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Bempedoic acid cuts LDL by 15% in patients already on maximal treatment

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Bempedoic acid’s place in cardiovascular risk reduction remains to be seen

Bempedoic acid may fill a niche for patients who don’t experience sufficient LDL cholesterol (LDL-C) reductions despite maximally tolerated statin treatment, Michael C. Honigberg, MD,and Pradeep Natarajan, MD, wrote in an accompany editorial.

“Given encouraging results from clinical trials, nonstatin LDL-C–lowering medicines are now guideline-recommended when the degree of LDL-C lowering attained by maximally tolerated statins is deemed insufficient,” they wrote (JAMA. 2019 Nov 12;322:1769-71).

However, other drugs in this category are available and have already been incorporated into practice. In view of this trend, the role of bempedoic acid is not yet clear. The picture may come more into focus in 2022, when the results of the related CLEAR Outcomes trial are reported. CLEAR Outcomes will assess how much bempedoic acid reduces cardiovascular risk in 12,600 patients.

“Given the results from all CLEAR trials for LDL-C–lowering efficacy and safety, should bempedoic acid similarly be used in clinical practice before results from CLEAR Outcomes are reported? If so, with the availability of several LDL-C–lowering agents, when should patients and their physicians consider bempedoic acid?”

One factor could be the increasing effort to reduce LDL cholesterol even further than the current target. In 2013, the American College of Cardiology/American Heart Association endorsed high-potency statins for the secondary prevention of atherosclerotic cardiovascular disease, with a target LDL cholesterol reduction of more than 50%. But recently, an even greater target reduction has been advised.

“Without an obvious ‘floor’ of efficacy or safety, the ... guidelines extended prior recommendations by establishing an LDL-C goal of less than 70 mg/dL for secondary prevention for individuals at very high risk of future [atherosclerotic cardiovascular disease] events. The 2018 guidelines now support the use of nonstatin LDL-C–lowering medicines, specifically ezetimibe, alirocumab, and evolocumab, to further reduce LDL-C levels as necessary among such very-high-risk individuals. ... The next few years will see results from trials of additional nonstatin LDL-C–reducing agents. After focusing the last three decades exclusively on statins, the increasingly diverse options to attain maximally tolerated LDL-C reduction are welcome additions for management of high-risk patients.”

Dr Natarajan and Dr. Honiberg are both from the Massachusetts General Hospital, Boston. Dr. Natarajan reported receiving research grant support from Amgen, Apple, and Boston Scientific and serving as a scientific adviser to Apple and Blackstone LifeSciences, all unrelated to the present work. Dr Honigberg reported no disclosure



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.

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