3±14.3 | ||
| K-924 LD | n | 62 | 55 | 61 | 60 | 61 | 60 | 60 | 62 |
| Mean±SD | 133.3±33.2 | 93.6±20.8 | 91.7±22.2 | 94.4±21.1 | 96.7±22.6 | 92.1±21.8 | 92.0±22.0 | 92.7±22.1 | |
| % change | -30.6±11.1 | -29.8±12.1 | -27.3±13.3 | -25.6±14.5 | -29.4±12.3 | -29.6±11.9 | -29.5±11.7 | ||
| K-924 HD | n | 47 | 43 | 46 | 46 | 46 | 46 | 46 | 47 |
| Mean±SD | 135.9±43.7 | 102.4±45.4 | 100.5±52.5 | 99.1±48.0 | 93.7±28.5 | 92.4±31.5 | 89.2±26.3 | 89.4±26.0 | |
| % change | -26.9±15.2 | -27.0±16.4 | -27.5±15.9 | -28.2±16.9 | -29.9±16.5 | -31.3±17.4 | -31.3±17.2 | ||
| HDL-C | |||||||||
| Total | n | 109 | 98 | 107 | 106 | 107 | 106 | 106 | 109 |
| Mean±SD | 55.0±14.4 | 56.3±14.4 | 56.9±14.8 | 59.0±14.9 | 60.0±16.2 | 60.9±16.1 | 57.8±15.9 | 57.6±15.9 | |
| % change | 1.9±8.5 | 3.8±9.9 | 7.5±9.8 | 9.3±12.8 | 10.7±13.0 | 4.9±12.1 | 5.3±13.3 | ||
| K-924 LD | n | 62 | 55 | 61 | 60 | 61 | 60 | 60 | 62 |
| Mean±SD | 56.0±13.9 | 57.8±13.0 | 57.2±13.6 | 60.3±14.6 | 61.3±15.5 | 61.3±15.0 | 60.1±16.4 | 60.1±16.1 | |
| % change | 2.4±8.2 | 2.8±8.0 | 7.5±8.4 | 9.9±13.1 | 9.4±11.4 | 6.6±11.1 | 7.5±13.1 | ||
| K-924 HD | n | 47 | 43 | 46 | 46 | 46 | 46 | 46 | 47 |
| Mean±SD | 53.6±15.0 | 54.4±15.9 | 56.4±16.4 | 57.4±15.3 | 58.3±17.1 | 60.4±17.5 | 54.7±15.0 | 54.3±15.1 | |
| % change | 1.3±8.8 | 5.2±11.8 | 7.5±11.4 | 8.5±12.4 | 12.3±14.8 | 2.6±13.2 | 2.3±13.2 | ||
| non-HDL-C | |||||||||
| Total | n | 109 | 98 | 107 | 106 | 107 | 106 | 106 | 109 |
| Mean±SD | 159.7±39.3 | 119.4±36.7 | 117.7±40.1 | 118.1±37.4 | 117.1±26.2 | 113.7±28.2 | 112.5±24.6 | 113.3±24.9 | |
| % change | -26.3±12.8 | -25.7±13.4 | -25.0±13.8 | -24.5±15.3 | -27.0±13.8 | -27.4±14.2 | -27.3±14.1 | ||
| K-924 LD | n | 62 | 55 | 61 | 60 | 61 | 60 | 60 | 62 |
| Mean±SD | 156.9±32.7 | 113.4±21.6 | 113.4±24.1 | 114.2±21.5 | 117.0±23.4 | 112.6±21.6 | 111.5±23.0 | 112.9±23.9 | |
| % change | -28.2±10.9 | -26.4±12.0 | -25.3±12.9 | -23.7±13.8 | -26.4±12.4 | -27.5±11.8 | -27.3±11.7 | ||
| K-924 HD | n | 47 | 43 | 46 | 46 | 46 | 46 | 46 | 47 |
| Mean±SD | 163.3±46.8 | 127.0±49.1 | 123.3±54.4 | 123.2±51.1 | 117.2±29.8 | 115.0±35.1 | 113.9±26.8 | 114.0±26.5 | |
| % change | -24.0±14.7 | -24.9±15.3 | -24.6±15.0 | -25.5±17.2 | -27.8±15.5 | -27.4±17.0 | -27.4±16.9 | ||
| Triglycerides | |||||||||
| Total | n | 109 | 98 | 107 | 106 | 107 | 106 | 106 | 109 |
| Mean±SD | 127.2±57.0 | 111.2±58.2 | 112.8±49.9 | 109.9±61.1 | 109.9±56.9 | 109.3±65.7 | 110.7±57.6 | 112.3±58.4 | |
| % change | -10.4±25.6 | -7.0±25.9 | -9.8±34.7 | -11.0±27.4 | -12.5±27.0 | -9.0±29.8 | -8.9±29.6 | ||
| K-924 LD | n | 62 | 55 | 61 | 60 | 61 | 60 | 60 | 62 |
| Mean±SD | 118.1±52.6 | 99.1±45.7 | 108.8±45.4 | 99.2±50.7 | 101.6±47.1 | 102.7±52.7 | 97.3±45.6 | 100.7±49.2 | |
| % change | -11.3±24.3 | -2.9±24.6 | -11.5±25.0 | -10.5±24.3 | -9.1±27.7 | -11.6±27.6 | -11.4±27.5 | ||
| K-924 HD | n | 47 | 43 | 46 | 46 | 46 | 46 | 46 | 47 |
| Mean±SD | 139.1±60.8 | 126.6±68.6 | 118.0±55.4 | 123.9±70.7 | 120.8±66.8 | 117.9±79.3 | 128.2±66.8 | 127.7±66.2 | |
| % change | -9.1±27.4 | -12.5±26.8 | -7.6±44.5 | -11.5±31.2 | -16.9±25.8 | -5.6±32.5 | -5.7±32.1 |
Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LOCF, last observation carried forward; SD, standard deviation
All panels show the time courses of the mean percent change in lipid parameters after switching from pitavastatin 2 and 4 mg to K-924 LD and HD, respectively. Error bars represent the standard deviation. In each panel, the time courses are shown for all patients (total), the K-924 LD group, and the HD group. Panels A through D show low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides, respectively. The LOCF denotes the last observation carried forward.
| Group | n | Baseline | Week 52 (LOCF) | % change | p | |
|---|---|---|---|---|---|---|
| LDL-C, mg/dL | Total | 109 | 134.4±37.9 | 91.3±23.8 | -30.3±14.3 | ＜0.001 |
| K-924 LD | 62 | 133.3±33.2 | 92.7±22.1 | -29.5±11.7 | ＜0.001 | |
| K-924 HD | 47 | 135.9±43.7 | 89.4±26.0 | -31.3±17.2 | ＜0.001 | |
| Total cholesterol, mg/dL | Total | 109 | 214.6±43.1 | 171.0±30.1 | -19.3±11.4 | ＜0.001 |
| K-924 LD | 62 | 212.9±38.6 | 173.0±31.0 | -18.3±9.4 | ＜0.001 | |
| K-924 HD | 47 | 216.9±48.9 | 168.3±29.0 | -20.5±13.7 | ＜0.001 | |
| Non-HDL-C, mg/dL | Total | 109 | 159.7±39.3 | 113.3±24.9 | -27.3±14.1 | ＜0.001 |
| K-924 LD | 62 | 156.9±32.7 | 112.9±23.9 | -27.3±11.7 | ＜0.001 | |
| K-924 HD | 47 | 163.3±46.8 | 114.0±26.5 | -27.4±16.9 | ＜0.001 | |
| HDL-C, mg/dL | Total | 109 | 55.0±14.4 | 57.6±15.9 | 5.3±13.3 | ＜0.001 |
| K-924 LD | 62 | 56.0±13.9 | 60.1±16.1 | 7.5±13.1 | ＜0.001 | |
| K-924 HD | 47 | 53.6±15.0 | 54.3±15.1 | 2.3±13.2 | 0.239 | |
| Triglycerides, mg/dL | Total | 109 | 127.2±57.0 | 112.3±58.4 | -8.9±29.6 | 0.002 |
| K-924 LD | 62 | 118.1±52.6 | 100.7±49.2 | -11.4±27.5 | 0.002 | |
| K-924 HD | 47 | 139.1±60.8 | 127.7±66.2 | -5.7±32.1 | 0.234 | |
| RLP-C, mg/dLa | Total | 109 | 6.3±3.8 | 3.7±3.0 | -37.4±37.1 | ＜0.001 |
| K-924 LD | 62 | 5.6±3.0 | 3.5±2.5 | -32.7±39.4 | ＜0.001 | |
| K-924 HD | 47 | 7.2±4.5 | 3.9±3.6 | -43.6±33.3 | ＜0.001 | |
| Lathosterol, mg/La | Total | 109 | 1.8±0.9 | 2.1±0.8 | 37.4±51.3 | ＜0.001 |
| K-924 LD | 62 | 1.7±0.8 | 2.2±0.7 | 42.5±47.7 | ＜0.001 | |
| K-924 HD | 47 | 1.8±1.1 | 2.0±0.8 | 30.8±55.6 | ＜0.001 | |
| Beta-sitosterol, mg/La | Total | 109 | 3.5±1.7 | 1.9±1.1 | -43.4±23.4 | ＜0.001 |
| K-924 LD | 62 | 3.6±1.8 | 2.0±1.3 | -42.9±27.6 | ＜0.001 | |
| K-924 HD | 47 | 3.3±1.6 | 1.7±0.7 | -44.2±16.6 | ＜0.001 | |
| Campesterol, mg/La | Total | 109 | 6.5±3.4 | 2.8±2.2 | -55.8±26.5 | ＜0.001 |
| K-924 LD | 62 | 6.8±3.5 | 3.0±2.8 | -55.1±32.5 | ＜0.001 | |
| K-924 HD | 47 | 6.1±3.4 | 2.4±1.1 | -56.6±15.8 | ＜0.001 |
Data are presented as the mean±standard deviation. P values were calculated using a one-sample t-test.
a Data were evaluated at week 40 (LOCF).
Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; RLP-C, remnant-like particle cholesterol; LOCF, last observation carried forward.
Changes in LDL-C level at week 52 (LOCF) from baseline in the subgroups are shown in Supplementary Table 3. The mean percent changes in LDL-C were -26.4±10.8% (p＜0.001) from 107.6±16.7 mg/dL in the low LDL-C subgroup (n=54, ＜median of baseline LDL-C), and -34.1±16.3% (p＜0.001) from 160.7±34.3 mg/dL in the high LDL-C subgroup (n=55, ≥ median of baseline LDL-C). Subgroups stratified by median values of baseline lathosterol, beta-sitosterol, and campesterol, showed similar percent changes in LDL-C (Supplementary Table 3). As for patients with FH, the mean percent changes in LDL-C were -37.2±29.8% (p=0.016) from 195.7±56.5 mg/dL in the FH group (n=7), and -29.8±12.7% (p＜0.001) from 130.2±32.7 mg/dL in the non-FH group (n=102).
| Subgroup | Group | n | LDL-C | p | ||
|---|---|---|---|---|---|---|
| Baseline, mg/dL |
Week 52 (LOCF), mg/dL |
% change | ||||
| Baseline LDL-C | ||||||
| ＜ median | Total | 54 | 107.6±16.7 | 79.4±17.3 | -26.4±10.8 | ＜0.001 |
| K-924 LD | 29 | 108.7±17.3 | 78.8±16.4 | -27.6±10.1 | ＜0.001 | |
| K-924 HD | 25 | 106.4±16.4 | 80.1±18.5 | -25.1±11.6 | ＜0.001 | |
| ≥ median | Total | 55 | 160.7±34.3 | 103.0±23.7 | -34.1±16.3 | ＜0.001 |
| K-924 LD | 33 | 154.9±28.4 | 105.0±19.0 | -31.2±12.9 | ＜0.001 | |
| K-924 HD | 22 | 169.3±40.9 | 99.9±29.6 | -38.4±19.9 | ＜0.001 | |
| Baseline Lathosterol | ||||||
| ＜ median | Total | 52 | 126.0±28.2 | 87.0±21.9 | -30.0±13.5 | ＜0.001 |
| K-924 LD | 26 | 124.6±22.8 | 87.7±20.7 | -29.6±11.4 | ＜0.001 | |
| K-924 HD | 26 | 127.3±33.1 | 86.4±23.4 | -30.3±15.5 | ＜0.001 | |
| ≥ median | Total | 57 | 142.0±43.8 | 95.2±25.0 | -30.6±15.1 | ＜0.001 |
| K-924 LD | 36 | 139.5±38.1 | 96.4±22.6 | -29.4±12.1 | ＜0.001 | |
| K-924 HD | 21 | 146.4±53.0 | 93.0±29.1 | -32.6±19.4 | ＜0.001 | |
| Baseline Beta-sitosterol | ||||||
| ＜ median | Total | 54 | 119.4±25.2 | 84.1±18.9 | -29.0±11.6 | ＜0.001 |
| K-924 LD | 28 | 118.7±21.9 | 83.8±17.7 | -28.9±10.7 | ＜0.001 | |
| K-924 HD | 26 | 120.2±28.7 | 84.4±20.4 | -29.0±12.7 | ＜0.001 | |
| ≥ median | Total | 55 | 149.1±42.5 | 98.4±26.1 | -31.6±16.5 | ＜0.001 |
| K-924 LD | 34 | 145.3±36.2 | 100.1±22.9 | -30.0±12.6 | ＜0.001 | |
| K-924 HD | 21 | 155.2±51.4 | 95.6±31.1 | -34.2±21.5 | ＜0.001 | |
| Baseline Campesterol | ||||||
| ＜ median | Total | 54 | 119.5±25.4 | 83.9±18.8 | -29.1±11.5 | ＜0.001 |
| K-924 LD | 29 | 119.4±22.0 | 84.8±18.3 | -28.6±10.4 | ＜0.001 | |
| K-924 HD | 25 | 119.6±29.3 | 82.9±19.7 | -29.7±12.9 | ＜0.001 | |
| ≥ median | Total | 55 | 149.0±42.4 | 98.5±26.1 | -31.4±16.6 | ＜0.001 |
| K-924 LD | 33 | 145.5±36.7 | 99.7±23.0 | -30.3±12.8 | ＜0.001 | |
| K-924 HD | 22 | 154.3±50.3 | 96.7±30.5 | -33.2±21.3 | ＜0.001 | |
| Type 2 diabetes mellitus | ||||||
| No | Total | 58 | 141.0±43.9 | 94.2±22.6 | -30.4±14.6 | ＜0.001 |
| K-924 LD | 32 | 138.2±38.5 | 95.7±20.2 | -29.1±11.4 | ＜0.001 | |
| K-924 HD | 26 | 144.5±50.3 | 92.3±25.4 | -32.0±18.0 | ＜0.001 | |
| Yes | Total | 51 | 126.8±28.3 | 88.0±25.0 | -30.2±14.1 | ＜0.001 |
| K-924 LD | 30 | 128.0±26.0 | 89.6±23.8 | -30.0±12.2 | ＜0.001 | |
| K-924 HD | 21 | 125.2±31.9 | 85.7±27.0 | -30.5±16.6 | ＜0.001 | |
| Familial hypercholesterolemia | ||||||
| No | Total | 102 | 130.2±32.7 | 89.9±22.0 | -29.8±12.7 | ＜0.001 |
| K-924 LD | 60 | 131.6±32.0 | 91.3±21.0 | -29.7±11.8 | ＜0.001 | |
| K-924 HD | 42 | 128.1±33.9 | 87.8±23.5 | -30.0±14.1 | ＜0.001 | |
| Yes | Total | 7 | 195.7±56.5 | 111.3±39.1 | -37.2±29.8 | 0.016 |
| K-924 LD | 2 | 181.8±41.7 | 134.4±10.5 | -24.7±11.5 | 0.202 | |
| K-924 HD | 5 | 201.2±65.0 | 102.1±43.6 | -42.2±34.5 | 0.052 | |
| Risk category of the JAS guideline 2017 | ||||||
| Primary Prevention: Low-risk | Total | 4 | 187.4±25.8 | 138.3±6.4 | -25.3±8.9 | 0.011 |
| K-924 LD | 1 | 211.2 | 141.8 | -32.9 | - | |
| K-924 HD | 3 | 179.5±25.0 | 137.1±7.3 | -22.8±9.0 | 0.049 | |
| Primary Prevention: Intermediate-risk | Total | 8 | 192.2±60.1 | 106.8±20.5 | -39.1±21.4 | 0.001 |
| K-924 LD | 5 | 181.2±44.6 | 119.0±12.9 | -31.4±17.3 | 0.015 | |
| K-924 HD | 3 | 210.3±88.8 | 86.5±12.6 | -52.0±24.7 | 0.068 | |
| Primary Prevention: High-risk | Total | 49 | 142.8±18.8 | 95.7±20.5 | -32.0±15.0 | ＜0.001 |
| K-924 LD | 34 | 139.5±14.3 | 97.7±17.0 | -30.0±11.0 | ＜0.001 | |
| K-924 HD | 15 | 150.4±25.2 | 91.4±27.1 | -36.9±21.2 | ＜0.001 | |
| Secondary Prevention | Total | 48 | 111.7±30.9 | 80.2±20.8 | -27.5±11.9 | ＜0.001 |
| K-924 LD | 22 | 109.2±31.4 | 76.9±18.8 | -28.5±12.2 | ＜0.001 | |
| K-924 HD | 26 | 113.8±30.8 | 83.0±22.3 | -26.7±11.7 | ＜0.001 | |
| Secondary Prevention: History of CAD | Total | 7 | 133.1±41.6 | 96.7±15.2 | -24.3±15.8 | 0.007 |
| K-924 LD | 5 | 140.0±48.8 | 96.3±14.7 | -27.9±14.2 | 0.012 | |
| K-924 HD | 2 | 115.7±2.1 | 97.8±22.9 | -15.3±21.4 | 0.496 | |
| Secondary Prevention: History of CAD with high-risk conditionsa | Total | 41 | 108.0±27.7 | 77.4±20.4 | -28.1±11.2 | ＜0.001 |
| K-924 LD | 17 | 100.1±17.8 | 71.2±16.1 | -28.7±12.1 | ＜0.001 | |
| K-924 HD | 24 | 113.7±32.1 | 81.8±22.3 | -27.6±10.8 | ＜0.001 | |
Data are presented as the mean±standard deviation. P values were calculated using a one-sample t-test. a High-risk conditions indicate familial hypercholesterolemia, acute coronary syndrome, or diabetes complicated by other high-risk conditions. Abbreviations: CAD, coronary artery disease; JAS, Japan Atherosclerosis Society; LDL-C, low-density lipoprotein cholesterol; LOCF, last observation carried forward.
The achievement rates at week 52 (LOCF) are presented in Table 3. In all patients, the achievement rate for primary and secondary prevention was 91.8% and 37.5%, respectively. Among the patients for secondary prevention, the achievement rate for those with a LDL-C management target of ＜70 mg/dL (n=41) was 34.1% (K-924 LD: 35.3%; K-924 HD: 33.3%). In this category, baseline LDL-C was 108.0±27.7 mg/dL, which decreased by 30.7±15.5% (p＜0.001).
| Risk category of JAS Guideline 2017 |
LDL-C management target |
Achievement rate | |||||
|---|---|---|---|---|---|---|---|
| Total | K-924 LD | K-924 HD | |||||
| n/total n | % | n/total n | % | n/total n | % | ||
| Primary prevention | |||||||
| Low-risk | ＜160 mg/dL | 4 / 4 | 100 | 1 / 1 | 100 | 3 / 3 | 100 |
| Intermediate-risk | ＜140 mg/dL | 8 / 8 | 100 | 5 / 5 | 100 | 3 / 3 | 100 |
| High-risk | ＜120 mg/dL | 44 / 49 | 89.8 | 31 / 34 | 91.2 | 13 / 15 | 86.7 |
| Overall | - | 56 / 61 | 91.8 | 37 / 40 | 92.5 | 19 / 21 | 90.5 |
| Secondary prevention | |||||||
| History of CAD | ＜100 mg/dL | 4 / 7 | 57.1 | 3 / 5 | 60 | 1 / 2 | 50 |
| History of CAD with high-risk conditions | ＜70 mg/dL | 14 / 41 | 34.1 | 6 / 17 | 35.3 | 8 / 24 | 33.3 |
| Overall | - | 18 / 48 | 37.5 | 9 / 22 | 40.9 | 9 / 26 | 34.6 |
Abbreviations: CAD, coronary artery disease; JAS, Japan Atherosclerosis Society; LDL-C, low-density lipoprotein cholesterol; LOCF, last observation carried forward.
The mean percent changes in other lipid-related parameters are shown in Table 2. In all patients, non-HDL-C, TC, TG, and RLP-C levels significantly decreased by 27.3±14.1% (p＜0.001), 19.3±11.4% (p＜0.001), 8.9±29.6% (p=0.002), and 37.4±37.1% (p＜0.001), respectively, and HDL-C significantly increased (p＜0.001). For non-HDL-C, TC, and RLP-C levels, significant reduction was observed in both the K-924 LD and HD groups. The TG level significantly decreased in the K-924 LD group (p=0.002) but not in the K-924 HD group (p=0.234). HDL-C level significantly increased only in the K-924 LD group (p＜0.001), whereas apolipoprotein AI level significantly increased in both the groups (K-924 LD: 5.2%, p＜0.001; K-924 HD: 5.1%, p=0.002; Supplementary Table 4). The changes in these parameters at each time point are shown in Supplementary Table 2.
| Group | n | Baseline | Week 40 (LOCF) | % change | p | |
|---|---|---|---|---|---|---|
| Apolipoprotein AI, mg/dL | Total | 109 | 143.3±20.7 | 150.2±22.8 | 5.1±10.1 | ＜0.001 |
| K-924 LD | 62 | 144.6±19.5 | 151.4±20.3 | 5.2±10.1 | ＜0.001 | |
| K-924 HD | 47 | 141.6±22.3 | 148.7±25.9 | 5.1±10.4 | 0.002 | |
| Apolipoprotein AII, mg/dL | Total | 109 | 33.9±6.3 | 33.9±5.5 | 1.0±10.7 | 0.339 |
| K-924 LD | 62 | 33.8±6.4 | 33.6±4.9 | 0.7±11.6 | 0.623 | |
| K-924 HD | 47 | 34.0±6.3 | 34.3±6.2 | 1.3±9.6 | 0.348 | |
| Apolipoprotein B, mg/dL | Total | 109 | 96.7±18.7 | 77.5±16.6 | -18.9±13.4 | ＜0.001 |
| K-924 LD | 62 | 94.9±17.0 | 77.0±13.4 | -18.1±11.5 | ＜0.001 | |
| K-924 HD | 47 | 99.0±20.8 | 78.2±20.1 | -20.1±15.7 | ＜0.001 | |
| Apolipoprotein B48, mg/dL | Total | 106 | 8.0±6.1 | 13.7±16.0 | 84.0±129.3 | ＜0.001 |
| K-924 LD | 62 | 7.6±6.1 | 13.5±14.5 | 94.0±131.9 | ＜0.001 | |
| K-924 HD | 44 | 8.6±6.0 | 13.9±18.0 | 69.9±125.8 | 0.001 | |
| Apolipoprotein CII, mg/dL | Total | 109 | 5.6±2.2 | 4.8±1.9 | -12.7±20.2 | ＜0.001 |
| K-924 LD | 62 | 5.4±2.2 | 4.7±1.8 | -10.3±18.8 | ＜0.001 | |
| K-924 HD | 47 | 5.9±2.1 | 4.8±2.0 | -15.9±21.7 | ＜0.001 | |
| Apolipoprotein CIII, mg/dL | Total | 109 | 11.7±3.5 | 10.4±3.8 | -10.0±19.8 | ＜0.001 |
| K-924 LD | 62 | 11.4±3.6 | 10.0±3.1 | -10.5±18.5 | ＜0.001 | |
| K-924 HD | 47 | 12.0±3.3 | 10.9±4.4 | -9.4±21.6 | 0.005 | |
| Apolipoprotein E, mg/dL | Total | 109 | 2.9±1.1 | 2.3±1.0 | -16.8±23.4 | ＜0.001 |
| K-924 LD | 62 | 2.8±1.1 | 2.3±1.0 | -16.9±23.6 | ＜0.001 | |
| K-924 HD | 47 | 2.9±1.0 | 2.4±1.1 | -16.7±23.5 | ＜0.001 |
Data are presented as the mean±standard deviation. P values were calculated using a one-sample t-test.
Abbreviations: LOCF, last observation carried forward.
Beta-sitosterol and campesterol levels significantly decreased (p＜0.001), whereas the lathosterol level was found to have significantly increased in all patients (p＜0.001). These significant changes were also observed in the K-924 LD and HD groups.
SafetyA summary of AEs and ADRs is shown in Table 4. A total of 15 serious AEs were observed in 12 patients (K-924 LD: six patients with eight events, K-924 HD: six patients with seven events), in which one patient with one event (lung adenocarcinoma) discontinued K-924 LD. However, none of these 15 events were judged as an ADR by the investigators. The incidence of AEs in all patients, the K-924 LD group, and the HD group were 59.6%, 58.1%, and 61.7%, respectively. The most frequent AE was arthralgia (six patients with six events: 5.5%). An ADR occurred in one patient (one event; blood creatine phosphokinase (CK) level increased) in the K-924 HD group (0.9%). In this case, CK was 202 U/L at week 0, but increased to 843 U/L at week 12, which was considered an ADR (reference range: 40–150 U/L). K-924 HD was continued thereafter, and the CK level recovered to near baseline at 287, 438, 125 and 151 U/L (Weeks 24, 32, 40 and 52, respectively). No patients showed increased alanine aminotransferase or aspartate aminotransferase levels ≥ 3×ULN for two consecutive time points, or an increased blood creatine phosphokinase level ≥ 10×ULN. Blood glucose and HbA1c levels were slightly, but significantly, increased from 113.6±17.8 to 116.1±22.1 mg/dL (p=0.049), and 6.39±0.72 to 6.55±0.85 % (p＜0.001) at Week 52 (LOCF), respectively (Supplementary Table 5). The results were similar in patients with or without T2DM (Supplementary Table 6). The findings from the laboratory and physiological tests, including glucose metabolism, revealed no clinically relevant changes following K-924 treatment.
| Total (n = 109) | K-924 LD (n = 62) | K-924 HD (n = 47) | |
|---|---|---|---|
| Adverse events | 65 (59.6) [129] | 36 (58.1) [70] | 29 (61.7) [59] |
| Serious adverse events | 12 (11.0) [15] | 6 (9.7) [8] | 6 (12.8) [7] |
| Adverse events leading to study drug discontinuation | 1 (0.9) [1] | 1 (1.6) [1] | 0 (0.0) [0] |
| Adverse events observed in ≥ 2 patients | |||
| Vertigo | 3 (2.8) [4] | 1 (1.6) [1] | 2 (4.3) [3] |
| Constipation | 2 (1.8) [3] | 2 (3.2) [3] | 0 (0.0) [0] |
| Diarrhoea | 2 (1.8) [2] | 1 (1.6) [1] | 1 (2.1) [1] |
| Large intestine polyp | 3 (2.8) [3] | 3 (4.8) [3] | 0 (0.0) [0] |
| Oedema peripheral | 3 (2.8) [3] | 2 (3.2) [2] | 1 (2.1) [1] |
| Pyrexia | 2 (1.8) [2] | 1 (1.6) [1] | 1 (2.1) [1] |
| Gastroenteritis | 2 (1.8) [2] | 2 (3.2) [2] | 0 (0.0) [0] |
| Nasopharyngitis | 3 (2.8) [4] | 0 (0.0) [0] | 3 (6.4) [4] |
| COVID-19 | 2 (1.8) [2] | 0 (0.0) [0] | 2 (4.3) [2] |
| Tooth fracture | 2 (1.8) [2] | 2 (3.2) [2] | 0 (0.0) [0] |
| Type 2 diabetes mellitus | 2 (1.8) [2] | 0 (0.0) [0] | 2 (4.3) [2] |
| Arthralgia | 6 (5.5) [6] | 3 (4.8) [3] | 3 (6.4) [3] |
| Back pain | 3 (2.8) [3] | 2 (3.2) [2] | 1 (2.1) [1] |
| Periarthritis | 2 (1.8) [2] | 1 (1.6) [1] | 1 (2.1) [1] |
| Carotid artery stenosis | 2 (1.8) [2] | 1 (1.6) [1] | 1 (2.1) [1] |
| Headache | 2 (1.8) [3] | 1 (1.6) [2] | 1 (2.1) [1] |
| Rash | 3 (2.8) [3] | 2 (3.2) [2] | 1 (2.1) [1] |
| Urticaria | 2 (1.8) [2] | 1 (1.6) [1] | 1 (2.1) [1] |
| Peripheral arterial occlusive disease | 2 (1.8) [2] | 2 (3.2) [2] | 0 (0.0) [0] |
| Adverse drug reactions | 1 (0.9) [1] | 0 (0.0) [0] | 1 (2.1) [1] |
| Blood creatine phosphokinase increased | 1 (0.9) [1] | 0 (0.0) [0] | 1 (2.1) [1] |
| Serious adverse drug reactions | 0 (0.0) [0] | 0 (0.0) [0] | 0 (0.0) [0] |
| Adverse drug reactions leading to study drug discontinuation | 0 (0.0) [0] | 0 (0.0) [0] | 0 (0.0) [0] |
Data are presented as the number of patients (%) [number of events].
| Group | n | Baseline | Week 52 (LOCF) | change | p | |
|---|---|---|---|---|---|---|
| AST, U/L | Total | 109 | 23.0±6.0 | 25.0±8.0 | 2.0±7.2 | ＜0.001 |
| K-924 LD | 62 | 22.1±5.9 | 23.4±5.7 | 1.2±5.1 | 0.067 | |
| K-924 HD | 47 | 24.2±6.1 | 27.1±9.9 | 3.0±9.2 | 0.001 | |
| ALT, U/L | Total | 109 | 23.0±10.7 | 25.8±11.6 | 2.8±9.6 | ＜0.001 |
| K-924 LD | 62 | 22.0±10.2 | 24.2±10.5 | 2.2±8.0 | 0.031 | |
| K-924 HD | 47 | 24.3±11.4 | 27.8±12.7 | 3.4±11.5 | 0.002 | |
| γ-GTP, U/L | Total | 109 | 33.6±24.3 | 32.2±24.7 | -1.4±12.9 | 0.098 |
| K-924 LD | 62 | 30.1±19.8 | 27.8±14.8 | -2.3±10.7 | 0.2 | |
| K-924 HD | 47 | 38.3±28.7 | 38.0±32.8 | -0.3±15.4 | 0.346 | |
| ALP, U/L | Total | 109 | 73.4±19.4 | 72.8±22.8 | -0.6±11.5 | 0.032 |
| K-924 LD | 62 | 71.6±20.7 | 72.0±25.0 | 0.4±12.5 | 0.429 | |
| K-924 HD | 47 | 75.9±17.4 | 74.0±19.9 | -2.0±10.1 | 0.022 | |
| CK, U/L | Total | 109 | 151.7±87.9 | 155.9±107.6 | 4.1±86.1 | 0.866 |
| K-924 LD | 62 | 146.1±75.0 | 162.5±95.5 | 16.4±68.0 | 0.114 | |
| K-924 HD | 47 | 159.2±102.9 | 147.1±122.2 | -12.1±103.9 | 0.151 | |
| Glucose, mg/dL | Total | 109 | 113.6±17.8 | 116.1±22.1 | 2.5±16.1 | 0.049 |
| K-924 LD | 62 | 113.2±18.5 | 113.6±19.7 | 0.4±15.4 | 0.249 | |
| K-924 HD | 47 | 114.1±17.1 | 119.4±24.6 | 5.3±16.7 | 0.063 | |
| HbA1c, % | Total | 109 | 6.39±0.72 | 6.55±0.85 | 0.16±0.34 | ＜0.001 |
| K-924 LD | 62 | 6.39±0.74 | 6.52±0.83 | 0.13±0.35 | ＜0.001 | |
| K-924 HD | 47 | 6.40±0.71 | 6.59±0.88 | 0.19±0.33 | ＜0.001 |
Data are presented as the mean±standard deviation. P-values were calculated using Wilcoxon signed-rank test.
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; γ-GTP, gamma-glutamyl transpeptidase; CK, creatine kinase; LOCF, last observation carried forward.
| Subgroup | Group | n | Baseline | Week 52 (LOCF) | Change | p |
|---|---|---|---|---|---|---|
| Patients without T2DM | ||||||
| Glucose | Total | 58 | 103.1±8.6 | 105.5±12.6 | 2.4±9.3 | 0.039 |
| K-924 LD | 32 | 101.8±8.9 | 102.8±8.8 | 0.9±5.7 | 0.243 | |
| K-924 HD | 26 | 104.7±8.2 | 109.0±15.7 | 4.3±12.2 | 0.064 | |
| HbA1c | Total | 58 | 5.83±0.32 | 5.95±0.40 | 0.12±0.19 | ＜0.001 |
| K-924 LD | 32 | 5.79±0.26 | 5.89±0.31 | 0.10±0.15 | 0.001 | |
| K-924 HD | 26 | 5.89±0.37 | 6.03±0.49 | 0.15±0.22 | ＜0.001 | |
| Patients with T2DM | ||||||
| Glucose | Total | 51 | 125.6±18.1 | 128.2±24.3 | 2.6±21.5 | 0.366 |
| K-924 LD | 30 | 125.4±18.3 | 125.2±21.6 | -0.2±21.6 | 0.622 | |
| K-924 HD | 21 | 125.8±18.3 | 132.4±27.7 | 6.6±21.3 | 0.437 | |
| HbA1c | Total | 51 | 7.03±0.49 | 7.23±0.70 | 0.20±0.45 | ＜0.001 |
| K-924 LD | 30 | 7.02±0.52 | 7.19±0.67 | 0.17±0.48 | 0.009 | |
| K-924 HD | 21 | 7.04±0.46 | 7.28±0.76 | 0.25±0.42 | 0.023 |
Data are presented as the mean±standard deviation.
Abbreviations: T2DM, Type 2 diabetes mellitus.
This clinical trial was designed to confirm the enhanced LDL-C lowering effect and long-term efficacy of K-924, the fixed-dose combination drug of pitavastatin/ezetimibe, primarily attributed to the action of ezetimibe 10 mg. In all patients, the LDL-C level was significantly reduced by -30.3±14.3% after switching to K-924 from pitavastatin monotherapy. This reduction was sustained for 52 weeks, with few ADRs. As a result, 91.8% of patients for primary prevention and 37.5% of those for secondary prevention could successfully reach their LDL-C management target. Thus, in this trial, K-924 was effective and well-tolerated in patients with hypercholesterolemia over a long period of 52 weeks.
Some patients do not achieve their recommended LDL-C targets; especially, in patients for secondary prevention, less than 30% of patients reach the LDL-C management target of ＜70 mg/dL6, 18, 19). This achievement rate was almost the same as that in patients on statin treatment20). In contrast, 58% of patients with ACS achieved the LDL-C management target of ＜70 mg/dL with a triple combination of statins, ezetimibe, and eicosapentaenoic acid21). Although the addition of ezetimibe or PCSK9 inhibitors to statin therapy is recommended by current guidelines when statin monotherapy is insufficient10-12), the use of these non-statin lipid-lowering drugs is limited22). One reason for this limitation may be attributable to the decreased medication adherence due to polypharmacy. Thus, K-924, as a fixed-dose combination drug may support optimal LDL-C management with potentially better adherence.
K-924 is a fixed-dose combination drug of pitavastatin and ezetimibe, the latter of which reduces cholesterol absorption in the gastrointestinal tract and consequently reduces LDL-C levels. Before enrollment in our trial, patients with hypercholesterolemia were mainly treated with LDL-C-lowering therapy, with the aim of achieving the LDL-C management target; this target was recommended according to the JAS Guideline 2017 based on a patient’s risk of atherosclerotic cardiovascular disease (ASCVD)17). By switching from pitavastatin to K-924, the LDL-C level reduced by approximately 30%, and the effect was sustained for 52 weeks. This finding is comparable with those of previous studies showing that the addition of ezetimibe 10 mg to ongoing statin therapy reduces LDL-C levels by 23–31%23-25). In our trial population, 37.6% of patients were for secondary prevention, with an LDL-C management target of ＜70 mg/dL. Their baseline LDL-C of 108.0 mg/dL was reduced by 30.7% with K-924, similar to the percent change of -30.3% in overall patients. Consequently, 34.1% of patients achieved the LDL-C management target of ＜70 mg/dL. Therefore, even in patients for secondary prevention, K-924 is effective options when more intensive LDL-C lowering therapy is needed compared with pitavastatin monotherapy.
Ezetimibe inhibits cholesterol absorption, which results in a reduction in LDL-C levels, but promotes a compensatory increase in cholesterol synthesis. Our results were consistent with Sudhop et al., who reported that ezetimibe reduced cholesterol absorption markers, such as beta-sitosterol and campesterol, by 41% and 48%, respectively, and increased cholesterol synthesis markers, such as lathosterol, by 53%26). Increased plasma lathosterol levels have been postulated to be associated with de novo hepatic cholesterol synthesis. In contrast, statins suppress cholesterol synthesis in the liver, resulting in lower LDL-C levels. These complementary actions may explain the favorable effects of statin-ezetimibe combination therapy. Diabetes mellitus has been associated with low levels of cholesterol absorption markers27). Considering the mechanism of ezetimibe, the levels of cholesterol absorption marker may affect the LDL-C lowering effect. In our trial, K-924 similarly reduced LDL-C regardless of the cholesterol absorption marker levels. Furthermore, the results were similar in patients with or without T2DM (Supplementary Table 3). These findings support those of the previous reports in that baseline cholesterol absorption does not predict responsiveness to LDL-C lowering drugs, including ezetimibe and statins28, 29). In addition to lowering LDL-C, ezetimibe also affects other lipid parameters. In a meta-analysis of 17 randomized controlled studies and pooled data analysis from 27 clinical trials30, 31), statin-ezetimibe combination therapy improved LDL-C, TG, and HDL-C levels when compared with statin monotherapy. Similar results were observed in our trial, in which TG and RLP-C levels reduced, and HDL-C and apolipoprotein AI levels increased in all patients. These effects may be more pronounced in patients with abnormal TG or HDL-C levels. Collectively, the additional lipid-modifying effects of K-924 after replacing pitavastatin in our trial were similar to those of ezetimibe.
From the viewpoint of safety, our trial revealed that the incidence of AEs and ADRs was 59.6% and 0.9%, respectively, over a period of 52 weeks. Notably, only one patient experienced an ADR (blood creatinine phosphokinase increased). As this ADR could occur with both pitavastatin and ezetimibe, we could not determine which drug was responsible. The low incidence of ADR may be due to the fact that patients who already exhibited good pitavastatin tolerance were enrolled in this trial. Recently, a phase III, 12-week, randomized trial comparing 1PC111 (a fixed-dose combination of pitavastatin 2 mg and ezetimibe 10 mg) with pitavastatin 2 mg and ezetimibe 10 mg reported similar incidences of ADRs across the three groups (8.6%, 6.1%, and 7.0%, respectively)15). A meta-analysis and pooled data analysis confirmed similar incidence of ADRs between statin-ezetimibe combination therapy and statin monotherapy30, 31). Regarding the safety of long-term treatment, Masara et al. reported no clinically meaningful differences in the incidence of ADRs between ezetimibe and placebo (19% and 17%, respectively) when these were added to ongoing statin therapy24). Hence, the statin-ezetimibe combination therapy is known to be safe and well-tolerated, and similar results were confirmed with K-924.
Several limitations should be considered when interpreting the trial results. First, although switching from pitavastatin to K-924, both of which are once-daily doses, is thought to have little effect on medication adherence, open-label medication may induce unexpected bias. However, in our previous phase 3, double-blind, randomized controlled trial, we had demonstrated the superiority of K-924 to pitavastatin monotherapy in reducing LDL-C over 12 weeks of treatment16). Second, it is possible that the upward titration of K-924 and use of other lipid-lowering agents during the study period in a total of nine patients may have affected our results. However, the results were similar regardless of whether these nine patients were excluded from the analysis. Finally, we used surrogate markers for ASCVD, including LDL-C, to examine the efficacy of K-924. Similar to statins, the addition of ezetimibe to statin therapy has also been shown to be effective in reducing LDL-C levels and the risk of cardiovascular events in the IMPROVE-IT and RACING trials8, 32). Based on the evidence for LDL-C-lowering agents, the concept “the lower, the better” is widely accepted, and current guidelines have set LDL-C management target levels according to ASCVD risks1, 2). K-924 LD and HD are expected to contribute to optimal LDL-C management, resulting in a reduced risk of cardiovascular events.
After switching from pitavastatin to either K-924 LD or HD, patients with hypercholesterolemia presented with a sustained LDL-C reduction over a period of 52 weeks. As a result, in all patients, 91.8% of the patients for primary prevention and 37.5% of those for secondary prevention could reach their LDL-C management target. Furthermore, both K-924 LD and HD were safe and well-tolerated. Thus, K-924 therapy is a viable option to intensify LDL-C-lowering therapy without increasing the number of medications.
The authors would like to acknowledge the investigators and patients who participated in this study. This study was conducted at the Miyanomori Memorial Hospital (Itaru Maeda), Yuri Ono Clinic (Yuri Ono), Hasegawa Medical Clinic (Atsushi Hasegawa), Tokyo-Eki Center-building Clinic (Arihiro Kiyosue), Minamino Cardiovascular Hospital (Yoshiki Hata), Tokyo Shinagawa Hospital (Takashi Matsumoto), Ota General Hospital (Kazunari Suzuki), Suwa Red Cross Hospital (Hiroshi Tsutsui), Chubu Rosai Hospital (Eitaro Nakashima), Daido Clinic (Kazuhisa Kondo), Shiraiwa medical clinic (Toshihiko Shiraiwa), Nippon Kokan Fukuyama Hospital (Tomomi Hakoda), and Nakamura Cardiovascular Clinic (Yuichiro Nakamura). This work was supported by Kowa Company, Ltd., which played a role in the study design, data collection, data analysis, data interpretation, and the preparation, review, and approval of this manuscript. We would like to thank Editage (www.editage.com) for English language editing.
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. 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. 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, 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. R.T., R.K., and H.S. are the employees of Kowa.
ACS, acute coronary syndrome; ADRs, adverse drug reactions; AEs, adverse events; ASCVD, atherosclerotic cardiovascular disease; CAD, coronary artery disease; CYP, cytochrome P450; FH, familial hypercholesterolemia; HDL-C, high-density lipoprotein cholesterol; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; JAS, Japan Atheroscrelosis Society; LDL-C, low-density lipoprotein cholesterol; LOCF, last observation carried forward imputation; PCSK9, proprotein convertase subtilisin/kexin 9; RLP-C, remnant-like particle cholesterol; TG, triglycerides; ULN, upper limit of normal
