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Long-Term Safety and Efficacy of Bempedoic Acid in Patients With Atherosclerotic Cardiovascular Disease and/or Heterozygous Familial Hypercholesterolemia (from the CLEAR Harmony Open-Label Extension Study)

Open AccessPublished:April 25, 2022DOI:https://doi.org/10.1016/j.amjcard.2022.03.020
      Limited data exist on the long-term safety and efficacy of bempedoic acid, an adenosine triphosphate–citrate lyase inhibitor, for lowering low-density lipoprotein cholesterol (LDL-C). This 78-week, phase 3, open-label extension (OLE) study followed the CLEAR Harmony phase 3 study, in which patients were randomized 2:1 to bempedoic acid or placebo for 52 weeks; during the OLE, patients who received bempedoic acid continued treatment (≤130 weeks) and patients who received placebo initiated bempedoic acid (≤78 weeks). Safety assessments included treatment-emergent adverse events, adverse events of special interest, and clinical laboratory abnormalities. Efficacy assessments included % change from the parent study baseline in LDL-C, other lipid parameters, and high-sensitivity C-reactive protein (hsCRP). Of 1,462 patients who enrolled in the OLE study, 970 received bempedoic acid in the parent study; laboratory abnormalities and reductions in LDL-C, other lipid parameters, and hsCRP observed in the parent study remained stable through 130 weeks of treatment. On initiation of bempedoic acid treatment, 492 patients who received placebo in the parent study experienced reductions in LDL-C, other lipid parameters, and hsCRP, mirroring reductions observed in patients who received bempedoic acid in the parent study who remained stable through 78 weeks of therapy. During the OLE, incidence of treatment-emergent adverse events and adverse events of special interest were comparable in patients who received 130 weeks (78%) versus 78 weeks (78%) of bempedoic acid treatment. In conclusion, bempedoic acid was generally well tolerated and demonstrated sustained efficacy with up to 2.5 years of continuous treatment. Bempedoic acid safety profiles were similar between the parent and OLE studies.
      Patients with atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) are at high risk for cardiovascular events.
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      In clinical practice, some patients may also discontinue statins or decrease statin dose because of adverse effects such as muscle-related symptoms.
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      Lipid and Blood Pressure Meta-Analysis Collaboration (LBPMC) Group and the International Lipid Expert Panel (ILEP)
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      Nonstatin treatments are, therefore, needed to help patients reach their LDL-C goals while minimizing side effects. Bempedoic acid is an oral adenosine triphosphate–citrate lyase inhibitor that lowers LDL-C levels in patients with hypercholesterolemia.
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      Lipid and Blood Pressure Meta-Analysis Collaboration (LBPMC) Group and the International Lipid Expert Panel (ILEP)
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      Ballantyne CM; CLEAR Harmony Trial. Safety and efficacy of bempedoic acid to reduce LDL cholesterol.
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      In the phase 3 Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Harmony study, patients with ASCVD and/or HeFH who had LDL-C ≥70 mg/dl at baseline and who were taking maximally tolerated background statin therapy were randomized 2:1 to receive bempedoic acid 180 mg or placebo once per day.
      • Ray KK
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      Bempedoic acid significantly lowered LDL-C levels at week 12 by –18.1% compared with placebo (p <0.001), and LDL-C–lowering was maintained during 52 weeks of treatment.
      • Ray KK
      • Bays HE
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      Ballantyne CM; CLEAR Harmony Trial. Safety and efficacy of bempedoic acid to reduce LDL cholesterol.
      Bempedoic acid was generally well tolerated, with adverse events reported at similar frequencies in patients who received bempedoic acid or placebo.
      • Ray KK
      • Bays HE
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      • Sterling LR
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      Bempedoic acid demonstrated durable efficacy with a favorable safety profile in 4 phase 3 studies;
      • Ray KK
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      • Lalwani ND
      • Bloedon LT
      • Sterling LR
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      Ballantyne CM; CLEAR Harmony Trial. Safety and efficacy of bempedoic acid to reduce LDL cholesterol.
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      • Leiter LA
      • Stroes ESG
      • Baum SJ
      • Hanselman JC
      • Bloedon LT
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      • Patel PM
      • Zhao X
      • Duell PB.
      Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR Wisdom randomized clinical trial [published correction appears in JAMA 2020;323:282].
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      • Banach M
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      • Lepor NE
      • Hanselman JC
      • Zhao X
      • Leiter LA.
      Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study.
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      • Bloedon LT
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      • Kelly S
      • Stroes ESG.
      Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance.
      however, long-term safety and efficacy beyond 52 weeks are currently unknown. The CLEAR Harmony open-label extension (OLE) study was conducted to build on findings from the CLEAR Harmony parent study and evaluate the long-term safety and efficacy of bempedoic acid for up to 130 weeks.

      Methods

      Patients with ASCVD and/or HeFH were eligible to enroll in the OLE study if they completed the CLEAR Harmony parent study, complied with all requirements outlined in the parent study, and tolerated the study drug (bempedoic acid or placebo) through the end of the parent study. Patients were ineligible to enroll if they did not provide informed consent or were unwilling to comply with the study requirements; had a medical condition that could affect study assessments or required adjustments to background lipid-modifying therapies during the first 12 weeks of treatment; had a known sensitivity to bempedoic acid; were receiving other investigational drugs during the parent study; or were female, of child-bearing age, and pregnant, lactating, or unwilling to use an accepted method of birth control during the study.
      This was a phase 3, multicenter, OLE study (NCT03067441) conducted in Europe and North America between February 2017 and November 2019 to assess the long-term safety and efficacy of 180-mg bempedoic acid therapy. Upon completion of CLEAR Harmony, patients who met entry criteria and who chose to enroll in the OLE study received open-label bempedoic acid treatment for 78 weeks and then underwent a 4-week follow-up (Figure 1). Patients who had taken bempedoic acid in the parent study continued to receive it for a total of up to 130 weeks, whereas patients who had received placebo and switched to bempedoic acid treatment in the OLE study received up to 78 weeks of bempedoic acid treatment. The study was conducted in accordance with the Good Clinical Practice Guideline as defined by the International Conference on Harmonization, the Declaration of Helsinki, and/or all applicable federal and local regulations. All protocols were approved by an institutional review board and all patients provided written informed consent.
      The primary end point of this long-term OLE study was safety, as assessed by the incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and adverse events of special interest (AESIs). AESIs were prespecified on the basis of theoretical risks of bempedoic acid or other lipid-lowering therapies and included muscular disorders, elevations in creatine kinase levels, new-onset or worsening diabetes, renal disorders, gout, hepatic enzyme elevations, hypoglycemia, metabolic acidosis, and neurocognitive disorders. Other safety end points included clinical laboratory assessments, cardiovascular events, physical measurements, and vital signs. Clinical laboratory assessments were predefined and included liver function tests and levels of serum creatinine, hemoglobin, creatine kinase, uric acid, and fasting serum glucose.
      Secondary efficacy end points were assessed by the absolute and % changes from baseline of the parent study to week 52 and week 78 of the OLE study (total of 130 weeks) in LDL-C, total cholesterol (TC), non–high-density lipoprotein cholesterol (non–HDL-C), HDL-C, triglycerides, apolipoprotein B (Apo B), and high-sensitivity C-reactive protein (hsCRP). The absolute and % changes in LDL-C levels over time by background statin intensity and the proportion of patients who achieved LDL-C levels <100, <70, and <55 mg/dl at week 78 of the OLE study were also assessed.
      The safety analysis population (n = 1,462) included all enrolled patients who received at least 1 dose of study drug during the OLE study. TEAEs and AESIs include only data reported during the OLE study (78 weeks), whereas laboratory parameters include data from both the parent and OLE studies (130 weeks). Exposure-adjusted incidence was calculated as the number of patients having an event per 100 person-years (PYs) and was compared with an integrated analysis of 4 phase 3 studies with various treatment exposures (12 to 52 weeks).
      • Bays HE
      • Banach M
      • Catapano AL
      • Duell PB
      • Gotto Jr, AM
      • Laufs U
      • Leiter LA
      • Mancini GBJ
      • Ray KK
      • Bloedon LT
      • Sasiela WJ
      • Ye Z
      • Ballantyne CM.
      Bempedoic acid safety analysis: pooled data from four phase 3 clinical trials.
      The efficacy analysis population included all patients enrolled in the OLE study; efficacy assessments include data reported from both the parent and OLE studies (130 weeks). Safety and efficacy data were reported as observed; no imputation was performed for missing data. Descriptive statistics (number, mean, SD, median, quartile 1, quartile 3, minimum, and maximum) were provided for continuous end points, and 95% confidence intervals were calculated for select continuous efficacy end points. For categoric data, count and percentages were summarized based on the number of nonmissing values.

      Results

      Of the 2,230 patients who were randomized in the CLEAR Harmony parent study, 2,110 completed the parent study
      • Ray KK
      • Bays HE
      • Catapano AL
      • Lalwani ND
      • Bloedon LT
      • Sterling LR
      • Robinson PL
      Ballantyne CM; CLEAR Harmony Trial. Safety and efficacy of bempedoic acid to reduce LDL cholesterol.
      and 1,742 completed 52 weeks of study drug treatment. Of the 1,462 patients who were enrolled in the OLE study, 66% received bempedoic acid during the parent study and OLE study (for up to 130 weeks total) and 34% received placebo for 52 weeks during the parent study and bempedoic acid during the OLE study (for up to 78 weeks; Figure 1). All enrolled patients received at least 1 dose of the study drug during the OLE. Most patients (82%) continued directly from the parent study to the OLE; 8% continued within 1 to 30 days, 6% within 31 to 60 days, and 4% >60 days. Most patients (86% overall, 87% of those receiving bempedoic acid, and 84% of those receiving placebo in the parent study) completed 78 weeks of bempedoic acid treatment in the OLE study. Mean exposure to bempedoic acid during the OLE study was 1.4 ± 0.3 years. At baseline of the OLE study, patient demographics and characteristics were generally similar regardless of whether they received bempedoic acid or placebo in the parent study (Table 1). At the time of randomization in the parent study, baseline lipid and hsCRP levels among patients enrolled in the OLE study were similar between the bempedoic acid and placebo groups.
      Table 1Patient demographics and baseline characteristics in the CLEAR Harmony open-label extension study
      Characteristic
      Patient demographics and baseline characteristics collected at the OLE study baseline, unless otherwise indicated.
      ,
      Data are presented as n (%) and mean ± standard deviation, unless otherwise indicated.
      Overall OLE study

      (n = 1462)
      Duration of bempedoic acid treatment
      ≤130 weeks

      (n = 970)
      ≤78 weeks

      (n = 492)
      Age (years)66.9 ± 8.766.5 ± 8.867.5 ± 8.5
      Male1081 (73.9%)731 (75.4%)350 (71.1%)
      Race
       White1411 (96.5%)931 (96.0%)480 (97.6%)
       Black29 (2.0%)23 (2.4%)6 (1.2%)
       Asian14 (1.0%)9 (0.9%)5 (1.0%)
       Other8 (0.5%)7 (0.7%)1 (0.2%)
      Hispanic or Latino24 (1.6%)16 (1.6%)8 (1.6%)
      Patients with ASCVD
      ASCVD without HeFH.
      1408 (96.3%)933 (96.2%)475 (96.5%)
      Patients with HeFH
      HeFH with or without ASCVD.
      54 (3.7%)37 (3.8%)17 (3.5%)
      BMI (kg/m2)29.5 ± 5.029.4 ± 4.929.5 ± 5.1
      History of diabetes409 (28.0%)272 (28.0%)137 (27.8%)
      History of hypertension1161 (79.4%)758 (78.1%)403 (81.9%)
      Baseline laboratory parameters
      Baseline values collected at the parent study baseline for patients who enrolled in the OLE study.
       LDL-C (mg/dL)101.6 ± 28.2102.9 ± 29.999.0 ± 24.2
       Total cholesterol (mg/dL)177.7 ± 34.2178.9 ± 36.1175.3 ± 30.0
       Apo B (mg/dL)87.2 ± 21.088.2 ± 21.785.1 ± 19.2
       HDL-C (mg/dL)48.9 ± 11.648.8 ± 11.848.9 ± 11.2
       Non–HDL-C (mg/dL)128.8 ± 32.8130.1 ± 34.7126.4 ± 28.5
       TG (mg/dL
      Data presented as median (Q1, Q3).
      )
      124.0

      (97.5, 166.5)
      125.0

      (97.0, 164.5)
      122.0

      (97.5, 169.2)
       hsCRP (mg/L
      Data presented as median (Q1, Q3).
      )
      1.5 (0.8, 3.3)1.5 (0.7, 3.2)1.5 (0.8, 3.5)
      Baseline statin intensity
      Baseline values collected at the parent study baseline for patients who enrolled in the OLE study.
       Low88 (6.0%)63 (6.5%)25 (5.1%)
       Moderate562 (38.4%)373 (38.5%)189 (38.4%)
       High812 (55.5%)534 (55.1%)278 (56.5%)
      Baseline LMT
       Statin plus other LMT234 (16.0%)156 (16.1%)78 (15.9%)
        Ezetimibe132 (9.0%)90 (9.3%)42 (8.5%)
        Bile acid sequestrants5 (0.3%)4 (0.4%)1 (0.2%)
        Fibrates53 (3.6%)32 (3.3%)21 (4.3%)
        Nicotinic acid derivatives7 (0.5%)6 (0.6%)1 (0.2%)
        Other LMTs54 (3.7%)38 (3.9%)16 (3.2%)
       Other LMT only6 (0.4%)5 (0.5%)1 (0.2%)
        Ezetimibe4 (0.3%)4 (0.4%)0
        Bile acid sequestrants000
        Fibrates1 (0.1%)01 (0.2%)
        Chromium1 (0.1%)1 (0.1%)0
        Nicotinic acid derivatives000
       Statin only1215 (83.1%)804 (82.9%)411 (83.5%)
       No LMT7 (0.5%)5 (0.5%)2 (0.4%)
      Apo B = apolipoprotein B; ASCVD = atherosclerotic cardiovascular disease; BMI = body mass index; HDL-C = high-density lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; hsCRP = high-sensitivity C-reactive protein; LDL-C = low-density lipoprotein cholesterol; LMT = lipid-modifying therapy; non–HDL-C = non–high-density lipoprotein cholesterol; OLE = open-label extension; TG = triglycerides.
      low asterisk Patient demographics and baseline characteristics collected at the OLE study baseline, unless otherwise indicated.
      Data are presented as n (%) and mean ± standard deviation, unless otherwise indicated.
      ASCVD without HeFH.
      § HeFH with or without ASCVD.
      Baseline values collected at the parent study baseline for patients who enrolled in the OLE study.
      Data presented as median (Q1, Q3).
      Bempedoic acid was generally well tolerated during the OLE study regardless of the duration of treatment (Table 2). The overall incidence of TEAEs (regardless of causality) was similar in patients who received up to 130 weeks versus up to 78 weeks of bempedoic acid (78% in both groups). Also, regardless of causality, serious TEAEs, TEAEs leading to discontinuation, and fatal outcomes reported during the OLE study occurred at generally similar frequencies for patients who received 130 versus 78 weeks of bempedoic acid. The most frequently reported (>0.5%) TEAEs during the OLE study that were considered related to the study drug were muscle spasms, myalgia, pain in extremity, arthralgia, and dizziness. TEAEs leading to discontinuation of bempedoic acid treatment during the OLE study occurred in 7.8% of patients. The most common TEAEs leading to discontinuation of bempedoic acid treatment were myalgia (0.6%) and muscle spasms (0.5%), the incidence of which did not increase with a longer duration of bempedoic acid treatment (Table 3). The overall incidence of tendon rupture was 0.3% in the OLE study (0.4% in the 130 weeks of bempedoic acid group and 0.2% within the 78 weeks); the exposure-adjusted incidence was 0.2/100 PY. All patients who developed tendon rupture had 1 or more risk factors (e.g., previous tendon injury, statin use, or advanced age), and none of these cases were determined by the investigator to be related to bempedoic acid (Supplementary Table 1).
      Table 2Safety summary and most common drug-related treatment-emergent adverse events during the open-label extension study
      Parameter
      Adverse events were coded using the Medical Dictionary for Regulatory Affairs (MedDRA), version 20.1. TEAEs are defined as adverse events that began or worsened in severity after the first dose of study drug in the OLE study until 30 days after last dose in the OLE study. Patients were counted only once for highest severity, once for most extreme outcome, once for most extreme action taken regarding study drug, and once for strongest relationship to study drug.
      Patients, n (%)
      Overall OLE study

      (n = 1,462)
      Duration of bempedoic acid treatment
      ≤130 weeks

      (n = 970)
      ≤78 weeks

      (n = 492)
      Safety overview
       Any TEAE1143 (78.2%)758 (78.1%)385 (78.3%)
       Serious TEAE299 (20.5%)202 (20.8%)97 (19.7%)
       TEAE leading to drug discontinuations114 (7.8%)69 (7.1%)45 (9.1%)
       TEAE with fatal outcome13 (0.9%)10 (1.0%)3 (0.6%)
      Most common drug-related TEAEs (≥0.5% in any group)
       Muscle spasms25 (1.7%)18 (1.9%)7 (1.4%)
       Myalgia21 (1.4%)14 (1.4%)7 (1.4%)
       Pain in extremity10 (0.7%)7 (0.7%)3 (0.6%)
       Arthralgia9 (0.6%)4 (0.4%)5 (1.0%)
       Dizziness9 (0.6%)7 (0.7%)2 (0.4%)
       Headache8 (0.5%)6 (0.6%)2 (0.4%)
       Aspartate aminotransferase increased7 (0.5%)3 (0.3%)4 (0.8%)
       Blood creatine phosphokinase increased7 (0.5%)6 (0.6%)1 (0.2%)
       Anemia6 (0.4%)3 (0.3%)3 (0.6%)
       Diarrhea6 (0.4%)3 (0.3%)3 (0.6%)
       Alanine aminotransferase increased5 (0.3%)2 (0.2%)3 (0.6%)
      OLE = open-label extension; TEAE = treatment-emergent adverse event.
      low asterisk Adverse events were coded using the Medical Dictionary for Regulatory Affairs (MedDRA), version 20.1. TEAEs are defined as adverse events that began or worsened in severity after the first dose of study drug in the OLE study until 30 days after last dose in the OLE study. Patients were counted only once for highest severity, once for most extreme outcome, once for most extreme action taken regarding study drug, and once for strongest relationship to study drug.
      Table 3Most common treatment-emergent adverse events leading to discontinuation of bempedoic acid during the open-label extension study in ≥3 patients overall
      Parameter
      TEAEs were coded using the Medical Dictionary for Regulatory Affairs (MedDRA), version 20.1.
      Patients, n (%)
      Overall OLE study

      (n = 1,462)
      Duration of bempedoic acid treatment
      ≤130 weeks

      (n = 970)
      ≤78 weeks

      (n = 492)
      Myalgia9 (0.6%)3 (0.3%)6 (1.2%)
      Muscle spasms8 (0.5%)4 (0.4%)4 (0.8%)
      Arthralgia4 (0.3%)2 (0.2%)2 (0.4%)
      Diarrhea4 (0.3%)2 (0.2%)2 (0.4%)
      Dizziness4 (0.3%)2 (0.2%)2 (0.4%)
      Alanine aminotransferase increased4 (0.3%)2 (0.2%)2 (0.4%)
      Aspartate aminotransferase increased4 (0.3%)2 (0.2%)2 (0.4%)
      Muscular weakness3 (0.2%)03 (0.6%)
      Pain in extremity3 (0.2%)1 (0.1%)2 (0.4%)
      Headache3 (0.2%)3 (0.3%)0
      Coronary artery disease
      Indicates worsening of known coronary heart disease.
      3 (0.2%)3 (0.3%)0
      OLE = open-label extension; TEAE = treatment-emergent adverse event.
      low asterisk TEAEs were coded using the Medical Dictionary for Regulatory Affairs (MedDRA), version 20.1.
      Indicates worsening of known coronary heart disease.
      Prespecified AESIs were reported during the OLE study at a similar rate as that reported in the parent study.
      • Ray KK
      • Bays HE
      • Catapano AL
      • Lalwani ND
      • Bloedon LT
      • Sterling LR
      • Robinson PL
      Ballantyne CM; CLEAR Harmony Trial. Safety and efficacy of bempedoic acid to reduce LDL cholesterol.
      For example, the incidence of gout was 2.6%, and the incidence of new-onset or worsening of diabetes was 5.5% (Table 4). No new safety signals were identified with a longer duration of bempedoic acid therapy. Patients with a history of diabetes were more likely to have fasting glucose levels ≥126 mg/dl and hemoglobin A1c levels ≥6.5% after 78 weeks of treatment in the OLE study (48.7% and 58.9%, respectively) than patients without a history of diabetes (4.6% and 5.3%, respectively), which was similar for patients who received bempedoic acid for up to 130 versus 78 weeks. Exposure-adjusted incidence per 100 PY was 3.9 for new-onset or worsening diabetes mellitus, 6.1 for muscular disorders, 1.9 for renal disorders, 1.8 for gout, 1.3 for creatine kinase elevations, 1.4 for hepatic enzyme elevations, 0.9 for hypoglycemia, and 0.6 for neurocognitive disorders.
      Table 4Adverse events of special interest and laboratory abnormalities during the open-label extension study
      Parameter
      Data presented are mean ± standard deviation, unless otherwise indicated.
      Overall OLE study

      (n = 1462)
      Duration of bempedoic acid treatment
      ≤130 weeks

      (n = 970)
      ≤78 weeks

      (n = 492)
      Adverse events of special interest, n (%)
       Muscular disorders124 (8.5%)81 (8.4%)43 (8.7%)
        Muscle spasms48 (3.3%)34 (3.5%)14 (2.8%)
        Myalgia41 (2.8%)28 (2.9%)13 (2.6%)
        Pain in extremity41 (2.8%)24 (2.5%)17 (3.5%)
        Muscular weakness8 (0.5%)4 (0.4%)4 (0.8%)
       Creatine kinase elevations
      Includes preferred term for blood creatine phosphokinase increased.
      27 (1.8%)23 (2.4%)4 (0.8%)
       New-onset or worsening diabetes mellitus81 (5.5%)52 (5.4%)29 (5.9%)
        Type 2 diabetes mellitus29 (2.0%)18 (1.9%)11 (2.2%)
        Glucose tolerance impaired18 (1.2%)12 (1.2%)6 (1.2%)
        Diabetes mellitus15 (1.0%)8 (0.8%)7 (1.4%)
        Blood glucose increased7 (0.5%)4 (0.4%)3 (0.6%)
        Hyperglycemia5 (0.3%)4 (0.4%)1 (0.2%)
        Diabetes mellitus inadequate control3 (0.2%)3 (0.3%)0
        Glycosylated hemoglobin increased2 (0.1%)2 (0.2%)0
        Diabetic ketoacidosis1 (0.1%)01 (0.2%)
        Blood glucose abnormal1 (0.1%)1 (0.1%)0
        Urine ketone body present1 (0.1%)1 (0.1%)0
        Glycosuria1 (0.1%)1 (0.1%)0
       Renal disorders41 (2.8%)28 (2.9%)13 (2.6%)
       Gout38 (2.6%)24 (2.5%)14 (2.8%)
       Hepatic enzyme elevations29 (2.0%)15 (1.5%)14 (2.8%)
       Hypoglycemia18 (1.2%)14 (1.4%)4 (0.8%)
       Metabolic acidosis000
       Neurocognitive disorders13 (0.9%)6 (0.6%)7 (1.4%)
      Laboratory abnormalities, n (%)
       Aminotransferase level elevation >3 × ULN
      Patients with repeated and confirmed elevations in aminotransferase or creatine kinase levels at any time during the trial, irrespective of whether the patient was receiving bempedoic acid.
      8 (0.6%)4 (0.4%)4 (0.8%)
       Aminotransferase level elevation >5 × ULN
      Patients with repeated and confirmed elevations in aminotransferase or creatine kinase levels at any time during the trial, irrespective of whether the patient was receiving bempedoic acid.
      3 (0.2%)1 (0.1%)2 (0.4%)
       Creatine kinase level >5 × ULN
      Patients with repeated and confirmed elevations in aminotransferase or creatine kinase levels at any time during the trial, irrespective of whether the patient was receiving bempedoic acid.
      4 (0.3%)4 (0.4%)0
       Hemoglobin
        Reduction of ≥2 g/dL and < LLN108 (7.4%)74 (7.6%)34 (6.9%)
        Reduction of ≥3 g/dL and < LLN27 (1.8%)20 (2.1%)7 (1.4%)
        Reduction of ≥5 g/dL and < LLN6 (0.4%)3 (0.3%)3 (0.6%)
        Patients with hemoglobin <8 g/dL1 (0.1%)01 (0.2%)
       Fasting glucose ≥126 mg/dL at week 78
        With history of diabetes169 (48.7%)
      n = 347.
      118 (50.4%)
      n = 234.
      51 (45.1%)
      n = 113.
        Without history of diabetes43 (4.6%)
      n = 944.
      29 (4.6%)
      n = 628.
      14 (4.4%)
      n = 316.
       HbA1c ≥6.5% at week 78
        With history of diabetes205 (58.9%)
      n = 348.
      138 (58.7%)
      n = 235.
      67 (59.3%)
      n = 113.
        Without history of diabetes50 (5.3%)
      n = 944.
      33 (5.3%)
      n = 628.
      17 (5.4%)
      n = 316.
      Laboratory parameters at week 78 (mean ± SD
      Percent change from parent study baseline.
      )
       Blood urea nitrogen, mg/dL
        % change17.0 ± 30.8
      n = 1298.
      16.5 ± 30.4
      n = 865.
      18.0 ± 31.7
      n = 433.
        Absolute change2.4 ± 5.0
      n = 1298.
      2.3 ± 4.9
      n = 865.
      2.6 ± 5.1
      n = 433.
       Creatinine (mg/dL)
        % change5.0 ± 24.6
      n = 1298.
      4.6 ± 16.7
      n = 865.
      5.7 ± 35.5
      n = 433.
        Absolute change0 ± 0.3
      n = 1298.
      0 ± 0.2
      n = 865.
      0.1 ± 0.5
      n = 433.
       Uric acid (mg/dL)
        % change16.9 ± 23.1
      n = 1296.
      16.6 ± 23.7
      n = 863.
      17.3 ± 22.0
      n = 433.
        Absolute change0.9 ± 1.3
      n = 1296.
      0.9 ± 1.3
      n = 863.
      0.9 ± 1.2
      n = 433.
       Hemoglobin (g/dL)
        % change−3.4 ± 6.9
      n = 1283.
      −3.3 ± 6.6
      n = 857.
      −3.6 ± 7.5
      n = 426.
        Absolute change−0.5 ± 1.0
      n = 1283.
      −0.5 ± 0.9
      n = 857.
      −0.5 ± 1.0
      n = 426.
       Leukocytes (109/L)
        % change2.2 ± 22.9
      n = 1283.
      1.2 ± 22.2
      n = 857.
      4.2 ± 24.2
      n = 426.
        Absolute change0 ± 1.5
      n = 1283.
      −0.1 ± 1.4
      n = 857.
      0.1 ± 1.6
      n = 426.
       Platelets (109/L)
        % change12.7 ± 35.7
      n = 1280.
      13.2 ± 41.6
      n = 854.
      11.7 ± 18.9
      n = 426.
        Absolute change24.5 ± 44.2
      n = 1280.
      25.0 ± 45.9
      n = 854.
      23.6 ± 40.7
      n = 426.
      HbA1c = glycosylated hemoglobin; LLN = lower limit of normal; OLE = open-label extension; SD = standard deviation; ULN = upper limit of normal.
      low asterisk Data presented are mean ± standard deviation, unless otherwise indicated.
      Includes preferred term for blood creatine phosphokinase increased.
      Patients with repeated and confirmed elevations in aminotransferase or creatine kinase levels at any time during the trial, irrespective of whether the patient was receiving bempedoic acid.
      § n = 347.
      n = 234.
      n = 113.
      £ n = 944.
      low asterisklow asterisk n = 628.
      †† n = 316.
      ‡‡ n = 348.
      §§ n = 235.
      ∥∥ Percent change from parent study baseline.
      ££ n = 1298.
      low asterisklow asterisklow asterisk n = 865.
      ††† n = 433.
      ‡‡‡ n = 1296.
      §§§ n = 863.
      ∥∥∥ n = 1283.
      £££ n = 857.
      low asterisklow asterisklow asterisklow asterisk n = 426.
      †††† n = 1280.
      ‡‡‡‡ n = 854.
      The overall incidence of positively adjudicated treatment-emergent cardiovascular clinical events was similar in patients who received up to 130 weeks versus up to 78 weeks of bempedoic acid (approximately 7% in both groups; Table 5). Laboratory abnormalities observed during the OLE study also followed similar patterns as those observed in the parent study
      • Ray KK
      • Bays HE
      • Catapano AL
      • Lalwani ND
      • Bloedon LT
      • Sterling LR
      • Robinson PL
      Ballantyne CM; CLEAR Harmony Trial. Safety and efficacy of bempedoic acid to reduce LDL cholesterol.
      and did not worsen with a longer duration of bempedoic acid exposure. Although biochemical levels of blood urea nitrogen, creatinine, and uric acid increased on initiation of bempedoic acid in patients who received placebo during the parent study, these changes mirrored those observed during the parent study in patients who received bempedoic acid, remained stable over the course of the OLE study, and returned toward baseline levels after treatment discontinuation in the follow-up period (Figure 2). Similarly, small, stable decreases in hemoglobin, platelet, and leukocyte levels during the OLE study, which were also observed in the parent study, returned toward baseline values after the treatment ended (Figure 3). Mean hemoglobin levels decreased by approximately 4.1% during the parent study in patients who received bempedoic acid; reductions in hemoglobin levels occurred gradually during the first year of bempedoic acid treatment and were also observed in patients who received placebo during the parent study. However, there was no further decrease in hemoglobin levels during the next 1.5 years of bempedoic acid therapy and no difference between patients who received up to 130 versus 78 weeks of bempedoic acid. Anemia was reported by 3.4% of patients in the OLE study, with 0.3% considered severe (0.2% with 130 weeks of bempedoic acid and 0.4% with 78 weeks of bempedoic acid); no patient discontinued bempedoic acid because of anemia. Of the 50 patients who reported anemia, 93% of the events were mild or moderate, and 48% of cases were resolved or resolving by the end of the follow-up period.
      Table 5Positively adjudicated treatment-emergent cardiovascular clinical events during the open-label extension study
      Parameter
      Treatment-emergent adverse events are defined as adverse events that began or worsened in severity after the first dose of study drug in the open-label extension study until 30 days after last dose in the open-label extension study. Patients were counted once in each category, regardless of how many times they experienced the event.
      Patients, n (%)
      Overall

      (n = 1462)
      Duration of bempedoic acid treatment
      ≤130 weeks

      (n = 970)
      ≤78 weeks

      (n = 492)
      Any positively adjudicated CV event
      Adjudicated CV events are those events confirmed by the Clinical Events Committee as meeting the definition per the charter.
      108 (7.4%)74 (7.6%)34 (6.9%)
      MACE
       CV death6 (0.4%)6 (0.6%)0 (0%)
       Nonfatal MI23 (1.6%)14 (1.4%)9 (1.8%)
       Nonfatal stroke14 (1.0%)9 (0.9%)5 (1.0%)
       Coronary revascularization53 (3.6%)38 (3.9%)15 (3.0%)
       Hospitalization for UA20 (1.4%)15 (1.5%)5 (1.0%)
      Non-MACE
       Non-CV death3 (0.2%)2 (0.2%)1 (0.2%)
       Non coronary revascularization24 (1.6%)12 (1.2%)12 (2.4%)
       Hospitalization for heart failure9 (0.6%)6 (0.6%)3 (0.6%)
      CV = cardiovascular; MACE = major adverse cardiovascular event; MI = myocardial infarction; UA = unstable angina.
      low asterisk Treatment-emergent adverse events are defined as adverse events that began or worsened in severity after the first dose of study drug in the open-label extension study until 30 days after last dose in the open-label extension study. Patients were counted once in each category, regardless of how many times they experienced the event.
      Adjudicated CV events are those events confirmed by the Clinical Events Committee as meeting the definition per the charter.
      Figure 2
      Figure 2Observed levels of (A) creatinine, (B) uric acid, and (C) blood urea nitrogen over the course of the CLEAR Harmony parent study and the OLE study. Data presented for patients enrolled in the OLE study; not all patients received 130 or 78 weeks of treatment. Dashed line indicates baseline of the OLE study. Error bars represent standard error. Open circles indicate placebo treatment; filled circles indicate bempedoic acid treatment. BA = bempedoic acid; PBO = placebo.
      Figure 3
      Figure 3Observed levels of (A) hemoglobin, (B) platelets, and (C) leukocytes over the course of the CLEAR Harmony parent study and the OLE study. Data presented for patients enrolled in the OLE study; not all patients received 130 or 78 weeks of treatment. Dashed line indicates baseline of the OLE study. Error bars represent standard error. Open circles indicate placebo treatment; filled circles indicate bempedoic acid treatment. BA = bempedoic acid; PBO = placebo.
      The decrease in LDL-C levels for patients who had received bempedoic acid in the parent study remained relatively stable during the OLE study with a mean percent change in LDL-C from parent study baseline to week 78 of the OLE study of –14.2 ± 0.9% (−16.0 ± 1.0 mg/dl; Figure 4). Patients who received placebo in the parent study experienced a similar degree of LDL-C–lowering within 12 weeks of initiating open-label bempedoic acid treatment (−14.5 ± 1.0% [−15.4 ± 1.0 mg/dl]), which also remained stable during the OLE study with a mean percent decrease in LDL-C from the parent study baseline to week 78 of the OLE study of −15.0 ± 1.1% (−16.1 ± 1.2 mg/dl).
      Figure 4
      Figure 4Observed levels of LDL-C over the course of the CLEAR Harmony parent study and the OLE study. Data presented for patients enrolled in the OLE study; not all patients received 130 or 78 weeks of treatment. Dashed line indicates baseline of the OLE study. Error bars represent standard error. Open circles indicate placebo treatment; filled circles indicate bempedoic acid treatment. BA = bempedoic acid; PBO = placebo.
      The proportions of patients who achieved LDL-C–lowering goals at week 78 of the OLE were similar regardless of the duration of bempedoic acid treatment (Supplementary Figure 1). The lowering of LDL-C was also consistent regardless of background statin intensity (14% to 16% from parent study baseline to week 78 of the OLE study), although patients on low-intensity statin background who received up to 78 weeks of bempedoic acid treatment experienced slightly greater lowering of LDL-C (18% from parent study baseline to week 78 of the OLE study; Supplementary Figure 2).
      Bempedoic acid also reduced non–HDL-C, Apo B, TC, and hsCRP levels irrespective of treatment duration (Supplementary Figure 3). As with LDL-C, changes in these other parameters were stable during the study. At week 78 of the OLE study, the mean % change from parent study baseline was −11% for non–HDL-C, −7% for Apo B, and −10% for TC; the median % change from parent study baseline was −17% for hsCRP.

      Discussion

      In the CLEAR Harmony OLE study, bempedoic acid was generally well tolerated and had sustained efficacy for up to 130 weeks. The safety profile was comparable with that observed in the parent study, and no new safety signals were identified. Laboratory abnormalities observed were consistent with those reported in the parent study, stable in patients who received bempedoic acid for up to 130 weeks, and reversible on discontinuation. Reductions in LDL-C, TC, non–HDL-C, Apo B, and hsCRP levels remained durable for up to 130 weeks.
      Prolonged treatment with bempedoic acid did not increase the incidence of the most common TEAEs reported in the phase 3 studies. The overall incidence of TEAEs was similar in both groups during the 78 weeks of treatment in the OLE study (78.2%) compared with patients who received 52 weeks of bempedoic acid during the parent study (78.5%).
      • Ray KK
      • Bays HE
      • Catapano AL
      • Lalwani ND
      • Bloedon LT
      • Sterling LR
      • Robinson PL
      Ballantyne CM; CLEAR Harmony Trial. Safety and efficacy of bempedoic acid to reduce LDL cholesterol.
      Serious TEAEs, TEAEs leading to discontinuation, and fatal outcomes reported also occurred at generally similar rates during the OLE study compared with the parent study.
      • Ray KK
      • Bays HE
      • Catapano AL
      • Lalwani ND
      • Bloedon LT
      • Sterling LR
      • Robinson PL
      Ballantyne CM; CLEAR Harmony Trial. Safety and efficacy of bempedoic acid to reduce LDL cholesterol.
      Exposure-adjusted incidence rates of prespecified AESIs were also similar to those observed in previous studies.
      • Bays HE
      • Banach M
      • Catapano AL
      • Duell PB
      • Gotto Jr, AM
      • Laufs U
      • Leiter LA
      • Mancini GBJ
      • Ray KK
      • Bloedon LT
      • Sasiela WJ
      • Ye Z
      • Ballantyne CM.
      Bempedoic acid safety analysis: pooled data from four phase 3 clinical trials.
      For example, the exposure-adjusted incidence of new-onset or worsening diabetes mellitus, muscular disorders, renal disorders, and gout during the OLE study was 3.9/100 PY, 6.1/100 PY, 1.9/100 PY, and 1.8/100 PY, respectively, compared with 4.7/100 PY, 15.4/100 PY, 1.9/100 PY, and 1.6/100 PY in a pooled analysis of 4 phase 3 studies.
      • Bays HE
      • Banach M
      • Catapano AL
      • Duell PB
      • Gotto Jr, AM
      • Laufs U
      • Leiter LA
      • Mancini GBJ
      • Ray KK
      • Bloedon LT
      • Sasiela WJ
      • Ye Z
      • Ballantyne CM.
      Bempedoic acid safety analysis: pooled data from four phase 3 clinical trials.
      For tendon rupture, the rate was 0.2/100 PY during the OLE study compared with 0.3/100 PY in the pooled analysis.
      • Bays HE
      • Banach M
      • Catapano AL
      • Duell PB
      • Gotto Jr, AM
      • Laufs U
      • Leiter LA
      • Mancini GBJ
      • Ray KK
      • Bloedon LT
      • Sasiela WJ
      • Ye Z
      • Ballantyne CM.
      Bempedoic acid safety analysis: pooled data from four phase 3 clinical trials.
      Laboratory abnormalities also occurred at similar rates (mean increases in creatinine and uric acid levels at week 12 of the OLE study were 0.038 and 0.86 mg/dl, respectively, and 0.048 and 0.82 mg/dl after 12 weeks of bempedoic acid treatment in the pooled phase 3 analysis), remained stable for up to 130 weeks of bempedoic acid, and were reversible upon discontinuation.
      • Bays HE
      • Banach M
      • Catapano AL
      • Duell PB
      • Gotto Jr, AM
      • Laufs U
      • Leiter LA
      • Mancini GBJ
      • Ray KK
      • Bloedon LT
      • Sasiela WJ
      • Ye Z
      • Ballantyne CM.
      Bempedoic acid safety analysis: pooled data from four phase 3 clinical trials.
      These results suggest that bempedoic acid as an adjunct to maximally tolerated statins is safe and efficacious for up to 2.5 years of clinical use to treat hypercholesterolemia in patients with ASCVD and/or HeFH. Lowering of LDL-C, other lipid parameters, and hsCRP was sustained for up to 130 weeks, demonstrating the maintenance of therapeutic efficacy with long-term bempedoic acid. Current United States recommendations for lowering LDL-C include the use of bempedoic acid for the treatment of hypercholesterolemia in patients with ASCVD and/or HeFH who are receiving maximally tolerated background therapy with or without other lipid-lowering therapies;
      • Handelsman Y
      • Jellinger PS
      • Guerin CK
      • Bloomgarden ZT
      • Brinton EA
      • Budoff MJ
      • Davidson MH
      • Einhorn D
      • Fazio S
      • Fonseca VA
      • Garber AJ
      • Grunberger G
      • Krauss RM
      • Mechanick JI
      • Rosenblit PD
      • Smith DA
      • Wyne KL.
      Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the management of dyslipidemia and prevention of cardiovascular disease algorithm −2020 executive summary.
      ,
      • Ballantyne CM
      • Bays H
      • Catapano AL
      • Goldberg A
      • Ray KK
      • Saseen JJ.
      Role of bempedoic acid in clinical practice.
      the absence of increased TEAEs or new safety findings with prolonged use support these recommendations. However, extra considerations should be addressed when contemplating bempedoic acid for patients with risk factors for tendon rupture or with a medical history of gout or elevated blood uric acid because these patients may have a higher risk of developing hyperuricemia or gout with bempedoic acid; additional monitoring of these patients is warranted.
      • Bays HE
      • Banach M
      • Catapano AL
      • Duell PB
      • Gotto Jr, AM
      • Laufs U
      • Leiter LA
      • Mancini GBJ
      • Ray KK
      • Bloedon LT
      • Sasiela WJ
      • Ye Z
      • Ballantyne CM.
      Bempedoic acid safety analysis: pooled data from four phase 3 clinical trials.
      ,
      • Ballantyne CM
      • Bays H
      • Catapano AL
      • Goldberg A
      • Ray KK
      • Saseen JJ.
      Role of bempedoic acid in clinical practice.
      Limitations of this study include the open-label and single-arm study design. A slightly higher proportion of patients who received up to 78 weeks of treatment (compared with those who received up to 130 weeks) discontinued bempedoic acid in the OLE study because of muscle-related adverse events or elevations in alanine aminotransferase/aspartate aminotransferase levels. Patients in the parent study who discontinued bempedoic acid because of an adverse event were ineligible to enroll in the OLE study, which may account for the difference.
      In addition, this study focused on patients with established ASCVD and/or HeFH, most of whom received bempedoic acid in combination with moderate- or high-intensity statin therapy. Bempedoic acid is approved in the United States and Switzerland as an adjunct to diet and maximally tolerated statin therapy to treat adults with established ASCVD or HeFH who require additional lowering of LDL-C (see Nexletol [prescribing information], Esperion Therapeutics; 2021).
      • Ballantyne CM
      • Bays H
      • Catapano AL
      • Goldberg A
      • Ray KK
      • Saseen JJ.
      Role of bempedoic acid in clinical practice.
      ,
      Nilemdo
      [Summary of Product Characteristics].
      Bempedoic acid is also approved in the European Union and United Kingdom for adults with primary hypercholesterolemia or mixed dyslipidemia in combination with a statin in patients who are unable to reach LDL-C goals with maximally tolerated statin and alone or in combination with other lipid-lowering therapies in patients who are unable to take statins.
      • Ballantyne CM
      • Bays H
      • Catapano AL
      • Goldberg A
      • Ray KK
      • Saseen JJ.
      Role of bempedoic acid in clinical practice.
      ,
      Nilemdo
      [Summary of Product Characteristics].
      Further investigation is needed to determine the safety and efficacy of bempedoic acid as monotherapy in patients who cannot tolerate statins or other lipid-lowering therapies and in all patients with hypercholesterolemia regardless of cardiovascular risk status or history of cardiovascular events. Additional data on the long-term safety and efficacy of bempedoic acid beyond 130 weeks will be forthcoming in the CLEAR Outcomes study—an event-driven, randomized, double-blind, placebo-controlled trial to determine the effect of bempedoic acid on cardiovascular risk in patients with statin intolerance. The CLEAR Outcomes study is currently ongoing with over 14,000 patients enrolled and will continue until all end point criteria are met, which is anticipated in 2022.
      • Nicholls S
      • Lincoff AM
      • Bays HE
      • Cho L
      • Grobbee DE
      • Kastelein JJ
      • Libby P
      • Moriarty PM
      • Plutzky J
      • Ray KK
      • Thompson PD
      • Sasiela W
      • Mason D
      • McCluskey J
      • Davey D
      • Wolski K
      • Nissen SE.
      Rationale and design of the CLEAR-outcomes trial: evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance.
      Overall, findings from the CLEAR Harmony OLE study support other reports on the safety and efficacy of bempedoic acid for the treatment of hypercholesterolemia and demonstrate that safety and efficacy are maintained for up to 130 weeks in patients with ASCVD and/or HeFH.

      Disclosures

      Dr. Ballantyne has received research grants/support from Abbott Diagnostics, Akcea, Amarin, Amgen, Esperion, Ionis, Novartis, Regeneron, Roche Diagnostic, Sanofi-Synthelabo, National Institutes of Health, American Diabetes Association and the American Heart Association (all paid to the institution, not to the individual); has also served as a consultant for Abbott Diagnostics, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Esperion, Intercept, Ionis, Matinas BioPharma, Merck, Novartis, Novo Nordisk, Regeneron, Roche Diagnostic, and Sanofi-Synthelabo. Dr. Banach has received research grants/support from Amgen, Sanofi, Mylan/Viatris, and Valeant, and has served as a consultant for or received honoraria from Amgen, Daichii Sankyo, Esperion, Freia Pharmaceuticals, Herbapol, Kogen, KRKA, Eli Lilly, Merck Sharp & Dohme (MSD), Novartis, Novo Nordisk, Polfarmex, Polpharma, Regeneron, Resverlogix, Sanofi-Aventis, Servier, Teva, Valeant, Viatris, Zentiva. Dr. Bays’ research site has received research grants from 89Bio, Acasti, Akcea, Allergan, Alon Medtech/Epitomee, Amarin, Amgen, AstraZeneca, Axsome, BioHaven, Bionime, Boehringer Ingelheim, Civi, Eli Lilly, Esperion, Evidera, Gan and Lee, Home Access, Janssen, Johnson & Johnson, Lexicon, Matinas, Merck, Metavant, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, Selecta, TIMI, and Urovant. He has served as a consultant/adviser for 89Bio, Amarin, Esperion, Matinas, and Gelesis, and as a speaker for Esperion and Novo Nordisk. Dr. Catapano has received research grants/support from Amgen, Menarini, Mylan, Sanofi, and Sanofi Regeneron, and has served as a consultant for or received honoraria from Akcea, Amgen, Daiichi Sankyo, Esperion, Ionis Pharmaceuticals, Kowa, Medco, Menarini, MSD, Mylan, Novartis, Recordati, Regeneron, and Sanofi. The work of ALC at MultiMedica been supported by the Ministry of Health – Ricerca Corrente – IRCCS MultiMedica. Dr. Laufs has received lecturing/advisory board fees or research grant support to his institution from Amgen, Daiichi Sankyo, Novartis, and Sanofi. Dr. Stroes has received research grant(s)/support to his institution from Amgen, Sanofi, Resverlogix, and Athera, and has received lecturing/advisory board fees from Amgen, Sanofi, Akcea, Esperion, and Novartis. Ms. Robinson and Dr. Lei are employees of Esperion Therapeutics, Inc., and may hold stock or stock options. Dr. Ray has received institutional research grant(s)/support from Amgen, MSD, Pfizer, Regeneron, and Sanofi, and served as a consultant for or received honoraria from AbbVie, Akcea, Algorithm, Amgen, AstraZeneca, Boehringer Ingelheim, Cerenis, Cipla, Dr Reddy's Laboratories, Eli Lilly, Esperion, Kowa, Medco, MSD, Novo Nordisk, Pfizer, Regeneron, Resverlogix, Sanofi, Takeda, and Zuellig Pharma.

      Data sharing statement

      The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedures.

      Acknowledgments

      All authors had access to the data and participated in the development, review, and approval of the manuscript. Rujun Teng, a former employee of Esperion Therapeutics, Inc., contributed to the study design, statistical analyses, and development of the first draft of the manuscript. Medical writing support (funded by Esperion Therapeutics, Inc.) was provided by Callie A. S. Corsa, PhD and Lamara D. Shrode, PhD, CMPP of JB Ashtin, who developed the first draft based on an author-approved outline and assisted in implementing author revisions while adhering to Good Publication Practice (GPP3) guidelines and International Committee of Medical Journal Editors (ICMJE) recommendations. Additional medical writing support (funded by Esperion Therapeutics, Inc.) was provided by Laurel Riemann, PharmD, BCPS of Spark Medica Inc.

      Appendix. Supplementary materials

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