Bempedoic Acid Improves Clinical Outcomes in Statin-Intolerant Patients
Presenter: Steven E. Nissen, MD, Cleveland Clinic, Cleveland, OH
The cholesterol-lowering drug bempedoic acid reduced the combined rate of major adverse cardiovascular events by 13% in a large trial of patients who were unable to tolerate statins.
Bempedoic acid, an ATP citrate lyase inhibitor, inhibits hepatic cholesterol synthesis upstream of HMG-Co-A reductase, the enzyme inhibited by statins. It is a pro-drug activated in the liver, but not peripheral tissues, resulting in a low incidence of muscle-related adverse events, which are commonly seen with statin use. Prior studies have reported LDL-C reduction of 15-25% with bempedoic acid, and the drug was approved for this indication in 2020.
The randomized, placebo-controlled, double-blind CLEAR Outcomes international trial is the first clinical trial to assess whether bempedoic acid could reduce cardiovascular outcomes. The primary end point, a composite of cardiovascular death, myocardial infarction, stroke or coronary revascularization, was reduced 13%, and cardiovascular death, myocardial infarction, and stroke was reduced by 15%, compared to placebo.
Bempedoic acid also led to statistically significant reductions in fatal and non-fatal myocardial infarctions (23%) and coronary revascularizations (19%), regardless of whether patients had previously experienced a cardiac event. The drug had no effect on cardiovascular death or all-cause mortality.
“These findings establish bempedoic acid as an effective approach to reduce major cardiovascular events in statin-intolerant patients,” said presenter Steven E. Nissen, MD, of Cleveland Clinic.
The trial enrolled 13,970 patients at 1,250 sites in 32 countries. Patients and their clinicians were required to acknowledge in writing that the patient was unable to tolerate statin therapy. All participants had LDL levels of 100 mg/dL or higher at baseline and either a previous cardiac event or other risk factors for heart disease. On average, patients were 65 years old, nearly half were women (48%), about half had diabetes (45-46%), and about 70% had experienced a previous cardiac event. Participants were randomly assigned to take bempedoic acid 180 mg daily or placebo, and were followed for more than 3 years, on average.
Bempedoic acid lowered LDL cholesterol levels by 21.7% and high-sensitivity C-reactive protein by 22.2%. Those on placebo also saw a modest reduction in LDL cholesterol (up to 10%, on average), which likely reflects closer monitoring and the addition of other cholesterol-lowering agents as part of their background therapy.
“Bempedoic acid was well-tolerated in a mixed population of primary and secondary prevention patients unable or unwilling to take statins,” said Nissen. Adverse events leading to discontinuation were similar in both arms (10%), and new-onset diabetes was not increased. There was a 1% increase in gout and in cholelithiasis, as well as slightly higher rates of renal impairment and elevated hepatic enzymes, in the bempedoic arm.
The effects of bempedoic acid in women were identical to men, said Nissen, noting that women may be less willing or able to tolerate statin therapy, for unknown reasons.
“Management of patients unable or unwilling to take statins represents a challenging and frustrating clinical issue. Regardless whether this problem represents the nocebo effect or actual intolerance, these high-risk patients need effective alternative therapies. The CLEAR Outcomes trial provides a sound rationale for use of bempedoic acid to reduce major adverse cardiovascular outcomes in patients who are intolerant to statins,” said Nissen.
The trial results were published simultaneously online in The New England Journal of Medicine.
References
Marrs JC, Anderson SL. Bempedoic acid for the treatment of dyslipidemia. Drugs Context. 2020 Aug 24;9:2020-6-5. doi: 10.7573/dic.2020-6-5. PMID: 32922503; PMCID: PMC7449648
Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. March 4, 2023 doi: 10.1056/NEJMoa2215024
Nissen SE. Bempedoic acid and cardiovascular outcomes in statin intolerant patients at high
cardiovascular risk. Presented at American College of Cardiology Annual Scientific Session & Expo
Together With World Congress of Cardiology, March 4, 2023, New Orleans, LA. Presentation Number: 402-06.
Disclosures
Steven Nissen: Research/Research Grants ‐ AbbVie, Inc., Amgen, AstraZeneca, AstraZeneca Pharmaceuticals, Bristol‐Myers Squibb Company, Eli Lilly, Esperion Therapeutics, Medtronic, Mineralys, MyoKardia, Novartis, Pfizer, Silence Therapeutics