Safety signals raise concerns
When added to maximally tolerated statin therapy, bempedoic acid reduced LDL cholesterol by more than 15%, compared with placebo, Anne C. Goldberg, MD, and colleagues reported in JAMA.
The prodrug also improved non-HDL cholesterol, total cholesterol, apolipoprotein B, and C-reactive protein in a group of patients who remained at high risk of cardiovascular events despite maximally tolerated statin treatment, said Dr. Goldberg of Washington University, St. Louis, and coauthors in reporting the results of CLEAR Wisdom (Evaluation of Long-Term Efficacy of Bempedoic Acid [ETC-1002] in Patients With Hyperlipidemia at High Cardiovascular Risk).
The prodrug bempedoic acid works differently than most statins. In the liver, the drug activates into bempedoyl-CoA. It interrupts ATP-citrate lyase, an enzyme critical to the main statin target, 3-hydroxy-3-methylglutaryl-CoA reductase. Although it reduces cholesterol synthesis in the liver, bempedoic acid isn’t active in skeletal muscle, unlike statins.
The 52-week placebo-controlled trial included 2,300 patients enrolled at 91 international sites. All of them had atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. They were randomized 2:1 to bempedoic acid 180 mg daily or placebo. Patients were a mean of 64 years old, with a mean LDL cholesterol level of 120.4 mg/dL. Most (89.6%) were receiving statin therapy, with 53% receiving high-intensity treatment.
The primary endpoint was change in LDL cholesterol. Secondary measures included overall lipid changes and changes in lipoprotein and biomarkers of cardiovascular disease.
After 12 weeks, patients taking bempedoic acid experienced significantly lowered LDL cholesterol, compared with those taking placebo (–15% vs. 2.4%; between-group difference, 17.4%). The key secondary endpoints were also positive, including non–LDL cholesterol (–10.8% vs. 2.3%), total cholesterol (–9.9% vs. 1.3%), apolipoprotein B (–9.3% vs 3.7%), and high-sensitivity C-reactive protein (median, –18.7% vs –9.4%)
Most patients in both groups (about 70%) experienced at least one adverse event. However, the majority of those (77.6%) were not related to the study drug. Most were mild to moderate and included myalgia (1% vs. 0.8%), increased aspartate aminotransferase level (0.6% vs. 0%), and arthralgia (0.6% vs. 0%).
Serious adverse events occurred in 19.8% of patients, with three possibly related to bempedoic acid. These were ulcerative colitis and ischemic stroke in the bempedoic acid group and upper abdominal pain in the placebo group.
Eight fatalities occurred during the CLEAR Wisdom. There were single cases of cardiac arrest, coronary artery arteriosclerosis, acute poisoning with carbon dioxide, myocardial infarction, and septic shock related to a prescheduled abdominal surgical procedure. One patient in the active group died from an unknown cause.
Four events in the bempedoic acid group and two events in the placebo group were cardiovascular deaths.
New or worsening diabetes developed in approximately 7% of each group, and less than 3% of those taking bempedoic acid developed gout or increased blood uric acid, as was the case for less than 1% of patients taking placebo.
In May, the Food and Drug Administration accepted a New Drug Application from Esperion for bempedoic acid. A response is expected in February 2020.
Dr. Goldberg reporter receiving research grants/support from Amgen, Amarin, Pfizer, Regeneron, Sanofi, IONIS, Novartis, and Merck and serving as a consultant for Esperion, Novartis, Akcea, OptumRX, 23andMe, Sanofi/Regeneron, and Merck.
SOURCE: Goldberg AC et al. JAMA. 2019 Nov 12;322:1780-8.