Introduction
Elevated blood cholesterol is a strong atherosclerotic cardiovascular disease (ASCVD) risk factor. Many clinical trials and high quality observational studies have documented the overwhelming cardiovascular benefits of lowering blood low-density lipoprotein cholesterol (LDL-C).¹ Periodically, such high quality evidence is incorporated into evidence-based clinical practice guidelines aimed at reducing cardiovascular morbidity and mortality globally.

The 2018 American Heart Association/American College of Cardiology/Multisociety (AHA/ACC/MS) Cholesterol guideline recommended treating LDL-C in all patients with clinical ASCVD and adults 40 to 75 years with 1) diabetes, 2) LDL-C≥ 190 mg/dL, 3) 10-year ASCVD risk ≥20% and 4) 10-year ASCVD risk of 7.5% to 19.9% in the presence of risk enhancing factors or at least mild coronary artery calcium (CAC).² Statin therapy in addition to lifestyle interventions remain the cornerstone therapy for hypercholesterolemia. However, in patients with statin-associated side effects or in whom guideline-recommended LDL-C targets are not achieved despite maximally tolerated or high-intensity statin therapy, nonstatin alternatives are recommended.²

Among the nonstatin LDL-C lowering drugs, PCSK9 inhibitors are the most potent and could further reduce LDL-C by 45% to 64% when added to a statin.² PCSK9 inhibitors are, however, costly and thus not widely accessible to all patients. Ezetimibe is the most commonly used nonstatin LDL-lowering drug but it only reduces LDL-C by 15% to 25% when added to a statin.²

Bempedoic acid is a new class of nonstatin LDL-lowering therapy that, like statins, targets the cholesterol biosynthesis pathway in the liver.³ Whereas statins inhibit HMG CoA reductase, bempedoic acid inhibits ATP-citrate lyase (ACL), two steps upstream of HMG CoA reductase.³ Unlike statins, bempedoic acid is administered as a prodrug and is converted to active coenzyme A form by enzymes found only in the liver and not in muscles.³ The lack of active metabolites of bempedoic acid in skeletal muscles makes it a promising alternative for patients with statin-associated muscle symptoms (SAMS).

Efficacy of Bempedoic Acid in LDL-C Lowering
The efficacy of bempedoic acid, an oral agent, was initially reported in several phase 2 trials. Ballantyne et al. demonstrated a dose-dependent LDL-lowering effect of bempedoic acid monotherapy in patients with hypercholesterolemia.⁴ In this phase 2 trial, participants were randomized to three incremental doses of bempedoic acid (40 mg, 80 mg and 120 mg daily) or placebo. Bempedoic acid 120 mg lowered LDL-C by 23% compared to 2.3% in the placebo group.

Additional phase 2 trials have assessed the combination of bempedoic acid with other lipid-lowering medications, in particular statins and ezetimibe.⁵ When compared to ezetimibe monotherapy, Thompson et al. reported that bempedoic acid monotherapy at a dose of 180 mg daily reduced LDL-C by 30% at 12 weeks compared to 21% LDL-C reduction for ezetimibe alone.⁶ A combination of bempedoic acid and ezetimibe resulted in 48% LDL-C reduction at 12 weeks.

Phase 3 trials as part of the ongoing CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL-inhibiting Regimen) trial series have investigated the efficacy of bempedoic acid.^7-10 The CLEAR Tranquility trial studied the efficacy and safety of bempedoic acid added to a background lipid-lowering therapy that included ezetimibe in statin-intolerant patients with LDL-C ≥100 mg/dl.¹⁰ Bempedoic acid led to a 28.5% reduction in LDL-C compared to placebo at 12 weeks. Similarly, the CLEAR Serenity trial by Laufs et al. also assessed the efficacy and safety of bempedoic acid in statin-intolerant patients with hypercholesterolemia over a period of 24 weeks.⁹ In this trial, approximately 8.4% of the participants continued their tolerated low-dose statin therapy. At 12 weeks, bempedoic acid yielded a 21.4% reduction in LDL-C level compared to placebo.

The CLEAR Wisdom and CLEAR Harmony trials both assessed the safety and efficacy of bempedoic acid in high risk cardiovascular patients with ASCVD, heterozygous familial hypercholesterolemia (HeFH) or both. In the CLEAR Wisdom trial, Goldberg et al. randomized 779 high risk cardiovascular patients with LDL-C ≥70 mg/dL on maximally tolerated statin therapy to bempedoic acid (180 mg) or placebo.⁷ The addition of bempedoic acid resulted in a 13.9% to 17.4% reduction in LDL-C at 12 weeks.

The CLEAR Harmony included high risk patients on maximally tolerated statin therapy with or without additional lipid-lowering therapy.⁸ Approximately 8% of participants were on ezetimibe and 4% were on a fibrate in addition to statins. Participants randomized to bempedoic acid attained an additional 18% LDL-C reduction compared to placebo.

Finally, a phase 3 trial of a fixed-dose combination of bempedoic acid 180 mg and ezetimibe 10 mg in high-risk patients with ASCVD, HeFH, or multiple cardiovascular risk factors and hypercholesterolemia on maximally tolerated statin therapy was performed.¹¹ In this trial, 301 participants were randomized to either a fixed-dose combination therapy or 180 mg bempedoic acid or 10 mg ezetimibe or placebo. At 12 weeks, the fixed-dose combination led to a 38% LDL-C lowering compared to placebo.

Bempedoic Acid and Glycemic Control
A recent pooled analysis of 3,621 participants from four phase 3 trials examined blood glucose and hemoglobin A1C (HbA1c) levels at 12 weeks compared to baseline. In participants randomized to bempedoic acid versus placebo on top of maximally tolerated statin therapy, bempedoic acid was not associated with increased incidence of new-onset diabetes or worsening glycemic control among patients with known diabetes.¹²

Bempedoic Acid and Cardiovascular Outcomes
The effect of bempedoic acid on cardiovascular morbidity and mortality has yet to be determined. The CLEAR Outcomes trial is an ongoing phase 3 trial that is seeking to bridge this knowledge gap by assessing the effect of bempedoic acid on major cardiovascular events in patients with or at high risk for cardiovascular disease and who have statin intolerance.¹³ This double-blind, placebo-controlled trial began enrollment in December 2016 and is estimated to enroll 14,032 participants. The primary composite endpoint includes time from randomization to the first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or coronary revascularization. Trial completion is anticipated in March 2022.

Safety and Side Effects of Bempedoic Acid
As anticipated, in light of its lack of active metabolites in skeletal muscles, bempedoic acid added to maximally tolerated statin therapy was not associated with an increased incidence of muscular disorders or serious adverse events compared to placebo in the CLEAR Harmony trial.⁸ However, bempedoic acid was associated with hyperuricemia and gout symptoms especially in patients with history of gout.

Of note, bempedoic acid was associated with a slightly increased risk of tendon rupture, involving the biceps tendon, rotator cuff, or Achilles tendon. This risk may be increased in patients over 60 years of age, patients taking corticosteroid or fluoroquinolone drugs, patients with renal failure, and patients with previous tendon disorders. Other more commonly reported adverse events in clinical trials were upper respiratory tract infection, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, and elevated liver enzymes.⁴

Regulatory Status of Bempedoic Acid
Given the above evidence demonstrating efficacy and safety, once-daily, oral bempedoic acid (branded as NEXLETOL™) at a dose of 180 mg was approved by the US Food and Drug Administration (FDA) in February 2020 as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or established ASCVD who require additional lowering of LDL-C.¹⁴ Considering the LDL-C lowering of about 40% seen in trials of bempedoic acid in combination with ezetimibe, the FDA also approved a fixed-dose combination of bempedoic acid and ezetimibe (branded as NEXLIZET™) for the same indications.

Expert Discussion
Bempedoic acid demonstrated efficacy in lowering LDL-C either as monotherapy or in combination with ezetimibe. A fixed-dose bempedoic acid and ezetimibe reduces LDL-C by approximately 40%. This amount of LDL-C lowering achieved with the combination drug is two-thirds the amount of LDL-C lowering typically achieved with PCSK9 inhibitors. Bempedoic acid offers an important opportunity for further LDL-C lowering in statin-intolerant patients or in those requiring further LDL-C reduction despite maximally tolerated statin therapy and who are unable to afford a PCSK9 inhibitor. Given that the 2018 ACC/AHA/MS Cholesterol guideline was assembled and published prior to data from phase 3 trials on the efficacy of bempedoic acid in LDL-C lowering, bempedoic acid was not officially included as a nonstatin option in the cholesterol guidelines in America.

Across the Atlantic, the 2019 European Society of Cardiology/ European Atherosclerosis Society (ESC/EAS) guideline for the management of dyslipidemias have included bempedoic acid as a potential novel therapy for LDL-C lowering.¹⁵ We eagerly await data on the impact of bempedoic acid on cardiovascular outcomes. Considering the well-established association of LDL-C with ASCVD, and experience thus far with bempedoic acid, a significant reduction is fully anticipated in the primary endpoint in the ongoing CLEAR Outcomes trial. Currently, bempedoic acid is FDA approved for ASCVD secondary prevention or primary prevention in patients with HeFH as an adjunct to diet and maximally tolerated statin therapy.

Conclusion
Bempedoic acid is a novel class of nonstatin therapy that targets hepatic cholesterol synthesis and has demonstrated significant LDL-C lowering ability as monotherapy and especially in combination with ezetimibe. If data on long-term safety and cardiovascular outcomes in ongoing trials are favorable, bempedoic acid will improve cardiovascular risk prevention in statin-intolerant patients and in resource limited settings.

References

1. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.
2. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. J Am Coll Cardiol 2019;73:3168-3209.
3. Agarwala A, Goldberg AC. Bempedoic acid: a promising novel agent for LDL-C lowering. Future Cardiol 2020;May 28 [Epub ahead of print].
4. Ballantyne CM, Davidson MH, Macdougall DE, et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J Am Coll Cardiol 2013;62:1154-62.
5. Ballantyne CM, McKenney JM, MacDougall DE, et al. Effect of ETC-1002 on serum low-density lipoprotein cholesterol in hypercholesterolemic patients receiving statin therapy. Am J Cardiol 2016;117:1928-33.
6. Thompson PD, MacDougall DE, Newton RS, et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance. J Clin Lipidol 2016;10:556-67.
7. Goldberg AC, Leiter LA, Stroes ESG, et al. Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR Wisdom randomized clinical trial. JAMA 2019;322:1780-8.
8. Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med 2019;380:1022-32.
9. Laufs U, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. J Am Heart Assoc 2019;8:e011662.
10. Ballantyne CM, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study. Atherosclerosis 2018;277:195-203.
11. Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol 2020;27:593-603.
12. Leiter LA, Banach M, Catapano AL, et al. Abstract 11417: Bempedoic acid and glycemic control: a pooled analysis of 4 Phase 3 Clinical Trials. Circulation 2019;140:A11417.
13. Esperion Therapeutics. Evaluation of major cardiovascular events in patients with, or at high risk for, cardiovascular disease who are statin intolerant treated with bempedoic acid (ETC-1002) or placebo (CLEAR Outcomes). 2016. Available at:  https://clinicaltrials.gov/ct2/show/NCT02993406. Accessed 07/15/2020. 
14. Markham A. Bempedoic acid: first approval. Drugs 2020;80:747-53.
15. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Dyslipidemias, Cholesterol, LDL, Hypercholesterolemia, Cardiovascular Diseases, Prodrugs, PCSK9 protein, human, Calcium, Proprotein Convertase 9, American Heart Association, Risk Factors, Hyperlipoproteinemia Type II, Coenzyme A, Hemoglobin A, Blood Glucose, Hyperuricemia, Secondary Prevention, Double-Blind Method, Pharmaceutical Preparations, Hydroxymethylglutaryl-CoA Reductase Inhibitors, ATP Citrate (pro-S)-Lyase

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