The 2023 American College of Cardiology (ACC) Annual Scientific Meeting/World Congress of Cardiology (WCC) 2023 (ACC.23/WCC) kicked off on March 4, local time in the United States. On the first day of the conference, the results of the CLEAR Outcomes trial were released, showing that the cholesterol-lowering drug Bempedoic acid reduced the risk of major cardiovascular adverse events by 13% in patients with high cholesterol who could not tolerate statins. The results were published simultaneously in the journal NEJM.
Study design
This trial was a double-blind, randomised, placebo-controlled trial of patients who were unable or unwilling to take statins due to unacceptable adverse effects (i.e. people who were intolerant to statins), those at high risk of cardiovascular disease. Patients were randomized to receive oral beperidic acid (180 mg daily) or placebo.
The primary endpoint was a composite endpoint event of major adverse cardiovascular events, defined as cardiovascular death, non-fatal myocardial infarction, nonfatal stroke, or coronary revascularization.
Figure 1 Study design
Study results
In the study, a total of 13,970 patients were randomized, of which 6,992 were randomized to beperidic acid and 6,978 to placebo.
At a median follow-up of 40.6 months, the mean LDL-C level at baseline was 139.0 mg/dl in both groups. After 6 months, LDL-C levels were reduced by 29.2 mg/dl in the beperidic acid group compared with placebo. The percentage difference observed for the reduction was 21.1 percentage points, suggesting that beperidic acid may benefit patients.
Figure 2 Results of the study
The primary endpoint event rate was significantly lower in the beperidic acid group than in the placebo group (819 [11.7%] vs. 927 [13.3%]; HR=0.87；95%CI：0.79-0.96；P=0.004）； non-fatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; HR=0.85; 95%CI: 0.76-0.96; P=0.006), fatal or non-fatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; HR=0.77; 95%CI: 0.66-0.91; P=0.002), coronary revascularization (435 [6.2%] vs. 529 [7.6%]; HR=0.81; 95%CI: 0.72-0.92; P=0.001).
In addition, beperidic acid had no significant effect on fatal or non-fatal stroke, cardiovascular mortality, and death from any cause.
Patients with beperidic acid had higher rates of gout and cholelithiasis than placebo (3.1% vs. 2.1% vs. 2.1% vs. 2.2% vs. 1.2%, respectively), and small increases in serum creatinine, uric acid, and liver enzymes were higher than in the placebo group.
Conclusion of the study
In statin-intolerant patients, beperidic acid therapy is associated with a lower risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization).
Research Review
Lead investigator, Dr. Steven E. Nissen of the Cleveland Clinic, said elevated low-density lipoprotein cholesterol (LDL-C) in the blood can lead to clogged arteries and increase the risk of cardiovascular disease attacks, stroke and other heart diseases. Statins are the standard first-line treatment strategy for reducing cholesterol and heart disease risk. Beperidic acid is an additional treatment approved by the U.S. Food and Drug Administration (FDA) to help lower cholesterol levels in patients who still have high cholesterol levels after receiving the highest dose of statin. Most patients benefit from statin therapy, but some do not.
The CLEAR Outcomes trial is a study that directly addresses the question of which treatment should be given for patients with statin intolerance. It is the first trial to assess whether beperidic acid reduces cardiovascular outcomes in patients. Studies have shown that beperidic acid significantly reduces the primary event endpoints of the trial, including cardiovascular death, heart attack, stroke, or coronary revascularization. Analysis of different types of cardiac events found that beperidic acid reduced heart attacks by 20% and coronary revascularization by 19%, regardless of previous cardiac events, all statistically significant. They were very pleased with the results of the study: those who could not tolerate statins did tolerate beperidic acid and benefited well.
Professor John H. Alexander from Duke University School of Medicine pointed out in a commentary that vascular atherosclerosis is associated with the incidence and mortality of coronary, cerebrovascular and peripheral vascular diseases. The basic treatment for contemporary atherosclerosis prevention and treatment is statins. It reduces LDL-C levels, slows atherosclerosis progression, and reduces the incidence and mortality associated with coronary, cerebrovascular, and peripheral vascular disease. However, a significant proportion (about 10%) of patients do not benefit from statin therapy or are unwilling to undergo statin therapy.
These patients are treated with ezetimibe, PCSK9 inhibitors, and beperidic acid. Beperidic acid is a competitive inhibitor of ATP citrate lyase that lowers LDL-C by inhibiting cholesterol biosynthesis in the liver and upregulating the low-density lipoprotein receptor (LDL-R), and it is a prodrug metabolized in the liver to its active metabolite but not metabolized in peripheral tissues, so there are few muscle-related side effects. However, it is unclear whether it reduces the risk of cardiovascular events. The release of the CLEAR Outcomes trial results fills this gap. Beperidic acid was shown to reduce the risk of major cardiovascular adverse events by 13% in patients with high cholesterol who could not tolerate statins, meeting the primary endpoint of the study.
In addition, Dr. John F. Keaney of Harvard University Brigham Hospital noted in a separate commentary that the trial brings good news for the patient population in the CLEAR Outcomes trial, which would otherwise be very difficult to achieve a reduced risk of LDL-C and cardiovascular events.
Source: ACC official website
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