New Class of Medications Lowers Cholesterol

The FDA recently approved Nexletol (bempedoic acid), manufactured by Esperion Therapeutics, as a cholesterol-lowering medication.

Statins have been and continue to be the first-choice therapy options for patients with elevated cholesterol levels. However, the addition of Nexletol as a new class of medications, adds a different new dimension to managing this disease.

Nexletol is indicated as an adjunct to diet, exercise, and the maximum tolerated dose of statin for adult patients with heterozygous familial hypercholesterolemia. This oral medication comes in tablet form, containing 180 mg of bempedoic acid and is taken once a day with or without food.

This drug, with its innovative mechanism, distinguishes itself from other cholesterol-lowering drugs on the market. When activated in the liver, bempedoic acid inhibits adenosine triphosphate lyase, which is also known as ACL, an enzyme 2 steps upstream from HMG-CoA reductase. By inhibiting ACL, bempedoic acid reduces cholesterol synthesis, which results in low-density lipoproteins (LPL) receptor upregulation, therefore increasing the clearance of LDL from the blood stream. Bempedoic acid is a prodrug, which must be converted to its active moiety, ACSVL1. The good news is that ACSVL1 is not present in the skeletal muscle. Therefore, this drug is not converted to active moiety in skeletal muscle, causing fewer adverse effects.

As a new drug, Nexletol’s impact on cardiac mortality and morbidity has not been studied yet. Patients taking this medication may need to be warned to watch for an increase in their uric acid levels, so those already predisposed to high levels of uric acid, including individuals with gout, should use caution when taking this medication. When it comes to adverse events, tendon rupture may also occur more frequently, in patients older than 60 years of age, especially those taking corticosteroids and fluoroquinolone drugs. Within the first few weeks of treatment, blood urea nitrogen, creatinine may increase, hemoglobin and leukocytes level may decrease, platelet counts may increase, as well as live enzymes, such as alanine transaminase and aspartate transaminase, and creatine kinase. However, after the initial weeks, these levels should go back to the baseline.

This drug should be used with caution with pravastatin and simvastatin. Concomitant use may result in increased concentrations and increased risk of pravastatin- or simvastatin-related myopathy. Therefore, its use with greater than 40 mg of pravastatin or 20 mg of simvastatin should be avoided.

One week after the FDA approved Nexletol, the agency approved Nexlizet. Nexlizet is combination of active ingredient Nexletol and Zetia (ezetimibe), another cholesterol-lowering option.

When it comes to clinical studies associated with Nexletol, CLEAR Outcome study is evaluating the drug. This is a controlled, double-blind, event-driven, multicenter, Phase 3, placebo-controlled, randomized, trial designed to evaluate whether treatment with bempedoic acid reduces the risk of cardiovascular events. The primary endpoint of the study is the effect of bempedoic acid on major adverse cardiovascular events. The study is expected to complete with a minimum of 1620 patients experiencing the primary endpoint. The study has so far enrolled about 14,032 patients at more than 1400 sites in 32 countries.¹ Based on estimated cardiovascular event rates, we expect the CLEAR Outcomes trial to conclude in the second half of 2022. In multiple phase 3 trials, Esperion’s Nexletol shows that it lowers the level of C-reactive protein in patients with high triglycerides levels. The data show that it lowers high-sensitivity c-reactive protein by 25% over the baseline.

Current treatment options may not be adequate for all patients with cardiovascular disease (CVD), which is the No. 1 cause of death in the United States, with 1 in 3 deaths related to it. CVD cost more than $351 billion in 2014-15, in health care services, medications’ cost and lost productivity.² Statins are mostly effective at lowering LDL-C. However not all patients can tolerate statins, and/or reach their LDL-C target goal with high doses of statins. Because of this and the adverse effects not tolerated with many patients, about 27.4 million individuals in the United States have elevated LDL-C levels and take statins. About 19.4 million patients with high LDL-C levels cannot achieve the desired LDL-C target, despite their current therapies.³

This is where Nexletol as a new novel therapy with a distinct new drug classification can play a role in managing elevated the LDL-C levels that lead to CVD. This drug, a first of its kind, can bring similar drugs, as well as combinations with other medications, to market.

Saro Arakelians, PharmD, is the general manager and pharmacist in charge at BioScrip Infusion in Burbank, California.

References

• Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics—2019 update: a report from the American Heart Association. Circulation. 2019;139(10):e56-e528. doi: 10.1161/CIR.0000000000000659.
• World Health Organization. Cardiovascular diseases (CVDs). who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds). Published May 17, 2017. Accessed February 15, 2019.
• Wong ND, Young D, Zhao Y, et al. Prevalence of the American College of Cardiology/American Heart Association statin eligibility groups, statin use, and low-density lipoprotein cholesterol control in US adults using the National Health and Nutrition Examination Survey 2011—2012. J Clin Lipidol. 2016;10(5):1109-1118. doi: 10.1016/j.jacl.2016.06.011.