Scientific Newsroom

Ages 18-85
History of cardiovascular disease, including coronary artery disease, symptomatic peripheral arterial disease, cerebrovascular atherosclerotic disease, or at high risk for having a cardiovascular event
Patient-reported history of statin intolerance defined as an adverse effect that started or increased during statin therapy and resolved or improved after therapy discontinued. Intolerance was due to inability to tolerate two or more statins at any dose or 1 statin at any dose and unwilling or advised by a physician to not attempt a second statin. Both the patient and investigator were required to provide written confirmation that the patient was aware of the benefits of statins to reduce the risk of cardiovascular events, including death, and acknowledge that many other patients who are unable to tolerate a statin can tolerate a different statin or dose.
Men and non-pregnant, non-lactating women
Fasting blood LDL-C ≥ 100 (2.6 mmol/L) at screening while receiving stable background lipid lowering therapy

Exclusion criteria:

Fasting blood triglycerides > 500 mg/dL (5.6 mmol/L) at screening
Recent (within 90 days of screening) history of major cardiovascular events, transient ischemic attack, or unstable or symptomatic cardiac arrhythmia
History of severe heart failure
Uncontrolled hypertension or uncontrolled diabetes

Primary endpoint:
The time to first occurrence of any of the following:

Cardiovascular death
Nonfatal myocardial infarction
Nonfatal stroke
Coronary revascularization ⁴

Key Secondary Time to Event Endpoints:

Time to first occurrence of the composite endpoint of CV death, nonfatal MI, or nonfatal stroke (MACE-3)
Time to first occurrence of (fatal + nonfatal) MI
Time to first occurrence of coronary revascularization
Time to first occurrence of (fatal + nonfatal) stroke
Time to CV death
Time to all-cause mortality

Secondary Efficacy Lipid and Biomarker Endpoints:

Percent change from baseline to Month 6 in LDL-C
Percent change from baseline to Month 6 in hsCRP
Absolute change from baseline to Month 12 in HbA_1c in patients in the inadequately controlled diabetes efficacy population (patients with type 2 diabetes mellitus and an HbA_1c of 7% or greater at baseline)

CLEAR Outcomes was an event-driven clinical trial that continued until all of the following criteria were met:

At least 1,620 adjudicated primary endpoints were accrued.

At least 810 patients experienced an adjudicated secondary composite endpoint event of cardiovascular death, nonfatal myocardial infarction, or non-fatal stroke.

24 months had elapsed since last patient was randomized

Assuming a 3.59% annual event rate in the placebo group and an estimated lost-to-follow up rate of 1% per year, a total sample size of 14,000 patients provided more than 95% power to detect a 17% reduction in the primary endpoint with bempedoic acid.⁴

For more details, see the full study design here.

Interesting Note on Patient Population:

The proportion of women in CLEAR Outcomes (48.2%) reflects the prevalence of heart disease in U.S. women overall. This is a significant improvement over the historical underrepresentation of women in cardiovascular clinical trials. ⁵
- Enrollment of women in other cardiovascular outcomes trials has ranged from 24% ⁶ to 38% ⁷ of total enrollment.
- The increased representation of women in CLEAR Outcomes is especially important given that women are significantly more likely than men to experience statin intolerance.⁸

FACTS AND FIGURES: Cholesterol and Atherosclerotic Heart Disease (ASCVD)

ASCVD: Prevalence, causes and consequences

Prevalence

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of illness and death in the United States and around the world.

In the U.S., it affects an estimated 10 percent of the adult population, or about 24 million people. ⁹
Someone in the United States dies every 34 seconds from cardiovascular disease, accounting for one in every five deaths. ¹⁰

Men and women have a similar risk of heart disease, but events such as myocardial infarction often cause different symptoms in women, sometimes presenting as indigestion or back pain instead of the more “classic” symptoms such as chest pain. ¹¹ An estimated 805,000 myocardial infarctions occur each year, and 20 percent of those attacks are believed to be “silent,” described as a person not knowing the event is happening, but considerable damage occurs. ¹⁰

Causes and consequences

ASCVD involves the buildup of fatty plaque inside arteries that can create life-threatening scenarios

Plaque buildup narrows the arteries, reducing or preventing blood flow.
Plaque can rupture inside arteries, creating dangerous clots that can block blood flow to the heart, brain, or other parts of the body.

ASCVD can lead to serious and sometimes deadly cardiovascular events such as:

Myocardial infarction
Stroke or transient ischemic attack
Angina
Peripheral artery disease

People with ASCVD who have had a first myocardial infarction, stroke, or other event are at increased risk of additional events. Over time, ASCVD can result in heart failure and other chronic, debilitating illness, and results in more than $200 billion USD each year in healthcare services, medicines, and lost productivity. ¹¹

The role of cholesterol in ASCVD

The role of elevated levels of LDL-cholesterol (LDL-C) in ASCVD is acknowledged and well understood. ¹² Multiple studies have shown that lowering LDL-C reduces the risk of cardiovascular events among people with ASCVD. To date, research has not demonstrated a low threshold where the risk-reduction benefit stops. ¹ As a result, treatment guidelines have focused on LDL-C lowering as a cornerstone in both prevention and management of ASCVD, predominantly through lipid-lowering medicines.

Treating ASCVD: Significant gaps remain

Statins are proven to be effective in lowering LDL-C and reducing adverse cardiac events, and are considered first-line therapy for lowering LDL-C. When they were first introduced, “getting to goal” became the mantra among both physicians and patients with high LDL cholesterol.

Yet nearly 30 years later, about two-thirds of people with ASCVD in the U.S. still are not at their LDL-C goal, despite the availability of statin treatment. ¹³ This leads to many repeat strokes, myocardial infarctions, revascularization procedures, and deaths that might have been prevented.

For very high-risk patients (those with existing ASCVD):

The American Heart Association (AHA)/American College of Cardiology (ACC) Task Force on Clinical Practice Guidelines recommends a target LDL-C of <70 mg/dL. ¹²
European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) Guidelines for the Management of Dyslipidemias suggest a lower target LDL-C of < 55 mg/dL. ¹⁴

Yet a 2019 analysis of medical records of ASCVD patients in U.S. commercial and Medicare health plans found that the majority of patients did not achieve the AHA/ACC guideline-recommended LDL-C goal of <70 mg/dL. In fact, more than one-third (37.5 percent) had LDL-C levels of 100 mg/dL or higher. ¹³

Specifically, 56.2% of these patients experienced a recent acute coronary syndrome, 69.2% of patients had an ischemic stroke, 80.8% of patients had a diagnosis of PAD, and 71.5% of patients had a diagnosis of coronary artery disease. ¹³

Still not getting to goal: Contributing to the treatment gap

Despite widespread statin use, discontinuation and/or lack of adherence to statin treatment continues to be a major gap in both preventing and treating ASCVD: ¹⁵

A key compliance barrier is limitations from side effects, notably myopathies. ¹⁶
One-third of people taking statins stop treatment within a year. ¹⁷
Women and people of Asian ethnicity are at particular risk of statin-related side effects. ¹⁸

Non-statin treatment options

Patients not achieving LDL-C targets on statins alone may benefit from combination therapy. There are a number of proven options for patients and physicians to consider:

PCSK9 inhibitors can lower LDL-C substantially (by more than 50% in people with very high baseline LDL-C levels) with no increase in muscle-related side effects among people with statin intolerance, ¹⁹ but they must be injected and cost significantly more than other treatments, both of which are barriers to widespread use. ⁴
Bempedoic acid has been shown to significantly reduce LDL-C and is approved for use in combination with diet and maximally tolerated statin therapy for adults with established ASCVD who require additional LDL-C lowering to reach their treatment goals. ²⁰ Bempodoic acid is also available in a fixed dose combination with ezetimibe. The effects of NEXLETOL and NEXLIZET on cardiovascular morbidity and mortality have not been determined.
The cholesterol absorption inhibitor ezetimibe can lower LDL-C levels 18% to 20%, with minimal rates of muscle-related side effects. ²¹ But treatment with ezetimibe alone is often unsuccessful at getting people to their LDL-C treatment goals. ⁴
Ezetimibe inhibition of cholesterol absorption from the small intestine provides a complementary LDL-C-lowering mechanism of action to bempedoic acid; these two agents are offered as a fixed-combination drug product (FCDP) under the brand name Nexlizet.^® Nexlizet has been proven to lower LDL cholesterol an additional 38% relative to placebo when added to maximally tolerated statin therapy. ²²

BACKGROUNDER

Bempedoic Acid: Mechanism of Action & Scientific Development

Bempedoic acid (BA) represents a new class of drug that lowers LDL-cholesterol (LDL-C) through a unique mechanism of action, making it an important treatment option for people at high risk of atherosclerotic cardiac events who cannot tolerate statins – or for whom statins are not enough to help them achieve their target LDL-C goals.

A prodrug, bempedoic acid is primarily activated in the liver, where it inhibits ACL. Unlike statins, it is not activated in skeletal muscle,²² ²³ ²⁴ ²⁵ offering the potential to avoid the muscle pain and weakness (myopathy) statins can cause. Bempedoic acid’s inhibition of ACL increases levels of LDL receptors in the liver, which adhere to circulating LDL particles, reducing LDL-C levels in the blood.²²

Because BA’s mechanism of action is different from other lipid-lowering therapies, it can be combined with other treatments to further lower LDL-C. This makes it an important treatment option in patients for whom statins alone are not effective in achieving their LDL-C goal or for those who experience side effects with statin therapy.

Importantly, bempedoic acid’s safety profile is generally comparable to placebo.

Click here for a video that describes bempedoic acid’s mechanism of action in more detail.

Scientific Development of Bempedoic Acid

Five randomized, double-blind, placebo-controlled, parallel-group, phase 3 multicenter clinical trials known as Cholesterol Lowering via Bempedoic Acid, an ACL-inhibiting Regimen (CLEAR) have established the safety, tolerability, and efficacy of bempedoic acid in lowering LDL-C in a total of 3,623 participants.

CLEAR Clinical Trials: Phase 3/4

Study	Publication	Key Results
CLEAR Tranquility	Ballantyne et al. Atherosclerosis. 2018;277:195-203	BA added to background lipid-modifying therapy that included ezetimibe reduced LDL-C by 28.5% (placebo-corrected) from baseline (95% CI; p < 0.001).
CLEAR Harmony	Ray et al. N Engl J Med. 2019 ;380: 1022-1032	BA added to background lipid-modifying therapy reduced mean LDL-C by 18.1% (placebo corrected) from baseline (95% CI; p<0.001).
CLEAR Serenity	Laufs et al. J Am Heart Assoc. 2019;8 :e011662	BA added to background lipid-modifying therapy reduced LDL-C by 21.4% (placebo-corrected) from baseline (95% CI; p<0.001)
CLEAR Wisdom	Goldberg et al. JAMA. 2019;322: 1780-1788	BA added to background lipid-modifying therapy reduced LDL-C by 17.4% (placebo-corrected) from baseline (95% CI, p <0.001).
BA + ezetimibe fixed-dose combination (FDC)	Ballantyne et al. Eur J Prev Cardiol. 2020; 27(6): 593–603 .	BA + ezetimibe FDC added to background lipid-modifying therapy reduced LDL-C significantly more than placebo (-38%, placebo-corrected), ezetimibe alone (-23.2%) or BA alone (-7.2%); p < 0.001.
CLEAR Outcomes	Not yet published.	Met primary endpoint, demonstrating statistically significant risk reduction in MACE-4 in patients treated with 180 mg/day bempedoic acid compared with placebo. This is an investigational trial. The effects of NEXLETOL on cardiovascular morbidity and mortality have not been determined.

LDL-C-Lowering Properties of Bempedoic Acid: Additional Studies of Interest

**Ballantyne C et al. Factors Associated With Enhanced Low-Density Lipoprotein Cholesterol Lowering With Bempedoic Acid. J Am Heart Assoc. 2022;11(15): e024531.**

This post-hoc analysis used pooled data from four phase 3 studies of bempedoic acid (BA) compared with placebo to determine what factors may contribute to the highest LDL-C reductions (30% or more) seen in these studies. The analysis identified the following factors (p<0.01 for each):

Not taking statins
Being female
Having a history of diabetes
Concurrent use of the lipid-lowering therapy ezetimibe
An increased level of high-sensitivity C-reactive protein at baselin

Gunn L et al. Estimated cardiovascular benefits of bempedoic acid in patients with established cardiovascular disease. Atherosclerosis Plus. 2022;49: 20-27.

This study assessed the potential cardiovascular benefits of bempedoic acid through a simulation study in patients with atherosclerotic cardiovascular disease (ASCVD) and elevated LDL-C.

Researchers used the validated SMART prediction model to predict the baseline 10-year risk of cardiovascular death, non-fatal heart attack, and non-fatal stroke) in people with ASCVD who were enrolled in four Phase 3, randomized, placebo-controlled studies of bempedoic acid. (The SMART model incorporates factors such as age, sex, smoking status, systolic blood pressure, history of diabetes, history of coronary artery disease, and levels of HDL-C.

They analyzed two groups of patients: those who were taking moderate to high doses of statins, and those who could only tolerate a low-dose statin (most patients in this group were not taking statins). The analysis predicted a reduced risk of cardiovascular events over time in both groups, with a more significant predicted benefit among patients with statin intolerance.

In the statin group, “if this reduction in LDL-C was maintained with continued treatment over 10 years, the predicted impact with bempedoic acid on the 10-year cardiovascular risk would translate to a 10.6% risk reduction relative to baseline, and an absolute difference of 3.3% compared with the placebo group,” the authors concluded.

In the statin-intolerant group, “if maintained over 10 years with treatment, the reduction in LDL-C with bempedoic acid therapy would be expected to result in a 18.9% relative reduction in cardiovascular risk,” the authors predicted. “Thus, the predicted 10-year cardiovascular risk with bempedoic acid would be estimated to be 6.0% lower with bempedoic acid than with placebo.”

Important Safety Information

INDICATION

NEXLETOL and NEXLIZET are indicated as adjuncts to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C.

Limitations of Use: The effect of NEXLETOL and NEXLIZET on cardiovascular morbidity and mortality has not been determined.

IMPORTANT SAFETY INFORMATION

Contraindications: NEXLETOL has no contraindications. NEXLIZET is contraindicated in patients with a known hypersensitivity to ezetimibe tablets. Hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria have been reported with ezetimibe.

Warnings and Precautions: Hyperuricemia: Bempedoic acid, a component of NEXLETOL and NEXLIZET, may increase blood uric acid levels. Hyperuricemia may occur early in treatment and persist throughout treatment, and may lead to the development of gout, especially in patients with a history of gout. Assess uric acid levels periodically as clinically indicated. Monitor for signs and symptoms of hyperuricemia, and initiate treatment with urate-lowering drugs as appropriate.

Tendon Rupture: Bempedoic acid is associated with an increased risk of tendon rupture or injury. In clinical trials, tendon rupture occurred in 0.5% of patients treated with bempedoic acid versus 0% of patients treated with placebo, and involved the rotator cuff (the shoulder), biceps tendon, or Achilles tendon. Tendon rupture occurred within weeks to months of starting bempedoic acid. Tendon rupture may occur more frequently in patients over 60 years of age, patients taking corticosteroid or fluoroquinolone drugs, patients with renal failure, and patients with previous tendon disorders. Discontinue NEXLETOL or NEXLIZET at the first sign of tendon rupture. Avoid NEXLETOL and NEXLIZET in patients who have a history of tendon disorders or tendon rupture.

Adverse Reactions: In NEXLETOL clinical trials, the most commonly reported adverse reactions were upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, and elevated liver enzymes. Reactions reported less frequently, but still more often than with placebo, included benign prostatic hyperplasia and atrial fibrillation.

In the NEXLIZET clinical trial, the most commonly reported adverse reactions observed with NEXLIZET, but not observed in clinical trials of bempedoic acid or ezetimibe, a component of NEXLIZET, and occurring more frequently than with placebo, were urinary tract infection, nasopharyngitis, and constipation.

Adverse reactions reported in clinical trials of ezetimibe, and occurring at an incidence greater than with placebo, included upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza. Other adverse reactions reported in postmarketing use of ezetimibe included hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria; erythema multiforme; myalgia; elevated creatine phosphokinase; myopathy/rhabdomyolysis; elevations in liver transaminases; hepatitis; abdominal pain; thrombocytopenia; pancreatitis; nausea; dizziness; paresthesia; depression; headache; cholelithiasis; cholecystitis.

Drug Interactions: Simvastatin and Pravastatin: Concomitant use with bempedoic acid results in increased concentrations and increased risk of simvastatin or pravastatin-related myopathy. Use of either NEXLETOL or NEXLIZET with greater than 20 mg of simvastatin or 40 mg of pravastatin should be avoided.

Cyclosporine: Caution should be exercised when using NEXLIZET and cyclosporine concomitantly due to increased exposure to both ezetimibe and cyclosporine. Monitor cyclosporine concentrations in patients receiving NEXLIZET and cyclosporine. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the benefits of alterations in lipid levels provided by NEXLIZET.

Fibrates: Coadministration of NEXLIZET with fibrates other than fenofibrate is not recommended. Fenofibrate and ezetimibe may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected in a patient receiving NEXLIZET and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered.

Cholestyramine: Concomitant use of NEXLIZET and cholestyramine decreases ezetimibe concentration. This may result in a reduction of efficacy. Administer NEXLIZET either at least 2 hours before, or at least 4 hours after, bile acid sequestrants.

Lactation and Pregnancy: It is not recommended that NEXLETOL or NEXLIZET be taken during breastfeeding. Discontinue NEXLETOL or NEXLIZET when pregnancy is recognized, unless the benefits of therapy outweigh the potential risks to the fetus. Based on the mechanism of action of bempedoic acid, NEXLETOL and NEXLIZET may cause fetal harm.

Please see full Prescribing Information here.

References:

Cholesterol Treatment Trialists C, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376(9753):1670-81.
Jones PH, Nair R, Thakker KM. Prevalence of dyslipidemia and lipid goal attainment in statin-treated subjects from 3 data sources: a retrospective analysis. J Am Heart Assoc 2012;1(6), e001800.
ZS Associates primary and secondary research, Sep-Oct 2018. Primary research N = 350 healthcare practitioners
Nicholls SJ, Lincoff AM, Bays HE, et al. Rationale and design of the CLEAR-outcomes trial: Evaluating the effect of Bempedoic acid on cardiovascular events in patients with statin intolerance. American Heart Journal. 2020.
A.Z. Sosinsky, J.W. Rick-Edwards, A. Wiley, K. Wright, P.A. Spagnolo, H. Joffe. Enrollment of female participants in United States drug and device phase 1–3 clinical trials between 2016–2019. Contemp. Clin. Trials, 115 (2022), 10.1016/j.cct.2022.106718
Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017; 376:1713-1722.
Ridker PM, Danielson E, Fonseca FAH et al. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med 2008; 359:2195-2207
Bytyci I. et al. Prevalence of statin intolerance: a meta-analysis, European Heart Journal 2022 7 Sept;43(34): 3213–3223.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8968014/
https://www.cdc.gov/heartdisease/facts.htm
Barouch, L. https://www.hopkinsmedicine.org/health/conditions-and-diseases/heart-disease-differences-in-men-and-women
Grundy SM, Stone NJ, Bailey AL, et al. AHA/ACC/AACVPR/AAPA/ABC/ACPM/ ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation 2018;139: e1082e143. 2019

Gu J, Sanchez R, Chauhan A, Fazio S, Wong N. Lipid treatment status and goal attainment among patients with atherosclerotic cardiovascular disease in the United States: A 2019 update. Am J Prev Cardiol. 2022 Mar 20;10:100336. doi: 10.1016/j.ajpc.2022.100336. PMID: 35368909; PMCID: PMC8968014.
Mach F, Baigent C, Catapano A et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. European Heart Journal (2020) 41, 111188. doi:10.1093/eurheartj/ehz455
https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.118.312782
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974266
Ofori-Asenso R, Zoungas S and Liew D. Reinitiation of Statin Therapy After Discontinuation: A Meta-analysis. Mayo Clin Proc. 2018;93:666-668.
Ward NC, Watts GF, Eckel RH. Statin Toxicity: Mechanistic Insights and Clinical Implications. Circulation Research 2019;124:328–350.
Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients–the PRIMO study. Cardiovasc Drugs Ther 2005;19(6):403-14.
Nexletol (bempedoic acid) Full Prescribing Information. Esperion Therapeutics, Inc.
Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372(25):2387-97.
NEXLIZET. Prescribing information. Esperion Therapeutics, Inc.; 09/2021
Pinkosky SL, Newton RS, Day EA et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun 7, 13457 (2016).
Pinkosky SL, Filippov S, Srivastava RA, et al. AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism. J Lipid Res. 2013;54(1):134-151.
Saeed A, Ballantyne CM. Bempedoic acid (ETC-1002): a current review. Cardiol Clin. 2018;36(2):257-264.
Esperion corporate presentation (slide 59), 31 Aug 2021.