Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients

Key Points

Question  In statin-intolerant primary prevention patients at high cardiovascular risk, does bempedoic acid reduce major adverse cardiovascular events?

Findings  In this randomized trial of 13 970 patients, 4206 participants were enrolled with high cardiovascular risk but without a prior cardiovascular event. In this subgroup, bempedoic acid treatment, 180 mg daily, was associated with a significant reduction in major cardiovascular events (hazard ratio, 0.70).

Meaning  These findings suggest that treatment with bempedoic acid in primary prevention patients has the potential to reduce major adverse cardiovascular events.

Importance  The effects of bempedoic acid on cardiovascular outcomes in statin-intolerant patients without a prior cardiovascular event (primary prevention) have not been fully described.

Objective  To determine the effects of bempedoic acid on cardiovascular outcomes in primary prevention patients.

Design, Setting, and Participants  This masked, randomized clinical trial enrolled 13 970 statin-intolerant patients (enrollment December 2016 to August 2019 at 1250 centers in 32 countries), including 4206 primary prevention patients.

Interventions  Participants were randomized to oral bempedoic acid, 180 mg daily (n = 2100), or matching placebo (n = 2106).

Main Outcome Measures  The primary efficacy measure was the time from randomization to the first occurrence of any component of a composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization.

Results  Mean participant age was 68 years, 59% were female, and 66% had diabetes. From a mean baseline of 142.2 mg/dL, compared with placebo, bempedoic acid reduced low-density lipoprotein cholesterol levels by 30.2 mg/dL (21.3%) and high-sensitivity C-reactive protein levels by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L. Follow-up for a median of 39.9 months was associated with a significant risk reduction for the primary end point (111 events [5.3%] vs 161 events [7.6%]; adjusted hazard ratio [HR], 0.70 [95% CI, 0.55-0.89]; P = .002) and key secondary end points, including the composite of cardiovascular death, MI, or stroke (83 events [4.0%] vs 134 events [6.4%]; HR, 0.64 [95% CI, 0.48-0.84]; P < .001); MI (29 events [1.4%] vs 47 events [2.2%]; HR, 0.61 [95% CI, 0.39-0.98]); cardiovascular death (37 events [1.8%] vs 65 events [3.1%]; HR, 0.61 [95% CI, 0.41-0.92]); and all-cause mortality (75 events [3.6%] vs 109 events [5.2%]; HR, 0.73 [95% CI, 0.54-0.98]). There was no significant effect on stroke or coronary revascularization. Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.

Conclusions  In a subgroup of high-risk primary prevention patients, bempedoic acid treatment was associated with reduced major cardiovascular events.

Trial Registration  ClinicalTrials.gov Identifier: NCT02993406

Statins reduce atherogenic lipoproteins and are recommended by current guidelines for administration to patients at high risk for a first major adverse cardiovascular event (primary prevention).¹ However, the current recommendations are predominantly derived from clinical trials conducted several decades ago during the initial development of statins to reduce low-density lipoprotein cholesterol (LDL-C) levels.^2,3 Most contemporary cardiovascular outcome trials of lipid-lowering therapies have enrolled only participants with a prior cardiovascular event. Recent data are limited on the effects of statins or other adjunctive treatments in patients without a history of a cardiovascular event, leading some authors to question whether the benefits of cholesterol lowering exceed the harms in these patients.^4-7 Currently, lipid-lowering therapies are underutilized in high-risk primary prevention patients, particularly women and patients from racial and ethnic minority populations.^8-10 More than half of eligible patients do not currently receive lipid-lowering therapies.⁹

The CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) trial reported cardiovascular outcomes in a mixed population of primary and secondary prevention patients unable or unwilling to take guideline-recommended doses of statins.¹¹ Among the 13 970 patients enrolled in the trial, 4206 (30%) had characteristics associated with a high risk of adverse cardiovascular outcomes but without a prior event. The current article reports a prespecified subgroup analysis of the effects of bempedoic acid on major adverse cardiovascular outcomes in this primary prevention population.

The rationale, design, and methods of the trial have been reported.^11,12 The trial was conducted at 1250 sites in 32 countries. The trial was designed by the Cleveland Clinic Coordinating Center for Clinical Research (C5Research) and an academic executive committee in collaboration with the sponsor, Esperion Therapeutics Inc. The protocol was approved by ethics committees at participating sites, and all patients provided written informed consent before enrollment (the study protocol and statistical analysis plan are available in Supplement 1). A contract research organization collected the data, which were transferred to C5Research at completion of the trial; C5Research statisticians conducted the analyses for this article. An independent data monitoring committee monitored the trial.

Primary prevention patients aged 18 to 85 years with an LDL-C level 100 mg/dL (2.59 mmol/L) or greater and with clinical features placing them at high risk for a first cardiovascular event were eligible. Criteria for high cardiovascular risk included risk scores described in eFigure 1 in Supplement 2,^13,14 a coronary artery calcium score greater than 400 Agatston units, or presence of either type 1 or 2 diabetes in women older than 65 years or men older than 60 years.

Investigators were responsible for assessing the patient for statin intolerance. Patients had to report statin intolerance due to an adverse effect that started or increased during statin therapy and resolved or improved after statin therapy was discontinued. Entry criteria required inability to tolerate 2 or more statins at any dose or 1 statin and unwillingness to attempt a second statin or advised by a physician not to attempt taking a second statin. Both the patient and site investigator were required to provide written confirmation that the patient was statin intolerant and aware of the benefits of statins to reduce the risk of cardiovascular events, including death, and acknowledge that many patients unable to tolerate a statin can tolerate a different statin or dose. Patients could be enrolled if they tolerated a very low average daily statin dose, defined as rosuvastatin less than 5 mg, atorvastatin less than 10 mg, simvastatin less than 10 mg, lovastatin less than 20 mg, pravastatin less than 40 mg, fluvastatin less than 40 mg, or pitavastatin less than 2 mg. Other background lipid-lowering therapies were permitted, including ezetimibe, niacin, bile acid resins, fibrates, and/or proprotein convertase subtilisin/kexin type 9 inhibitors. The study design and primary publications provide the full inclusion and exclusion criteria.^11,12

Eligible patients entered a 4-week run-in period during which they were treated with single-masked placebo. If patients were intolerant to placebo treatment or if adherence was less than 80% by tablet count, they were not eligible for randomization. Patients who successfully completed the run-in period were randomly assigned in a 1:1 ratio to receive a 180-mg oral dose of bempedoic acid or matching placebo, administered daily. During the trial, LDL-C and high-sensitivity C-reactive protein (hsCRP) results were masked. Beginning 6 months after randomization, the central laboratory notified the investigator, who remained masked to treatment assignment, if the patient’s LDL-C level was 25% or more higher than baseline. Repeat testing was performed after the patient was counseled about diet and encouraged to take all medications as prescribed. The patient returned for a repeat fasting blood lipid profile to confirm whether the LDL-C value exceeded the threshold criteria. If confirmed, the patient’s treatment regimen for LDL-C lowering could be adjusted, per standard of care and local practice. The flow of patients through the trial is shown in Figure 1.

The primary end point was the time to first occurrence of a composite of death from cardiovascular causes, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization (4-component major adverse cardiovascular events [MACE]). Key secondary end points included (1) time to the first occurrence of a composite of cardiovascular death, nonfatal stroke, or nonfatal MI (3-component MACE); (2) fatal or nonfatal MI; (3) coronary revascularization; (4) fatal or nonfatal stroke; (5) cardiovascular death; and (6) all-cause mortality. Additional adjudicated time-to-event end points included hospitalization for unstable angina and a 5-component composite that included cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, and hospitalization for unstable angina. End points were adjudicated by C5Research clinical end points committee personnel masked to treatment assignments.

The efficacy end points were analyzed using a Cox proportional hazards model with treatment as a factor to generate the hazard ratio (HR) and 95% confidence interval. P values were obtained from a log-rank test (2-sided). Significance testing was performed using 2-sided tests (α = .05). All efficacy outcomes were adjusted for baseline characteristics including geographic region, age, sex, race and ethnicity (assessed to determine if the response to treatment differed among individuals based on their racial or ethnic background), LDL-C level, body mass index, hsCRP level, estimated glomerular filtration rate, use of any lipid-modifying therapy at baseline, and glycemic status (diabetes, prediabetes, normoglycemia). A time-dependent covariate with treatment was created to assess for proportionality. The P value was not statistically significant; therefore, the assumption of proportional hazards was determined to be met. Change and percent change in lipids were calculated using least-square means adjusted for baseline. Hodges-Lehmann estimate of location shift was used to summarize changes in hsCRP and triglyceride levels. Baseline data for 2 patients with missing body mass index data were imputed for efficacy models using the average measurement of the overall cohort. The statistical analysis plan prespecified subgroup analyses for 4-component MACE and 3-component MACE. Therefore, P values are provided only for these end points. Efficacy analyses included all randomized patients based on the intent-to-treat principle. Outcomes were not adjusted for multiplicity. Adverse event summaries were based on the safety population that included all patients who underwent randomization and received at least 1 dose of study drug.

Between December 2016 and August 2019, 22 084 patients were screened and 14 016 were randomized, with 13 970 included in the full analysis after exclusion of 46 participants from a site determined to have created fraudulent patients. Within the full analysis set, 4206 patients (30%) met primary prevention criteria, 2100 randomized to the bempedoic acid treatment group and 2106 to the placebo group. For the pooled treatment groups, mean age was 67.9 (SD, 6.8) years, 59.0% of patients were female, 66.1% had diabetes, and 19.3% were taking a statin and 8.0% ezetimibe. Mean LDL-C level was 142.5 mg/dL, mean high-density lipoprotein cholesterol, 51.0 mg/dL; median triglycerides, 161.8 mg/dL (to convert cholesterol values to mmol, multiply by 0.0259); and median hsCRP, 2.4 mg/L. These baseline characteristics were similar in both treatment groups (Table 1). High-risk primary prevention patients were followed up for a median of 39.9 months. Complete assessment for the primary end point was available for 94.7% and vital status for 99.5% of these patients. Efficacy end points at sites in Ukraine were censored after the start of the conflict on February 24, 2022. The flow of patients through the trial is shown in Figure 1.

The effects of trial regimens on lipid parameters after 6 months of treatment and hsCRP level after 12 months of treatment are reported in Table 2. From a baseline mean LDL-C level of 142.2 mg/dL, least-square mean reduction in the bempedoic acid group compared with placebo after 6 months of treatment was 30.2 mg/dL (95% CI, –32.1 to –28.3), a least-square mean difference of 21.3%. With administration of additional lipid-modifying therapies to 12.4% of patients in the placebo group and 6.7% in the bempedoic acid group (eTable 1 in Supplement 2), the time-averaged difference in LDL-C level in the primary prevention subgroup over the course of the trial was 23.2 mg/dL (eFigure 2 in Supplement 2). From a median baseline value of 2.4 mg/L, after 12 months of treatment, using Hodges-Lehman estimate of location shift, bempedoic acid reduced hsCRP level by 0.34 mg/L (95% CI, −0.42 to −0.29) compared with a reduction of 0.01 mg/L (95% CI, −0.04 to 0.09) for placebo, a difference of 0.56 mg/L (21.5%).

The primary 4-component composite end point occurred in 111 patients (5.3%) in the bempedoic acid group and 161 patients (7.6%) in the placebo group (HR, 0.70 [95% CI, 0.55-0.89]; P = .002) (Table 3 and Figure 2A). The number needed to treat (NNT) to prevent 1 primary composite outcome was 43 patients. Bempedoic acid was associated with a significant reduction in the risk of the secondary 3-component composite end point of time to cardiovascular death, nonfatal MI, or stroke, which occurred in 83 patients (4.0%) in the bempedoic acid group and 134 patients (6.4%) in the placebo group (HR, 0.64 [95% CI, 0.48-0.84]; P < .001) (Table 3 and Figure 2B). For the other secondary end points, fatal or nonfatal MI occurred in 29 patients (1.4%) in the bempedoic acid group and 47 patients (2.2%) in the placebo group (adjusted HR, 0.61 [95% CI, 0.39-0.98]) (Table 3 and Figure 2C). Fatal or nonfatal stroke occurred in 27 patients (1.3%) in the bempedoic acid group and 37 patients (1.8%) in the placebo group (adjusted HR, 0.76 [95% CI, 0.46-1.26]) (Table 3 and Figure 2D). Cardiovascular death occurred in 37 patients (1.8%) in the bempedoic acid group and 65 patients (3.1%) in the placebo group (adjusted HR, 0.61 [95% CI, 0.41-0.92]) (Table 3 and Figure 2E). All-cause mortality occurred in 75 patients (3.6%) in the bempedoic acid group and 109 patients (5.2%) in the placebo group (adjusted HR, 0.73 [95% CI, 0.54-0.98]) (Table 3 and Figure 2F).

The first occurrence of the 5-component composite of death from cardiovascular causes, MI, stroke, coronary revascularization, or hospitalization for unstable angina occurred in 112 patients (5.3%) in the bempedoic acid group and 164 patients (7.8%) in the placebo group (HR, 0.69 [95% CI, 0.54-0.88]) (Table 3; eFigure 3 in Supplement 2). Coronary revascularization occurred in 50 patients (2.4%) in the bempedoic acid group and 68 patients (3.2%) in the placebo group (HR, 0.71 [95% CI 0.49-1.03]) (Table 3; eFigure 4 in Supplement 2). Hospitalization for unstable angina occurred in 10 patients (0.5%) in the bempedoic acid group and 17 patients (0.8%) in the placebo group (HR, 0.58 [95% CI, 0.26-1.27]) (Table 3; eFigure 5 in Supplement 2). Unadjusted analyses of the primary and secondary end points showed results similar to those from the adjusted analyses (eTable 2 in Supplement 2).

Adverse events are reported in Table 4. There were no between-group differences in serious adverse events or adverse events leading to drug discontinuation. However, investigator-reported prespecified adverse events included more frequent elevations in hepatic enzyme levels (4.5% vs 2.6%) and more frequent kidney adverse events (10.3% vs 8.1%) in the bempedoic acid group compared with the placebo group. Myalgias were reported in 4.2% of bempedoic acid–treated patients compared with 5.9% of placebo-treated patients. A higher incidence of hyperuricemia (12.1% vs 6.3%), gout (2.6% vs 2.0%), and cholelithiasis (2.5% vs 1.1%) occurred in the bempedoic acid group. Rates of new-onset diabetes and the change in hemoglobin A_1c levels in patients with diabetes at baseline were similar in both randomized groups.

In patients with elevated cardiovascular risk but without a prior clinical event, this prespecified subgroup analysis showed that administration of bempedoic acid in patients unable or unwilling to take guideline recommended doses of a statin was associated with a significant reduction in the primary end point, 4-component MACE (2.3% absolute risk reduction). The NNT to prevent 1 primary event was 43 patients. This primary prevention cohort was a prespecified subgroup that represented 30% of the total enrolled within a larger trial that included a mixed population of primary and secondary prevention patients.¹¹ Treatment was also associated with significant benefits for several key secondary end points, including the prespecified 3-component MACE (2.4% absolute risk reduction); an NNT of 42 patients to prevent 1 event; and significant reductions in MI, cardiovascular death, and all-cause mortality. Stroke and coronary revascularization were not significantly reduced. Although prespecified, this study reports on outcomes in a subgroup within a larger clinical trial; therefore, the results should be interpreted as hypothesis-generating rather than definitive evidence of benefits. Adverse events included a higher incidence of gout, elevated hepatic enzyme levels, and increased serum creatinine levels.

Bempedoic acid, compared with placebo, reduced levels of LDL-C by 30.2 mg/dL (21.3%) after 6 months of treatment and after 12 months of treatment reduced hsCRP levels by 0.56 mg/L (21.5%). Although the time-averaged difference in LDL-C over the duration of the trial was moderate (23.2 mg/dL [16.3%]), there were substantial reductions in major adverse cardiovascular outcomes and cardiovascular and all-cause mortality. These findings emphasize the potential value of lipid-modulating therapy in patients who have had no prior cardiovascular event but who have a high risk for a first event, a population that is currently undertreated.^8-10,15-18 Because diabetes was an enrollment criterion for increased cardiovascular risk, approximately two-thirds of the participants had previously diagnosed diabetes. The current findings support the guideline recommendation that primary prevention patients with diabetes should be treated with statins to lower cholesterol levels.

Only 1 major clinical trial during the last decade has reported on the effects of lipid-lowering treatment in patients without a prior cardiovascular event. The Heart Outcomes Prevention Evaluation 3 (HOPE-3), published in 2016, showed that low-dose statin therapy reduced the composite cardiovascular outcome by 24% but had no significant effect on mortality.¹⁹ The 2 classic trials of primary prevention patients published in the 1990s showed a reduction in morbidity but not mortality.^2,3 The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study published 15 years ago showed a 44% reduction in the primary composite outcome and a 20% reduction in all-cause mortality with statin therapy in primary prevention patients with an hsCRP level greater than 2.0 mg/L.²⁰ Although the current study was not designed to assess factors mediating the results, both LDL-C and hsCRP levels were significantly reduced. Reduction in LDL-C has been strongly associated with improved cardiovascular outcomes, and 3 recent trials have demonstrated favorable effects with anti-inflammatory therapies.^21-24

Primary prevention patients are currently undertreated with lipid-modulating therapies.^4-7 In a registry of nearly 50 000 US patients with LDL-C levels greater than 190 mg/dL but without cardiovascular disease, only 58.5% were taking a statin.¹⁵ Another study of US patients eligible for treatment based on current guidelines reported that 53% of patients treated in cardiology practices were not taking a statin.¹⁶ In a Danish study of more than 90 000 patients, 81% of primary prevention patients with a 10-year risk greater than 10% for a cardiovascular event were not treated to LDL-C goals according to the European guidelines.¹⁷ In a registry that studied reasons why eligible patients were not taking a statin, 59% reported never being offered treatment, 10% declined a statin, and 31% discontinued therapy.¹⁸ Statin use in primary prevention patients was particularly low in minority groups in a recent national survey.¹⁰ Current guidelines do not specifically address the use of nonstatin treatments in high-risk primary prevention patients.

The Cholesterol Treatment Trialists Collaboration (CTTC) meta-analysis reported on outcomes for statin treatment in patients without vascular disease.²⁴ The CTTC analysis showed a 22% reduction in major coronary events for each 38.7-mg/dL (1-mmol/L) decrease in LDL-C level and a 15% reduction in vascular death. In the current study, a time-averaged reduction of 23.2 mg/dL (0.60 mmol/L) was associated with larger reductions in cardiovascular morbidity and mortality than predicted by the CTTC analysis. The CTTC analysis reported that the benefits of lowering LDL-C level were consistent across a wide spectrum of baseline risk varying from less than 5% to 30% or greater. However, a more recent modeling study challenged these findings, suggesting that benefits would exceed harms only for patients at higher risk levels, particularly women.⁶ In the current study, women comprised nearly 60% of the population.

This study has several limitations. First, this is a secondary analysis of a subpopulation in a larger randomized trial. Such analyses can result in false-positive findings due to the testing of multiple subgroups and may represent the play of chance. However, the consistency of event reduction for the primary end point, secondary end points, and components of end points strengthens the likelihood that these results are reliable. Second, because the sample size represented a fraction of the total enrolled population, the number of events was smaller, resulting in wider confidence intervals. Third, the inclusion of patients who reported inability to tolerate statins resulted in a high mean baseline LDL-C level. The effects of cholesterol lowering on cardiovascular events in populations with lower pretreatment LDL-C levels was not studied. Fourth, the trial selected patients using specific criteria for a high level of risk of a first cardiac event. Whether outcomes would be similar in patients identified using other criteria for an increased risk remains uncertain.

In primary prevention patients unable to tolerate recommended doses of statins, bempedoic acid was associated with a significant reduction in the primary composite end point, time to death from cardiovascular causes, nonfatal MI, nonfatal stroke, or coronary revascularization. Treatment was also associated with significant reductions in MI, cardiovascular death, and all-cause mortality.

Accepted for Publication: May 19, 2023.

Published Online: June 24, 2023. doi:10.1001/jama.2023.9696

Corresponding Author: Steven E. Nissen, MD, C5Research, Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (nissens@ccf.org).

Author Contributions: Dr Nissen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Nissen, Nicholls, Ridker, Mason, Kastelein, Cho, Libby, Foody, Louie, Lincoff.

Acquisition, analysis, or interpretation of data: Nissen, Menon, Nicholls, Brennan, Laffin, Ridker, Ray, Cho, Libby, Li, Foody, Louie, Lincoff.

Drafting of the manuscript: Nissen, Brennan, Cho, Libby, Li, Louie.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Brennan, Libby, Li, Foody.

Obtained funding: Nissen, Nicholls, Foody.

Administrative, technical, or material support: Nissen, Menon, Ridker, Mason, Cho, Libby, Foody, Lincoff.

Supervision: Nissen, Nicholls, Ray, Foody.

Conflict of Interest Disclosures: Dr Nissen reported receiving grants to perform clinical trials from AbbVie, AstraZeneca, Amgen, Bristol Myers Squibb, Eli Lilly, Esperion Therapeutics Inc, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics. Dr Nicholls reported receiving grants from Esperion, AstraZeneca, New Amsterdam Pharma, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and LipoScience; receiving honoraria to his institution from AstraZeneca, Amarin, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, Boehringer Ingelheim, Vaxxinity, and Sequiris; and that he is a named inventor on a patent for PCSK9 inhibitors and atherosclerosis. Dr Laffin reported receiving compensation from Esperion and C5Research for acting as ARO for the CLEAR Outcomes trial; receiving personal fees from Lilly, CRISPR Therapeutics, and Medtronic; serving on a steering committee for Mineralys; and holding stock options in Gordy Health and LucidAct Health. Dr Ridker reported receiving a grant to his institution to perform clinical research related to bempedoic acid; receiving consulting fees from Esperion; receiving institutional research grant support from Kowa, Novartis, Amarin, Pfizer, Novo Nordisk, and the National Heart, Lung, and Blood Institute; serving as a consultant for Novartis, Flame, Agepha, AstraZeneca, Janssen, Civi Biopharm, GlaxoSmithKline, SOCAR, Novo Nordisk, Omeicos, Health Outlook, Montai Health, New Amsterdam, Boehringer-Ingelheim, Research Triangle Institute, Zomagen, Cytokinetics, Horizon Therapeutics, and Cardio Therapeutics; holding minority shareholder equity positions in Uppton, Bitteroot Bio, and Angiowave; and receiving compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation, and the Baim Institute. Dr Ray reported serving on the Esperion executive committee; receiving grants to his institution from Amgen, Daiichi Sankyo, Regeneron, and Sanofi; and receiving consulting fees from Daiichi, Esperion, Amgen, Novartis, Sanofi, Eli Lilly, Silence Therapeutics, Kowa, Bayer, Abbott, AstraZeneca, Cargene, New Amsterdam, Scribe, Vaxxinity, CRISPR, Beren, Novo Nordisk, and Boehringer Ingelheim. Dr Kastelein reported receiving consulting fees from Esperion Therapeutics, CiVi Biotech, Draupnir, and Scribe and serving as CSO of New Amsterdam Pharma. Dr Cho reported serving on the steering committee for CLEAR Outcomes trial. Dr Libby reported serving as an unpaid consultant for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Novo Nordisk, Novartis, Pfizer, Sanofi-Regeneron, Cartesian, Esperion, Genentech, and Moderna; serving as an unpaid scientific advisory board member for Baim Institute, Medimmune, Dewpoint, Pfizer, DalCor Pharmaceuticals, Olatec Therapeutics, XBiotech Inc, Caristo, CSL Behring, PlaqueTech, TenSixteen Bio, Soley Therapeutics, and Elucid Bioimaging; receiving laboratory funding from Pfizer and CSL Behring; holding patents pending for use of canakinumab and for treatment for brain ischemia-reperfusion injury; serving as an unpaid consultant to, or involved in clinical trials for, Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Moderna, Novo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron; serving on the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, Soley Therapeutics, and XBiotech Inc; that his laboratory has received research funding in the last 2 years from Novartis, Novo Nordisk, and Genentech; serving on the board of directors of XBiotech Inc; that he has a financial interest in Xbiotech (a company developing therapeutic human antibodies), in TenSixteen Bio (a company targeting somatic mosaicism and clonal hematopoiesis of indeterminate potential [CHIP] to discover and develop novel therapeutics to treat age-related diseases), and in Soley Therapeutics (a biotechnology company combining artificial intelligence with molecular and cellular response detection for discovering and developing new drugs, currently focusing on cancer therapeutics); and that his interests were reviewed and are managed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict of interest policies. Dr Lincoff reported receiving Esperion research funding for this trial; receiving grants from Eli Lilly, AbbVie, CSL, AstraZeneca, and Novartis; and receiving personal fees from Novo Nordisk, Glaxo, Akebia, Endologix, Fibrogen, Provention, and Becton Dickson. No other disclosures were reported.

Funding/Support: The trial was funded by Esperion Therapeutics and coordinated by the Cleveland Clinic Coordinating Center for Clinical Research (C5Research).

Role of the Funder/Sponsor: The sponsor, Esperion Therapeutics Inc, participated actively in designing the study and developing the protocol in collaboration with the executive committee, provided logistical support during the trial, and managed sites in collaboration with C5Research. A contract research organization maintained the trial database. After completion of the trial, as specified in the study contract, a complete copy of the database was transferred to C5Research, where statistical analyses were performed by an independent statistician (Danielle Brennan, MS). The academic authors made the decision to publish the manuscript and take responsibility for the completeness and accuracy of the data. The first author drafted the manuscript with input from all authors. The sponsor was permitted to review the manuscript and make suggestions, but the final decisions on content were performed by the academic authors. While the executive committee and coordinating center had confidentiality agreements with the sponsor, there were no contractual limits on the rights of the academic authors to publish.

Meeting Presentation: Presented at the American Diabetes Association Scientific Sessions, June 24, 2023.

Data Sharing Statement: See Supplement 3.