Abstract
Background
Lowering low‐density lipoprotein cholesterol (LDL‐C) reduces the risk of major vascular events across all age groups. We analyzed phase 3 studies of bempedoic acid to characterize the safety and efficacy in patients aged ≥75 years with and without a concomitant statin.
Methods
Post hoc analysis of bempedoic acid in high‐risk patients with cardiovascular disease by age from phase 3 placebo‐controlled, randomized clinical trials: two 52‐week primary hyperlipidemia studies with maximal background statin (“max‐statins pool”), and 1 cardiovascular outcomes trial (“statin‐intolerant pool”). Efficacy (LDL‐C, non–high‐density lipoprotein cholesterol, total cholesterol, high‐sensitivity C‐reactive protein) and safety were evaluated.
Results
The max‐statins pool included 3009 (2010 bempedoic acid, 999 placebo) patients. The statin‐intolerant pool included 13 970 patients (6992 bempedoic acid, 6978 placebo). In total 7022 patients were aged 18 to <65 years; 7372 were aged 65 to <75 years; 2585 were aged ≥75 years. Placebo‐corrected mean percentage change in LDL‐C at week 12 in the max‐statin pool with bempedoic acid was −18.4% (95% CI, −21.3 to −15.6) for patients aged 18 to <65 years, −18.6% (95% CI, −21.2 to −16.1) for 65 to <75 years, and −18.3% (95% CI, −22.2 to −14.5) for ≥75 years. In the statin‐intolerant pool, LDL‐C change was −21.9% (95% CI, −23.1 to −20.7) for patients aged 18 to <65 years, −22.9% (95% CI, −24.0 to −21.8) for 65 to <75 years, and −24.5% (95% CI, −26.2 to −22.7) for ≥75 years. Frequency of adverse events compared with placebo was similar across the ages, but more frequent among patients ≥75 years regardless of background statin. Cardiovascular event reduction was statistically comparable across all ages.
Conclusions
Bempedoic acid was well tolerated in patients aged ≥75 years with efficacy and safety comparable with younger subgroups regardless of background statin usage. Bempedoic acid may be considered a viable strategy for managing hypercholesterolemia in adults, regardless of age.
Keywords: bempedoic acid, elderly, LDL‐C, muscle pain, safety, statin, statin intolerant
Subject Categories: Clinical Studies, Inflammation, Lipids and Cholesterol, Aging
Nonstandard Abbreviations and Acronyms
- AE
adverse event
- AESI
adverse event of special interest
- CLEAR
Cholesterol Lowering via Bempedoic Acid (ECT1002), an ACL‐Inhibiting Regimen
- MACE
major adverse cardiovascular event
- SAE
serious adverse event
- TEAE
treatment‐emergent adverse event
Clinical Perspective.
What Is New?
This analysis provides a comprehensive review of the efficacy and safety of bempedoic acid by age among patients from 3 phase 3 data sets stratified into 2 distinct groups on the basis of statin tolerability; across all age groups, bempedoic acid was well tolerated and consistently lowered low‐density lipoprotein cholesterol. Among patients aged ≥75 years compared with younger patients, muscle adverse events were more frequent with both placebo and bempedoic acid in patients receiving primarily moderate or high‐intensity statins compared with patients who were statin intolerant.
What Are the Clinical Implications?
Patients aged ≥75 years achieved a similar benefit in terms of lowering low‐density lipoprotein cholesterol levels while being treated with bempedoic acid, as did patients from younger cohorts, whether on maximally tolerated statins or intolerant to statins; bempedoic acid may be an attractive low‐density lipoprotein cholesterol lowering strategy, especially for statin‐intolerant patients of advanced age.
These findings add to growing evidence in support of the benefit and safety of low‐density lipoprotein cholesterol–lowering therapies in an ever‐aging global population.
The importance of low‐density lipoprotein cholesterol (LDL‐C) lowering in patients aged ≥75 years is similar to younger patients for reducing the incidence of major adverse cardiac events as demonstrated in recent meta‐analyses of clinical trials. 1 , 2 A meta‐analysis of observational studies showed statins in primary prevention effectively reduce cardiovascular events and all‐cause death in all age subgroups, including patients aged ≥75 years. 3 A recent study investigating statin use in patients with atherosclerotic cardiovascular disease (ASCVD) in community practice found that 22% and 25% of ASCVD patients aged 65 to 74 years and ≥75 years, respectively, are not taking a statin, and that among patients aged >55 years, increasing age is associated with decreasing rates of high‐intensity statin use. 4 Many patients with ASCVD have LDL‐C above suggested levels (>70 mg/dL [1.8 mmol/L], or >55 mg/dL [1.4 mmol/L] for very‐high‐risk patients) including some patients already on lipid‐lowering therapy. 4 , 5 , 6 , 7 , 8 Factors contributing to lower rates of statin use in older patients include the higher risk of statin intolerance observed in this population, unwillingness or reluctance to take a statin, and perceived uncertainty by clinicians about the safety and efficacy of statins in patients aged ≥75 years. 9 , 10
Bempedoic acid is an oral adenosine triphosphate–citrate lyase inhibitor that significantly lowers LDL‐C levels compared with placebo in patients with ASCVD or heterozygous familial hypercholesterolemia. 11 , 12 , 13 , 14 In CLEAR (Cholesterol Lowering via Bempedoic Acid [ECT1002], an ACL‐Inhibiting Regimen) Outcomes, a large cardiovascular outcomes trial that randomized 13 970 statin‐intolerant patients aged 18 to 85 years at high risk of ASCVD, bempedoic acid significantly lowered the incidence of major adverse cardiovascular events (MACEs) by 13% and LDL‐C by 21.1% compared with placebo. 15 The aim of the current study was to investigate the efficacy, safety, and tolerability of bempedoic acid by age and with respect to background statin therapy.
METHODS
Data Sharing
The data that support these findings will not be made available to outside parties.
Study Design
This post hoc analysis investigated the use of bempedoic acid in patients from 3 phase 3 trials stratified by 3 age ranges (18 to <65 years, 65 to <75 years, ≥75 years), and with respect to background statin therapy. In 2 trials, 90% of patients received moderate‐ or high‐intensity statins (CLEAR Wisdom [NCT02991118], CLEAR Harmony [NCT0266666]), 12 , 14 while patients who were statin intolerant were included in the long‐term cardiovascular outcomes trial (CLEAR Outcomes [NCT02993406]). 15 The design and primary results from CLEAR Wisdom, CLEAR Harmony, and CLEAR Outcomes have been published. CLEAR Wisdom 12 and CLEAR Harmony 14 were randomized, double‐blind, placebo‐controlled, parallel‐group, multicenter studies in adult patients with established ASCVD and/or heterozygous familial hypercholesterolemia who were receiving stable, maximally tolerated statin therapy with or without other lipid‐lowering therapies. Patients were randomized 2:1 to receive bempedoic acid 180 mg or placebo once daily for 52 weeks. For this analysis, the pooled data from these 2 trials are referred to as the “maximally tolerated statin pool,” or “max‐statin.” The CLEAR Outcomes study was a long‐term, placebo‐controlled cardiovascular outcomes trial evaluating bempedoic acid for cardiovascular risk reduction in patients with statin intolerance. To be eligible for CLEAR Outcomes, patients had to attest to being unable or unwilling to receive statins owing to an adverse effect that had started or increased during statin therapy and resolved or improved after statin therapy was discontinued. Patients receiving stable background therapy, which could include a low average daily statin dose (atorvastatin <10 mg, rosuvastatin <5 mg, lovastatin <20 mg, simvastatin <10 mg, pravastatin <40 mg, fluvastatin <40 mg, pitavastatin <2 mg) without unacceptable adverse effects, were eligible. 15 Patients were randomized 1:1 to bempedoic acid 180 mg or placebo once daily and followed for a minimum of 2 years.
Each study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and all study participants provided written informed consent. Study protocols were approved by the local independent ethics committees at each study site.
End Points and Assessments
In the 2 phase 3 max‐statin hyperlipidemia trials (CLEAR Harmony and CLEAR Wisdom), the primary efficacy end point was the percentage change in LDL‐C from baseline to week 12; key secondary end points included change in non–high‐density lipoprotein cholesterol (non‐HDL‐C), total cholesterol, and hsCRP (high‐sensitivity C‐reactive protein). The same parameters at 6 months were secondary end points in CLEAR Outcomes, though to provide consistent data across the studies, the week 12 results for LDL‐C, non–HDL‐C, and total cholesterol are reported. LDL‐C values were calculated for the current manuscript using the Friedewald equation unless triglyceride levels were >400 mg/dL (>4.5 mmol/L) or LDL‐C levels were <50 mg/dL (<1.3 mmol/L), in which case LDL‐C was measured directly using the Multigent Direct LDL assay (Architect system; Abbott Laboratories, Abbott Park, IL). Lipid and biomarker quantification was performed at a central laboratory (Q2 Solutions). Safety assessments were laboratory based or investigator reported and included exposure‐adjusted treatment‐emergent adverse events (TEAEs); adverse events of special interest (AESIs); TEAEs leading to discontinuation of study treatment, serious TEAEs, and clinical laboratory results including standard chemistry, metabolic, and hematologic parameters. AESI were predefined on the basis of adverse events (AEs) observed with other lipid‐modifying therapies (ie, neurocognitive events, events of hepatic enzymes elevated, events related to diabetes, and muscular safety events); or prior clinical or nonclinical observations with bempedoic acid (ie, hepatic events, events related to hypoglycemia, and renal failure). Additional AESIs in CLEAR Outcomes included atrial fibrillation, tendon rupture/tendinopathies, and malignancy, which were added following bempedoic acid approval in the United States in 2020. All AESIs were based on a prespecified list of AE terms with or without laboratory thresholds.
CLEAR Outcomes was an event‐driven trial with predefined clinical end points including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and coronary revascularization. The determination and analyses of these clinical end points have been described in detail previously 15 , 16 and are not reported here as AEs or serious AEs (SAEs). In CLEAR Wisdom and CLEAR Harmony, these events were adjudicated but were reported as AEs as is standard practice.
Statistical Analysis
While data from CLEAR Harmony and CLEAR Wisdom were integrated to create the max‐statin pool, this pool was analyzed separately from CLEAR Outcomes (statin‐intolerant pool) because of multiple confounding differences in study design between the first 2 studies compared with CLEAR Outcomes. Data from CLEAR Harmony and CLEAR Wisdom were pooled together given the similarities in study design: identical 52‐week duration, as well as comparable population size, randomization scheme, and background use of a maximally tolerated statin dose. CLEAR Outcomes was an event‐driven trial with a less frequent visit schedule, included a substantially larger population, was longer in duration, used a different randomization scheme, and included patients with statin intolerance, the majority of whom (78%) were not receiving any background statin. The efficacy analysis population included all randomized patients, and the safety analysis population included all patients who received at least 1 dose of the study treatment (bempedoic acid or placebo). The efficacy of bempedoic acid versus placebo for lowering LDL‐C, total cholesterol, and non–HDL‐C within each age group was evaluated using least squares means and 95% CIs from an ANCOVA model, with percentage change at week 12 from baseline as the dependent variable, study (in max‐statin pool analysis) and treatment as fixed factors, and baseline as a covariate. No multiplicity adjustment was performed. The difference in least squares means between the bempedoic acid arm versus the placebo arm is reported as a placebo‐corrected mean. Comparisons of hsCRP percentage changes from baseline between treatments were based on a nonparametric method (Hodges–Lehman location shift). Based on when the trials were completed, AEs were coded using the applicable Medical Dictionary for Regulatory Activities version 20.1 (max‐statins pool) and version 23.1 (statin‐intolerant pool) and summarized as patient incidences. Due to varying study durations, AESI data were summarized as exposure‐adjusted incidences, defined as the number of patients having an event divided by the total person time (in 100 person‐years) at risk during this period to allow for between‐group comparisons. Laboratory values were summarized using descriptive statistics.
RESULTS
Patients
Across the 3 studies, a total of 7022 patients aged 18 to <65 years, 7372 patients aged 65 to <75 years, and 2585 patients aged ≥75 years were enrolled (Figure 1). The max‐statin pool enrolled 3009 (2010 bempedoic acid and 999 placebo) patients with a median follow‐up of 12 months. The proportion of patients who completed treatment with the study drug was 79.2% with bempedoic acid and 81.3% with placebo in the 18‐ to <65‐year age group (79.9% overall completion rate), 78.1% with bempedoic acid and 83.1% with placebo in the 65‐ to <75‐year age group (79.8% overall), and 71.2% with bempedoic acid and 77.6% with placebo in the ≥75‐year age group (73.4% overall).
Figure 1. Study characteristics and population.
*Very‐low‐dose statin doses (daily) include atorvastatin <10 mg, rosuvastatin <5 mg, lovastatin <20 mg, simvastatin <10 mg, pravastatin <40 mg, fluvastatin <40 mg, pitavastatin <2 mg. ASCVD indicates atherosclerotic cardiovascular disease.
CLEAR Outcomes enrolled 13 970 patients (6992 bempedoic acid and 6978 placebo) with a median follow‐up of 40.6 months. The proportion of patients who completed treatment with the study drug according to the CLEAR Outcomes protocol was 73.5% with bempedoic acid and 73.2% with placebo in the 18‐ to <65‐year age group (73.3% overall completion rate), 70.5% with bempedoic acid and 65.8% with placebo in the 65‐ to <75‐year age group (68.2% overall), and 64.8% with bempedoic acid and 61.8% with placebo in the ≥75‐year age group (63.3% overall). Baseline demographics, clinical characteristics, and statin intensity are provided in Tables 1 and 2. Aside from differing baseline statin use, other notable differences between the max‐statin pool and statin‐intolerant pool included a lower proportion of female patients and higher proportion of patients with a prior history of ASCVD in the max‐statin pool (of note, CLEAR Outcomes inclusion criteria allowed high‐risk primary prevention patients). There was a higher prevalence of hypertension and diabetes, higher baseline lipid parameters, and higher baseline hsCRP in the statin intolerant pool. When comparing baseline characteristics across age categories in both data sets, as age increased, body mass index was lower. Within the statin‐intolerant pool data set, fewer patients aged ≥75 years were on a very‐low‐dose statin (18%) compared with the younger age groups (20.1%–26.1%).
Table 1.
Baseline Demographics and Characteristics in Patients Max‐Statin Pool (CLEAR Harmony and CLEAR Wisdom)
| Characteristic | 18 to <65 y | 65 to <75 y | ≥75 y | |||
|---|---|---|---|---|---|---|
| Bempedoic acid (n=871) | Placebo (n=385) | Bempedoic acid (n=826) | Placebo (n=449) | Bempedoic acid (n=313) | Placebo (n=165) | |
| Age, y, mean±SD | 57.1±6.1 | 57.5±5.7 | 69.2±2.7 | 69.2±2.8 | 78.3±3.1 | 78.5±3.0 |
| Female sex, n (%) | 227 (26.1) | 128 (33.2) | 268 (32.4) | 131 (29.2) | 88 (28.1) | 43 (26.1) |
| White race, n (%) | 809 (92.9) | 370 (96.1) | 795 (96.2) | 429 (95.5) | 310 (99.0) | 161 (97.6) |
| Body mass index, kg/m2, mean±SD | 30.4±5.0 | 30.8±5.5 | 29.6±5.0 | 29.4±4.6 | 28.7±4.5 | 27.9±4.1 |
| ASCVD status, n (%) | ||||||
| Yes | 825 (94.7) | 366 (95.1) | 816 (98.8) | 445 (99.1) | 311 (99.4) | 163 (98.8) |
| History of hypertension, n (%) | 675 (77.5) | 306 (79.5) | 671 (81.2) | 373 (83.1) | 266 (85.0) | 139 (84.2) |
| History of diabetes, n (%) | 237 (27.2) | 103 (26.8) | 255 (30.9) | 135 (30.1) | 88 (28.1) | 55 (33.3) |
| Statin use, n (%) | 842 (96.7) | 372 (96.6) | 811 (98.2) | 439 (97.8) | 302 (96.5) | 159 (96.4) |
| Baseline statin intensity, n (%) | ||||||
| No | 29 (3.3) | 13 (3.4) | 15 (1.8) | 10 (2.2) | 11 (3.5) | 6 (3.6) |
| Low | 45 (5.2) | 20 (5.2) | 56 (6.8) | 29 (6.5) | 24 (7.7) | 10 (6.1) |
| Moderate | 302 (34.7) | 135 (35.1) | 355 (43.0) | 194 (43.2) | 154 (49.2) | 75 (45.5) |
| High | 495 (56.8) | 217 (56.4) | 400 (48.4) | 216 (48.1) | 124 (39.6) | 74 (44.8) |
| Ezetimibe use, n (%) | 86 (9.9) | 39 (10.1) | 47 (5.7) | 24 (5.3) | 17 (5.4) | 13 (7.9) |
ASCVD indicates atherosclerotic cardiovascular disease; and CLEAR, Cholesterol Lowering via Bempedoic Acid (ECT1002), an ACL‐Inhibiting Regime.
Table 2.
Baseline Demographics and Characteristics of Patients in Statin‐Intolerant Pool (CLEAR Outcomes)
| Characteristic | 18 to <65 y | 65 to <75 y | ≥75 y | |||
|---|---|---|---|---|---|---|
| Bempedoic acid (n=2859) | Placebo (n=2907) | Bempedoic acid (n=3070) | Placebo (n=3027) | Bempedoic acid (n=1063) | Placebo (n=1044) | |
| Age, y, mean±SD | 56.8±6.23 | 57.2±6.13 | 69.1±2.8 | 69.2±2.7 | 78.3±2.8 | 78.2±2.8 |
| Female sex, n (%) | 1151 (40.3) | 1162 (40.0) | 1654 (53.9) | 1657 (54.7) | 556 (52.3) | 560 (53.6) |
| White race, n (%) | 2554 (89.3) | 2607 (89.7) | 2850 (92.8) | 2767 (91.4) | 993 (93.4) | 961 (92) |
| Body mass index, kg/m2, mean±SD | 30.2±5.4 | 30.3±5.3 | 30.0±5.0 | 30.2±5.3 | 28.7±5.0 | 28.6±4.5 |
| ASCVD status (n, %) | ||||||
| Yes | 2317 (81.0) | 2345 (80.7) | 1820 (59.3) | 1811 (59.8) | 755 (71) | 716 (68.6) |
| History of hypertension, n (%) | 2339 (81.8) | 2381 (81.9) | 2657 (86.5) | 2634 (87.0) | 948 (89.2) | 917 (87.8) |
| History of diabetes, n (%) | 997 (34.9) | 1059 (36.4) | 1534 (50.0) | 1506 (49.8) | 432 (40.6) | 457 (43.8) |
| Statin use,* n (%) | 756 (26.4) | 762 (26.2) | 658 (21.4) | 618 (20.4) | 187 (17.6) | 193 (18.5) |
| Baseline statin intensity, n (%) | ||||||
| No | 2103 (73.6) | 2145 (73.8) | 2412 (78.6) | 2409 (79.6) | 876 (82.4) | 851 (81.5) |
| Very low | 745 (26.1) | 746 (25.7) | 644 (21.0) | 607 (20.1) | 184 (17.3) | 185 (17.7) |
| Ezetimibe use, n (%) | 320 (11.2) | 323 (11.1) | 374 (12.2) | 358 (11.8) | 109 (10.3) | 128 (12.3) |
ASCVD indicates atherosclerotic cardiovascular disease; and CLEAR, Cholesterol Lowering via Bempedoic Acid (ECT1002), an ACL‐Inhibiting Regime.
Included a very low average daily statin dose (atorvastatin <10 mg, rosuvastatin <5 mg, lovastatin <20 mg, simvastatin <10 mg, pravastatin <40 mg, fluvastatin <40 mg, pitavastatin <2 mg).
Efficacy Assessments
Change in Lipid Parameters and hsCRP
Baseline lipid parameters and hsCRP are presented in Tables S1 and S2. The placebo‐corrected mean percentage change in LDL‐C at week 12 with bempedoic acid was −18.4% (95% CI, −21.3 to −15.6) for patients aged 18 to <65 years, −18.6% (95% CI, −21.2 to −16.1) for 65 to <75 years, and −18.3% (95% CI, −22.2 to −14.5) for ≥75 years in the max‐statin pool (Figure 2). LDL‐C lowering with bempedoic acid was greater in each age category in the statin‐intolerant pool compared with the max‐statin pool and consistent across age categories. Placebo‐corrected least squares mean percentage changes in LDL‐C with bempedoic acid in the statin intolerant pool were −21.9% (95% CI, −23.1 to −20.7) for patients aged 18 to <65 years, −22.9% (95% CI, −24.0 to −21.8) for 65 to <75 years, and −24.5% (95% CI, −26.2 to −22.7) for ≥75 years (Figure 2). Placebo‐corrected mean percentage change in LDL‐C and median percentage change in hsCRP for the max‐statin pool and statin‐intolerant pool are shown in Figure 2. The percentage change in non–HDL‐C and total cholesterol, across the age categories in both the max‐statin pool and statin‐intolerant pool are reported in Table S3.
Figure 2. Change from baseline to week 12 in LDL‐C and hsCRP by age and baseline statin use.
Top, Change in LDL‐C (%) with bempedoic acid treatment from baseline to week 12 reported as placebo‐corrected LS means. Bottom, Change in hsCRP (%) with bempedoic acid treatment from baseline to week 12 reported as location shift vs placebo. Error bars represent the 95% CI. hsCRP indicates high sensitivity C‐reactive protein; and LDL‐C, low‐density lipoprotein cholesterol.
MACEs in the Statin‐Intolerant Pool
The reduction of MACE risk with bempedoic acid did not significantly differ among patients aged 18 to <65 years (hazard ratio [HR], 0.87 [95% CI, 0.74–1.02]; n=596 events), 65 to <75 years (HR, 0.83 [95% CI, 0.72–0.96]; n=781 events), and 75 to 85 years (HR, 0.95 [95% CI, 0.77–1.16]; n=369 events), with an interaction P value of 0.60. 15
Safety
The safety analysis included 7020 patients aged 18 to <65 years, 7370 patients aged 65 to <75 years, and 2583 patients aged ≥75 years. Due to differences in study duration and method for reporting AEs, safety data for the max‐statin pool (Table 3) and the statin‐intolerant pool (Table 4) are described separately below.
Table 3.
Summary of Safety Data From Max‐Statin Pool (CLEAR Harmony and CLEAR Wisdom) (n=3008) TEAEs and AESIs Stratified by Age
| TEAEs, n (%) | 18 to <65 y | 65 to <75 y | ≥75 y | |||
|---|---|---|---|---|---|---|
| Bempedoic acid (n=871) | Placebo (n=385) | Bempedoic acid (n=826) | Placebo (n=449) | Bempedoic acid (n=312) | Placebo (n=165) | |
| Overview of AEs | ||||||
| Any TEAE | 619 (71.1) | 279 (72.5) | 661 (80.0) | 352 (78.4) | 253 (81.1) | 135 (81.8) |
| Any serious TEAE | 121 (13.9) | 57 (14.8) | 127 (15.4) | 70 (15.6) | 74 (23.7) | 25 (15.2) |
| Any TEAE related to study treatment | 183 (21.0) | 70 (18.2) | 227 (27.5) | 112 (24.9) | 83 (26.6) | 33 (20.0) |
| Any TEAE leading to study‐treatment discontinuation | 70 (8.0) | 31 (8.1) | 99 (12.0) | 32 (7.1) | 50 (16.0) | 12 (7.3) |
| Most common TEAE leading to drug discontinuation* | ||||||
| Gastrointestinal disorders system organ class | 11 (1.3) | 2 (0.5) | 17 (2.1) | 4 (0.9) | 3 (1.0) | 1 (0.6) |
| Musculoskeletal and connective tissue disorders system organ class | 16 (1.8) | 8 (2.1) | 24 (2.9) | 10 (2.2) | 17 (5.4) | 1 (0.6) |
| Nervous system disorders system organ class | 8 (0.9) | 7 (1.8) | 5 (0.6) | 7 (1.6) | 8 (2.6) | 2 (1.2) |
| Any TEAE with fatal outcome† | 6 (0.7) | 2 (0.5) | 6 (0.7) | 2 (0.4) | 7 (2.2) | 0 |
| Exposure adjusted AESI, n (per 100 person‐years) | ||||||
| New‐onset diabetes/hyperglycemia | 35 (4.3) | 29 (7.8) | 37 (4.8) | 22 (5.0) | 13 (4.8) | 8 (5.1) |
| Hepatic enzyme elevation | 36 (4.4) | 8 (2.2) | 10 (1.3) | 5 (1.1) | 5 (1.8) | 2 (1.3) |
| Muscular disorders | 102 (12.4) | 38 (10.2) | 124 (16.1) | 50 (11.5) | 39 (14.3) | 14 (8.9) |
| Myalgia | 42 (5.1) | 19 (5.1) | 45 (5.9) | 27 (6.2) | 17 (6.2) | 7 (4.5) |
| Muscle spasms | 25 (3.0) | 6 (1.6) | 39 (3.2) | 14 (5.1) | 9 (3.3) | 3 (1.9) |
| Blood creatine phosphokinase levels increased | 24 (2.9) | 8 (2.2) | 12 (1.6) | 5 (1.1) | 3 (1.1) | 3 (1.9) |
| Pain in extremity | 19 (2.3) | 6 (1.6) | 34 (4.4) | 8 (1.8) | 8 (2.9) | 3 (1.9) |
| Muscular weakness | 5 (0.6) | 3 (0.8) | 3 (0.4) | 1 (0.2) | 3 (1.1) | 1 (0.6) |
| Myositis | 1 (0.1) | 0 | 0 | 0 | 2 (0.7) | 0 |
| Neurocognitive disorders | 3 (0.4) | 2 (0.5) | 3 (0.4) | 2 (0.5) | 8 (2.9) | 4 (2.6) |
| Renal disorders | 13 (1.6) | 3 (0.8) | 29 (3.8) | 7 (1.6) | 17 (6.2) | 3 (1.9) |
| Blood creatinine increased | 5 (0.6) | 2 (0.5) | 10 (1.3) | 2 (0.5) | 1 (0.4) | 0 |
| Glomerular filtration rate decreased | 3 (0.4) | 1 (0.3) | 8 (1.0) | 0 | 1 (0.4) | 0 |
| Blood urea increased | 0 | 1 (0.1) | 2 (0.3) | 1 (0.2) | 0 | 0 |
| Kidney and urinary disorders | 6 (0.7) | 1 (0.3) | 11 (1.4) | 4 (0.9) | 15 (5.5) | 3 (1.9) |
| Uric acid elevations | ||||||
| Blood uric acid levels increased | 17 (2.1) | 3 (0.8) | 13 (1.7) | 1 (0.2) | 3 (1.1) | 0 |
| Hyperuricemia | 18 (2.2) | 1 (0.3) | 16 (2.1) | 5 (1.1) | 3 (1.1) | 1 (0.6) |
| Gout | 12 (1.5) | 0 | 14 (1.8) | 2 (0.5) | 3 (1.1) | 2 (1.3) |
Patients in the max‐statins pool were followed for a median of 12 wks. Related, a TEAE with a relationship of “possibly related,” “probably related,” or “definitely related” to randomized; System organ class from the Medical Dictionary of Regulatory Activities version 20.1. AE indicates adverse event; AESI, adverse event of special interest; CLEAR, Cholesterol Lowering via Bempedoic Acid (ECT1002), an ACL‐Inhibiting Regime; and TEAE, treatment emergent adverse event.
Incidence >2% and more frequent than placebo in any age category.
All fatal AEs were judged by the investigator and medical monitor as unrelated to treatment.
Table 4.
Summary of Safety Data From Statin‐Intolerant Pool (CLEAR Outcomes) (n=13 965) TEAE and AESI by Age Category
| TEAEs, n (%) | 18 to <65 y | 65 to <75 years | ≥75 years | |||
|---|---|---|---|---|---|---|
| Bempedoic acid (n=2860) | Placebo (n=2904) | Bempedoic acid (n=3075) | Placebo (n=3020) | Bempedoic acid (n=1066) | Placebo (n=1040) | |
| Overview of AE | ||||||
| Any TEAE | 2405 (84.1) | 2426 (83.5) | 2732 (88.8) | 2628 (87.0) | 969 (90.9) | 934 (89.8) |
| Any serious TEAE | 619 (21.6) | 592 (20.4) | 929 (30.2) | 932 (30.9) | 437 (41) | 421 (40.5) |
| Any TEAE related to study treatment | 511 (17.9) | 409 (14.1) | 691 (22.5) | 576 (19.1) | 240 (22.5) | 205 (19.7) |
| Any TEAE leading to study‐treatment discontinuation | 227 (7.9) | 204 (7.0) | 384 (12.5) | 371 (12.3) | 148 (13.9) | 147 (14.1) |
| Exposure adjusted AESI, n (per 100 person‐years) | ||||||
| New‐onset diabetes* | 319 (18.0) | 336 (19.1) | 215 (14.6) | 226 (15.9) | 87 (14.2) | 78 (14.0) |
| Worsening hyperglycemia† | 298 (9.2) | 297 (8.8) | 347 (7.8) | 336 (7.7) | 68 (5.5) | 113 (9.1) |
| Hepatic enzyme increased | 182 (2.2) | 126 (1.5) | 109 (1.3) | 69 (0.8) | 22 (0.8) | 14 (0.5) |
| Muscular disorders | 370 (4.4) | 351 (4.1) | 511 (5.9) | 528 (6.5) | 171 (5.9) | 191 (7.0) |
| Myalgia | 123 (1.5) | 162 (1.9) | 205 (2.4) | 230 (2.8) | 65 (2.3) | 79 (2.9) |
| Muscle spasms | 88 (1.0) | 59 (0.7) | 134 (1.5) | 132 (1.6) | 53 (1.8) | 49 (1.8) |
| Pain in extremity | 109 (1.3) | 80 (0.9) | 146 (1.7) | 158 (1.9) | 41 (1.4) | 58 (2.1) |
| Muscular weakness | 12 (0.1) | 11 (0.1) | 33 (0.4) | 29 (0.4) | 15 (0.5) | 23 (0.8) |
| Neurocognitive disorders | 14 (0.2) | 8 (<0.1) | 27 (0.3) | 39 (0.5) | 17 (0.6) | 22 (0.8) |
| Positively adjudicated tendon rupture, patients (%) | 36 (1.3) | 24 (0.8) | 36 (1.2) | 33 (1.1) | 14 (1.3) | 9 (0.9) |
| Renal impairment | 236 (2.8) | 203 (2.4) | 376 (4.3) | 261 (3.2) | 193 (6.7) | 135 (5.0) |
| Blood creatinine levels increased | 40 (0.5) | 38 (0.4) | 61 (0.7) | 49 (0.6) | 23 (0.8) | 19 (0.7) |
| Glomerular filtration rate decreased | 83 (1.0) | 76 (0.9) | 107 (1.2) | 86 (1.1) | 62 (2.2) | 39 (1.4) |
| Uric acid elevations | ||||||
| Blood uric acid levels increased | 154 (1.8) | 87 (1.0) | 185 (2.1) | 70 (0.9) | 55 (1.9) | 29 (1.1) |
| Hyperuricemia | 320 (3.8) | 162 (1.9) | 330 (3.8) | 178 (2.2) | 113 (3.9) | 53 (1.9) |
| Gout | 62 (0.7) | 51 (0.6) | 107 (1.2) | 68 (0.8) | 46 (1.6) | 24 (0.9) |
Patients in the statin‐intolerant pool were followed for a median of 40.6 mo. Related, a TEAE with a relationship of “possibly related,” “probably related,” or “definitely related” to randomized. AE indicates adverse event; AESI, adverse event of special interest; CLEAR, Cholesterol Lowering via Bempedoic Acid (ECT1002), an ACL‐Inhibiting Regime; and TEAE, treatment emergent adverse events.
Includes patients with no documented diabetes at baseline in the statin‐intolerant pool: 18 to <65 y, n=1774 bempedoic acid, n=1758 placebo; ≥65 to <75 years, n=1469 bempedoic acid, n=1425 placebo; ≥75 y, n=613 bempedoic acid, n=557 placebo.
In patients with diabetes at baseline in the statin‐intolerant pool: 18 to <65 y, n=1086 bempedoic acid, n=1146 placebo; n=1606 bempedoic acid, n=1595 placebo; n=453 bempedoic acid, n=483 placebo.
Max‐Statin Pool
Treatment‐Emergent AEs
TEAEs occurred at an incidence of 71.1% and 72.5% for patients aged 18 to <65 years, 80% and 78.4% for patients aged 65 to <75 years, and 81.1% and 81.8% for patients aged ≥75 years in the bempedoic acid and placebo arms, respectively (Table 3).
TEAEs leading to treatment discontinuation occurred in 8.0% and 8.1% of patients aged 18 to <65 years, 12.0% and 7.1% of patients aged 65 to <75 years, and 16.0% and 7.3% of patients aged ≥75 years on bempedoic acid and placebo, respectively. TEAEs related to the musculoskeletal and connective tissue disorder system organ class contributed to the difference in frequency in TEAEs leading to treatment discontinuation within the ≥75 years age category (5.4% and 0.6% for bempedoic acid and placebo, respectively); however, this difference was not caused by an excess incidence of a single preferred term event and was primarily driven by the terms myalgia (bempedoic acid, 2.6%; and placebo, 0) and muscle spasms (bempedoic acid, 1.0%; and placebo, 0).
No notable differences were observed in the percentage of SAEs between treatment groups across the 18‐ to <65‐year and 65‐ to <75‐year age categories (Table 3). Among patients aged ≥75 years, any SAEs occurred in 23.7% of patients with bempedoic acid and 15.2% with placebo. The highest incidence of SAEs for age ≥75 years occurred in the cardiac disorder system organ class (25 [8%] patients on bempedoic acid, 7 [4.2%] patients on placebo), which was driven by atrial fibrillation (1.0% of patients receiving bempedoic acid and 0% in placebo) and unstable angina (1.6% and 0.6%, respectively).
No notable differences between treatment groups were observed in the 2 younger age categories for any TEAE with a fatal outcome (Table 3). Any TEAE with a fatal outcome was reported in 7 (2.2%) patients aged ≥75 years who received bempedoic acid and in no patients receiving placebo. The following preferred terms occurred in 1 patient each: cardiac arrest, cardiac failure, myocardial infarction, multiple organ dysfunction syndrome, sepsis, lung adenocarcinoma, lung neoplasm malignant, metastases to liver, and chronic obstructive pulmonary disease. All fatal events were judged unrelated to study treatment by the investigator and sponsor medical monitor.
AESIs and Select Laboratory Parameters
Exposure‐adjusted rates of AESIs are reported in Table 3. In general, there were similar reports of events across treatments and age categories, including AESIs traditionally associated with statins such as new‐onset diabetes/hyperglycemia, hepatic enzyme elevation, and muscular disorders.
The AESIs related to muscular disorders occurred at rates of 12.4/100 person‐years (PY) and 10.2/100 PY for age 18 to <65 years, 16.1/100 PY and 11.5/100 PY for age 65 to <75 years, and 14.3/100 PY and 8.9/100 PY for age ≥75 years in the bempedoic acid and placebo groups, respectively (Table 3). No notable differences were observed between age categories and treatment group with respect to skeletal muscle AEs commonly attributable to statins (eg, myalgia, muscular weakness, muscle spasms).
Exposure‐adjusted rates of renal disorders were 1.6/100 PY and 0.8/100 PY in patients aged 18 to 65 years, 3.8/100 PY and 1.6/100 PY for ages 65 to <75 years, and 6.2/100 PY and 1.9/100 PY for age ≥75 years in the bempedoic acid and placebo groups, respectively (Table 3). The incidence of kidney and urinary disorders system organ class (bempedoic acid, 5.5/100 PY; and placebo, 1.9/100 PY) in patients aged ≥75 years were numerically higher in bempedoic acid than placebo patients with the preferred terms renal failure (bempedoic acid, 2.6/100 PY; and placebo, 0) and acute kidney injury (bempedoic acid, 1.5/100 PY; and placebo, 0) primarily driving the difference. The mean absolute change in creatinine from baseline to week 24 was 0.018 mg/dL and −0.007 mg/dL for age 18 to <65 years, 0.044 mg/dL and −0.006 mg/dL for age 65 to <75 years, and 0.069 and −0.006 mg/dL for age ≥75 years observed in the bempedoic acid and placebo groups, respectively (Table 5).
Table 5.
Mean Change From Baseline to Week 24 in Select Laboratory Parameters in Patients Stratified by Statin Use and Age (Safety Population*)
| Laboratory parameters | Max‐statins pool | Statin‐intolerant pool | ||
|---|---|---|---|---|
| Bempedoic acid | Placebo | Bempedoic acid | Placebo | |
| ≥75 y | N=312 | N=165 | N=1066 | N=1040 |
| Creatinine | ||||
| mg/dL | 0.069 | −0.006 | 0.076 | −0.004 |
| % change | 6.646 | −0.489 | 8.171 | 1.016 |
| Hemoglobin | ||||
| g/dL | −0.46 | −0.03 | −0.43 | −0.06 |
| % change | −3.22 | −0.08 | −2.91 | −0.22 |
| Uric acid | ||||
| mg/dL | 0.81 | −0.03 | 0.80 | −0.05 |
| % change | 14.66 | 0.61 | 15.91 | 0.41 |
| 65 to <75 y | N=826 | N=449 | N=3075 | N=3020 |
| Creatinine | ||||
| mg/dL | 0.044 | −0.006 | 0.057 | 0.012 |
| % change | 4.867 | −0.163 | 7.127 | 2.030 |
| Hemoglobin | ||||
| g/dL | −0.30 | −0.02 | −0.36 | −0.03 |
| % change | −2.01 | −0.01 | −2.43 | −0.05 |
| Uric acid | ||||
| mg/dL | 0.83 | −0.01 | 0.81 | −0.02 |
| % change | 15.19 | 0.89 | 16.15 | 0.95 |
| 18 to <65 y | N=871 | N=385 | N=2860 | N=2904 |
| Creatinine | ||||
| mg/dL | 0.018 | −0.007 | 0.034 | 0.011 |
| % change | 2.309 | −0.299 | 4.515 | 2.191 |
| Hemoglobin | ||||
| g/dL | −0.25 | 0.01 | −0.34 | −0.01 |
| % change | −1.61 | 0.21 | −2.20 | 0.07 |
| Uric acid | ||||
| mg/dL | 0.77 | 0.02 | 0.71 | −0.02 |
| % change | 14.35 | 0.98 | 14.44 | 1.39 |
The safety analysis population is defined as all randomized study participants who received at least 1 dose of study drug, according to the treatment received.
Bempedoic acid was associated with a mean change in uric acid of ≈0.8 mg/dL across all age groups (Table 5). The observed rate of gout was 1.5/100 PY and 0 for age 18 to <65 years, 1.8/100 PY and 0.5/100 PY for age 65 to <75 years, and 1.1/100 PY and 1.3/100 PY for age ≥75 years in the bempedoic acid and placebo groups, respectively (Table 3).
Statin‐Intolerant Pool
Treatment‐Emergent AEs
Rates of TEAEs in the statin intolerant pool by age and treatment are reported in Table 4. TEAEs occurred at an incidence of 84.1% and 83.5% for patients aged 18 to <65 years, 88.8% and 87% for patients aged 65 to <75 years, and 90.9% and 89.8% for patients aged ≥75 years for bempedoic acid and placebo, respectively.
The incidence of reported SAEs was 21.6% and 20.4% for age 18 to <65 years, 30.2% and 30.9% for age 65 to <75 years, and 41% and 40.5% for age ≥75 years in the bempedoic acid and placebo groups, respectively. While no notable differences in severity of AEs between treatment arms were observed, the incidence of severe AEs increased with increasing age category: 15.4% and 15.1% for age 18 to <65 years, 21.9% and 23.3% for age 65 to <75 years, and 32% and 31.3%% for age ≥75 years in the bempedoic acid and placebo groups, respectively.
TEAEs leading to treatment discontinuation occurred in 7.9% and 7.0% of patients 18 to <65 years, 12.5% and 12.3% of patients aged 65 to <75 years, and 13.9% and 14.1% of patients aged ≥75 years on bempedoic acid and placebo.
AESIs and Select Laboratory Parameters
Exposure adjusted rates of AESIs are reported in Table 4. In general, there were similar reports of events across treatment and age categories, including AESIs traditionally associated with statins such as new‐onset diabetes/hyperglycemia, hepatic enzyme elevation, and muscular disorders.
The mean change in uric acid from baseline to week 24 with bempedoic acid was ≈0.8 mg/dL across all age categories (Table 5). Rates of gout increased in frequency with increasing age: 0.7/100 PY and 0.6/100 PY for age 18 to <65 years, 1.2/100 PY and 0.8/100 PY for age 65 to <75 years, and 1.6/100 PY and 0.9/100 PY for age ≥75 years (Table 4).
DISCUSSION
This analysis provides a comprehensive review of the efficacy and safety of bempedoic acid by age group among patients from 3 phase 3 data sets stratified into 2 distinct groups on the basis of statin intensity and tolerability. This allowed evaluation of the effects of bempedoic acid across age groups treated with maximum tolerated statin therapy, where 90% were receiving moderate or high intensity statin, or in patients with statin intolerance, where only 22% were receiving a statin at less than the lowest approved starting dose. Bempedoic acid significantly lowered LDL‐C by ≈18% in the max‐statin pool and by 22% to 25% in the statin‐intolerant pool, and significantly reduced non–HDL‐C, total cholesterol, and hsCRP compared with placebo in all age groups. Greater reductions in LDL‐C, non–HDL‐C, total cholesterol, and hsCRP were previously observed for patients not treated with a statin in phase 3 primary hyperlipidemia trials, and most likely attributable to the shared mechanistic pathway involving inhibition of cholesterol biosynthesis by both statins and bempedoic acid. 17 Consistent with the comparable reductions in LDL‐C across age categories in the statin‐intolerant pool, there was no statistically significant age‐related heterogeneity in MACE‐4 reduction in CLEAR Outcomes. 15
Bempedoic acid was generally well tolerated in patients across treatment arms and age categories in both data pools. In both the max‐statin pool and statin‐intolerant pool, the incidence of overall TEAEs and serious TEAEs was higher in patients aged ≥75 years, but generally comparable with bempedoic acid compared with placebo. Statin‐associated muscle symptoms are the most common reason for statin intolerance. Bays et al previously reported that across the 4 integrated Phase 3 trials (CLEAR Harmony, 14 CLEAR Wisdom, 12 CLEAR Tranquility, 11 CLEAR Serenity 13 ) evaluating bempedoic acid for primary hyperlipidemia, the incidence of skeletal muscle TEAEs often associated with statins was similar in patients treated with bempedoic acid and placebo (myalgia, 5.8/100 PY versus 6.0/100 PY; muscular weakness, 0.6/100 PY versus 0.7/100 PY, respectively). 18 The current analysis allows for characterization of muscle‐related AEs by age in patients receiving predominantly moderate‐ or high‐intensity statins compared with statin‐intolerant patients on no statin or less than the lowest approved starting dose. Interestingly, in the statin‐intolerant pool, the exposure‐adjusted incidence of muscle‐related AE terms (myalgia, muscle spasms, pain in extremity, and muscular weakness) was not only comparable for bempedoic acid compared with placebo but was also less in both treatment groups compared with the exposure‐adjusted incidence in the max‐statin pool. In the max‐statin pool, there were small numerical differences between treatment groups for some of the terms in some age groups, but no general pattern was observed. Discontinuation due to any TEAE or muscular disorder TEAEs was numerically greater in the bempedoic acid treatment group compared with placebo in patients ≥75 years in the max‐statin pool. However, this was a small number of patients (n=18), and this finding was not demonstrated in patients aged ≥75 years within the statin‐intolerant pool, suggesting that this may be a chance finding or that managing older patients on multiple lipid‐lowering therapies may be more challenging than in younger patients.
In both the max‐statin and statin‐intolerant pools, the incidence of other AESIs associated with statins, including new‐onset diabetes, hyperglycemia, or elevated liver enzymes, was comparable between treatment arms across all age groups.
Bempedoic acid inhibits organic anion transporter 2, which mediates renal transport of serum uric acid. 18 , 19 Uric acid increased ≈0.8 mg/dL in the bempedoic acid arms in both the max‐statin pool and CLEAR Outcomes pool, with similar rates of elevated blood uric acid/hyperuricemia reported across age groups. Patients aged ≥75 years receiving bempedoic acid experienced comparable rates of gout compared with younger cohorts.
Risk of ASCVD increases with age, and LDL‐C is predictive of MACEs regardless of age. 20 , 21 , 22 A patient‐centered approach to lipid‐lowering therapies is particularly important with older adults because this population demonstrates tremendous heterogeneity in physical and functional health and because competing personal and health priorities are more common and more complex. Any expected benefit of therapy must be weighed against these factors in addition to the impact of polypharmacy and associated adverse effects. The current analysis suggests that bempedoic acid is safe and effective in older adults with or without a high‐intensity background statin. This analysis is relevant considering the limited availability of data characterizing the efficacy and safety of nonstatin lipid‐lowering therapies in older patients, particularly with statin intolerance. In a large meta‐analysis involving >4 million patients, age (as a continuous variable) was significantly associated with higher risk for statin intolerance (odds ratio, 1.33 [95% CI, 1.25–1.41]; P= 0.04). 9
In conjunction with the previously reported CLEAR Outcomes MACE‐4 data stratified by age, the efficacy, tolerability, and safety data presented here for patients aged ≥75 years provides additional support for and clinical relevance to the recent 2b recommendation from the National Lipid Association and the American Geriatrics Society to consider use of bempedoic acid for reduction of LDL‐C and ASCVD risk in patients who are statin intolerant. These data also provide additional support for use of bempedoic acid in older patients in conjunction with background statins as well. 22 The 2025 Focused Update of the 2019 European Society of Cardiology/European Atherosclerosis Society Guidelines for the management of dyslipidemias recommends bempedoic acid, alone or in combination with other nonstatin therapies, in patients who are unable to take statin therapy to lower LDL‐C and reduce the risk of cardiovascular events as a class I recommendation, and the addition of bempedoic acid to the maximally tolerated dose of statin with or without ezetimibe should be considered in patients at high or very high risk to achieve the LDL‐C goal as a class IIa recommendation, irrespective of age. 23
Limitations
This is a descriptive, post hoc analysis which provides a comprehensive study of the safety and efficacy of bempedoic acid stratified by age, but the derivation of data from placebo‐controlled studies in well‐characterized patients meeting specific eligibility criteria for the trials is a strength. The results may not fully reflect real‐world safety and efficacy among patients aged ≥75 years not participating in clinical trials or who may require complex care. The results also may not be generalizable to all races, as <10% of patients identified their race as other than White. The smaller number of subjects in the ≥75‐year age group compared with younger subjects is an additional limitation, but the inclusion of 2585 individuals in this age range provides meaningful data. The short 12‐month duration of follow‐up for the max‐statin pool may be considered a limitation in interpreting safety data for that portion of the study; however, the majority of patients in this analysis (82% of a total of 16 979) participated in longer (median, 40.6 month) follow‐up in the cardiovascular outcomes trial, which helps validate the long‐term safety of bempedoic acid.
Conclusions
Overall, bempedoic acid was well‐tolerated with comparable efficacy and safety across all age categories, except for musculoskeletal disorders in patients receiving concomitant statins. The reduction in MACE‐4 was not statistically different among younger and older individuals, supporting the goal of LDL‐C lowering with bempedoic acid for cardiovascular prevention in older individuals aged ≥75 years. These data further support the role of bempedoic acid as a viable strategy for managing hypercholesterolemia and preventing cardiovascular events in a broad range of older patients.
Sources of Funding
CLEAR Harmony, CLEAR Wisdom, and CLEAR Outcomes were funded by Esperion Therapeutics, Inc.
Disclosures
G.B.J.M. received research grant(s)/support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, HLS Therapeutics, Merck, Novo Nordisk, and Sanofi; and has served as a consultant for these companies, as well as Esperion Therapeutics, Inc., Novartis, and Servier. A.M.L. reports receipt of honoraria/consultancy from Novo Nordisk, Eli Lilly, Alnylam, Amgen, Ardelyx, Brainstorm Cell, Cadrenal, GlaxoSmithKline, Johnson & Johnson, Medtronic, Neovasc, ReCor, and TD Cowen; and has received research funding to Cleveland Clinic from AbbVie, AstraZeneca, CSL Behring, Eli Lilly, Esperion, and Novartis. A.C.G. has received research grant(s)/support from Amarin, Amgen, Akcea/IONIS, Arrowhead, Esperion Therapeutics, Inc., Merck, NewAmsterdam Pharma, Novartis, Pfizer, Regeneron, and Sanofi; has served as a consultant for 23andMe, Akcea, Esperion, IONIS, Merck, NewAmsterdam Pharma, Novartis, OptumRX, Regeneron, and Sanofi; and has provided editorial work for Merck. C.B. is an employee of Esperion Therapeutics, Inc., and receives compensation via salary or company stock. N.L. is an employee of Esperion Therapeutics, Inc., and receives compensation via salary or company stock. P.B.D. has received institutional research grant(s)/support from Regeneron, Regenxbio, and Retrophin/Travere Therapeutics; and has served as a consultant for Akcea/Ionis, Esperion Therapeutics, Inc., Kaneka, Novo Nordisk, and Regeneron. U.L. has received research grants or funding from Amgen, Daiichi Sankyo, Novartis, and Sanofi. A.L.C. has received research grant(s)/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 Therapeutics, Inc., Ionis Pharmaceuticals, Kowa, Medco, Menarini, Merck, Mylan, Novartis, Recordati, Regeneron, Sanofi, The Corpus, and Viatris. L.A.L. has received research grants/support from Amgen, AstraZeneca, Kowa, and Novartis; and has served as an advisor or provided continuing medical education on behalf of Amarin, Amgen, AstraZeneca, Esperion Therapeutics, Inc., HLS, Merck, Novartis, Pfizer, and Sanofi. M.B. has received research grant(s)/support from Amgen, Daiichi Sankyo, Sanofi, Mylan, and Valeant; and has served as a consultant for Abbott/Mylan, Abbott Vascular, Amgen, Daiichi Sankyo, Esperion Therapeutics, Inc., Freia Pharmaceuticals, KRKA, Lilly, MSD, NewAmsterdam Pharma, Novo Nordisk, Pfizer, Polfarmex, Polpharma, Regeneron, Sanofi‐Aventis, Servier, Teva, and Zentiva. P.M.H. is an employee of Esperion Therapeutics, Inc. and receives compensation via salary or company stock. S.J.N. has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Eli Lilly, Esperion, Resverlogix, Novartis, InfraReDx, and Sanofi‐Regeneron; and is a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi‐Regeneron, Vaxxinity, CSL Sequiris, and Novo Nordisk. L.B. is an employee of Esperion Therapeutics, Inc. and receives compensation via salary or company stock. H.A.P. is an employee of Esperion Therapeutics, Inc. and receives compensation via salary or company stock. S.E.N. reports that the Cleveland Clinic Center for Clinical Research has received funding to perform clinical trials from Abbvie, AstraZeneca, Amgen, Bristol Myers Squibb, Eli Lilly, Esperion, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis, Pfizer, and Silence Therapeutics; he is involved in these clinical trials but receives no personal remuneration for his participation. He consults for these pharmaceutical companies but does not accept compensation. D.M. has no disclosures to report.
Supporting information
Tables S1–S3
Acknowledgments
Author contributions: G.B.J.M., A.M.L., A.C.G., P.B.D., U.L., A.L.C., L.A.L., M.B., S.J.N., L.B., and S.E.N. were involved in the conceptualization, design, execution, and interpretation of the original phase 3 clinical trials. G.B.J.M., C.B., P.M.H., and D.M. prepared the first draft of the article. N.L. performed the statistical analysis. All authors critically reviewed and revised the article. All authors had full access to all data in the study and had final responsibility for the decision to submit for publication.
This manuscript was sent to Daniel E. Clark, MD, MPH, Associate Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.125.047897
For Sources of Funding and Disclosures, see page 11.
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Associated Data
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Supplementary Materials
Tables S1–S3