Rationale and design of the CLEAR-outcomes trial: Evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance

doi:10.1016/j.ahj.2020.10.060

American Heart Journal

Volume 235, May 2021, Pages 104-112

https://doi.org/10.1016/j.ahj.2020.10.060 Get rights and content

Background

Although statins play a pivotal role in the prevention of atherosclerotic cardiovascular disease, many patients fail to achieve recommended lipid levels due to statin-associated muscle symptoms. Bempedoic acid is an oral pro-drug that is activated in the liver and inhibits cholesterol synthesis in hepatocytes, but is not activated in skeletal muscle which has the potential to avoid muscle-related adverse events. Accordingly, this agent effectively lowers atherogenic lipoproteins in patients who experience statin-associated muscle symptoms. However, the effects of bempedoic acid on cardiovascular morbidity and mortality have not been studied.

Study design

Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes is a randomized, double-blind, placebo-controlled clinical trial. Included patients must have all of the following: (i) established atherosclerotic cardiovascular disease or have a high risk of developing atherosclerotic cardiovascular disease, (ii) documented statin intolerance, and (iii) an LDL-C ≥100 mg/dL on maximally-tolerated lipid-lowering therapy. The study randomized 14,014 patients to treatment with bempedoic acid 180 mg daily or matching placebo on a background of guideline-directed medical therapy. The primary outcome is a composite of the time to first cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. The trial will continue until 1620 patients experience a primary endpoint, with a minimum of 810 hard ischemic events (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) and minimum treatment duration of 36 months and a projected median treatment exposure of 42 months.

Conclusions

CLEAR Outcomes will determine whether bempedoic acid 180 mg daily reduces the incidence of adverse cardiovascular events in high vascular risk patients with documented statin intolerance and elevated LDL-C levels.

Section snippets

Statin intolerance

While statins are widely used for lipid management and prevention of cardiovascular disease, multiple studies report that at least one-third of patients stop taking prescribed statin within 12 months of initiation of therapy.⁶ Furthermore, many patients reduce statin dose, mainly due to perceived adverse effects. Statin-Associated Muscle Symptoms (SAMS) are the most commonly cited reason for both statin cessation and dose reduction.⁷ Cohort studies have reported a prevalence of myalgias as high

Existing approaches to management of statin intolerance

The present management of statin intolerance aims to reduce LDL-C by initiating reduced doses of statin when possible, and addition of non-statin LDL-lowering agents. Patients often tolerate the use of a different statin or reductions in the dose or frequency of administration, which provides some degree of lipid lowering in many patients.¹⁶^,¹⁷ Anecdotal and small cohort studies have reported variable effects of co-administration of non-prescription agents such as coenzyme Q10, nutraceuticals

CLEAR clinical trial series

The Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) studies are designed to examine the effectiveness of bempedoic acid in cholesterol management. CLEAR Tranquility studied 269 patients with statin intolerance and LDL-C >= 100 mg/dL and demonstrated that administration of bempedoic acid 180 mg daily for 12 weeks, in addition to background ezetimibe, produced placebo-corrected lowering of LDL-C by 28.5% and hsCRP by 31%, was well tolerated and not associated with an

Study objectives and design

The CLEAR Outcomes study (clinicaltrials.gov NCT02993406) is testing the hypothesis that administration of bempedoic acid, added to standard medical therapy, will lower the risk for cardiovascular events in patients with high vascular risk and statin intolerance. (Figure 1) CLEAR Outcomes is a randomized, double-blind, placebo-controlled, event-driven trial. Participants receive bempedoic acid 180 mg or matching placebo administered once daily. The trial will continue until 1620 primary

Treatment regimen and follow-up

All eligible patients underwent a 4-week single blind (blinded to patients only) run-in period in which all patients were treated with placebo to assess for tolerability and study drug adherence. If patients were intolerant to the single-blind treatment or if their adherence was <80% by tablet count, they were not eligible for randomization. Patients who successfully completed the run-in period were randomized using an interactive web response system in a 1:1 fashion to treatment to either

Clinical endpoints, sample size, and statistical analysis

An independent, central clinical events committee, blinded to treatment status, will adjudicate all reported clinical events. The primary efficacy measure is the time to first occurrence of any component of the major adverse cardiovascular event composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. Secondary endpoints include the time to first occurrence of (i) the composite of cardiovascular death, nonfatal myocardial infarction, or

Conclusion

Bempedoic acid is an FDA approved LDL-C lowering pharmacotherapy, administered either as monotherapy or in combination with existing lipid lowering agents. Bempedoic acid treatment presents a novel, additional strategy for reducing LDL-C in high risk patients, in whom such an intervention is clearly warranted even if often not achieved in clinical practice. The CLEAR Outcomes trial is the first large-scale clinical outcomes trial performed exclusively in patients with statin intolerance and

Acknowledgements and disclosures

SJN is a recipient of a Principal Research Fellowship from the National Health and Medical Research Council of Australia, has received research support from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron and LipoScience and is a consultant for AstraZeneca, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, Boehringer Ingelheim. AML has received

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Cited by (87)

Impact of Bempedoic acid on LDL-C reduction and cardiovascular outcomes: A comprehensive meta-analysis of randomized controlled trials
2024, Current Problems in Cardiology
The management of LDL-C levels is pivotal in the prevention of cardiovascular morbidity, particularly among patients at high risk or those intolerant to statins. Bempedoic acid emerges as a novel agent in this therapeutic arena.
This systematic review and meta-analysis endeavor to quantify the effectiveness of Bempedoic acid in attenuating LDL-C levels and explore its impact on cardiovascular morbidity, emphasizing its role as an adjunctive or alternative therapy in statin-intolerant or high-risk patients.
A comprehensive search spanning PubMed, Google Scholar, and Cochrane Library databases furnished studies for this review. The inclusion was critiqued based on predefined PICOS parameters, ensuring a robust analytical framework.
Bempedoic acid showcased a significant plunge in LDL-C levels (MD -20.69 %, 95 % CI [-23.20, -18.19]), outperforming placebo and ezetimibe monotherapy. The cardioprotective effect was further echoed with a reduced risk of major adverse cardiac events (MACE) in the Bempedoic acid cohort (RR 0.86, 95 % CI [0.80, 0.94]). However, a dive into the safety profile revealed no substantial augmentation in adverse events, affirming its tolerance and efficacy.
Bempedoic acid represents a potent therapeutic ally, affirming its capacity to significantly pare down LDL-C levels and curtail cardiovascular events. Its favorable safety profile underscores its suitability, especially among those with statin intolerance or individuals categorized within the high-risk vascular bracket, necessitating a paradigm shift in current lipid management strategies.
Efficacy and safety of bempedoic acid among patients with and without diabetes: prespecified analysis of the CLEAR Outcomes randomised trial
2024, The Lancet Diabetes and Endocrinology
Statins reduce LDL cholesterol and cardiovascular events among those with or without diabetes but have been reported to increase new-onset diabetes. The CLEAR Outcomes trial demonstrated that bempedoic acid reduced the risk of major adverse cardiovascular events among statin-intolerant patients at high cardiovascular risk. In this prespecified analysis, our dual aims were to evaluate the cardiovascular benefits of bempedoic acid, an ATP-citrate lyase inhibitor, in individuals with diabetes, and to evaluate the risk of new-onset diabetes and HbA_1c among those without diabetes in the CLEAR Outcomes trial.
CLEAR Outcomes was a randomised, double-blind, placebo-controlled trial conducted across 1250 primary care and outpatient sites in 32 countries. Patients with or without cardiovascular disease who were unwilling or unable to take guideline-recommended doses of statins and an LDL cholesterol of 2·59 mmol/L or more were randomly assigned (1:1) in a double-blinded manner to either bempedoic acid 180 mg once per day or placebo. In this prespecified analysis, the efficacy endpoint was a time-to-event analysis of four-component major adverse cardiovascular event (MACE-4), which is the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularisation, using the intention-to-treat population stratified by baseline glycaemia status. The prespecified analysis of risk of new-onset diabetes and HbA_1c increase was evaluated in patients without diabetes at baseline. The CLEAR Outcomes trial was completed on Nov 7, 2022, and is registered with ClinicalTrials.gov (NCT02993406).
Between Dec 22, 2016, and Nov 7, 2022, 13 970 patients were screened and randomly assigned; 6373 (45·6%) with diabetes, 5796 (41·5%) with prediabetes, and 1801 (12·9%) with normoglycaemia. Over a median of 3·4 years follow up, patients with diabetes had significant relative and absolute cardiovascular risk reductions in MACE-4 endpoints with bempedoic acid (HR 0·83; 95% CI 0·72–0·95; absolute risk reduction of 2·4%) compared to placebo, with no statistical evidence of effect modification across glycaemic strata (interaction p=0·42). The proportion of patients who developed new-onset diabetes were similar between the bempedoic acid and placebo groups, with 429 of 3848 (11·1%) with bempedoic acid versus 433 of 3749 (11·5%) with placebo (HR 0·95; 95% CI 0·83–1·09). HbA_1c concentrations at month 12 and the end of the study were similar between randomised groups in patients who had prediabetes and normoglycaemia. Placebo-corrected LDL cholesterol concentrations and high-sensitivity C-reactive protein at 6 months were reduced in each glycaemic stratum (diabetes, prediabtes, and normoglycaemia) for patients randomly assigned to bempedoic acid (all p<0·001).
Among patients with diabetes, bempedoic acid reduces LDL cholesterol and high-sensitivity C-reactive protein and risk of cardiovascular events. Patients without diabetes had no increase in new-onset diabetes or worsening HbA_1c with bempedoic acid. The efficacy and cardiometabolic safety profile of bempedoic acid makes it a clinical option for those with and without diabetes.
Esperion Therapeutics.
Safety of bempedoic acid in patients at high cardiovascular risk and with statin intolerance
2024, Journal of Clinical Lipidology
Bempedoic acid is an oral adenosine triphosphate citrate lyase (ACL) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) blood levels. The Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes study demonstrated that bempedoic acid reduced cardiovascular (CV) risk in patients at high risk for CV events who were unwilling or unable to take guideline-recommended doses of statins.
To describe detailed safety information from CLEAR Outcomes, including events in the United States (US) prescribing information based on previous phase 3 hyperlipidemia studies.
CLEAR Outcomes was a double-blind trial conducted in 13,970 patients randomized to oral bempedoic acid 180 mg daily or placebo and followed for a median of 3.4 years.
In patients who received at least one dose (7,001 bempedoic acid, 6,964 placebo), treatment emergent adverse events (AE) occurred in 86.3 % and 85 % of patients, respectively. COVID-19 was the most frequently reported AE in both groups. Changes in serum creatinine, blood urea nitrogen, hemoglobin, aminotransaminases, and uric acid were consistent with the known safety profile of bempedoic acid. Gout or gouty arthritis occurred in 3.2 % of bempedoic acid and 2.2 % of placebo patients. AE associated with tendinopathies, including tendon rupture, occurred in 2 % of patients in both treatment groups. Cholelithiasis occurred in 2.2 % of bempedoic acid and 1.2 % of placebo patients; AE related to gallbladder disease were similar between treatment groups.
Bempedoic acid was well-tolerated compared with placebo. Safety data from the long-term CLEAR Outcomes study reinforce the positive benefit-risk profile of bempedoic acid.
Evaluation of the efficacy and safety of bempedoic acid in women and men: Pooled analyses from phase 3 trials
2023, Atherosclerosis
Sex-specific differences in the response to lipid-lowering therapies have been reported. Here, we assessed the effect of bempedoic acid in women and men using pooled, patient-level data from four phase 3 clinical trials of bempedoic acid.
Patients were grouped into two pools: 1) atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) “on statins” and 2) “low-dose or no statin”. Percent changes from baseline to at least week 12 in low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol (non–HDL-C), total cholesterol (TC), apolipoprotein B (Apo B), and high-sensitivity C-reactive protein (hsCRP), as well as safety, were analyzed by statin pool and sex.
Overall, 3623 patients were included (bempedoic acid, 2425; placebo, 1198). Significant reductions in lipid parameters and hsCRP were observed with bempedoic acid vs. placebo in both sexes in the ASCVD and/or HeFH on statins (n = 3009) and the low-dose or no statin (n = 614) pools (p ≤ 0.002). Compared with men, women had significantly greater placebo-corrected reductions in LDL-C (−21.2% vs. −17.4%; p = 0.044), non–HDL-C (−17.3% vs. −12.1%; p = 0.003), TC (−13.8% vs. −10.5%; p = 0.012), and Apo B (−16.0% vs. −11.3%; p = 0.004) in the ASCVD and/or HeFH on statins pool. Women had similar reductions to men in lipid parameters in the low-dose or no statin pool and hsCRP in both pools. The safety of bempedoic acid was comparable between sexes.
In this pooled analysis, women experienced significant improvements in levels of LDL-C and other lipid parameters with bempedoic acid.
Bempedoic acid in the management of lipid disorders and cardiovascular risk. 2023 position paper of the International Lipid Expert Panel (ILEP)
2023, Progress in Cardiovascular Diseases
Cardiovascular disease (CVD) is a chronic non-communicable disease (NCD) and the predominant cause of morbidity and mortality worldwide. Substantial reductions in the CVD prevalence have been achieved in recent years by the attenuation of risk factors (particularly hypertension and dyslipidaemias) in primary and secondary prevention. Despite the remarkable success of lipid lowering treatments, and of statins in particular, in reducing the risk of CVD, there is still an unmet clinical need for the attainment of guideline lipid-targets in even 2/3 of patients.
Bempedoic acid, the first in-class inhibitor of ATP-citrate lyase presents a new approach to lipid-lowering therapy. By reducing the endogenous production of cholesterol, upstream of the rate-limiting enzyme HMG-CoA-reductase, i.e., the target of statins, bempedoic acid reduces circulating plasma concentrations of low-density lipoprotein cholesterol (LDL-C), and major adverse CVD events (MACE). Bempedoic acid has the potential to contribute to the reduction of CVD risk not only as monotherapy, but even further as part of a lipid-lowering combination therapy with ezetimibe, reducing LDL-C cholesterol up to 40%.
This position paper of the International Lipid Expert Panel (ILEP) summarises the recent evidence around the efficacy and safety of bempedoic acid and presents practical recommendations for its use, which complement the ‘lower-is-better-for-longer’ approach to lipid management, which is applied across international guidelines for the management of CVD risk. Practical evidence-based guidance is provided relating to the use of bempedoic acid in atherosclerotic CVD, familial hypercholesterolaemia, and statin intolerance. Although there are still no sufficient data avilable for the role of bempedoic acid in the primary prevention of CVD, its favourable effects on plasma glucose and inflammatory markers makes this drug a rational choice in the patient-centred care of specific groups of primary prevention.
Current and future options in cholesterol lowering treatments
2023, European Journal of Internal Medicine
The relative risk reduction of cardiovascular events is proportional to the absolute reduction in LDL-C levels, the primary target of therapy, no matter the way of reduction. During the last decades, the therapeutic regimens for reducing the LDL-C levels have been immerged and improved, with favorable effects on the atherosclerotic process and clinical benefits of various cardiovascular outcomes.
From a practical view of point, this review is focusing only on the current available lipid lowering agents: statins, ezetimibe, anti PCSK9 monoclonal antibodies, the small interfering RNA (siRNA) agent, Inclisiran, and Bempedoic acid. The recent changes in lipid lowering regimens, including the early combination of lipid lowering agents and “Low LDL-C” levels <30 mg/dL for high/very high cardiovascular risk patients will also be discussed.

View all citing articles on Scopus

¹: Contributed equally to this manuscript

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Trial DesignRationale and design of the CLEAR-outcomes trial: Evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance

Background

Study design

Conclusions

Section snippets

Statin intolerance

Existing approaches to management of statin intolerance

CLEAR clinical trial series

Study objectives and design

Treatment regimen and follow-up

Clinical endpoints, sample size, and statistical analysis

Conclusion

Acknowledgements and disclosures

J Am Coll Cardiol

Mayo Clin Proc

Neurotherapeutics

J Am Coll Cardiol

Lancet

Am Heart J

J Am Coll Cardiol

J Am Coll Cardiol

J Lipid Res

J Lipid Res

J Lipid Res

J Am Coll Cardiol

J Clin Lipidol

Am J Cardiol

J Clin Lipidol

Atherosclerosis

Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials

Lancet

AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol

Circulation

Prevalence of dyslipidemia and lipid goal attainment in statin-treated subjects from 3 data sources: a retrospective analysis

J Am Heart Assoc

Association of a combined measure of adherence and treatment intensity with cardiovascular outcomes in patients with atherosclerosis or other cardiovascular risk factors treated with statins and/or ezetimibe

JAMA Netw Open

Trial Design
Rationale and design of the CLEAR-outcomes trial: Evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance