Efficacy of Bempedoic Acid, Novel Treatment for Elevated LDL Cholesterol

By Anthony Rice

Bempedoic acid is a novel non-statin drug produced by Esperion Therapeutics to treat hypercholesterolemia, elevated levels of low-density lipoprotein (LDL) cholesterol in the blood.1 In the double-blind, placebo-controlled, phase 3 2022 CLEAR Outcomes trial conducted by Esperion, bempedoic acid treatment was associated with reductions in major adverse cardiovascular events among patients intolerant to traditionally prescribed statin medication.2 Following this clinical trial, the United States Food and Drug Administration (FDA) approved label expansions of Esperion’s NEXLETOL® (bempedoic acid) and NEXLIZET® (bempedoic acid and ezetimibe) tablets.3 The updated labels are expected to expand hypercholesterolemia treatment access to a population of approximately 70 million patients in the United States.3

Existing hypercholesterolemia treatments

Cholesterol, a fatty substance carried in the blood, is vital for constructing cell membranes, hormones, and vitamins; however, too much cholesterol can be unhealthy.4 Two lipoproteins transport cholesterol between cells: high-density lipoproteins (HDLs) and low-density lipoproteins (LDLs).4 HDL cholesterol, known as “good” cholesterol, lowers one’s risk for coronary artery disease and heart attack.4 LDL cholesterol, known as “bad” cholesterol, is the target of Esperion’s treatment. High LDL cholesterol can accumulate in the blood to form plaque on the arterial walls, raising heart disease and stroke risk.4

Many individuals are prescribed a class of medications called statins to lower their LDL cholesterol.5 These drugs reduce the rate of cholesterol synthesis by competitively binding to the HMG coenzyme A reductase, which inhibits the mevalonate metabolic process by blocking the natural HMG-CoA substrate.6 The side effects of statins include muscle aches and pains, broadly classified as statin-associated muscle symptoms (SAMS).7 In addition, statin medications’ enzymatic activity can cause liver damage. Some patients who are prescribed statins report memory loss, confusion, and other neurological effects.5 For these reasons, statins may be unsuitable for hypercholesterolemia treatment in certain individuals.

Novel bempedoic acid treatment

Esperion Pharmaceuticals’ novel FDA-approved bempedoic acid treatments differ from statins in inhibiting the ATP citrate lyase (ACL) enzyme.6 This blocks the conversion of citrate into Acetyl coenzyme A, a cholesterol precursor.6 An additional benefit of bempedoic acid is that it gradually upregulates LDL receptors on the surface of the liver, enabling the body to remove even more LDL cholesterol from the blood.6 This alternative treatment benefits individuals who require LDL cholesterol reduction but are intolerant to statin therapy due to its side effects. In addition, bempedoic acid and statin combination therapy can be used for patients sensitive to high statin doses.6

Diagram of how bempedoic acid inhibits cholesterol synthesis within the liver. Adapted from Rusisca et al.

At the 2024 American College of Cardiology’s Annual Science Session, Esperion Pharmaceuticals presented data conducted on bempedoic acid treatment outcomes in populations often underrepresented in clinical tests: women, Hispanic patients, and obese patients.8 The data for Esperion’s Nexletol treatment showed that obese patients were 23% less likely to suffer from a major adverse cardiovascular event (stroke, heart attack, sudden cardiac death) when compared to placebo treatment.3

Limitations and Ongoing Research

While bempedoic acid minimizes some side effects commonly associated with statins, bempedoic acid alone is less effective, reducing LDL cholesterol by 24.5% on average, compared to 38-40% when used alongside another drug, ezetimibe.9 The long-term benefits of statins on cardiovascular function are well-documented, but this data is less established for bempedoic acid.9 During metabolism, bempedoic acid binds onto OAT2 (Organic Anion Transporter 2) in the kidneys and competes with uric acid for secretion.9 This can lead to hyperuricemia, or increased uric acid levels, that could potentially increase the risk of kidney stones and gout.9

The current scientific and clinical consensus positions bempedoic acid as a specialized treatment for statin-intolerant patients.10 Future clinical trials are required to better understand bempedoic acid’s impacts on kidney function and uric acid levels and establish it as a standalone treatment for patients.

Anthony Rice is a staff writer at The Princeton Medical Review. He can be reached at ar5395@princeton.edu.

References

  1. Esperion Announces Bempedoic Acid (NEXLETOL®) Recommended as Oral Non-Statin Therapy for LDL-Cholesterol Lowering in American College of Cardiology Expert Consensus Decision Pathway. Esperion.com. Published August 26, 2022. Accessed November 18, 2024. https://www.esperion.com/news-releases/news-release-details/esperion-announces-bempedoic-acid-nexletolr-recommended-oral-non
  2. Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388(15):1353-1364. doi:10.1056/nejmoa2215024
  3. U.S. FDA Approves Broad New Labels for NEXLETOL® and NEXLIZET® to Prevent Heart Attacks and Cardiovascular Procedures in Both Primary and Secondary Prevention Patients, Regardless of Statin Use. Esperion.com. Published March 22, 2024. Accessed November 18, 2024. https://www.esperion.com/news-releases/news-release-details/us-fda-approves-broad-new-labels-nexletolr-and-nexlizetr-prevent#:~:text=ANN%20ARBOR%2C%20Mich.%2C%20March,on%20positive%20CLEAR%20Outcomes%20data
  4. HDL (good), LDL (bad) cholesterol and triglycerides. American Heart Association. Published October 14, 2024. Accessed November 18, 2024. https://www.heart.org/en/health-topics/cholesterol/hdl-good-ldl-bad-cholesterol-and-triglycerides
  5. Statins: Are these cholesterol-lowering drugs right for you? Mayo Clinic. Published March 6, 2024. Accessed November 18, 2024. https://www.mayoclinic.org/diseases-conditions/high-blood-cholesterol/in-depth/statins/art-20045772
  6. Biolo G, Vinci P, Mangogna A, et al. Mechanism of action and therapeutic use of bempedoic acid in atherosclerosis and metabolic syndrome. Frontiers in Cardiovascular Medicine. 2022;9. doi:10.3389/fcvm.2022.1028355 
  7. Zhou Z, Albarqouni L, Breslin M, Curtis AJ, Nelson M. Statin-associated muscle symptoms (SAMS) in primary prevention for cardiovascular disease in older adults: A protocol for a systematic review and meta-analysis of randomised controlled trials. BMJ Open. 2017;7(9):e017587. doi:10.1136/bmjopen-2017-017587
  8. Esperion Presents Important New Data from CLEAR Outcomes at ACC.24 Highlighting Value of NEXLETOL® (bempedoic acid) Tablets in Diverse Populations Including Women, Hispanics/Latinx, and Patients with Obesity. Esperion.com. Published April 7, 2024. Accessed November 18, 2024. https://www.esperion.com/news-releases/news-release-details/esperion-presents-important-new-data-clear-outcomes-acc24
  9. Ruscica M, Sirtori CR, Carugo S, Banach M, Corsini A. Bempedoic acid: For whom and when. Curr Atheroscler Rep. 2022;24(10):791-801. doi:10.1007/s11883-022-01054-2
  10. Serour MH, Egaimi M, Khan Z. A systematic review and meta-analysis on the role of bempedoic acid in cardiovascular outcomes for patients with statin intolerance. Cureus. Published June 3, 2024. doi:10.7759/cureus.61572

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