New lipid-lowering treatment available to prescribe

Currently being evaluated by NICE, bempedoic acid is available alone as Nilemdo and as a fixed-dose combination (Nustendi) with the cholesterol absorption inhibitor ezetimibe. It inhibits ATP citrate lyase, an enzyme involved in cholesterol synthesis, and in contrast to statins its action is liver-specific.

Nilemdo and Nustendi are indicated as an adjunct to diet in adults with primary hypercholesterolaemia or mixed dyslipidaemia.

Nilemdo can be prescribed with a statin, with or without other lipid-lowering therapies, in patients unable to reach LDL-C goals on the maximum tolerated dose of a statin; or without a statin in patients who are statin-intolerant or for whom a statin is contraindicated.

Nustendi can be prescribed with a statin in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin in addition to ezetimibe; alone in patients who are statin-intolerant or for whom a statin is contraindicated and who are unable to reach LDL-C goals with ezetimibe alone; or in patients already taking bempedoic acid and ezetimibe as separate tablets.

CLEAR studies

The efficacy of bempedoic acid was demonstrated in four randomised, double-blind, placebo-controlled trials involving 3623 adults with hypercholesterolaemia or mixed dyslipidaemia. The mean age of participants was 64–66 years and more than 50% of participants in each study were >65 years old. The proportion of women in the studies ranged from 27% to 61% and 4–11% of participants were non-white.

In two trials (CLEAR Wisdom and CLEAR Harmony), patients were taking the maximum tolerated dose of statin, with or without other lipid-modifying therapies; the other two trials (CLEAR Serenity and CLEAR Tranquility) enrolled patients who were intolerant of statins. The primary efficacy endpoint in all four trials was the mean percentage point reduction from baseline in LDL-C at week 12 compared with placebo.

With statins

CLEAR Wisdom included 779 patients randomised 2:1 to receive either bempedoic acid (n=522) or placebo (n=257) (mean baseline LDL-C 120.4mg/dL [3.1mmol/L]). At the time of randomisation, 91% of patients were receiving statin therapy and 53% were receiving high-intensity statin therapy.

CLEAR Harmony enrolled 2230 patients randomised 2:1 to receive either bempedoic acid (n=1488) or placebo (n=742) (mean baseline LDL-C 103.2mg/dL [2.7mmol/L]). At the time of randomisation all participants were receiving statins and 50% were receiving high-intensity statin therapy.

Bempedoic acid significantly reduced LDL-C from baseline to week 12 compared with placebo in both trials (-17.4% in CLEAR Wisdom and -18.1% in CLEAR Harmony; p < 0.001 for both). In CLEAR Harmony, a significantly higher proportion of patients achieved an LDL-C of <70 mg/dL (< 1.81mmol/L) in the bempedoic acid group compared with the placebo group at week 12 (32% vs 9%, p < 0.001).

With other lipid-lowering agents

CLEAR Tranquility evaluated the efficacy of bempedoic acid when added to ezetimibe in patients who were unable to tolerate more than the lowest approved starting dose of a statin. The trial included 269 patients randomised 2:1 to receive either bempedoic acid (n=181) or placebo (n=88) as add-on to ezetimibe 10mg daily for 12 weeks (mean baseline LDL-C 127.6mg/dL [3.3mmol/L]). At the time of randomisation, 33% of patients on bempedoic acid versus 28% on placebo were receiving statin therapy at less than or equal to lowest approved doses. 

CLEAR Serenity evaluated the efficacy of bempedoic acid in patients with elevated LDL-C who were statin-intolerant or unable to tolerate two or more statins, one at the lowest dose. Patients able to tolerate a dose that was less than the approved starting dose of a statin were allowed to stay on that dose during the study. The trial included 345 patients randomised 2:1 to receive either bempedoic acid (n=234) or placebo (n=111) for 24 weeks (mean baseline LDL-C 157.6mg/dL [4.1mmol/L]). At the time of randomisation, 8% of patients on bempedoic acid versus 10% on placebo were receiving statin therapy at less than the lowest approved doses and 36% of patients on bempedoic acid versus 30% of patients on placebo were on other lipid-modifying therapies. 

In both trials bempedoic acid significantly reduced LDL-C from baseline to week 12 compared with placebo (-28.5% in CLEAR Tranquility and -21.4% in CLEAR Serenity; p < 0.001 for both), including in the subset of 200 patients in CLEAR Serenity who were receiving no background lipid-modifying therapies.

Bempedoic acid also significantly reduced non-HDL-C, apo B, and total cholesterol in all four CLEAR trials. 

Fixed-dose combination

The fixed-dose combination of bempedoic acid/ezetimibe was evaluated in a randomised, double-blind study involving 301 patients receiving maximally tolerated statin therapy (mean baseline LDL-C 149.8mg/dL [3.87mmol/L]).

At week 12, the fixed-dose combination lowered LDL-C (-36.2%) significantly more than placebo (1.8%), ezetimibe alone
(-23.2%) or bempedoic acid alone (-17.2%) (p < 0.001 for all).

Myopathy

The most commonly reported adverse reactions with bempedoic acid during pivotal trials were hyperuricaemia (3.8%), pain in extremity (3.1%), and anaemia (2.5%). 

Bempedoic acid increases plasma concentrations of statins. Patients receiving the drug as adjunctive therapy to a statin should be monitored for adverse reactions that are associated with the use of high doses of statins, such as myopathy. 

When bempedoic acid is coadministered with simvastatin, the simvastatin dose should generally be limited to 20mg daily.