941083

review-article2020
AOPXXX10.1177/1060028020941083Annals of PharmacotherapyNguyen et al

Review Article - New Drug Approval

Annals of Pharmacotherapy

A Review of Bempedoic Acid: A New Drug

1­–6
© The Author(s) 2020
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DOI: 10.1177/1060028020941083
https://doi.org/10.1177/1060028020941083
journals.sagepub.com/home/aop

Dat Nguyen, PharmD1, Nathan Du, PharmD1,

Elisabeth M. Sulaica, PharmD1, and Matthew A. Wanat, PharmD1

Abstract
Objective: To review the pharmacology, pharmacokinetics, safety, and efficacy of bempedoic acid for low-density
lipoprotein cholesterol (LDL-C) reduction. Data Sources: A PubMed search was conducted from January 2000 to June
15, 2020, using the keyword bempedoic acid for phase III clinical trials published in the English language. Study Selection
and Data Extraction: Articles related to the Food and Drug Administration (FDA) approval of bempedoic acid and
other trials relating to the safety and efficacy of this drug were included. Data Synthesis: The findings from this review
show that bempedoic acid is a safe and effective option for lowering LDL-C levels in patients requiring LDL-C lowering
for primary or secondary prevention of cardiovascular events. Relevance to Patient Care and Clinical Practice:
Statin therapy remains the mainstay of treatment for both primary and secondary prevention. However, many patients
cannot tolerate statin therapy because of statin-associated muscle symptoms. Bempedoic acid may be a reasonable adjunct
for LDL-C reduction, though further evaluation of cardiovascular outcomes with bempedoic acid in this population is
needed. Conclusions: The recent FDA approval of bempedoic acid offers an additional option for lowering LDL-C levels
in patients with atherosclerotic cardiovascular disease or heterozygous familial hyperlipidemia. Additional data regarding
effect on long-term cardiovascular outcomes with bempedoic acid are currently being studied.

Keywords
cholesterol, cardiology, cardiovascular drugs, lipids, hyperlipidemia

Introduction Bempedoic acid (Nexletol), a novel LLT agent, was

The efficacy of statins, or 3-hydroxy-3-methyl-glutaryl-
CoA (HMG-CoA) reductase inhibitors, have been well
established for reductions in both low-density lipoprotein
cholesterol (LDL-C) and cardiovascular events in patients
with risk factors.1,2 Statins are used for a multitude of dis-
ease states, including dyslipidemia and acute coronary syn-
dromes. In a meta-analysis of statin trials, a 38.7 mg/dL
LDL-C reduction resulted in a 21% reduction of athero­
sclerotic cardiovascular disease (ASCVD).3
Not all patients are able to tolerate statin therapy.
Approximately 72% of statin-related adverse effects are
muscle related.4 Despite cardiovascular benefit with statin
use, 15.4% of patients have been found to discontinue
statin therapy within 30 days and 40% to 75% within 2
years.5,6 Clinical trials have demonstrated varying levels of
statin intolerance, ranging from 1% to 2% up to 30%.7,8
Recommendations for managing statin intolerance include
prescribing an alternate statin, rechallenging with a lower
dose, or utilizing nonstatin therapy.1 Additional lipid-low-
ering therapy (LLT) options are needed for high-risk
patients who qualify for statins but are unable to take them
because of actual or perceived intolerance.
approved in February 2020 as an adjunctive once-daily reg-
imen to diet and maximally tolerated statin therapy in adult
patients requiring additional LDL-C lowering for treatment
of established ASCVD and heterozygous familial hyper-
cholesterolemia (HeFH).9 The purpose of this article is to
review the pharmacology, pharmacokinetics, safety, and
efficacy of bempedoic acid.
Data Selection
We performed a literature search from January 2000 to
June 15, 2020, using the keyword bempedoic acid in the
PubMed database and the National Institutes of Health
Clinical Trials Registry (http://www.clinicaltrials.gov).
Phase III trials, in English, evaluating bempedoic acid
1
University of Houston College of Pharmacy, Houston, TX, USA
Corresponding Author:
Matthew A. Wanat, Department of Pharmacy Practice and Translational
Research, University of Houston College of Pharmacy, 4849 Calhoun
Road—Health 2, Room 3044, Houston, TX 77204-5039, USA.
Email: mawanat@uh.edu
2 Annals of Pharmacotherapy 00(0)
efficacy (LDL-C reduction, cardiovascular outcomes)
and safety were included.
Pharmacology
Mechanism of Action
Bempedoic acid is a prodrug activated by very-long-chain
acyl-CoA synthetase 1 (ACSVL1) to ETC-1002-CoA.9
This active metabolite inhibits adenosine triphosphate-
citrate lyase (ACL), an enzyme upstream of HMG-CoA
reductase. Inhibition of ACL decreases cholesterol biosyn-
thesis and causes an upregulation in lipoprotein receptors to
increase LDL-C clearance. Of note, ACSVL1 is mostly
present in the liver as compared with HMG-CoA reductase,
which is also present in the skeletal muscle.9
Pharmacokinetics
Bempedoic acid is administered orally as a 180-mg tablet
and reaches steady-state concentration after 7 days.9
Bempedoic acid reaches maximum concentration at a
median time of 3.5 hours and has a mean half-life of 21
hours. It is reversibly metabolized to ESP15228, another
active metabolite. Both bempedoic acid and ESP15228 are
converted by UGT2B7 to glucuronide conjugates that are
inactive. Mean bempedoic acid area under the curve is
elevated in patients with renal impairment when compared
with those with normal renal function.9 Urinary excretion
was 70% after a 240-mg dose. Additionally, patients with
an estimated glomerular filtration rate (eGFR) <30 mL/
min/1.73 m2 and end-stage renal disease on dialysis were
excluded from clinical studies. Concurrent use of bempe-
doic acid with greater than 20 mg of simvastatin or 40 mg
of pravastatin increases the risk of myopathies and should
be avoided.
Clinical Trials
The safety and efficacy of bempedoic acid for the treatment
of hyperlipidemia was evaluated in 4 randomized, double-
blind, placebo-controlled, phase III trials prior to Food and
Drug Administration (FDA) approval in February 2020
(Table 1). The Cholesterol Lowering via Bempedoic Acid
and ACL-inhibiting Regimen (CLEAR) Outcomes trial
evaluating cardiovascular outcomes is estimated to be com-
pleted in March 2022.
CLEAR Tranquility
CLEAR Tranquility was a phase III randomized controlled
trial (RCT) evaluating the addition of bempedoic acid to
ezetimibe therapy in patients unable to tolerate at least 1
statin.10 Patients underwent a 1-week screening period
followed by a 4-week run-in period in which everyone
received ezetimibe 10 mg daily. If patients were adherent
and tolerated study medication during screening, they were
randomized to oral bempedoic acid 180 mg daily or placebo
in a 2:1 ratio for 12 weeks.
Patients with a fasting LDL-C ≥100 mg/dL and receiv-
ing no greater than low-dose statin therapy were included.10
Patients excluded were those with uncontrolled hyperten-
sion, New York Heart Association class IV heart failure, or a
planned revascularization procedure. The primary end point
was the LDL-C percentage change from baseline to 12
weeks. Of the 269 patients included, 181 and 88 were ran-
domized to the bempedoic acid and placebo groups, respec-
tively. At baseline, the mean age of patients was 64 years;
61% were female, and 25% had previous atherosclerotic
disease. Baseline LDL-C levels were 123.0 and 129.8 mg/
dL in the placebo and bempedoic acid arms, respectively,
and 28.4% in the placebo group and 32.6% in the treatment
group were on background low-dose statin therapy.
The bempedoic acid arm was found to have a decrease in
LDL-C (−23.5%) compared with placebo (+5%) at week
12.10 Overall, the bempedoic acid arm had an LDL-C reduc-
tion of 28.5% (95% CI = −34.4% to −22.5%; P < 0.001)
more than the placebo arm. Adverse events (AEs) occurred
in 48.6% of patients on bempedoic acid compared with
44.8% on placebo.10 Muscle-related AEs were similar
(3.3% vs 3.4%).
CLEAR Serenity
CLEAR Serenity was a phase III RCT that evaluated the
efficacy and safety of bempedoic acid in patients who were
statin intolerant but still required LLT for primary or sec-
ondary prevention.11 Patients were randomized in a 2:1 ratio
to bempedoic acid 180 mg daily or placebo for 24 weeks
after first completing a 5-week screening phase. The pri-
mary outcome was the percentage change of LDL-C from
baseline to week 12. Patients were required to have an
LDL-C of ≥100 mg/dL for a secondary prevention indica-
tion or HeFH and an LDL-C of ≥130 mg/dL for a primary
prevention indication.11 Participants were also required to
have a history of statin intolerance, defined as being unable
to tolerate ≥2 statins. Key exclusion criteria included
patients with a recent cardiovascular or cerebrovascular
event or procedure, a planned major procedure, and fasting
triglycerides ≥500 mg/dL.11
A total of 345 patients were randomized to bempedoic
acid (n = 234) or placebo (n = 111). At baseline, the mean
age was 65 years, and patients had a mean LDL of 158 mg/
dL.11 The majority of patients were not receiving LLT
(58%), with 33% on nonstatin therapy and 8.4% on low-
intensity statin therapy. Of patients included, 61% required
LLT for primary prevention, 39% for secondary prevention,
and 2% for HeFH.11
 Table 1.  Overview of Trials.

Baseline LDL-C, mg/

Trial Trial design Patient population Intervention dL, mean (±SD) Results
CLEAR Phase III, 269 Adult patients with a history After a 1-week screening Placebo: 123.0 (27.2) • Percentage LDL-C lowering, 12 weeks:
Tranquility9 multicenter of statin intolerance (on no period and 4-week run-in BPA: 129.8 (30.9) −23.5% BPA vs +5% placebo
(2018) (US, Canada, statin or low-intensity statin), period on ezetimibe 10 (P < 0.001; −28.5% placebo-corrected change,
and Europe), with baseline LDL-C ≥100 mg/ mg daily, patients were P < 0.001)
randomized, dL randomized 2:1 to BPA • Serious AEs: 2.8% BPA vs 3.4% placebo
double blind 180 mg daily or placebo • Discontinuation caused by AEs:
for 12 weeks 6.1% BPA vs 5.7% placebo
CLEAR Phase III, 345 Adult patients with After a 5-week screening Placebo: 155.6 (38.8) • Percentage LDL-C lowering, 12 weeks:
Serenity10 multicenter hyperlipidemia and a history phase, patients BPA: 158.5 (40.4) −23.6% BPA vs −1.3% placebo
(2019) (US and of intolerance to at least 2 randomized 2:1 to BPA (−21.4% placebo corrected change, P < 0.001)
Canada), statins, who required additional 180 mg daily or placebo • Serious AEs: 6% BPA vs 3.6% placebo
randomized, lipid lowering for primary or for 24 weeks • Discontinuation caused by AEs: 18.4% BPA vs
double blind secondary prevention 11.7% placebo
CLEAR Phase III, 2230 Adult patients with ASCVD Patients randomized 2:1 Placebo: 102.3 (30) • Any ADR: 78.5% BPA vs 78.7% placebo
Harmony11 multicenter and/or heterozygous familial to BPA 180 mg daily or BPA: 103.6 (29.1) (P = 0.91)
(2019) (US, Canada, hypercholesterolemia, on placebo for 52 weeks • Serious ADR: 14.5% BPA vs 14.0% placebo
and Europe), maximally tolerated statin (P = 0.80)
randomized, therapy for at least 4 weeks, • Major CV event: 4.6% BPA vs 5.7% placebo
double blind with an LDL-C of ≥70 mg/dL (P = 0.30)
• LDL-C lowering at 52 weeks: −12.6% BPA vs
1% placebo (P < 0.001)
CLEAR Phase III, 779 Adult patients with ASCVD After 1 week of screening Placebo: 122.4 (38.3) • Percentage LDL-C lowering, 12 weeks:
Wisdom12 multicenter and/or heterozygous familial and 4-week placebo run- BPA: 119.4 (37.7) −15.1% BPA vs 2.4% placebo (P < 0.001;
(2019) (North hypercholesterolemia, on in, patients randomized −17.4% placebo corrected change, P < 0.001)
America and maximally tolerated statin with 2:1 to BPA 180 mg daily • Serious AEs: 20.3% BPA vs 18.7% placebo
Europe), LDL-C ≥100 mg/dL at first visit or placebo for 52 weeks • Discontinuation caused by AEs: 10.9% BPA vs
randomized, and LDL-C ≥70 mg/dL a week 8.6% placebo
double blind before randomization

Abbreviations: ADR, adverse drug reaction; AE, adverse event; ASCVD, atherosclerotic cardiovascular disease; BPA, bempedoic acid; CV, cardiovascular disease; LDL-C, low-density lipoprotein
cholesterol.

3
4 Annals of Pharmacotherapy 00(0)
Bempedoic acid significantly reduced LDL-C from
baseline to week 12 compared with placebo (difference
= −21.4%; 95% CI = −25.1% to −17.7%; P < 0.001)
and at week 24 (difference = −18.9%; 95% CI = −23.0%
to −14.9%; P < 0.001).11 A post hoc analysis of data
showed greater LDL-C lowering in patients on no back-
ground or nonstatin background therapy compared with
patients on background statins. AEs occurred in 64.1%
in the bempedoic acid group and 56.8% in the placebo
group. Muscle-related AEs occurred in 12.8% and 16.2%
of those in the bempedoic acid and placebo arms,
respectively.
CLEAR Harmony
CLEAR Harmony was a phase III RCT assessing the
safety and efficacy of bempedoic acid treatment in addi-
tion to maximally tolerated statins.12 Patients were ran-
domized in a 2:1 ratio to bempedoic acid 180 mg daily or
placebo, and the primary end point assessed was safety,
defined as the incidence of AEs and changes in safety
laboratory variables over a 1-year period. Patients were
included if they had ASCVD, HeFH, or both. Participants
had to have been taking maximally tolerated statins at
stable doses for at least 4 weeks prior to screening and
have a fasting LDL-C of ≥70 mg/dL. Key exclusion cri-
teria included use of gemfibrozil or simvastatin at doses
greater than 40 mg/d and the use of PCSK9 inhibitors
within 4 weeks of trial entry.12
A total of 2230 patients were randomized to bempedoic
acid (n = 1488) or placebo (n = 742).12 At baseline, the
mean age was 66.3 years; 73% were male and 95.9%, white;
97.6% had ASCVD; and 3.5% had HeFH. The mean base-
line LDL-C levels were 103.6 and 102.3 mg/dL in the bem-
pedoic acid and placebo groups, respectively. Approximately
50% of patients were on a high-intensity statin and 44% on
a moderate-intensity statin at baseline.12
AEs were reported in 78.5% of those in the bempedoic
acid arm and 78.7% of those in the placebo arm (P =
0.91).12 The majority of events were mild to moderate
(bempedoic acid: 84.1%; placebo: 88%), with a smaller
percentage reported to have serious AEs (bempedoic acid:
14.5%; placebo: 14%). No statistically significant differ-
ences were found between the groups with regard to
myalgia (bempedoic acid 6% vs placebo 6.1%; P = 0.92),
muscle spasms (bempedoic acid 4.2% vs placebo 2.7%;
P = 0.09), or muscular weakness (bempedoic acid 0.6%
vs placebo 0.5%; P = 1.00). An increase in gout was seen
in patients on bempedoic acid (1.2% vs 0.3%, P = 0.03).
Bempedoic acid reduced the mean LDL-C by 19.2 mg/dL
(−16.5% from baseline) at week 12. The difference in
change of mean LDL-C level from baseline compared
with placebo was −18.1% (95% CI = −20.0% to −16.1%;
P < 0.001).12
CLEAR Wisdom
CLEAR Wisdom was a phase III RCT evaluating the effi-
cacy of bempedoic acid on LDL-C lowering compared with
placebo in patients with high cardiovascular risk, in addi-
tion to maximally tolerated LLT.13 Patients were random-
ized in a 2:1 ratio to bempedoic acid 180 mg daily or
placebo for 52 weeks after a 1-week screening period and
4-week run-in period. The primary efficacy outcome was
the LDL-C percentage change from baseline to week 12.13
Patients were enrolled if they had ASCVD, HeFH, or
both.13 Participants were required to have a fasting LDL-C
≥100 mg/dL at first screening and a fasting LDL-C ≥70
mg/dL a week before randomization. Patients were
required to be on stable, maximally tolerated LLT.
Exclusion criteria were the following: fasting triglycer-
ides ≥500 mg/dL, body mass index ≥50 kg/m2, severe
renal impairment (eGFR <30 mL/min/1.73 m2), or a
recent coronary heart disease event.13
A total of 779 patients were randomized to bempedoic
acid (n = 522) or placebo (n = 257).13 A total of 94.5% of
patients had ASCVD only, and 5.5% of patients had HeFH
with or without ASCVD. Of those included, 78.6% of
patients were on a maximally tolerated statin without other
nonstatin therapy, and 11% were on a statin with other non-
statin therapy. The baseline LDL-C levels for those in the
bempedoic acid and placebo groups were 119.4 and 122.4
mg/dL, respectively.
At week 12, bempedoic acid reduced LDL-C levels sig-
nificantly more than placebo (15.1% vs +2.4%, P <
0.001).13 The mean LDL-C levels at week 12 for bempedoic
acid and placebo were 97.6 and 122.8 mg/dL. More patients
in the bempedoic group (10.9%) discontinued the study
treatment as a result of AEs compared with patients in the
placebo group (8.6%). Myalgia occurred in 2.9% of those
on bempedoic acid and in 3.1% of those on placebo.13
Adverse Events/Precautions
In the clinical trials, most AEs attributed to the use of
bempedoic acid were considered mild to moderate in
severity. Notable AEs in those on bempedoic acid included
nasopharyngitis (2.2%-9.8%), urinary tract infection
(2.8%-4.8%), arthralgia (3.4%-6%), gout (1.2%-2.1%),
and a decrease in GFR (0.8%-2.2%).10-13 Increases in
blood uric acid were noted in CLEAR Wisdom and
CLEAR Tranquility (2.7%-7.7%).10,13 Bempedoic acid
can cause elevated liver enzymes (2.1%), which should
be monitored. Discontinuation rates resulting from AEs
in the bempedoic acid group were consistent between tri-
als (6.1%-10.9%), with CLEAR Serenity as an outlier
with a discontinuation rate of 18.4%.
The FDA package insert highlights risk of hyperuricemia
and tendon rupture with bempedoic acid use.9 Bempedoic
Nguyen et al 5
acid inhibits the renal organic anion transporter 2 inhibitor,
which may contribute to increased uric acid levels. Other
contributors such as diet and concomitant medications were
not reported. Patients should be counseled about the signs
and symptoms of hyperuricemia and monitored. Another
rare, but serious, adverse reaction of bempedoic acid is ten-
don rupture or injury (0.5%). Those at greater risk may
include patients with kidney dysfunction, >60 years old, or
on certain concomitant medications (ie, fluroquinolones).
Bempedoic acid should be discontinued immediately if
tendon rupture or injury occurs or discontinuation consid-
ered if the patient develops signs of joint pain, swelling, or
inflammation.9
Dosing and Administration
Bempedoic acid is administered orally at a dose of 180 mg
daily. It can be taken with or without food.9
Cost
The estimated cost of bempedoic acid at the time of writing
this article is approximately 10 dollars per pill. This would
result in an annual expected cost of approximately $3500.
More information is needed regarding bempedoic acid cost,
insurance coverage, and patient assistance programs.
Relevance to Patient Care and Clinical
Practice
Statins remain first-line therapy for both primary and second-
ary prevention of cardiovascular events.1 However, some
patients on maximally tolerated statins may need additional
LLT to reach target LDL-C levels. Bempedoic acid acts
within the same pathway as statins but may be better toler-
ated because ACSVL1 is present only in the liver and not in
skeletal muscle. In 2 of the 4 trials reviewed, the incidence of
muscle-related AEs with bempedoic acid were similar to
rates with placebo.2,12,13 Although myalgia rates were noted
to be similar, patients on bempedoic acid still reported myal-
gias. This may be attributed to statin-intolerant patients being
on low-dose statins. Thus, bempedoic acid may have a role as
an alternative adjunct therapy for patients who may need
additional LLT on a maximally tolerated statin.
Compared with other cholesterol-lowering therapies, on
average, bempedoic acid decreased LDL similarly com-
pared with ezetimibe (13%-24% vs 13%-20%, respectively)
but significantly less than a high-intensity statin or PCSK9
inhibitor.14,15 The ongoing CLEAR Outcomes trial will
evaluate the effect of bempedoic acid on cardiovascular
outcomes in both primary prevention and secondary pre-
vention populations over a time period of more than 4 years.
These clinical outcomes data are needed to truly determine
bempedoic acid’s place in therapy.
In addition to a lack of clinical outcomes with bempe-
doic acid, another barrier to use is its projected high cost
of therapy. Newer agents such as the PCSK9 inhibitors
are also expensive but have shown a reduction in cardio-
vascular events in high-risk patients.14,15 Another non-
statin medication, ezetimibe, has modest LDL-lowering
effects (13%-20%) but has been shown to reduce cardio-
vascular events in combination with statins. A combina-
tion tablet with bempedoic acid 180 mg and ezetimibe 10
mg (NEXLIZET) was recently FDA approved and may
improve adherence and outcomes. Additional data are
needed on cardiovascular outcomes to assess the benefit-
to-cost ratio with bempedoic acid and its place in therapy
combined with other lipid-lowering medications. It is
also important to consider the overall small number of
patients evaluated between these 4 phase III trials (2425
patients), that 3 of the 4 trials conducted a placebo run-in
phase, and the trial follow-up periods were short, with the
longest being 52 weeks.
Conclusion
Bempedoic acid has demonstrated that it can decrease
LDL-C levels in patients with ASCVD and/or HeFH on
background LLTs that requiring additional LDL-C reduc-
tion. The long-term safety and cardiovascular outcomes
data with bempedoic acid remain to be determined. Serious
AEs associated with bempedoic acid use include hyperuri-
cemia and tendon rupture, but most AEs were mild to mod-
erate in severity.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iD
Matthew A. Wanat https://orcid.org/0000-0003-4832-8200
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