Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen - CLEAR Outcomes

Aug 27, 2023
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC; Kim A. Eagle, MD, MACC
Trial Sponsor:
Esperion Therapeutics
Date Presented:
08/26/2023
Date Published:
03/04/2023
Date Updated:
08/27/2023
Original Posted Date:
03/04/2023
References

Contribution To Literature:

Highlighted text has been updated as of August 26, 2023.

The CLEAR Outcomes trial showed that bempedoic acid improves long-term CV outcomes and effectively reduces LDL-C compared with placebo among patients with either established ASCVD or who have a high risk for it, and with intolerance to statin therapy.

Description:

The goal of the trial was to compare the safety and efficacy of bempedoic acid compared with placebo among patients with or at high risk for cardiovascular disease (CVD) and were intolerant of statin therapy.

Study Design

Patients were randomized in a 1:1 fashion to either bempedoic acid 180 mg (n = 6,992) or placebo once (n = 6,978) daily. All patients were statin intolerant. Patients who were receiving a very low average daily statin dose without unacceptable adverse effects could be enrolled. Other lipid-lowering therapies were permitted, such as ezetimibe, niacin, bile acid resins, fibrates, or proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors, administered as monotherapy or in combination.

  • Total number of enrollees: 13,970
  • Duration of follow-up: 40.6 months (median)
  • Mean patient age: 65.5 years
  • Percentage female: 48%
  • Percentage with diabetes: 46%

Inclusion criteria:

  • Age between 18 and 85 years
  • History of, or at high risk for, CVD including coronary artery disease (CAD), symptomatic peripheral arterial disease, cerebrovascular atherosclerotic disease, or at high risk for a cardiovascular (CV) event
  • Patient-reported history of statin intolerance (inability to tolerate ≥2 statins, one at a low dose)
  • Men and nonpregnant, nonlactating women
  • Fasting blood low-density lipoprotein cholesterol (LDL-C) ≥100 (2.6 mmol/L) at screening

Exclusion criteria:

  • Fasting blood triglycerides >500 mg/dL (5.6 mmol/L) at screening
  • Recent (within 90 days of screening) history of major CV events, transient ischemic attack (TIA), or unstable or symptomatic cardiac arrhythmia
  • History of severe heart failure
  • Uncontrolled hypertension or uncontrolled diabetes

Other salient features/characteristics:

  • Secondary prevention: 70% (CAD: 51%, peripheral artery disease: 11.5%, CVD: 14.8%)
  • Baseline LDL-C: 139 mg/dL; high-density lipoprotein: 49 mg/dL; high-sensitivity C-reactive protein (hsCRP): 2.3 mg/L
  • Baseline statin use: 23%, ezetimibe: 11.5%

Principal Findings:

The primary outcome, four-component major adverse CV events (MACE: nonfatal myocardial infarction [MI], nonfatal stroke, coronary revascularization, or CV death) for bempedoic acid compared with placebo, was: 11.7% vs. 13.3%, hazard ratio 0.87, 95% confidence interval 0.79-0.96 (p = 0.004).

Secondary outcomes for bempedoic acid compared with placebo:

Three-component MACE (nonfatal MI, nonfatal stroke, CV death): 8.2% vs. 9.5% (p = 0.006)

  • Fatal or nonfatal MI: 3.7% vs. 4.8% (p = 0.002)
  • Coronary revascularization: 6.2% vs. 7.6% (p = 0.001)
  • Fatal or nonfatal stroke: 1.9% vs. 2.3% (p = 0.16)
  • All-cause mortality: 6.2% vs. 6.0%
  • Change in LDL-C at 6 months: -21.1 vs. -0.8 mg/dL (p < 0.06)
  • Change in hsCRP from baseline at 12 months: -20.6% vs. 0% (p < 0.05)
  • Any muscle disorder: 15.0% vs. 15.4%
  • Hyperuricemia: 10.9% vs. 5.6%
  • Gout: 3.1% vs. 2.1%
  • Cholelithiasis: 2.2% vs. 1.2%

Analysis by glycemic status: Results of bempedoic acid vs. placebo were similar across patient glycemic status (normoglycemia, pre-diabetes, or diabetes). Absolute reductions were greater among patients with diabetes (who had the highest risk). There were no changes in HbA1c or glucose levels with bempedoic acid in those without diabetes at baseline.

Interpretation:

The results of this trial indicate that bempedoic acid improves long-term CV outcomes and effectively reduces LDL-C compared with placebo among patients with either established atherosclerotic CVD (ASCVD) or who have a high risk for it, and with intolerance to statin therapy. These are very promising findings and extend our current armamentarium of lipid-lowering therapies. Future studies comparing bempedoic acid to other nonstatin lipid-lowering agents such as ezetimibe and PCSK9 inhibitor as well as a potential alternative to statins are awaited. Longer-term data and cost-effectiveness data are also awaited.

References:

Presented by Dr. Kausik K. Ray at the European Society of Cardiology Congress, Amsterdam, Netherlands, August 26, 2023.

Nissen SE, Lincoff AM, Brennan D, et al., on behalf of the CLEAR Outcomes Investigators. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med 2023;388:1353-64.

Editorial: Alexander JH. Benefits of Bempedoic Acid — Clearer Now. N Engl J Med 2023;388:1425-6.

Editorial: Keaney JF Jr. Bempedoic Acid and the Prevention of Cardiovascular Disease. N Engl J Med 2023;388:1427-30.

Presented by Dr. Steven E. Nissen at the American College of Cardiology Annual Scientific Session (ACC.23/WCC), New Orleans, LA, March 4, 2023.

Clinical Topics: Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Cardiac Surgery and Arrhythmias, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and Coronary Artery Disease, Interventions and Vascular Medicine

Keywords: ACC23, ACC Annual Scientific Session, Atherosclerosis, Cholesterol, LDL, Coronary Artery Disease, C-Reactive Protein, Dyslipidemias, ESC Congress, ESC23, Ezetimibe, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Myocardial Infarction, Myocardial Revascularization, PCSK9 protein, human, Peripheral Arterial Disease, Primary Prevention, Secondary Prevention, Stroke


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