Bempedoic acid

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
  events (1):
  
  • 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
    symptom
  • 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

The CLEAR Outcomes study (10):

• a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects ("statin-intolerant" patients) and had, or were at high risk for, cardiovascular disease
  • patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo
  • primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization
• showed that among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization)
  • at 6 months, bempedoic acid reduced LDL-c by 21.7% and hsCRP by 22.2%. In comparison, a 0.6% reduction in LDL-c and an increase of 2.2% in hsCRP was observed in the placebogroup at 6 months.
  • bempedoic acid reduced the primary endpoint of 4-component MACE by 13% (HR 0.87, 95%CI 0.79-0.96, P=0.004, ARR 1.6%, NNT 63)

A review with respect to bempedoic acid and the CLEAR study stated (11):

• bempedoic acid is licensed for primary hypercholesterolaemia or mixed dyslipidaemia alone or alongside statins and other lipid-lowering therapies.
• it has been shown to moderately lower low-density lipoprotein cholesterol in clinical trials but evidence of its effect on cardiovascular outcomes has been lacking.
• a study found that in statin-intolerant patients, it reduced the risk of a composite outcome of four major adverse cardiovascular events.

Reference:

• 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
• Nissen SE et al; CLEAR Outcomes Investigators. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med. 2023 Mar 4. doi: 10.1056/NEJMoa2215024
• Drug and Therapeutics Bulletin (October 13th 2023). Bempedoic acid and cardiovascular outcomes.