By Cortney Mospan, PharmD, BCACP, BCGP
Associate Professor of Pharmacy, Wingate University Levine College of Health Sciences
Clinical Pharmacist Practitioner, Novant Health Arboretum Family & Sports Medicine
In March 2020, the Food and Drug Administration approved a new non-statin cholesterol medication, bempedoic acid (Nexletol®) which is also available in combination with ezetimibe (Nexlizet®).1 This medication is approved as an adjunctive treatment to diet and maximally tolerated statin in individuals who have established cardiovascular disease or heterozygous familial hypercholesterolemia who require additional LDL lowering.2 While an adjunctive treatment to statin therapy, it is important to note that the drug label includes language that the “effect of Nexletol on cardiovascular morbidity and mortality has not been determined”, compared to the well-established cardiovascular risk reduction benefits of statin therapy and other non-statin therapies.3
Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) through inhibition of cholesterol synthesis in the liver. The ACL enzyme works upstream of the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase enzyme in the cholesterol biosynthesis pathway.2,4 Statins inhibit the HMG-CoA reductase enzyme, thus bempedoic acid and statin therapy work synergistically to further inhibit LDL-C production. Bempedoic acid is supplied as a 180 mg tablet (Nexletol®) or a 180 mg combination tablet with 10 mg of ezetimibe (Nexlizet®) that is taken once daily. The medication can be taken irrespective of food as food does not impact the absorption.4
In clinical trials, bempedoic acid was generally well-tolerated with all adverse effects occurring in <5% of participants. The most common adverse effect was upper respiratory tract infection (4.5%) with pain and muscle spasms occurring in ~3% of patients. Notably, patients did not report myalgia which is often a cause for cessation of therapy or suboptimal dosing with statins, which is due to the lack of active metabolites of bempedoic acid in skeletal muscle. Liver enzyme elevations did occur in ~2% of patients. These elevations were generally transient and resolved with time or discontinuation of therapy. It is recommended that a lipid panel be obtained 8-12 weeks after initiation of therapy.4
Considering bempedoic acid is recommended as an adjunct to maximally tolerated statin dose, there are two key drug interactions to be aware of. When used in conjunction with pravastatin, pravastatin dose should not exceed 40 mg and when used in conjunction with simvastatin, simvastatin dose should not exceed 20 mg. This is due to inhibition of the OATP1B1/B3 transporter by bempedoic acid, which leads to accumulation of statin dosages.4
There are no boxed warnings for bempedoic acid, but there are precautions for risk of tendon rupture and hyperuricemia. Bempedoic acid should not be prescribed in individuals with a history of tendon rupture and should be carefully considered in individuals with a history of hyperuricemia, as 11.2% of individuals with a history of gout did experience hyperuricemia in clinical trials.4 Serum uric acid levels on average increase by 0.73 mg/dL and there is an increased risk of gout by 3.5 times.5 In individuals with gout, ezetimibe would be preferred to bempedoic acid for the first add-on therapy after statins are maximally dosed. If bempedoic acid is required, serum uric acid should be monitored 4-6 weeks after initiation and urate lowering therapy considered in alignment with the 2020 American College of Rheumatology treatment guidelines.
The 2018 guideline endorsed by multiple societies on the management of blood cholesterol advocate for use of non-statin therapies such as ezetimibe and PCSK9 inhibitors in people with very-high risk ASCVD who do not reach an LDL-C goal of < 70 mg/dL.6 Those guidelines did not mention bempedoic acid, as the drug had not yet been brought to market. When comparing bempedoic acid to other non-statin therapies, its role in treatment is currently limited due to its lack of long-term cardiovascular outcome data and LDL-C lowering capabilities. PCSK9 inhibitors lower LDL-C by ~60% and have shown reduction in risk of major vascular events.7 However, these therapies are extremely expensive and patient access is often suboptimal as a result. Compared to ezetimibe, bempedoic acid offers slightly better LDL-C reduction of 21-29% compared to 15-25%, although ezetimibe has been shown to decrease risk of cardiovascular events when used in combination with statin therapy.8-10 An ongoing Phase III trial is studying the impact of bempedoic acid on cardiovascular outcomes with results expected in March 2022. Until then, bempedoic acid provides a nice second-line option to add to maximally tolerated statin therapy if ezetimibe does not offer enough LDL-C reduction and PCSK9 inhibitor therapy is not affordable.
- Drug Approval Package: Nexletol. Updated March 24, 2020. Accessed February 1, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/211616Orig1s000TOC.cfm.
- Nexletol. Package insert. Esperion Pharmaceuticals, Inc; 2020.
- Statin use for the primary prevention of cardiovascular disease in adults: Recommendation statement. U.S. Preventative Services Task Force. Am Fam Physician. 2017;95(2):online. https://www.aafp.org/afp/2017/0115/od1.html.
- Bempedoic acid. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Accessed February 1, 2021. http://online.lexi.com.
- Cicero AFG, Pontremeoli R, Fogaaci F, Viazzi F, Borghi C. Effect of bempedoic acid on serum uric acid and related outcomes: A systematic review and meta-analysis of the available phase 2 and phase 3 clinical studies. Drug Saf. 2020;43(8):727-736.
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/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 Foundation/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol. 2019;73(24):e285-e350.
- Sabatine MS. PCSK9 inhibitors: Clinical evidence and implementation. Nature Reviews Cardiology. 2019;16:155-165.
- Goldberg AC, Leiter LA, Stroes ES, 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;322:1780-1788.
- Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med. 2019;380:1022-1032.
- Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.
About the Author
Cortney Mospan is an Associate Professor of Pharmacy at Wingate University School of Pharmacy. Cortney graduated with her Doctorate of Pharmacy from Ohio Northern University and completed a Community Care Pharmacy Practice Residency at The Ohio State University. She is Board Certified as both an Ambulatory Care Pharmacist and Geriatric Pharmacist. Cortney is a Clinical Pharmacist Practitioner at Novant Health Arboretum Family & Sports Medicine/Internal Medicine Providence.
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