bempedoic acid

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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)

NICE suggest (8):

  • 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.

Reference:

Last edited 01/2022 and last reviewed 01/2022

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