Efficacy and Safety of Bempedoic Acid Added to Maximally Tolerated Statins in Patients With Hypercholesterolemia and High Cardiovascular Risk - CLEAR Wisdom

Dec 17, 2019
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Esperion Therapeutics, Inc.
Date Presented:
03/18/2019
Date Published:
11/12/2019
Date Updated:
12/17/2019
Original Posted Date:
03/18/2019
References

Contribution To Literature:

The CLEAR Wisdom trial showed that bempedoic acid is safe and effective in reducing LDL-C compared with placebo among patients with ASCVD or heterogeneous FH on maximum-tolerated statin therapy.

Description:

The goal of the trial was to compare the safety and efficacy of bempedoic acid compared with placebo among patients already on intensive or maximum-tolerated statin therapy.


Study Design

Patients were randomized in a 2:1 fashion to either bempedoic acid 180 mg or placebo once daily for 52 weeks. All patients were on maximal tolerated statin and other lipid-lowering therapy.

  • Total number screened: 2,300
  • Total number of enrollees: 779
  • Duration of follow-up: 52 weeks
  • Mean patient age: 64.5 years
  • Percentage female: 36%
  • Percentage with diabetes: 30%

Inclusion criteria:

  • Pre-existing atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (FH)
  • Baseline low-density lipoprotein cholesterol (LDL-C) ≥100 mg/dl (2.6 mmol/L) at screening and ≥70 mg/dl (1.8 mmol/L) following placebo run-in while receiving maximally tolerated statins

Exclusion criteria:

  • Total fasting triglyceride level ≥500 mg/dl
  • Body mass index ≥50 kg/m2
  • Severe renal impairment (estimated glomerular filtration rate <30 ml/min/1.73 m2)
  • Recent (within 3 months of screening) coronary heart disease event
  • Clinically significant disease that could interfere with study participation

Other salient features/characteristics:

  • ASCVD alone: 94%
  • Baseline LDL-C: 120 mg/dl; non-high-density lipoprotein (non-HDL): 153 mg/dl
  • High-intensity statin: 53%, moderate-intensity statin: 31%

Principal Findings:

The primary outcome, change in LDL-C at week 12 from baseline for bempedoic acid compared with placebo, was -15.1% vs. 2.4%, p < 0.001.

  • Observed LDL-C at 4 weeks for bempedoic acid vs. placebo: 97.6 vs. 122.8 mg/dl; at 52 weeks: 99.6 vs. 116.9 mg/dl

Secondary outcomes:

  • Change in apolipoprotein B from baseline at week 12: -9.3% vs. 3.7%, p < 0.001
  • Change in high-sensitivity C-reactive protein from baseline at week 12: -18.7% vs. -9.4%, p = 0.039
  • Serious side effects: 20.3% vs. 18.7%, p = 0.63
  • Three-point major adverse cardiac events: 2.7% vs. 4.7%, p > 0.05
  • Nonfatal myocardial infarction: 1.1% vs. 3.5%

Interpretation:

The results of this trial indicate that bempedoic acid is safe and effective in reducing LDL-C compared with placebo among patients with ASCVD or heterogeneous FH on maximum-tolerated statin therapy. No difference was noted for clinical outcomes, although the trial was not powered for this. These are encouraging data, but outcomes data are needed prior to recommending this agent to patients. Several agents have impacted on surrogate markers (such as niacin for HDL), which were then found to have a neutral or in some cases, a harmful effect on clinical outcomes. Also, future studies comparing bempedoic acid to other nonstatin lipid-lowering agents such as ezetimibe and PCSK9 inhibitors would be helpful for patient management.

References:

Goldberg AC, Leiter LA, Stroes ES, et al. Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: The CLEAR Wisdom Randomized Clinical Trial. JAMA 2019;322:1780-8.

Presented by Dr. Anne C. Goldberg at the American College of Cardiology Annual Scientific Session (ACC 2019), New Orleans, LA, March 18, 2019.

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

Keywords: ACC19, ACC Annual Scientific Session, Apolipoproteins B, Biomarkers, Cholesterol, HDL, Cholesterol, LDL, C-Reactive Protein, Dicarboxylic Acids, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, Myocardial Infarction, Primary Prevention


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