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Next Up in the World of Hyperlipidemia: Nexletlol TM

By: Preethi Samuel, Pharm.D. Candidate c/o of 2021

             In the United States, at least one person has a heart attack every 40 seconds and 1 of every 5 is silent.1 Heart attacks are commonly a result of atherosclerotic cardiovascular disease (ASCVD). Preceding plaque buildup in arterial walls can potentially lead to a heart attack or stroke.2 Plaques that accumulate are composed of cholesterol. LDL is the “bad” cholesterol, which increases ASCVD risk.3 By lowering LDL levels, the potential for a life- threatening cardiovascular event is reduced. First line pharmacologic therapy for hyperlipidemia are statins. However, in February 2020, a new treatment strategy was introduced to the market with the U.S. Food and Drug Administration’s approval of bempedoic acid (NexletolTM).4

Bempedoic acid, by Esperion Therapeutics, is the world’s first ever adenosine triphosphate lyase (ACL) inhibitor. It is indicated in the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD as an adjunct to diet and maximally tolerated statin therapy. 4 Bempedoic acid, a prodrug, is activated in the liver by acyl-CoA synthetase 1 (ACSVL1). It is not active in skeletal muscle due to lack of ACSVL1.5 Once activated, inhibition of the ACL enzyme occurs. Inhibition occurs two steps upstream of HMG-CoA in the cholesterol synthesis pathway.5 As a result, reduced cholesterol synthesis is observed, as well as LDL receptor upregulation and increased clearance of LDL from the bloodstream.5 (Figure 1 — see PDF)

Two double-blind, randomized controlled trials were conducted to demonstrate the safety and efficacy of bempedoic acid. CLEAR Harmony was the first of these trials, lasting 52 weeks. Patients (n= 2,230) were randomized 2:1 to either receive bempedoic acid (n=1,488) or placebo (n=742).  The second trial, CLEAR Wisdom, like its sister trial, lasted a total of 52 weeks. Patients (n= 779) were randomized 2:1 to either receive bempedoic acid (n=522) or placebo (n=257). For both trials, it was required that all participants had to be at least 18 years of age and had a fasting LDL-C > 70 mg/dl/. Patients needed to have either established ASCVD or heterozygous familial hypercholesterolemia. If the patient was randomized to bempedoic acid, he or she would continue to take their maximally tolerated statin, or any other lipid lowering therapies that they were already using.6

The primary endpoint of CLEAR Harmony was its general safety, including ADR’s, clinical safety labs, physical examinations, ECG, and vitals. The percent change in baseline LDL-C by week 12 was the secondary endpoint. Incidence of any adverse event, such as upper respiratory tract infections, muscle spasms, and hyperuricemia, was similar and not statistically significant (p=0.91) between both groups, bempedoic acid (78.5%) and placebo (78.7%). Serious adverse reactions were also statistically insignificant (p=0.80) in this trial. Secondary endpoints of  CLEAR Harmony proved to be significant (95% CI: -20%, -16%; p < 0.001) with an 18% mean decrease in LDL from baseline when comparing bempedoic acid to placebo.

The primary endpoint of CLEAR Wisdom was the percent change in baseline LDL-C from baseline to week 12. The secondary endpoints were the percent change by week 24, change in baseline by week 12 in HDL, total cholesterol, apolipoprotein B, and hsCRP, and absolute change in baseline weeks 12-24 in LDL. The difference in CLEAR Wisdom between treatment and placebo mean percent change in LDL-C from baseline to Week 12 was -17 percent (95% CI: -21%, -14%; p < 0.001). Bempedoic acid has shown significant LDL reduction regardless of what dose of statin, or other lipid lowering agents, the patient was on.6

             Dosing of this novel drug therapy is currently set to be 180 mg daily without regard to meals and in combination with the maximally tolerated statin. No titration is required for initiation of the medication.7 Following initiation, changes in LDL levels should be detected in 8 to 12 weeks. Use in pediatric, pregnant, or lactating patients has yet to be approved due to a lack of data. Dose adjustments are not needed in both mild to moderate renal and hepatic impairment. Clinical trials did not include patients with severe renal impairment (eGFR < 30 ml/min), end stage renal disease on dialysis, or severe hepatic impairment. Bempedoic acid should not be used in combination with doses greater than simvastatin 20 mg or pravastatin 40 mg, as it increases the concentration of these statins. This elevates the risk of myopathy. Bempedoic acid also carries a risk of tendon rupture and hyperuricemia. Elevated uric acid levels can lead to the development of gout, as seen in 1.5% of patients treated with bempedoic acid. Tendon rupture occurred in 0.5 % of patients treated with the drug versus placebo treated patients. Common sites of tendon rupture are the rotator cuff, biceps tendon, or Achilles tendon- all which occurred within weeks of starting therapy. The likelihood of tendon rupture is increased in patients who are over 60 years of age, in patients with renal failure, or those with previous tendon issues. Other side effects include cold or flu-like symptoms, stomach pain, muscle spasms, elevated liver enzymes, and bronchtits.4

Belonging to an entirely new class of medications, bempedoic acid is one-of-a-kind. From a pharmacist’s perspective, bempedoic acid shows promise as an adjunctive therapy to statins. It is by no means a replacement for evidence-based use of antihyperlipidemic agents and diet- a point that should be stressed to patients during counseling. It has proven itself to be generally well tolerated when given to patients who fit the necessary criteria. This novel drug has shown significant LDL reduction and can prove to be an option for those who are not candidates for other lipid lowering agents. In combination with the statins, hyperlipidemia might have just met its match!


  1. Heart Disease Facts. Centers for Disease Control and Prevention Website. https://www.cdc.gov/heartdisease/facts.htm. Updated June 22, 2020. Accessed July 11, 2020.
  2. Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline. Kaiser Permanente website. https://wa.kaiserpermanente.org/static/pdf/public/guidelines/ascvd-primary.pdf. Updated April 2018. Accessed July 12, 2020.
  3. Patient education: High cholesterol (The Basics). Up-to-Date website.
    https://www-uptodate-com.jerome.stjohns.edu/contents/high-cholesterol-the-basics?search=cholesterol&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3#H25074010. Accessed July 12, 2020.
  4. Nexletol [package insert]. Ann Arbor, MI: Esperion Therapeutics Inc; 2020
    https://pi.esperion.com/nexletol/nexletol-pi.pdf. Accessed July 12, 2020.
  5. NEXLETOL (bempedoic acid) and NEXLIZET (bempedoic acid and ezetimibe): Mechanism of Action. Nexletol HCP website. https://www.nexletolhcp.com/mechanism-of-action. Accessed July 12, 2020.
  6. NEXLETOL (bempedoic acid): Efficacy CLEAR Harmony Trial CLEAR Wisdom Trial. Nexletol HCP website. https://www.nexletolhcp.com/efficacy. Accessed July 12, 2020.
  7. NEXLETOL (Bempedoic Acid) and NEXLIZET (Bempedoic Acid and Ezetimibe): Dosing. Nexletol HCP website. https://www.nexletolhcp.com/dosing. Accessed July 12,2020.
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