In short Article

New drug: bempedoic acid (Nilemdo®)


Bempedoic acid (Nilemdo®) is a new cholesterol-lowering drug with a mode of action that should make muscle-related adverse effects less likely. It has been authorised as an adjunctive treatment alongside, for instance, a statin, for patients with excessive LDL-cholesterol concentration. It has also been authorised as an alternative for patients who cannot tolerate statins or for whom a statin is contra-indicated. Since bempedoic acid has only been compared with placebo in registration studies, and since all of these studies allowed statin treatment to be continued, it is difficult, if not impossible, to assess the value of bempedoic acid as part of the treatment for an excessive LDL-cholesterol concentration. This concerns both effectiveness and adverse effects. 

What is Ge-Bu’s opinion?
  • Registration studies have compared bempedoic acid with placebo using the surrogate outcome of LDL-cholesterol concentration.
  • The placebo-controlled Phase 3 studies show that bempedoic acid reduces LDL-cholesterol concentrations by 17 to 29% after 12 weeks, compared to placebo.
  • In a registration study using adverse effects as the primary outcome measure, significantly more patients in the bempedoic acid group that in the placebo group discontinued the treatment (10.9 vs. 7.1%).
  • Since a direct comparison is lacking, it cannot yet be concluded that fewer patients discontinue treatment due to adverse effects compared to statins.
  • There is as yet no evidence that bempedoic acid is a suitable alternative for patients with statin intolerance.

Bempedoic acid is a new cholesterol-lowering drug with a different mode of action than existing drugs (Figure 1). It was authorised in Europe in 2020 under the brand name Nilemdo®. It is registered as an adjunctive treatment in case existing therapy with statins, ezetimibe, etc. insufficiently lowers the LDL-cholesterol concentration. In addition, it has been approved for patients who are statin-intolerant or for whom a statin is contra-indicated.1 

The Dutch National Health Care Institute (ZIN) is expected to have assessed before the summer of 2022 whether this drug is to be included in the Dutch drug reimbursement system (Geneesmiddelenvergoedingssysteem, GVS), and on what conditions this will be done.2 A combination drug containing 10 mg ezetimibe has also been authorised in Europe (Nustendi®), but ZIN provides no information on this product.

Effectiveness as an adjunctive treatment

A comparison using hard endpoints, like the number of myocardial infarctions, is currently not possible, as it takes a while before one or more endpoints have been reached by a sufficient number of participants for robust conclusions to be drawn. A study into the effectiveness of bempedoic acid using hard endpoints, the so-called CLEAR-Outcomes Trial, is currently underway, but no results have so far been published.3 There have not yet been any randomised trials using LDL-cholesterol concentration as the outcome measure in which the cholesterol lowering drugs were compared with each other. The registration studies have only included randomised trials that compared the efficacy of bempedoic acid with placebo in terms of the lowering of LDL-cholesterol concentrations. In view of the differences between the study samples used in the various studies, and the fact that a background therapy with statins and other drugs was continued in all studies, the results of these placebo-controlled trials cannot be adequately interpreted. The registration studies, i.e. the ‘CLEAR trials’ series, do not provide robust evidence that bempedoic acid is non-inferior to the statins.

Alternative to statins?

The 2018 Dutch guideline on second- and third-line treatment of hereditary dyslipidaemia indicates an alternative treatment for patients with statin intolerance, who are unable to use a statin at the usual dosage due to unpleasant adverse effects. The guideline expresses an emphatic preference for continuation of the statin treatment, in view of the proven reduction of cardiovascular risk among patients with familial hypercholesterolaemia. The guideline also states that patients with a verified intolerance not caused by reversible circumstances (such as diet, hypothyroidism or vitamin D deficiency) can be prescribed a potent statin at low dosage or dosing frequency. Only if this fails could replacement of the statin by a different cholesterol-lowering drug be considered as an alternative.4

Judging whether bempedoic acid represents a suitable alternative to statins, or to any other alternative cholesterol-lowering drug treatments like PCSK9 inhibitors (whether or not in combination with ezetimibe), requires randomised studies directly comparing these drugs. There have so far been no such studies. Since little experience has been gained with bempedoic acid, this drug should only be considered as a last option to replace a statin.

The registration study using the incidence of adverse effects as an outcome measure found that significantly more of the participants in the bempedoic acid group discontinued their treatment than of the participants in the placebo group (10.9% vs. 7.1%). Whether this is a higher proportion than among the statin users cannot yet be ascertained, as bempedoic acid has not been compared with statins in randomised studies.


Bempedoic acid is a prodrug which is converted in the liver to the biologically active bempedoyl-CoA by the enzyme ‘very long-chain acyl-CoA synthetase 1’ (ACSVL1). Bempedoyl-CoA binds to adenosine triphosphate citrate lyase (ACL), thereby inhibiting the formation of the enzyme Acetyl-CoA and thus the formation of hydroxy-methylglutaryl co-enzyme A (HMG-CoA) (Figure 1). The net result is a reduction of intrahepatic cholesterol, inhibiting the downregulation of LDL receptors. The increased number of LDL receptors on the hepatocytes leads to increased clearance of LDL-cholesterol and to a reduction of LDL-cholesterol concentrations in circulation. The enzyme ACSVL1 is absent from muscle cells, so that bempedoic acid could be expected to cause no muscle-related adverse effects.

Statins intervene in a later part of the cycle. They inhibit the enzyme hydroxy-methylglutaryl-co-enzyme-A reductase, which also inhibits the formation of HMG-CoA, with the net effect, as with bempedoic acid, of an increase in the number of LDL receptors and a reduction of the circulating LDL-cholesterol concentrations. Unlike bempedoic acid, statins do affect muscle cells.5

Since bempedoic acid intervenes in an earlier part of the pathway, the theory would be that the more effective bempedoic acid is, the less added value is obtained by the simultaneous use of a statin. A synergistic action, in which the two drugs strengthen each other’s effect, is unlikely.

Figure 1. Mechanism of action of bempedoic acid

ACL: adenosine triphosphate citrate lyase, ACSVL1: ‘very long-chain acyl-CoA synthetase 1’, HMG-CoA: hydroxy-methylglutaryl co-enzyme A, HMGR: HMG-CoA reductase, LDLR: LDL-cholesterol receptor.


A retrospective cohort study based on population-based databases of the general population* found that in 2010, 18% of statin users in Denmark discontinued the treatment.6 A consensus document of the European Atherosclerosis Society mentions percentages ranging from 7 to 29%.7 In more than 90% of cases, the treatment is discontinued due to muscular symptoms, particularly myalgia, probably resulting from mitochondrial dysfunction caused by the statin.8 

A systematic review of observational studies including 3 million statin users aged 65 years and older found that after 1 year, 59.7% of the patients were still using the statin.9 The percentage users fell further after that in the group aged 75 years and older. After 3 years, only 55% of the patients were still using the statin. After more than 10 years this was only 28%.9


Three randomised placebo-controlled Phase 3 trials into the efficacy of bempedoic acid have been published, viz. the CLEAR Tranquility, Serenity and Wisdom trials.10,11,12 All three of these registration studies used the percentage reduction of LDL-cholesterol concentrations as the primary outcome measure. A fourth trial, the CLEAR Harmony registration study, investigated the percentage reduction of LDL-cholesterol concentrations as a secondary outcome measure.5 Patients included in the CLEAR trials continued their statin treatment if necessary (whether or not at low dosage). The cardiovascular risk profiles of the patients included varied. In all CLEAR trials, about 90% of the study sample consisted of white patients.5,10,11,12 Their results cannot simply be extrapolated to other sections of the population.

CLEAR Tranquility

The CLEAR Tranquility study included 269 adult patients with an LDL-cholesterol concentration of 2.6 mmol/l or more and a statin intolerance.10 Patients with serious cardiovascular diseases, such as therapy-resistant hypertension or Class IV heart failure, were excluded from participating. The participants were allowed to continue using a low-dose statin if necessary. In addition, the participants received 10 mg ezetimibe daily. A total of 181 participants received bempedoic acid at a dosage of 180 mg daily, while 88 received a placebo. The primary outcome measure was the change in LDL-cholesterol concentration after 12 weeks compared to baseline. Other cholesterol-lowering drugs were also used by 47.5% of the participants in the bempedoic acid group and 39.1% in the placebo group. After 12 weeks, the LDL-cholesterol concentration had fallen by 23.5% in the bempedoic acid group, while it had risen by 5% in the placebo group, a statistically significant difference (adjusted net effect -28.5% [95% confidence interval (CI) -34.4% to -22.5%]). In the bempedoic acid group, the average LDL-cholesterol concentration fell from 3.36 to 2.49 mmol/l, while in the placebo group it rose from 3.18 to 3.33 mmol/l.10

CLEAR Serenity

In the CLEAR Serenity study, 345 patients with hypercholesterolemia and an intolerance to at least two statins were randomised into two groups.11 Patients at elevated risk of cardiovascular events were not excluded from this study. 234 participants received bempedoic acid at a dosage of 180 mg daily, while 111 participants received a placebo. Just as in the CLEAR Tranquility study, participants were allowed to continue using low-dose statins. The primary outcome measure was the change in the LDL-cholesterol concentration after 12 weeks compared to baseline. Other cholesterol-lowering drugs were also used by 7.7% of the participants in the bempedoic acid group and 9.9% in the placebo group. After 12 weeks, the LDL-cholesterol concentration had fallen by 23.6% in the bempedoic acid group, while it had risen by 1.3% in the placebo group (adjusted net effect -21.4% [95% CI -25.1% to -17.7%]). In the bempedoic acid group, the average LDL-cholesterol concentration fell from 4.10 to 3.08 mmol/l, while in the placebo group it fell from 4.02 to 3.94 mmol/l.11

CLEAR Wisdom

In the CLEAR Wisdom trial, 779 adult patients with an LD-cholesterol concentration of 2.6 mmol/l or more and an elevated risk of cardiovascular events were randomised.[12][Goldberg 2019] 522 participants received bempedoic acid at a dosage of 180 mg daily, while 257 participants received a placebo. About 90% of the participants were being treated with a statin, 53% of whom were using a high dosage. The primary outcome measure was the change in the LDL-cholesterol concentration compared to baseline. After 12 weeks, the LDL-cholesterol concentration had fallen by 15.1% in the bempedoic acid group, while it had risen by 2.4% in the placebo group (adjusted net effect -17.4% [95% CI -21.0% to -13.9%]).  In the bempedoic acid group, the average LDL-cholesterol concentration fell from 3.09 to 2.52 mmol/l, while in the placebo group it rose from 3.17 to 3.18 mmol/l.12

CLEAR Harmony

The CLEAR Harmony trial used the change in LDL-cholesterol concentration as a secondary outcome measure (the primary outcome measure being the incidence of adverse effects). This randomised placebo-controlled Phase 3 trial included 2230 patients with hypercholesterolemia and an elevated cardiovascular risk, as well as an LDL-cholesterol concentration of over 1.8 mmol/l despite treatment. 1448 participants received 180 mg bempedoic acid daily, while 742 participants received a placebo. With very few exceptions, all participants were also using a statin, and about 7.5% were using ezetimibe as well. After 12 weeks, the LDL-cholesterol concentration had fallen by 16.5% in the bempedoic acid group, while it had risen by 1.6% in the placebo group (adjusted difference -18.1% (95% CI -20.0% to -16.1%). In the bempedoic acid group, the average LDL-cholesterol concentration fell from 2.68 to 2.16 mmol/l, while in the placebo group the (rounded) LDL-cholesterol concentration remained unchanged at 2.65 mmol/l.5

Overview of the results of the CLEAR studies 

Table 1. Overview of the (primary) outcomes for bempedoic acid compared to placebo in the four CLEAR studies, regarding the LDL-cholesterol concentration after 12 weeks

CLEAR study

Number of patients

Co-medication

% statin use

% patients at elevated cardiovascular risk

% reduction of LDL-cholesterol*

(95% CI)

Baseline LDL-C in bempedoic acid group (mmol/l)

LDL-C after 12 wks. in bempedoic acid group (mmol/l)

Tranquility

269

ezetimibe + low-dose statin in some patients**

30.5

 

0

28.5

 (22.5 – 34.4)

3.36

2.49

Serenity

345

Low-dose statin**

8.8

39.6***

21.4

(17.7 – 25.1)

4.10

3.08

Wisdom

779

statins at usual dosages

89.4

94.5***

17.4

(13.9 – 21.0)

3.09

2.52

Harmony

2.230

statins at usual dosages

99.9

97.7***

18.1

(16.1 – 20.0)

2.68****

2.16****

* percentage reduction of LDL-cholesterol concentration after 12 weeks compared to placebo; **low-dose statin: an average daily dose of 5 mg rosuvastatin, 10 mg atorvastatin, 10 mg simvastatin, 20 mg lovastatin, 40 mg pravastatin, 40 mg fluvastatin or 2 mg pitavastatin; *** secondary prevention after a cardiovascular event; **** not the primary outcome measure


Only the CLEAR Harmony trial used the incidence of adverse effects as an outcome measure. The other CLEAR studies only kept track of adverse effects as part of the standard checks in all participants. Since some participants in all studies also used statins, whether or not at low dosage, the adverse cannot be adequately interpreted.

CLEAR Harmony

The outcome measure in this trial was the incidence of adverse effects and the changes in specific laboratory values like the creatinine level.5 the trial ran for 52 weeks. Nearly all participants in this trial also used a statin, at a usual dosage (Table 1). The sample size had been chosen to ensure that an adverse effect that occurred in 0.5% or more of the patients in the bempedoic acid group could be detected. The authors fail to report the exact method used to record adverse effects. Adverse effects were about equally common in both study groups: 78.5% in de bempedoic acid group and 78.7% in the placebo group. Significantly more participants in the bempedoic acid group discontinued the treatment due to adverse effects: 10.9% in the bempedoic acid group vs 7.1% in the placebo group. Adverse effects that occurred significantly more often in the bempedoic acid group compared to the placebo group included gout (1.2% vs. 0.3%) and muscle disorders (13.1% vs. 10.1%). Individual muscle disorders, like aching muscles, or painful extremities, were not significantly more common in the bempedoic acid group. The average change in the creatinine concentration relative to baseline was significantly higher in the bempedoic acid group than in the placebo group (1.77 mmol/l vs. -1.77 mmol/l), as was the uric acid concentration (43.42 mmol/l vs. -3.57 mmol/l).5

It is clear, then, that muscle-related adverse effects also occur with bempedoic acid, and significantly more participants in the bempedoic acid group discontinued the treatment due to adverse effects. Since nearly all participants in this trial were also using a statin at a usual dosage, it is also unclear whether new muscle-related disorders in connection with bempedoic acid would have clearly emerged.

CLEAR Tranquility, Serenity and Wisdom

The CLEAR Tranquility, Serenity and Wisdom studies did not use the incidence of adverse effects as an outcome measure.10,11,12 The studies ran for 12, 24 and 52 weeks, respectively. Specific adverse effects that were seen in multiple studies included gout (1.7–2.1%), elevated uric acid concentrations (2.7–7.7%) and reduced glomerular filtration rates (0.8–2.2%).

Table 2. Overview of the incidence of adverse effects in the CLEAR studies5,10,11,12

CLEAR study

Study period

(weeks)

Total adverse effects

(%)

Adverse effects leading to discontinuation of treatment

(%)

Treatment-related adverse effects

(%)

 

 

Bempedoic acid

Placebo

Bempedoic acid

Placebo

Bempedoic acid

Placebo

Harmony* (n=2.230)

52

78.5

78.7

10.9**

7.1

unknown

unknown

Tranquility (n=269)

12

48.6

44.8

6.1

5.7

21.5

9.2

Serenity (n=345)

24

64.1

56.8

18.4

11.7

21.8

18

Wisdom (n=779)

52

70.1

70.8

10.9

8.6

17.4

12.5

                   

* the incidence of adverse effects was the primary outcome measure in this trial
**significant difference relative to placebo


CLEAR Outcomes

Currently, a trial is underway which should provide more information about the effectiveness of bempedoic acid in terms of a composite endpoint of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke or a coronary revascularisation procedure. This so-called CLEAR Outcomes trial is a randomised placebo-controlled study with a minimum duration of 36 months. At present, 14,041 patients have been included who are at elevated risk of a cardiovascular event, are statin-intolerant and have an LDL-cholesterol concentration exceeding 2.6 mmol/l. The trial is expected to be completed by the end of 2022. This trial does not compare with other cholesterol-lowering drugs either.3,13

Authorised indication and other characteristics
Bempedoic acid in a 180-mg tablet has been authorised in Europe since March 2020, under the brand name Nilemdo®. The authorised indication is as follows: “Nilemdo is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet:

  • in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or,
  • alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated.”1

The dosage for adults is 180 mg once daily.1

The authorisation holder Daiichi Sankyo B.V. has requested the Dutch National Health Care Institute (ZIN) to include the drug in the drug reimbursement system (Geneesmiddelenvergoedingssysteem, GVS), in list IB (unique medicine, no reimbursement limit). Reimbursement has been requested for the use of bempedoic acid by adults with primary hypercholesterolaemia or mixed dyslipidaemia and an elevated (or highly elevated) risk of cardiovascular diseases and:

  • insufficient effect of a diet and the maximum tolerated dose of a statin with ezetimibe;
  • a contraindication or intolerance to statins;
  • ineligibility for treatment with a PCSK9 inhibitor.

An advisory report by ZIN to the Ministry of Health, Welfare and Sport is expected to be published this summer.2 As far as is currently known, no application has been submitted to ZIN for the combination of bempedoic acid and ezetimibe (Nustendi®).

The cost of 30 days of treatment with Nilemdo® is 54 euros. By comparison, the cost of 30 days of simvastatin (generic) at a dosage of 20 mg daily ranges from 0.67 to 0.89 euros depending on the supplier.14

Details of the studies discussed

CLEAR Tranquility10
Study name: Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Tranquility
Design: randomised double-blind placebo-controlled Phase 3 study
Inclusion criteria: adults aged 18 years or over with a statin intolerance, whether or not using low-dose statin therapy; fasting LDL-cholesterol concentration ≥ 2.6 mmol/l (100 mg/dl). Low-dose statin therapy defined as an average daily dose of 5 mg rosuvastatin, 10 mg atorvastatin, 10 mg simvastatin, 20 mg lovastatin, 40 mg pravastatin, 40 mg fluvastatin or 2 mg pitavastatin
Main exclusion criteria: patients with clinically relevant cardiovascular diseases, such as insufficiently controlled hypertension, a planned revascularization procedure, Class IV heart failure and cardiovascular diseases like myocardial infarction, occurring within 3 months after screening. Additionally, a BMI > 50 kg/m2, fasting triglyceride concentration ≥ 5.6 mmol/l, HbA1c ≥ 10% (86 mmol/mol), use of a PCSK9 inhibitor in the 4 months preceding screening, and patients taking less than 80% of the run-in medication 
Intervention: bempedoic acid 180 mg/day vs. placebo, all patients receiving ezetimibe 10 mg daily
Primary endpoint(s) and duration: percentage reduction of the average LDL-cholesterol concentration from baseline after 12 weeks of treatment with bempedoic acid
Intended number of patients and power: the researchers calculated that a group size of 225 participants would be needed to be able to detect a 15% difference at a power of at least 95% (150 participants in the bempedoic acid group and 75 in the placebo group)
Randomisation: using an interactive web response systeem (2:1 bempedoic acid or placebo)
Blinding: double-blind for patients, researchers and pharmacists
Population analysed: intention-to-treat
Number of patients included and patient characteristics: 181 in the bempedoic acid group and 88 in the placebo group, 61.3% women, average age 63.8 years, 89.2% white race, 25% with an existing cardiovascular disorder
Trial registration: NCT03001076
Funding: by Esperion Therapeutics (manufacturer of bempedoic acid)
Conflict of interest: 7 of the de 7 authors
CLEAR Serenity11
Study name: Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Serenity
Design: randomised double-blind placebo-controlled Phase 3 study 
Inclusion criteria: adults with statin intolerance, whether or not using low-dose statin therapy, who needed supplementary lipid-lowering therapy for primary or secondary prevention of cardiovascular disorders. Fasting LDL-cholesterol concentration ≥ 2.6 mmol/l (100 mg/dl) for patients with heterozygous familial hypercholesterolaemia, or for secondary prevention, while for primary prevention it had to be ≥ 3.4mmol/l (130 mg/dl) at screening.
Low-dose statin therapy was defined as an average daily dose of 5 mg rosuvastatin, 10 mg atorvastatin, 10 mg simvastatin, 20 mg lovastatin, 40 mg pravastatin, 40 mg fluvastatin or 2 mg pitavastatin
Main exclusion criteria: total glycerides concentration ≥ 5.6 mmol/l (500 mg/dl) or BMI ≥ 50 kg/m2, or cardiovascular events or a clinically relevant disease in the 3 months before screening
Intervention: bempedoic acid 180 mg/day vs. placebo
Primary endpoint(s) and duration: percentage reduction of the average LDL-cholesterol concentration from baseline after 12 weeks of treatment with bempedoic acid
Intended number of patients and power: The researchers calculated that a group size of 300 participants would be needed to be able to detect a 15% difference at a power of at least 95% (200 participants in the bempedoic acid group and 100 in the placebo group)
Randomisation: method not reported (2:1 bempedoic acid or placebo)
Blinding: double-blind (patients and study staff)
Population analysed: intention-to-treat
Number of patients included and patient characteristics: 234 patients received bempedoic acid, 111 received placebo; 56.2% women, average age 65.2 years, 89.0% white race, 2% of the patients had heterozygous familial hypercholesterolaemia.
Trial registration: NCT02988115
Funding: by Esperion Therapeutics (manufacturer of bempedoic acid)
Conflicts of interest: 8 of the 8 authors
CLEAR Wisdom12
Study name: Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen CLEAR Wisdom
Design: randomised double-blind placebo-controlled Phase 3 clinical trial
Inclusion criteria: adults at elevated cardiovascular risk due to existing coronary heart diseases or other severe risk factors or heterozygous familial hypercholesterolaemia. Stable cholesterol-lowering therapy (background therapy) at maximum tolerable dosage. Fasting LDL-cholesterol concentration ≥ 2.6 mmol/l (100 mg/dl) at screening and ≥ 1.8 mmol (70 mg/dl) 1 week before randomisation
Main exclusion criteria: cholesterol-lowering therapy with simvastatin ≥ 40 mg/day, total glycerides concentration ≥ 5.6 mmol/l (500 mg/dl) or BMI ≥ 50 kg/m2, or cardiovascular events or a clinically relevant disease in the 3 months before screening
Intervention: 180 mg/day bempedoic acid vs. placebo
Primary endpoint(s) and duration: percentage reduction of the average LDL-cholesterol concentration from baseline after 12 weeks of treatment with bempedoic acid
Intended number of patients and power: The researchers calculated that a group size of 750 participants would be needed to be able to detect a 15% difference at a power of at least 95% (500 participants in the bempedoic acid group and 250 in the placebo group)
Randomisation: using an interactive web response system (2:1 bempedoic acid or placebo)
Blinding: double-blind
Population analysed: intention-to-treat
Number of patients included and patient characteristics: 779 patients were randomised to bempedoic acid (955 patients) or placebo (257 patients); 63.7% were men, average age 64.3 years, 95.4% white race; 94.5% of patients had a cardiovascular risk factor, but no heterozygous familial hypercholesterolaemia, with a stable,  maximum tolerated dosage of statins, whether or not supplemented with other cholesterol-lowering drugs for at least 4 weeks before screening
Trial registration: NCT02991118
Funding: by Esperion Therapeutics (manufacturer of bempedoic acid)
Conflicts of interest: 5 of the 10 authors
CLEAR Harmony5
Study name: Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Harmony
Design: randomised double-blind placebo-controlled Phase 3 trial
Inclusion criteria: adults with atherosclerotic cardiovascular disorders and/or heterozygous familial hypercholesterolaemia with a fasting LDL-cholesterol concentration ≥ 1.8 mmol (70 mg/dl) during the 2-week screening period
Main exclusion criteria: use of gemfibrozil or simvastatin > 40 mg or a PCSK9 inhibitor during the 4 weeks before the start of the study; if insufficient effect in terms of cholesterol lowering, restarting the use of these drugs was permitted after study week 24
Intervention: bempedoic acid 180 mg/day vs. placebo
Primary endpoint(s) and duration: safety of the treatment in terms of the incidence of adverse effects and changes in safety-related laboratory values 
Intended number of patients and power: The researchers calculated that a group size of 1950 participants would be needed to be able to detect a relative risk of 2.0 or more at an adverse effects frequency of 1.6 to 13.6%, and the lower limit of the confidence interval had to exceed 1 (1300 participants in the bempedoic acid group and 650 in the placebo group). At this group size, it should be possible to find rare adverse effects with a frequency of 0.5% or more
Randomisation: method not reported, stratification on intensity of the statin therapy (2:1 bempedoic acid or placebo)
Blinding: double-blind, patients and study staff
Population analysed: all patients who had received at least 1 dose of bempedoic acid or placebo 
Number of patients included and patient characteristics: 2230 patients, 1488 in the bempedoic acid groups, 742 in the placebo group, average age 66.1 years, 73% men, 95.9% white, 3.5% had heterozygous familial hypercholesterolaemia, 97.6% atherosclerotic disorders
Trial registration: NCT02666664
Funding: by Esperion Therapeutics (manufacturer of bempedoic acid)
Conflicts of interest: 8 of the 8 authors

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  13. ClinicalTrials.gov. Protocol: Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid (ETC-1002) or Placebo (CLEAR Outcomes). NCT02993406. Via: https://clinicaltrials.gov/ct2/show/NCT02993406?term=CLEAR+outcomes&draw=2&rank=1. Accessed 15-03-2022.
  14. G-Standaard mei 2022. Available at: https://www.z-index.nl. Accessed 24 May 2022.

Authors

  • Marielle A.E. Nieuwhof, pharmacist
  • Frans M. Helmerhorst, prof. dr