Last edited 07/2022
Bempedoic acid is a first-in-class, small-molecule inhibitor of ATP-citrate lyase, a component of the cholesterol biosynthesis pathway that works upstream of beta-hydroxy beta-methylglutaryl-coenzyme A.
- Bempedoic acid is a prodrug that is activated by very-longchain acyl-CoA synthetase-1, an enzyme that is not present in skeletal muscle
- therefore bempedoic acid acts
on the same pathway as statins - however lack of the activating enzyme
in skeletal muscle may prevent the muscular adverse effects
associated with statins (1)
- in phase 2 and phase 3 clinical
trials, bempedoic acid significantly reduced atherogenic
lipoproteins and high-sensitivity C-reactive protein (hsCRP)
levels, and was associated with a low risk for adverse events
typically associated with statins such as muscle-related
symptoms and new-onset diabetes mellitus
- the results of CLEAR (Cholesterol Lowering via
Bempedoic acid, an ACL-Inhibiting Regimen) Serenity, a
phase 3 clinical trial designed to evaluate the efficacy, safety and tolerability of bempedoic acid 180 mg daily versus
placebo in statin-intolerant patients requiring lipid-lowering
therapy for primary or secondary prevention of cardiovascular
- study randomized 345 patients with hypercholesterolemia and a history of intolerance to at least 2 statins (1 at the lowest available dose) 2:1 to bempedoic acid 180 mg or placebo once daily for 24 weeks
- primary end point was mean percent change from baseline to week 12 in low-density lipoprotein cholesterol
- mean age was 65.2 years, mean
baseline low-density lipoprotein cholesterol was 157.6 mg/dL, and 93% of patients reported a history of statin-associated muscle
- bempedoic acid treatment significantly reduced low-density lipoprotein cholesterol from baseline to week 12 (placebo corrected difference, -21.4% [95% CI, -25.1% to -17.7%]; P<0.001)
- significant reductions with bempedoic acid versus placebo were also observed in non-high-density lipoprotein cholesterol (-17.9%), total cholesterol (-14.8%), apolipoprotein B (-15.0%), and high-sensitivity C-reactive protein (-24.3%; P<0.001 for all comparisons)
- the study authors concluded that bempedoic acid was safe and well tolerated
- most common muscle-related adverse event, myalgia, occurred in 4.7% and 7.2% of patients who received bempedoic acid or placebo, respectively
Consistent with inhibition of cholesterol synthesis, bempedoic acid significantly lowers elevated levels of LDL-C in hypercholesterolemic patients by 30% as monotherapy, up to an additional 24% when added on to stable statin therapy and up to 50% when combined with ezetimibe, suggestive of a distinct mechanism for LDL lowering (2,3,4,5).
Bempedoic acid used in combination with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy (6):
- a study of 2 Months of bempedoic acid treatment added to a PCSK9i therapy in patients with hypercholesterolemia reduced LDL-c levels further compared to those with a PCSK9i and placebo. The addition of bempedoic acid was safe and well-tolerated
Bempedoic acid significantly lowered LDL-C across glycaemic strata and did not worsen glycaemic parameters nor increase incidence of new-onset diabetes vs placebo over a median follow-up of 1 year (7)
Bempedoic acid as an adjunct to maximally tolerated statins was generally well tolerated and showed sustained efficacy in lowering LDL-c levels with up to 2.5 years of continuous treatment in patients with ASCVD (atherosclerotic cardiovascular disease) and/or HeFH (heterozygous familial hypercholesterolaemia) (8).
NICE suggest (9):
- bempedoic acid with ezetimibe is recommended as an option for treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia as an adjunct to diet in adults. It is recommended only if:
- statins are contraindicated or not tolerated,
- ezetimibe alone does not control low-density lipoprotein cholesterol well enough, and
- the company provides bempedoic acid and bempedoic acid with ezetimibe according to the commercial arrangement
- bempedoic acid with ezetimibe can be used as separate tablets or a fixed-dose combination
A Drug and Therapeutics Bulletin review (10):
- concluded that although bempedoic acid has been shown to produce a modest reduction in LDL-C in short term, its long-term safety & effect on important CV outcomes are not known thus it is difficult to see a major role for it in the primary and secondary prevention of CVD
- Laufs U et al. Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia and Statin Intolerance.J Am Heart Assoc. 2019;8: e011662.
- Ballantyne CM et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J. Am. Coll. Cardiol. 2013; 62, 1154-1162
- Gutierrez, MJ et al. Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus. Arterioscler. Thromb. Vasc. Biol. 2014; 34, 676-683
- Ballantyne CM et al. ETC-1002 incrementally lowers low-density lipoprotein cholesterol in patients with hypercholesterolemia receiving stable statin therapy. Circulation 2015; 132, A17499.
- Thompson PD et al. Use of ETC-1002 to treat hypercholesterolemia in patients with statin intolerance. J. Clin. Lipidol. 2015;9, 295-304.
- Rubino J, MacDougall DE, Sterling LR, et al. Lipid lowering with bempedoic acid added to a proprotein convertase subtilisin/kexin type 9 inhibitor therapy: A randomized, controlled trial J Clin Lipidol. 2021, DOI: https://doi.org/10.1016/j.jacl.2021.05.002
- Leiter LA et al. Bempedoic acid in patients with type 2 diabetes mellitus, prediabetes, and normoglycaemia: a post hoc analysis of efficacy and glycaemic control using pooled data from phase 3 clinical trials.Diabetes, Obesity & Metabolism 2022 January 3
- Ballantyne CM, Banach M, Bays HE, et al. Long-Term Safety and Efficacy of Bempedoic Acid in Patients With Atherosclerotic Cardiovascular Disease and/or Heterozygous Familial Hypercholesterolemia (from the CLEAR Harmony Open-Label Extension Study) Am J Cardiol. 2022;S0002-9149(22)00322-8. doi: 10.1016/j.amjcard.2022.03.020
- NICE (April 2021). Bempedoic acid with ezetimibe for treating primary hypercholesterolaemia or mixed dyslipidaemia
- DTB (July 2022). Bempedoic acid: another cholesterol-lowering drug. http://dx.doi.org/10.1136/dtb.2022.000035