Abstract
Background: Statins can effectively reduce low-density lipoprotein cholesterol (LDL-C), but additional options are needed for inadequate responses to statins or statin intolerance. Bempedoic acid is a small-molecule oral LDL-C-lowering drug that inhibits ATP citrate lyase, an enzyme 2 steps upstream of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the metabolic pathway for cholesterol synthesis.
Methods and Results: The CLEAR-J trial evaluated bempedoic acid 180 mg/day for 12 weeks in Japanese patients with inadequately controlled LDL-C. Percentage changes in LDL-C between baseline and Week 12 (primary endpoint) were −25.25% and −3.46% in the bempedoic acid and placebo groups, respectively, with a significant between-group difference (−21.78%; 95% confidence interval [CI] –26.71%, –16.85%; P<0.001). Changes in secondary endpoints in the bempedoic acid and placebo groups were as follows: non-high-density lipoprotein cholesterol, −20.33% and −2.76%, respectively (between-group difference −17.57%; 95% CI −22.03%, −13.12%); total cholesterol −16.36% and −2.23%, respectively (between-group difference –14.13%; 95% CI −17.79%, −10.47%); and apolipoprotein B −18.10% and −0.67%, respectively (between-group difference −17.43%; 95% CI –21.97%, −12.89%). At 12 weeks, 62.5% of the bempedoic acid group had achieved target LDL-C values. Treatment-emergent adverse events appeared in 3 patients taking bempedoic acid and 2 patients taking placebo.
Conclusions: This study confirmed the safety and efficacy of bempedoic acid after 12 weeks treatment in Japanese patients with high LDL-C who had inadequate response to statins or statin intolerance.
High levels of low-density lipoprotein cholesterol (LDL-C) in the blood are a major risk factor in the progression of atherosclerotic cardiovascular disease (ASCVD).1–3 The effectiveness of LDL-C-lowering therapy in the prevention of ASCVD has been demonstrated in Japanese patients, and guidelines recommend LDL-C management to target levels.4,5 In the 2022 edition of the Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases, more detailed target values in lipid management have been established for different risk categories, with lower LDL-C target values typically recommended for high-risk groups.5 To achieve these target values, appropriate lipid management must be tailored to individual patients.5
Statins are the first-line treatment for high LDL-C,5 and numerous studies have demonstrated that reducing LDL-C by statin therapy decreases the risk of ASCVD.6 Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the cholesterol synthesis pathway, reducing cholesterol synthesis in the liver. This action increases the number of free LDL receptors on the surface of liver cells, which promotes the uptake of LDL from the blood into the liver, thereby reducing the concentration of LDL-C in the blood.7 However, although the advent of statins has made LDL-C control feasible for many patients, others experience statin-associated muscle symptoms (SAMS) or statin-induced hepatic dysfunction. These statin-intolerant patients must reduce their statin dose or discontinue statins entirely. Combination therapy is available, using non-statin drugs that target different mechanisms of action, but the high cost of some of these drugs can limit their use and interfere with optimal LDL-C management. As a result, a relatively low percentage of Japanese patients are able to achieve their LDL-C target, both in primary and secondary prevention.8 There is an unmet need for therapies with mechanisms of action distinct from statins to help patients achieve their lipid management targets for LDL-C without the excessive burden of high cost or adverse effects.
Bempedoic acid is a small-molecule oral LDL-C-lowering drug that inhibits ATP citrate lyase, 2 steps upstream of HMG-CoA reductase in the metabolic pathway for cholesterol synthesis. As a prodrug, bempedoic acid is activated by the enzyme ACSVL1, which is highly expressed in the liver but not in muscle tissue, potentially reducing SAMS.9 Approved in the US and Europe in 2020, bempedoic acid has shown a favorable safety profile in real-world clinical practice10 and has been shown to reduce cardiovascular events in the CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid, an ACL-inhibiting Regimen) trial in statin-intolerant patients with hyper-LDL cholesterolemia.11 Bempedoic acid has been approved for the reduction of LDL-C and cardiovascular risk in the US and Europe.
In Japan, a Phase 2 dose-finding study has been conducted in Japanese patients, confirming the suitability of the 180-mg dose of bempedoic acid as used in Western countries.12 The aim of the present study was to evaluate the superiority of bempedoic acid 180 mg/day over placebo during a 12-week period in patients with hyper-LDL cholesterolemia whose previous treatment provided inadequate control of LDL-C.
Methods
Study Design
This was a placebo-controlled randomized multicenter double-blind parallel-group Phase 3 study. It was planned that approximately 35 participating university hospitals, core hospitals, and clinics staffed by lipidology specialists in Japan would be included in the study.
The study consisted of a 1-week screening period, a single-blind 4-week placebo run-in period, a double-blind 12-week treatment period, and a 4-week follow-up period (Supplementary Figure 1). After obtaining written informed consent for trial participation, the investigators conducted a screening examination to determine patient eligibility. If patients met the eligibility criteria, they proceeded to the placebo run-in period. During this period, they continued their pre-consent cholesterol-lowering medications at the same dose and regimen while also receiving placebo tablets for 4 weeks. At the end of the run-in period, eligible patients were randomly assigned in a 1 : 1 ratio to 12 weeks of daily bempedoic acid 180 mg or placebo. Dietary and exercise therapy that had been started before the patient provided consent was to remain unchanged from Week −5 until the completion of treatment at Week 12. Patients were advised to refrain from strenuous exercise during the trial to prevent any effects on laboratory test results.
This clinical trial followed the Guideline for Good Clinical Practice of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, as well as the local laws and regulatory requirements of Japan. The trial was conducted in accordance with the principles of the Declaration of Helsinki. Before the start of the trial, the institutional review board at each investigational site reviewed and approved the protocol, any amendments, and the informed consent form. All patients provided informed consent before study procedures were initiated.
Participants
This study targeted patients aged 18–85 years with hyper-LDL cholesterolemia who were at risk of ASCVD and had inadequately controlled LDL-C despite conventional LDL-C-lowering therapy. In this study, “inadequate response to statins” was defined as patients who were taking statins but had not achieved their target values for LDL-C by risk category.13 “Statin intolerance” was defined as patients experiencing safety issues while taking ≥1 type of statin in whom those issues were resolved by discontinuation or reduction of the dose, and who were unable to achieve their target values for LDL-C by risk category. Details are presented in Supplementary Table 1.
Major exclusion criteria included patients with a diagnosis of homozygous familial hypercholesterolemia, complications of cardiovascular disease or with a history of such disease, uncontrolled hypertension, complications of poorly controlled serious hematologic disorders or coagulation disorders, poorly controlled diabetes, poorly controlled hypothyroidism, liver disease or liver dysfunction, a history or complications of chronic musculoskeletal symptoms, renal dysfunction, nephrotic syndrome, or a history or complications of nephritis, and prior gastrointestinal surgery. Details are presented in Supplementary Table 1.
Randomization and Study Drug Administration
To ensure a balanced distribution of inadequate response to statins and statin intolerance across the treatment groups, a stratified randomization based on statin response (inadequate response to statins or statin intolerance) was used to assign patients in a 1:1 ratio to either the bempedoic acid 180 mg group or the placebo group. A computer-generated random number list was used to allocate patients according to the randomization sequence. The investigator or subinvestigator determined eligibility based on observations and results from the screening examination, and registered eligible patients in the Interactive Web Response System. The registration center then communicated the assigned treatment group for each participant to the investigator or subinvestigator, who then provided each patient with once-daily bempedoic acid 180 mg or placebo based on those allocation results.
Endpoints
The primary efficacy endpoint was the percentage change in LDL-C between baseline and Week 12. Secondary efficacy endpoints were percentage changes in non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (apoB), high-sensitivity C-reactive protein (hsCRP), and glycosylated hemoglobin (HbA1c) between baseline and Week 12, as well as the proportion of patients achieving their target values at Week 12 for LDL-C by risk category. That target was LDL-C <100 mg/dL in very high-risk patients (history of coronary artery disease or heterozygous familial hypercholesterolemia [HeFH]), <120 mg/dL in high-risk patients, and <140 mg/dL in intermediate-risk patients, based on the 2017 version of the JAS guidelines for prevention of atherosclerotic cardiovascular diseases,13 which was the version in use when this study was being planned. Other efficacy endpoints were percentage changes in HDL-C and triglycerides (TG) between baseline and Week 12. Safety endpoints were adverse events (AEs), findings from laboratory tests, physical examination, vital signs (blood pressure, pulse rate, body temperature), 12-lead electrocardiogram, and body weight.
Statistical Analysis
The study targeted a total of 84 patients for randomization: 42 in the bempedoic acid 180 mg group and 42 in the placebo group. In a Phase 2 trial conducted in Japan, a –19% difference was detected between the bempedoic acid 180 mg and placebo groups for percentage change in LDL-C between baseline and 12 weeks.12 For the standard deviation (SD), a conservative estimate of 25% was assumed for this trial. Based on these assumptions, a total of 76 participants (38 per group) would be required to ensure 90% power. Therefore, estimating a discontinuation or dropout rate of 10%, the study designers targeted a total enrollment of 84 patients.
The full analysis set included all participants who received at least 1 dose of the study drug during the treatment period and whose LDL-C had been measured at baseline and at ≥1 time points after receiving the study drug. The safety analysis set included all participants who received at least 1dose of the study drug during the treatment period.
The primary endpoint was the percentage change in LDL-C between baseline and Week 12, measured by the direct method, with baseline defined as the mean of the LDL-C values on Day 1 and Week −1. Mixed model for repeated measures (MMRM) analysis was performed, using observed cases data, under the assumption that any missing data were missing at random. Between-group comparisons were based on the least-squares mean difference between the bempedoic acid and placebo groups at Week 12. The significance level was set at 5% (2-tailed). The model included treatment group, stratification factor, time period, and the interaction between treatment group and time period as fixed factors, and baseline and the interaction between baseline and time period as covariates.
For the secondary endpoints of percentage changes in non-HDL-C and TC, the same MMRM analysis was conducted as for the primary endpoint. The baseline values for both non-HDL-C and TC were the means of the Day 1 and Week −1 values. For apoB, hsCRP, and HbA1c, an analysis of covariance (ANCOVA) was performed using observed cases data. The model included treatment group and the stratification factor of statin response (inadequate response to statin/statin intolerance) as fixed factors and the baseline values of each endpoint as covariates. For all efficacy endpoint parameters including hsCRP, robust analysis was performed using the model with treatment group and statin response as factors and baseline values as covariates. For the proportion of patients achieving their target values at Week 12 for LDL-C by risk category, a Cochran-Mantel-Haenszel test was performed with statin response (inadequate response to statins/statin intolerance) as a stratification factor. The differences between proportions and the 95% confidence intervals (CIs) for the 2-tailed test in the bempedoic acid and placebo groups were calculated. Patients who had missing LDL-C values at Week 12 were considered not to have reached their LDL-C target. The other secondary endpoints of percentage changes in HDL-C and TG also underwent the same MMRM analysis as for the primary endpoint.
In addition, prespecified subgroup analyses were performed for the primary endpoint of percentage change in LDL-C between baseline and Week 12, with subgroup stratification by statin response (inadequate response to statins/statin intolerance), HeFH (yes/no), diabetes (yes/no), age group (<65, 65‒75, or ≥75 years), statin use (yes/no), body mass index (BMI; <25, 25–30, or ≥30 kg/m2), estimated glomerular filtration rate (eGFR; <60, 60–90, or ≥90 mL/min/1.73 m2), and baseline LDL-C (<100, 100–120, 120–140, or ≥140 mg/dL).
Safety was analyzed using the safety analysis set, and those data were summarized. The data were also summarized by the stratification factor of statin response. The terms for AEs as recorded by investigators and subinvestigators were replaced by System Organ Class and MedDRA Preferred Term, and the incidence proportion of treatment-emergent AEs (TEAEs) was calculated for each treatment group by category. For laboratory parameters, vital signs, physical findings, electrocardiograms, and body weight, descriptive statistics were calculated for the actual values at the end of each time period and for the changes between baseline and the end of each time period in each treatment group. The number and proportion of patients who met predefined clinically significant criteria were also determined for each treatment group.
SAS version 9.4 was used for analysis.
Results
Patient Characteristics
The study was conducted from February 2023 to March 2024 at 28 facilities across Japan. Informed consent was obtained from 188 patients, of whom 130 proceeded to the placebo run-in period. In all, 96 eligible patients were randomly assigned to either bempedoic acid (48 participants) or placebo (48 participants). Of these, 91 (46 in the bempedoic acid group and 45 in the placebo group) completed the 12-week treatment. During the treatment period, 1 patient in each group was discontinued from the trial because of AEs. An additional patient in the bempedoic acid group was discontinued for protocol deviation, and 2 patients in the placebo group withdrew at their own request (Figure 1).
The mean (±SD) age of patients in the bempedoic acid and placebo groups was 64.6±13.02 and 63.9±12.98 years, respectively. Men comprised 41.7% (20 patients) and 52.1% (25 patients) of the bempedoic acid and placebo groups, respectively, and HeFH was identified in 27.1% (13 patients) and 16.7% (8 patients), respectively. In each group, 36 patients were classified as having inadequate response to statins and 12 were classified as having statin intolerance (Table 1; Supplementary Table 2).
Table 1.
Patient Characteristics
| |
Bempedoic acid
(n=48) |
Placebo
(n=48) |
Total
(n=96) |
| Sex |
| Male |
20 (41.7) |
25 (52.1) |
45 (46.9) |
| Female |
28 (58.3) |
23 (47.9) |
51 (53.1) |
| AgeA (years) |
64.6±13.02 |
63.9±12.98 |
64.2±12.93 |
| <65 |
20 (41.7) |
25 (52.1) |
45 (46.9) |
| ≥65, <75 |
19 (39.6) |
11 (22.9) |
30 (31.3) |
| ≥75 |
9 (18.8) |
12 (25.0) |
21 (21.9) |
| WeightA (kg) |
60.58±12.330 |
65.64±12.297 |
63.11±12.509 |
| HeightA (cm) |
159.04±8.711 |
162.47±11.676 |
160.75±10.390 |
| BMIA (kg/m2) |
23.81±3.409 |
24.72±2.925 |
24.26±3.193 |
| <25 |
31 (64.6) |
25 (52.1) |
56 (58.3) |
| ≥25, <30 |
14 (29.2) |
20 (41.7) |
34 (35.4) |
| ≥30 |
3 (6.3) |
3 (6.3) |
6 (6.3) |
| eGFRB (mL/min/1.73 m2) |
70.63±17.730 |
72.87±16.321 |
71.75±16.988 |
| <60 |
11 (22.9) |
11 (22.9) |
22 (22.9) |
| ≥60, <90 |
30 (62.5) |
31 (64.6) |
61 (63.5) |
| ≥90 |
7 (14.6) |
6 (12.5) |
13 (13.5) |
| Comorbidity |
47 (97.9) |
47 (97.9) |
94 (97.9) |
| LDL-C, direct methodB (mg/dL) |
134.50±25.134 |
137.67±21.661 |
136.08±23.392 |
| <100 |
1 (2.1) |
1 (2.1) |
2 (2.1) |
| ≥100, <120 |
13 (27.1) |
10 (20.8) |
23 (24.0) |
| ≥120, <140 |
19 (39.6) |
17 (35.4) |
36 (37.5) |
| ≥140 |
15 (31.3) |
20 (41.7) |
35 (36.5) |
| HeFH |
13 (27.1) |
8 (16.7) |
21 (21.9) |
| Risk category |
| HeFH or history of CAD |
28 (58.3) |
21 (43.8) |
49 (51.0) |
| High riskC |
18 (37.5) |
23 (47.9) |
41 (42.7) |
| Intermediate riskD |
2 (4.2) |
4 (8.3) |
6 (6.3) |
| Diabetes |
17 (35.4) |
25 (52.1) |
42 (43.8) |
| Statin response |
| Inadequate response to statins |
36 (75.0) |
36 (75.0) |
72 (75.0) |
| Statin intolerance |
12 (25.0) |
12 (25.0) |
24 (25.0) |
| Statin intensity |
| Low-intensity statin (pravastatin, simvastatin, fluvastatin) |
5 (10.4) |
7 (14.6) |
12 (12.5) |
| High-intensity statin (atorvastatin, pitavastatin, rosuvastatin) |
36 (75.0) |
30 (62.5) |
66 (68.8) |
| No statin |
7 (14.6) |
11 (22.9) |
18 (18.8) |
| History of ASCVD |
17 (35.4) |
13 (27.1) |
30 (31.3) |
Data are given as n (%) or mean±SD. AData at screening. BData at baseline. CPatients whose LDL-C levels from Week −5 to −1 were ≥120 mg/dL and who had peripheral arterial disease, history of non-cardiogenic cerebral infarction, chronic kidney disease, type 2 diabetes, or a total score of ≥56 points in the CAD risk prediction model using the Suita score specified by the Japan Atherosclerosis Society. DPatients whose LDL-C levels from Week −5 to −1 were ≥140 mg/dL and who had a total score of ≥41 and ≤55 points in the CAD prediction model using the Suita score specified by the Japan Atherosclerosis Society. ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; CAD, coronary artery disease; eGFR, estimated glomerular filtration rate; HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol.
Efficacy
The percentage change in LDL-C between baseline and Week 12 (the primary endpoint) was −25.25% in the bempedoic acid group and −3.46% in the placebo group (Figure 2). The between-group difference was statistically significant (P<0.001) at −21.78% (95% CI −26.71%, −16.85%; see Supplementary Table 3). In the bempedoic acid group, the reduction in LDL-C was first noted in Week 2 (Figure 3). The magnitude of change in LDL-C at each time point is presented in Supplementary Table 3. A waterfall plot was generated to show overall trends in LDL-C reduction, indicating that most patients in the bempedoic acid group experienced decreases in LDL-C levels (Supplementary Figure 2).
When inadequate responses to statins and statin intolerance were analyzed, both subgroups showed a significantly greater percentage change in LDL-C with bempedoic acid than placebo (Figure 4). The reduction in LDL-C also started from Week 2 in both bempedoic acid subgroups.
The subgroup analysis showed that, in all subgroups, the percentage change in LDL-C between baseline and Week 12 was greater for bempedoic acid than for placebo (Figure 5).
With regard to the secondary endpoints, percentage changes between baseline and Week 12 in the bempedoic acid and placebo groups were, respectively, −20.33% and −2.76% for non-HDL-C (between-group difference −17.57%; 95% CI −22.03%, −13.12%), −16.36% and −2.23% for TC (between-group difference −14.13%; 95% CI −17.79%, −10.47%), and −18.10% and −0.67% for apoB (between-group difference −17.43%; 95% CI −21.97%, −12.89%). All differences were statistically significant (P <0.001; Figure 2; Supplementary Table 4). The same trends were seen in the inadequate response to statins and statin intolerance subgroups as in the overall population (data not shown).
In the case of hsCRP, robust regression analysis showed a greater percentage change in the bempedoic acid than placebo group, with a between-group difference of −26.57% (95% CI −47.77%, −5.37%; P=0.014). The between-group difference in HbA1c was −1.03% (95% CI −2.56%, 0.50%; P=0.183). The percentage change in HDL-C between baseline and Week 12 was −6.79% and −0.89% in the bempedoic acid and placebo groups, respectively, with a between-group difference of −5.90% (95% CI −12.63%, 0.83%; P=0.085), whereas TG increased from baseline to Week 12 by 4.94% and 2.87%, respectively with a between-group difference of 2.07% (95% CI −12.53%, 16.67%; P=0.778; Supplementary Table 4).
At Week 12, the proportion of patients in the bempedoic acid group who had achieved their target LDL-C values by risk category was 62.5% (30/48 patients), which was significantly higher than the 8.3% (4/48 patients) in the placebo group, with a between-group difference of 54.2% (95% CI 38.4%, 69.9%; P <0.001; Supplementary Table 5). The same trends were noted in the inadequate response to statins and statin intolerance subgroups as for the overall population (data not shown).
Safety
TEAEs occurred in 56.3% of patients (n=27) in the bempedoic acid group and 50.0% of patients (n=24) in the placebo group. Among these, treatment-related TEAEs were reported in 6.3% (n=3) and 4.2% (n=2) of patients in the bempedoic acid and placebo groups, respectively. There were no deaths or serious/severe TEAEs in either group. AEs leading to treatment discontinuation occurred in 1 (2.1%) patient in each group, with arthralgia in the bempedoic acid group and abnormal hepatic function in the placebo group. Both AEs were considered by investigators to be related to the study drug (Table 2). AEs that were observed in ≥5% of patients in the bempedoic acid group included nasopharyngitis (14.6% [n=7] vs. 10.4% [n=5] in the placebo group), arthralgia (6.3% [n=3] vs. 0% in the placebo group), and back pain (6.3% [n=3] vs. 2.1% [n=1] in the placebo group). Arthralgia was the only AE that occurred in ≥5% of patients, with an incidence ≥5% higher in the bempedoic acid than placebo group (data not shown). There were no major differences in AEs based on statin response. In the bempedoic acid group, treatment-related TEAEs were reported in 3 patients: arthralgia (moderate), muscle spasms (mild), and limb discomfort (mild). The patient with arthralgia discontinued the study drug, and the other 2 patients continued treatment. No adverse drug reactions were observed in more than 2 patients in the bempedoic acid group. There were no significant differences in adverse drug reactions based on statin response.
Table 2.
Overall Summary of Adverse Events
| |
Bempedoic acid
(n=48) |
Placebo
(n=48) |
Total
(n=96) |
| AEs |
32 (66.7) |
29 (60.4) |
61 (63.5) |
| No. AE events |
56 |
55 |
111 |
| TEAEs |
27 (56.3) |
24 (50.0) |
51 (53.1) |
| No. TEAEs events |
42 |
41 |
83 |
| Treatment-related TEAEs |
3 (6.3) |
2 (4.2) |
5 (5.2) |
| Deaths |
0 (0.0) |
0 (0.0) |
0 (0.0) |
| Discontinuation of study drug due to AEs |
1 (2.1) |
1 (2.1) |
2 (2.1) |
| ≥1 treatment-related TEAEA |
3 (6.3) |
2 (4.2) |
|
| Bundle branch block left |
0 (0.0) |
1 (2.1) |
|
| Bundle branch block right |
0 (0.0) |
1 (2.1) |
|
| Hepatic function abnormal |
0 (0.0) |
1 (2.1) |
|
| Arthralgia |
1 (2.1) |
0 (0.0) |
|
| Muscle spasms |
1 (2.1) |
0 (0.0) |
|
| Limb discomfort |
1 (2.1) |
0 (0.0) |
|
Unless indicated otherwise, data are presented as the number of patients with percentages in parentheses. Adverse events (AEs) are coded as per MedDRA v26.1. AIncidence of treatment-emergent adverse events (TEAEs) by preferred term.
The incidence of AEs of special interest in the bempedoic acid and placebo groups was 2.1% (n=1) and 2.1% (n=1), respectively, for abnormal hepatic function, 2.1% (n=1) and 0%, respectively, for increased blood uric acid, and 2.1% (n=1) and 4.2% (n=2), respectively, for musculoskeletal and connective tissue disorders (Table 3). Conditions such as diabetes and renal dysfunction were also monitored, but no related AEs were noted.
Table 3.
AE of Special Interest and Laboratory Results
| |
Bempedoic acid
(n=48) |
Placebo
(n=48) |
| AEs of special interest |
| Hepatic function abnormal |
1 (2.1) |
1 (2.1) |
| Muscle spasms |
1 (2.1) |
0 (0.0) |
| Pain in extremity |
0 (0.0) |
2 (4.2) |
| Hypoglycemia |
0 (0.0) |
1 (2.1) |
| Blood uric acid increased |
1 (2.1) |
0 (0.0) |
| Laboratory results |
| ALT or AST >3× ULN |
1 (2.1) |
0 (0.0) |
| Creatinine kinase >4× ULN |
0 (0.0) |
0 (0.0) |
| Uric acid (mg/dL) |
0.73±0.595 |
0.11±0.496 |
| Creatinine (mg/dL) |
0.036±0.0652 |
0.011±0.0613 |
Data are given as n (%) or mean±SD change from baseline. Adverse events (AEs) are coded as per MedDRA v26.1. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.
No safety-related changes were identified in clinical laboratory tests, vital signs, body weight, or electrocardiogram parameters. The mean change in uric acid levels between baseline and final evaluation was 0.73 mg/dL (baseline median: 5.20 mg/dL; final evaluation median: 5.55 mg/dL) in the bempedoic acid group and 0.11 mg/dL (baseline median: 4.85 mg/dL; final evaluation median: 5.05 mg/dL) in the placebo group (Table 3). The higher value in the bempedoic acid group was not considered clinically problematic.
Discussion
This 12-week placebo-controlled randomized multicenter double-blind parallel-group Phase 3 study was designed to investigate the efficacy and safety of bempedoic acid 180 mg/day for hyper-LDL cholesterolemia in Japanese patients with inadequate response to statins or with statin intolerance. Results showed significantly greater reductions in LDL-C with bempedoic acid 180 mg/day than placebo after 12 weeks of treatment. These findings are supported by the percentage changes in non-HDL-C, TC, and apoB, as well as the proportion of patients who achieved their target LDL-C values after 12 weeks of treatment with bempedoic acid 180 mg/day. Bempedoic acid 180 mg/day was well tolerated, with no major safety concerns.
In the bempedoic acid group, the percentage change in LDL-C after 12 weeks was −25.25% (−23.29% in patients with inadequate response to statins and −30.41% in patients with statin intolerance), whereas in the placebo group the corresponding values were −3.46% (−3.12% and −4.65%). These results are consistent with previous reports from the US and Europe and suggest that bempedoic acid can be a valuable therapeutic option in Japanese patients with inadequate response to statins or with statin intolerance. Notably, the CLEAR Outcomes trial in the US and Europe showed that bempedoic acid reduced cardiovascular events in statin-intolerant patients, the only study using non-statin therapy to demonstrate this effect.11 The present study showed a similar effect of LDL-C lowering for statin intolerance, indicating that a reduction in cardiovascular events could be expected in Japanese patients. Furthermore, the waterfall plot confirmed that most patients in the bempedoic acid group experienced a reduction in LDL-C.
Although statins and bempedoic acid target the same pathway of cholesterol synthesis, the combination of bempedoic acid with statin therapy results in a greater LDL-C reduction than the 6% reduction that has been reported from doubling the statin dose.14 These reductions were similar to those reported when ezetimibe is added to statin therapy.15,16 In addition, a global study in patients with high LDL-C showed that bempedoic acid 180 mg/day provided a significantly greater percentage reduction in LDL-C than ezetimibe 10 mg/day monotherapy, regardless of inadequate response to statins or statin intolerance.17 These findings emphasize the importance of tailoring lipid-lowering therapy to individual patient needs.18
In this study, bempedoic acid administration resulted in more patients achieving target LDL-C by risk category than did placebo during a short treatment period of 12 weeks.
In the overall study population, 21.9% of patients had HeFH, and prespecified subgroup analysis showed a significant effect of LDL-C lowering in that patient group. Early therapeutic intervention is necessary for these patients,19 and the availability and convenience of additional oral treatment options can be a major benefit in terms of patient quality of life. The results of subgroup analysis stratified by statin use and intensity showed the least-squares mean differences in LDL-C change between the bempedoic acid and placebo groups were −32.99% in the no-statin group, −42.90% in the low-intensity statin group, and −16.59% in the high-intensity statin group.
Taking into consideration the results of US and European studies, robust regression was prespecified and applied to the efficacy parameters, including hsCRP, in the present study. Those results showed similar trends between Japanese and non-Japanese patients for hsCRP. Bempedoic acid exerts anti-inflammatory effects by activating AMP-activated protein kinase (AMPK) in in vitro primary human monocyte-derived macrophages and in vivo inflammation models through a liver kinase B1 (LKB1)-dependent mechanism,20 although those effects have not yet been established in humans. Further studies are needed to understand this mechanism in a clinical setting.
The findings in this study after 12 weeks of treatment showed that bempedoic acid 180 mg/day was well tolerated, with no major safety concerns compared with placebo. Three patients developed AEs (arthralgia, muscle spasms, and limb discomfort) that were associated with the study drug. All these AEs occurred in women, and none were serious. Bempedoic acid is a prodrug activated by ACSVL1, which is abundantly expressed in the liver but not in muscle tissue, making muscle-related adverse drug reactions less likely than with statins.21
Our results indicated an increase in uric acid levels in 1 patient, which is difficult to interpret because of our small sample size. Associations between the use of bempedoic acid and increases in uric acid have been documented in other studies. Urinary organic anion transporter 2 (OAT2), which contributes to the renal excretion of uric acid through the kidneys, is weakly inhibited by bempedoic acid and its active metabolite, leading to minor increases in plasma concentrations of uric acid.21 Thus, caution is recommended when prescribing bempedoic acid to patients with a history of gout or elevated baseline uric acid levels. However, although the present study involved only a short 12-week observation period, and long-term effects remain unknown in the Japanese population, our findings show that the increases in uric acid did not pose major clinical concerns, and there were no cases of gout due to elevated uric acid levels.
HbA1c levels did not differ between the bempedoic acid and placebo groups during the study period, and no diabetes-related AEs, which were included as AEs of interest, occurred during the study. Consistent with previous findings reported internationally,22 there were no between-group differences related to new-onset diabetes or effects on glucose tolerance in the present study. This suggests a minimal impact on diabetes, as indicated in previous studies.23
Our study has several limitations. It was a relatively small study, with a sample size sufficient to achieve the primary endpoint and with each group limited to 50 patients. The treatment period was 12 weeks, which is relatively short for this type of drug. A long-term study is currently underway to provide further information on the safety and efficacy of bempedoic acid in Japanese patients (NCT05687071). In addition, at the time this study was planned, the 2017 version of the JAS guidelines13 was in use, so those criteria for risk categories and their target values for LDL-C were adopted in our study design. In 2022, the guidelines were revised,5 and the epidemiological data used for the risk score criteria were updated from the Suita Study to the Hisayama Study. This change may affect risk assessment and the target LDL-C values by risk category in our study population.
Conclusions
In hyper-LDL cholesterolemia patients with inadequately controlled LDL-C, bempedoic acid 180 mg/day was superior to placebo in reducing LDL-C after 12 weeks of treatment. The percentage changes in non-HDL-C, TC, and apoB, as well as the proportion of patients who achieved their target LDL-C values after 12 weeks of treatment with bempedoic acid 180 mg/day, supported the primary endpoint results in demonstrating superior LDL-C reduction. After 12 weeks of treatment, bempedoic acid 180 mg/day was well tolerated, and no major safety concerns were noted relative to placebo.
Acknowledgments
The authors acknowledge the investigators and patients who participated in this study. Medical writing support was provided by EDIT, Inc. (Tokyo, Japan) and was funded by Otsuka Pharmaceutical Co., Ltd.
Sources of Funding
This study was funded by Otsuka Pharmaceutical Co., Ltd. The study sponsor had a role in the study design; data collection, analysis, and interpretation; and writing of the report.
Disclosures
S. Yamashita is a member of Circulation Journal’s Editorial Team; has been reimbursed for attending meetings by Kowa Company, Ltd., Novartis Pharma K.K., and Otsuka Pharmaceutical Co., Ltd.; and has worked as an advisor to Immuno-Biological Laboratories Co., Ltd. H.F., D.Y., and Y.N. are employees of Otsuka Pharmaceutical Co., Ltd. S. Yasuda is a member of Circulation Journal’s Editorial Team; has been reimbursed for attending meetings by Daiichi Sankyo Co. Ltd., Bayer Yakuhin, Ltd., and Otsuka Pharmaceutical Co., Ltd.; has received research grants from NEC Solution Innovators, Ltd., Daiichi Sankyo Co. Ltd., Fujitsu Limited, NEC Corporation, Nippon Shinyaku Co., Ltd., and Novartis Pharma K.K.; has received scholarship funds or donations from Abbott Medical Japan LLC, Nippon Boehringer Ingelheim Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Roche Diagnostics K.K., Sumitomo Pharma Co., Ltd., Boston Scientific Corporation, and Bayer Yakuhin, Ltd.; and has had departments endowed by the commercial entities BIOTRONIK Japan, Inc., TESCO CO., LTD., Japan Lifeline Co., Ltd., KANEKA CORPORATION, FUKUDA DENSHI, INC., MEDTRONIC JAPAN Co., Ltd., Philips Japan Ltd., Terumo Corporation, Abbott Medical Japan LLC, and INTEC Inc. A.K. has no conflicts of interest.
IRB Information
This study was approved by the Institutional Review Board (IRB) of Medical Corporation Shintokai Yokohama Minoru Clinic (approval date is December 8, 2022). The study was also approved by the IRBs at all participating sites: Nakakinen Clinic IRB, Rinku General Medical Center IRB, Tokushukai Group IRB, Kohnodai Hospital National Center for Global Health and Medicine IRB, Tohoku University Hospital IRB, Oita Prefectural Hospital IRB, Kimitsu Chuo Hospital IRB, JOHAS Chubu Rosai Hospital IRB, NHO Kanazawa Medical Center IRB, and the Review Board of Human Rights and Ethics for Clinical Studies IRB.
Data Availability
The deidentified participant data, data dictionaries, study protocol, and statistical analysis plan will be shared on a request basis upon provision of a methodologically sound meta-analysis proposal. Data will be available after marketing approval in global markets, or starting 1–3 years after publication. There is no end date to the availability of the data. Anyone wishing to access that data should contact the corresponding author directly to discuss how the data will be shared.
Supplementary Files
Please find supplementary file(s);
https://doi.org/10.1253/circj.CJ-25-0089
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