By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved first-in-class adenosine triphosphate-citrate lyase (ACL) inhibitor for lowering low-density lipoprotein cholesterol (LDL-C). Bempedoic acid is a prodrug that is activated in the liver by long chain acyl-CoA synthetase-1 (ACSVL1).1,2 Bempedoic and its active metabolite inhibit ACL, which is upstream for HMG-CoA reductase, the target for statins. Bempedoic acid is available as monotherapy and in combination with ezetimibe, a cholesterol absorption inhibitor. They are distributed as Nexletol and Nexlizet.

INDICATIONS

Bempedoic acid and bempedoic acid/ezetimibe should be prescribed as a supplement to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who need additional LDL-C lowering.1,3

DOSAGE

The recommended dose is 180 mg (monotherapy) or 180 mg plus 10 mg ezetimibe, once daily with or without food.1,3 Simvastatin > 20 mg and pravastatin > 40 mg should be avoided due to the increased risk of statin-related myopathy.1 Bempedoic acid is available as 180 mg tablets and in a fixed combination with ezetimibe (180 mg + 10 mg) tablets.

POTENTIAL ADVANTAGES

Bempedoic acid provides a new mechanism of action to reduce LDL-C. It may carry a low risk of statin-associated myopathy due to the absence of ACSVL1 in the skeletal muscle.2 Inhibition of HMG-CoA is one the proposed mechanisms of action for statin-related myopathy.3

POTENTIAL DISADVANTAGES

Bempedoic acid may increase blood uric acid levels by inhibiting renal tubular organic anion transporter 2 (OAT2).1 After 12 weeks, the mean difference between bempedoic acid and placebo was 0.8 mg/dL.1 Incidence of gout was particularly significant in patients with a history of gout (11.2% vs. 1.7% for placebo). There appears to be a higher risk of tendon rupture or injury (0.5% vs. 0% for placebo).1 The risk may be greater for those > age 60 years of age, those taking corticosteroids or fluoroquinolones, those with renal disorder, or those with previous tendon disorders. While low in frequency, there were some disproportionate differences between bempedoic acid and placebo, including doubling of BUN (3.8% vs. 1.5%), decrease in hemoglobin ≥ 2 g/dL (5.1% vs. 2.3%), and increased platelet counts ≥ 100 × 109/L (10.1% vs. 4.7%). Common adverse events (3-5% vs. 2-4% for placebo) include bronchitis, back pain, upper respiratory tract infections, muscle spasms, hyperuricemia, abdominal pain/discomfort, and pain in extremity.1 Trial discontinuation rates due to adverse reactions were 11% for bempedoic acid vs. 8% for placebo.

COMMENTS

The efficacy of bempedoic acid monotherapy was evaluated in two randomized, double-blind, placebo-controlled, 52-week trials that included subjects with primarily ASCVD (94-98%; 3-6% with HeFH) and on maximally tolerated lipid-lowering therapy.1,5,6 Subjects were randomized to bempedoic acid (n = 2,010) or placebo (n = 999), with the primary efficacy endpoint of percent change from baseline to week 12 in LDL-C. In trial 1, bempedoic acid showed a mean LDL-C reduction of 18% from placebo from a baseline mean of 103 mg/dL. In trial 2, the mean reduction was 17% from a mean baseline of 120 mg/dL. In both studies, non-LDL-C, apo B, total cholesterol, and high-sensitivity C-reactive protein also were reduced significantly. Those reductions were maintained for 52 weeks.

The fixed combination of bempedoic acid and ezetimibe was evaluated in a randomized, double-blind, four-arm study that included 301 subjects with HeFH, established ASCVD, or multiple risk factors for CV disease and mean LDL-C of 150 mg/dL.1,7 Subjects were randomized to bempedoic acid (180 mg), ezetimibe (10 mg), bempedoic acid/ezetimibe, or placebo. Bempedoic acid/ezetimibe provided a 38% reduction in LDL-C compared to placebo, with 34% exhibiting a greater than 50% reduction in LDL-C. The LDL-C reductions for bempedoic acid and ezetimibe individually were -19% and -25%, respectively.

CLINICAL IMPLICATIONS

Bempedoic acid provides a modest reduction in LDL-C and is much more effective in combination with ezetimibe. LDL-C reductions seen with proprotein convertase subtilisin/kexin type 9 monoclonal antibodies inhibitors (e.g., evolocumab, alirocumab) when added to maximally tolerated statins ranged from 60% to 70%, along with reduction in risk of CV events.8,9 The effect of bempedoic acid monotherapy or in a fixed combination with ezetimibe on cardiovascular morbidity and mortality has not been determined. An ongoing placebo-controlled trial with bempedoic acid in 12,600 subjects will evaluate the occurrence of major cardiovascular events in patients with, or at high risk for, cardiovascular disease who are statin-intolerant (NCT02993406). The estimated completion date is March 2022. The cost for bempedoic acid and bempedoic acid/ezetimibe is $11 per tablet.

REFERENCES

  1. Esperion Therapeutics, Inc. Nexletol Prescribing Information, February 2020. Available at: http://bit.ly/2Q8nfJ9.
  2. Pinkosky SL, et al. Nat Commun 2016;7:13457.
  3. Esperion Therapeutics, Inc. Nexlizet Prescribing Information, February 2020. Available at: http://bit.ly/2Q8AOYX.
  4. Tomaszewski M1, et al. Pharmacol Rep 2011;63:859-866.
  5. Ray KK, et al. N Engl J Med 2019;380:1022-1032.
  6. Goldberg AC, et al. JAMA 2019;322:1780-1788.
  7. Ballantyne CM, et al. Eur J Prev Cardiol 2019;2047487319864671.
  8. Amgen Inc. Repatha Prescribing Information, February 2019. Available at: http://bit.ly/3aPJJ9w.
  9. Sanofi US Group. Praluent Prescribing Information, April 2019. Available at: http://bit.ly/2IAUuR8.