LDL Cholesterol

Pam R. Taub, MD, on a New Approach for Managing Lipids

Earlier this year, the US Food & Drug Administration (FDA) approved bempedoic acid for the lowering of low-density lipoprotein (LDL) cholesterol.1 

According to the FDA’s label1 for bempedoic acid, the novel, oral, nonstatin therapy is “indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL [cholesterol].”

Pam R. Taub, MD, is the director of the Step Family Foundation Cardiovascular Rehabilitation and Wellness Center and an associate professor of medicine at the University of California’s San Diego Health System, Division of Cardiovascular Medicine. We asked her about the novel therapy and its potential impact on LDL management.

CARDIOLOGY CONSULTANT: Can you briefly provide insight into bempedoic acid? Why is this new approach needed?

Pam Taub: Statins are the cornerstone of management of hyperlipidemia, and we have more than 30 years of data demonstrating their benefits for improving cardiovascular outcomes. However, up to 20% of patients prescribed statins are unable to take them due to various adverse effects, including muscle and joint pain.2 In addition, 7 out of every 10 patients who are taking statin therapy are not near their LDL goal.3 Thus, there is an unmet need for additional LDL lowering in patients who are not optimized on statins or those who are intolerant to statins.

Bempedoic acid was recently FDA approved for LDL lowering. Its mechanism of action is unique, as it inhibits the enzyme adenosine triphosphate citrate lyase (ACL), which is upstream of HMG-CoA reductase—the target for statins. Inhibition of ACL results in decreased cholesterol synthesis and increased expression of the LDL receptor, which helps clear LDL from circulation. In the CLEAR Harmony trial, there was a reduction of in LDL levels of 18% when bempedoic acid was added to maximally tolerated statin therapy in patients with ASCVD or heterozygous familial hypercholesteremia.4

In addition, there is a combination of bempedoic acid and ezetimbe—which also recently received FDA approval in February 20205—that lowers LDL by 29% when added to maximally tolerated statins.6

Cardiovascular outcome studies with bempedoic acid are in progress.

CARDIO CON: How might bempedoic acid help alleviate LDL- management challenges? 

PT: This is an oral drug that is well tolerated and priced lower than injectable proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and may be a useful adjunct to statin therapy.

CARDIO CON: Which patients may benefit most from the novel therapy? Are there any patient populations that you would recommend against initiating the therapy?

PT: These drugs will be especially useful for patients with ASCVD and heterozygous familial hypercholesterolemia who cannot achieve their LDL target on statins alone.

In clinical trials, bempedoic acid was shown to increase uric acid levels and should be used with caution in patients who have gout.1

CARDIO CON: What should a clinician consider when determining if and when a patient should initiate bempedoic acid as an adjunct therapy to statins?

PT: Ideally, all patients should be on statins. If they cannot tolerate a particular statin, they should be challenged with other statins (eg, water-soluble statins). Factors that can contribute to statin intolerance, such a low vitamin D levels and hypothyroidism, should be corrected. If patients continue to be statin intolerant, then a drug like bempedic acid maybe useful. The current data on LDL lowering with bempodoic acid is from clinical trials when it is added to statin therapy—as opposed to switching from statin therapy to the novel nonstatin therapy altogether. 

For patients with ASCVD who need aggressive LDL- lowering (50% or more), PCSK9 inhibitors are the more-potent option.

Inclisiran, which is a small-interfering RNA therapy that inhibits production of PSCK9 protein, is also a promising therapy that builds on the well-validated PCKS9 inhibition platform and should be on the market in the next year.

CARDIO CON: How do you see the new therapy fitting into the current management landscape? Does it highlight any improvement that has been made or the need for further improvement in lipid management?

PT: This is good adjunct therapy to statins. Many patients taking statins are often unable to tolerate high-dose statins, and this is an add-on therapy that could lower LDL levels by an additional 29%.

Disclosures: Pam R. Taub, MD, is a consultant for Esperion, Amarin, Novo-Nordisk, and Boehringer Ingelheim and has research grants from Amgen, National Institutes of Health, American Heart Association, and the Department of Homeland Security.

References:

  1. US Food & Drug Administration. Nexletol (bempedoic acid) label. Revised February 2020. Accessed April 6, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211616s000lbl.pdf
  2. Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med. 2013;158(7):526-534. doi:10.7326/0003-4819-158-7-201304020-00004
  3. 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
  4. Ray KK, Bays HE, Catapan AL, et al; CLEAR Harmony Trial. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med. 2019;380:1022-1032. doi: 10.1056/NEJMoa1803917
  5. US Food & Drug Administration. Nexlizet (bempedoic acid and ezetimibe) label. Revised February 2020. Accessed April 6, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211617s000lbl.pdf
  6. 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. doi:10.1016/j.atherosclerosis.2018.06.002