Bempedoic Acid Boosts LDL Cholesterol-Lowering in Statin-Treated CVD Patients: CLEAR Harmony

Adding bempedoic acid to maximally tolerated statin therapy in patients with atherosclerotic cardiovascular disease significantly lowers LDL cholesterol levels without causing any harm, according to the results of a new study.

The CLEAR Harmony trial results, published this week in the New England Journal of Medicine, come days ahead of a late-breaking presentation of CLEAR Wisdom, slated for Monday, March 18, 2019, at the American College of Cardiology Scientific Session in New Orleans, LA.

The yearlong, phase III study suggests that bempedoic acid—an inhibitor of ATP citrate lyase (ACL), a key enzyme involved in the cholesterol biosynthesis pathway—might one day be a potential treatment option for patients priced out of additional lipid-lowering with the monoclonal antibodies alirocumab (Praluent; Regeneron/Sanofi) and evolocumab (Repatha; Amgen).

“We know that people at high risk for cardiovascular disease, lowering LDL cholesterol reduces events,” lead investigator Kausik Ray, MD (Imperial College, London, England), told TCTMD. “It actually doesn’t matter how you lower it. What matters is how much you lower it and for how long. With that in mind, we know there are many people who can’t get sufficient reduction in LDL cholesterol, possibly because their levels are very high, or they can’t tolerate existing treatments like statins because they get side effects at high doses, or even low doses. And we know with the monoclonal antibodies, cost has limited their uptake. There is a clinical need for new therapies.”

The PCSK9 inhibitors were initially priced at more than $14,000 per year, and while the cost of the alirocumab and evolocumab have been significantly reduced, they are expensive agents when compared with statins and ezetimibe, which are available as generic drugs. Esperion, the maker of bempedoic acid, has already announced plans to price the drug, assuming efficacy and regulatory approval, cheaper than the PCSK9 inhibitors.

The large cardiovascular outcomes study testing bempedoic acid is still ongoing, and its results are not expected until 2022. At the moment, the researchers remain cautious, although optimistic, about the drug’s prospects. “There are currently people who will be taking a statin, maybe ezetimibe, and can’t afford a monoclonal antibody,” said Ray. “Potentially it could be added in there as a daily oral drug.”

18% Reduction in LDL Cholesterol

CLEAR HARMONY included 2,230 patients with cardiovascular disease, familial hypercholesterolemia, or both who had LDL cholesterol levels 70 mg/dL or greater despite taking maximally tolerated statin therapy with or without additional lipid-lowering therapy (more than 97% had atherosclerotic cardiovascular disease). In total, half were taking high-intensity statin therapy, while 43% were taking a moderate-intensity regimen. A little more than 7% of patients were taking ezetimibe. Mean baseline LDL cholesterol was 103.6 mg/dL in the 1,488 patients who received bempedoic acid and 102.3 mg/dL in the placebo arm.

At week 12, LDL cholesterol levels were reduced by an average of 19.2 mg/dL in the bempedoic-acid arm, a reduction not observed in the placebo-treated patients. The between-group difference in LDL cholesterol was statistically significant at 12, 24, and 52 weeks. Similar effects were observed in the reductions of total cholesterol, non-HDL cholesterol, and apolipoprotein B. Treatment with bempedoic acid was also associated with a 22% reduction in C-reactive protein.

“When you double the dose of statins, you only ever get another 6% lowering of LDL cholesterol,” said Ray, noting that adverse effects are also more pronounced at the highest doses. “What’s interesting about this study is that you add [bempedoic acid] to a statin and you can get a further 18% reduction in LDL without causing any excess liver or [creatine kinase] abnormalities. It appears to be well tolerated overall.”

Although more patients in the bempedoic-acid arm discontinued the study drug, there were no significant differences in adverse events or serious adverse events, including muscle disorders, elevations in liver enzymes, or rises in creatine kinase levels, between the treatment groups. New-onset diabetes was significantly lower in the bempedoic-acid arm, while rates of gout were significantly higher, as were blood concentrations of uric acid.

To TCTMD, Ray said the mechanism underlying the higher rate of gout can be explained, noting that the bempedoic acid and uric acid are both excreted by the kidneys. As a result of competition for the renal transporters involved in excretion, uric-acid levels rise. He noted that while gout is rare in the general population, if the drug is approved by regulators, physicians would need to be mindful if treating patients with a history of gout.

Mendelian Randomization of ACLY and CVD

The CLEAR Harmony trial was not designed to assess cardiovascular outcomes, and there was no difference in clinical events observed in study. Still, investigators believe they are on the right track with lowering LDL cholesterol through the inhibition of ACL. Accompanying CLEAR Harmony in NEJM was a mendelian randomization study of ACLY, the gene responsible for encoding ACL. 

Led by Brian Ference, MD (University of Cambridge, England), and including Ray as second author, the study showed that variants in the genes encoding ACL and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the target of statins, had similar effects on plasma LDL cholesterol levels. Importantly, for each unit decrease in LDL cholesterol associated with ACLY and HMGCR variants, there was a “nearly identical effect on the risk of cardiovascular events.”   

In an editorial accompanying both studies, Michael Holmes, MD, PhD (University of Oxford, England), states that cumulative data, including the human genetics study, look positive so far. “For a given reduction in the LDL cholesterol level, drugs that inhibit ACL (and do not have off-target effects) ought to yield reductions in the risk of cardiovascular disease that are similar to those achieved with statins,” he writes. Ultimately, though, that question will be addressed in the cardiovascular outcomes trial, according to Holmes.

To TCTMD, Ray made similar comments, citing the mendelian randomization analysis in support of targeting ACL with bempedoic acid, but reiterated the ultimate goal with these therapies is the prevention of cardiovascular events.

CLEAR Wisdom, coming out at ACC, is an 800-patient study looking at the safety and efficacy of bempedoic acid versus placebo on top of maximal statins in patients with hypercholesterolemia and high cardiovascular risk.