Bempedoic Acid, the Next LDL Cholesterol-Lowering Medication to Join the Arsenal? Insights From the CLEAR Wisdom Trial

Recent developments in low-density lipoprotein cholesterol (LDL-C) lowering could mean even more treatment options for our patients. The mainstay, statin therapy, acts on HMG-CoA reductase to reduce cholesterol synthesis, in turn increasing LDL-receptor (LDL-R) expression and LDL catabolism. At high intensity doses, statins are highly efficacious in lowering LDL-C, offering a reduction of 50% or more. Adding ezetimibe, which inhibits cholesterol absorption at the brush border of the small intestine, and also upregulates LDLR, can lower LDL-C an additional 20% on average.

In the last few years, there has been much excitement over the development and use of PCSK9 monoclonal antibodies, which bind PCSK9 to inhibit its binding to LDL-R, thereby preventing degradation, and resulting in increased LDL clearance. Treatment with FDA approved PCSK9 inhibitors decreases LDL-C approximately 60% on average, but these agents are delivered by subcutaneous injection and have been historically expensive.

Bempedoic acid is an oral pro-drug, activated in the liver to inhibit ATP-citrate lyase (ACL), which acts upstream of HMG-CoA reductase. This upregulates LDL-R, increasing LDL-C clearance. It is an oral medication, intended to be taken once daily.

The CLEAR Wisdom (Efficacy and Safety of Bempedoic Acid Added to Maximally Tolerated Statins in Patients With Hypercholesterolemia and High Cardiovascular Risk) trial is one of five studies run by Esperion to evaluate safety, tolerability and LDL-C lowering efficacy of bempedoic acid. All trials are Phase 3 clinical trials and were designed as randomized, double-blinded, placebo controlled multi-center studies with parallel groups.

The CLEAR Harmony (Assessment of the Long-Term Safety and Efficacy of Bempedoic Acid) and CLEAR Wisdom trials aimed to evaluate the safety and efficacy of bempedoic acid in patients already on maximally tolerated statin therapy. The CLEAR Serenity (Evaluation of the Efficacy and Safety of Bempedoic Acid in Patients With Hyperlipidemia and Statin Intolerance) and CLEAR Tranquility (Evaluation of the Efficacy and Safety of Bempedoic Acid as Add-on to Ezetimibe Therapy in Patients With Elevated LDL-C) trials evaluated change in LDL-C in patients unable to tolerate statin therapy at doses greater than those defined as "low dose."

Results of the CLEAR Harmony trial were presented at the European Society of Cardiology conference in Munich in August 2018 and published recently in The New England Journal of Medicine. Bempedoic acid was associated with a modest increase in adverse events of new-onset or worsening diabetes and gout compared to placebo. While bempedoic acid reduced LDL-C levels by 18% at 12 weeks. The trial was not powered to evaluate for a reduction in clinical events.

The CLEAR Wisdom trial, presented at the American College of Cardiology 2019 Scientific Sessions recently in New Orleans, was structured similarly to the CLEAR Harmony trial. Notably, CLEAR Wisdom identified percent change in LDL-C as its primary outcome measure, while CLEAR Harmony listed this as a secondary outcome measure with a primary outcome measure of enumerating treatment-related adverse events.

CLEAR Wisdom enrolled 779 participants (bempedoic acid arm n = 522 and placebo arm n = 257), while CLEAR Harmony enrolled 2,229 total participants (bempedoic acid arm n = 1,487 and placebo n = 742). Inclusion criteria of both trials include: 1) pre-existing atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (FH); and 2) baseline LDL-C ≥100 mg/dL at screening and ≥70 mg/dL following placebo run-in while receiving maximally tolerated statin therapy. Twenty percent of the bempedoic acid group (n = 107) discontinued the study drug with 10.3% (n = 54) citing adverse events compared to 16.7% (n = 43) of the placebo group with 8.2% (n = 21) citing adverse events.

At week 12, bempedoic acid decreased LDL-C levels by 15.1%, compared to a 2.4% increase in the placebo arm (p <0.001). In sub-group analysis by background statin intensity, this difference decreased as the statin dose increased. In participants not on statin therapy, bempedoic acid reduced LDL-C 24.6% compared to a 2.6% decrease in the placebo group; when used in addition to high-intensity statin therapy, bempedoic acid reduced LDL-C levels 14.4% compared to a 2.8% decrease in the placebo group.

Bempedoic acid also significantly reduced total cholesterol (-9.9% compared to +1.3% in placebo), ApoB (-9.3% compared to 3.7% in placebo), and non-HDL-C (-10.8% compared to +2.3% in placebo) levels. High-sensitivity CRP also decreased in the bempedoic acid arm (-18.7% compared to -9.4% placebo, p = 0.039).

Addressing the increase in new-onset or worsened diabetes observed in the CLEAR Harmony trial, the CLEAR Wisdom trial reported no increase in blood glucose levels or hemoglobin A1c at 12 weeks in the bempedoic acid group compared to placebo. The most common observed adverse events were nasopharyngitis and urinary tract infection, similar to findings from CLEAR Harmony. There were two fatal events in the bempedoic acid arm that were not deemed secondary to the study drug; one due to gas poisoning and one due to septic shock.

The incidence of cardiovascular death was equal in both groups (0.8% in both groups), while the bempedoic acid group had a lower incidence of nonfatal MI (1.1% compared to 3.5% in placebo) as well as coronary revascularization (3.8% compared to 5.8% in placebo). Rates of nonfatal stroke were the same in both groups (0.8% both groups). It should be emphasized the primary endpoint of both CLEAR Harmony and CLEAR Wisdom was to assess for safety and LDL-C lowering efficacy of bempedoic acid, and that all clinical outcome findings were observatory. Esperion does have larger trials in the pipeline planned to run over a longer time period with the aim of assessing clinical outcomes.

Thus far, the results of CLEAR Wisdom, in addition to previous results from CLEAR Harmony, show bempedoic acid is efficacious in reducing LDL-C. Furthermore, these decreases have been sustained over a period of at least 52 weeks. However, the magnitude of LDL-C reduction is moderate and decreases as statin intensity is increased. Evaluation of the net benefit to patients awaits clinical outcome trial data.

Though bempedoic acid does not lower LDL-C nearly as much as the PCSK9 inhibitors, its appeal may lie in a lower expected price and oral administration. In addition, bempedoic acid is specifically designed to avoid myalgias, one of the possible side effects of statin therapy. Though bempedoic acid works in the same cholesterol synthesis pathway as statins, activated bempedoic acid is not present in skeletal muscle.

Though bempedoic acid will not replace statin therapy as the mainstay of LDL-C lowering therapy, it will eventually be another option for LDL-C lowering in difficult to manage patients. A combination bempedoic acid and ezetimibe pill is also being developed, with plans to seek FDA approval concomitantly with bempedoic acid alone. A clinical trial enrolling 382 participants is assessing safety and efficacy of this new medication, with a primary outcome of percent change in LDL-C.

Bempedoic acid has not yet been evaluated for clinical outcomes. An open-label extension of CLEAR Harmony was initiated in 2017. Additionally, CLEAR Outcomes (Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid or Placebo) is a global, randomized trial aiming to enroll 12,600 patients with ASCVD or high risk CVD to evaluate cardiovascular events over 4.75 years and is set to read out in 2022.

Table 1

Trial Name

Primary Endpoint

Secondary Endpoint(s)

Number of Participants

Adverse Events

Change in LDL-C


Bempedoic acid


Bempedoic Acid



Bempedoic Acid


CLEAR Harmony

Number of participants with treatment- related adverse events

1. Percent change in LDL-C
2. Percent change in hs-CRP









CLEAR Wisdom

Percent change in low-density lipoprotein cholesterol (LDL-C) at week 12

1. Percent change in LDL-C through week 24
2. Percent change from baseline to week 12 in non-HDL-C, TC, apoB, hsCRP










  1. Goldberg A. Efficacy and Safety of Bempedoic Acid Added to Maximally Tolerated Statins in Patients with Hypercholesterolemia and High Cardiovascular Risk: The CLEAR Wisdom Trial. Oral Presentation at: American College of Cardiology Annual Scientific Session (ACC 2019), New Orleans, LA, March 18, 2019.
  2. Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med 2019;380:1022-32.
  3. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Cholesterol, LDL, Hypercholesterolemia, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Apolipoproteins B, Prodrugs, Blood Glucose, Hyperlipoproteinemia Type II, Myalgia, Cardiovascular Diseases, Antibodies, Monoclonal, Microvilli, Nasopharyngitis, Shock, Septic, Risk Factors, Hydroxymethylglutaryl CoA Reductases, Cholesterol, Diabetes Mellitus, Stroke, Injections, Subcutaneous, Receptors, LDL, Dyslipidemias, ACC Annual Scientific Session, ACC19

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