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.
The U.S. Food and Drug Administration (FDA) is expected to update the indications for bempedoic acid and bempedoic acid/ezetimibe.1 Bempedoic acid is the first-in-class adenosine triphosphate-citrate lyase inhibitor that lowers low-density lipoprotein cholesterol (LDL-C). The current prescribing information states that bempedoic acid’s effect on cardiovascular (CV) mortality and morbidity has not been determined. Esperion has submitted clinical evidence in the form of Cholesterol Lowering via Bempedoic Acid an ACL-inhibiting Regimen (CLEAR) that demonstrated that bempedoic acid was associated with a lower risk of major adverse cardiovascular events (MACE) compared to placebo.2 Bempedoic acid and bempedoic acid/ezetimibe are distributed by Esperion as Nexletol and Nexlizet, respectively.
INDICATIONS
Bempedoic acid and bempedoic acid/ezetimibe currently are indicated as adjuncts to diet and statin therapy for the treatment of primary hyperlipidemia in adults with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL-C.3,4
DOSAGE
The recommended dose for bempedoic acid 180 mg or bempedoic acid 180 mg plus ezetimibe 10 mg is once daily with or without food.3,4 Bempedoic acid is available as 180 mg and in combination with ezetimibe 10 mg tablets.
POTENTIAL ADVANTAGES
Bempedoic acid provides an option for statin-intolerant patients that has now been demonstrated to lower the risk of major adverse CV events.2 It has a low incidence of muscle-related adverse events.2,5
POTENTIAL DISADVANTAGES
Bempedoic acid may increase blood uric acid levels by inhibiting renal tubular organic anion transporter 2.3,4 In the CLEAR trial (n = 13,970), the change in uric acid from baseline after six months was 0.76 ± 1.2 mg/dL vs. -0.03 ± 1.0, with an incidence of hyperuricemia of 10.9% vs. 5.6%.2 The incidence of gout was significant in patients with a prior history of gout (11.2% vs. 1.7% for placebo).3,4 There appears to be an increased risk of adjudicated tendon rupture or injury (1.2% vs. 0.9% for placebo).2 The risk may be greater for those > 60 years of age, taking corticosteroids or fluoroquinolones, or with renal disorder or previous tendon disorders.3,4 While low in frequency, there were some disproportionate differences between bempedoic acid and placebo, including a doubling of blood urea nitrogen (3.8% vs. 1.5%), a 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% to 5% vs. 2% to 4% for placebo) include upper respiratory tract infections, muscle spasms, hyperuricemia, back pain, abdominal pain/discomfort, bronchitis, and pain in an extremity.3,4 Trial discontinuation rates due to adverse reactions were 11% for bempedoic acid vs. 8% for placebo.3,4
COMMENTS
The efficacy of bempedoic acid and CV outcomes was assessed in a double-blind, randomized, placebo-controlled trial in “statin-intolerant” (unable or unwilling to receive statin due to adverse effects) participants at high risk for CV disease.2 They were randomized to the bempedoic acid group (n = 6,992) or placebo group (n = 6,978). The primary endpoint was a four-component composite of MACE. These were defined as death from CV causes, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization. The median duration of follow-up was 40.6 months. There was a 13% reduction in the primary outcome, 11.7% vs. 13.3% (hazard ratio, 0.87; 95% confidence interval, 0.79 to 0.96). There was a 15% reduction in the three-component MACE (death from CV causes, nonfatal MI, or nonfatal stroke), a 23% reduction in fatal or nonfatal MI, and a 19% reduction in coronary revascularization. Bempedoic acid did not significantly affect the rates of fatal or nonfatal stroke, death from CV causes, or death from any cause. At six months, there was a mean 20.3% reduction in LDL-C (baseline 139 ± 35 mg/dL) and 21.6% median reduction in high-sensitivity C-reactive protein (baseline median 2.5 mg/L).
CLINICAL IMPLICATIONS
The American College of Cardiology Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of ASCVD Risk recommends PCSK9 monoclonal antibodies, alirocumab, and evolocumab as current statin alternative therapies that beneficially affect CV outcome.6 Bempedoic acid with or without ezetimibe offers another nonstatin therapy to manage atherosclerotic CV disease risk, now with evidence for positive CV outcome. The cost for bempedoic acid with or without ezetimibe is $408 for a 30-day supply.
REFERENCES
- Esperion. U.S. FDA updates LDL-C lowering indication for Esperion’s Nexletol (bempedoic acid) tablet and Nexlizet (bempedoic acid and ezetimibe) tablet. Dec. 13, 2023. https://www.esperion.com/node/16026/pdf
- Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med 2023;388:1353-1364.
- Nexletol Prescribing Information. Esperion Therapeutics, Inc. December 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211616s000lbl.pdf
- Nexlizet Prescribing Information. Esperion Therapeutics, Inc. December 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211617s000lbl.pdf
- 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.
- Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. Expert Consensus Decision Pathway. 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk. A report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2022;14:1366-1418. https://www.jacc.org/doi/epdf/10.1016/j.jacc.2022.07.006
