Fixed-Dose Bempedoic Acid, Ezetimibe Combo for Statin Intolerance?

Liam Davenport

May 30, 2019

MAASTRICHT, The Netherlands — A fixed-dose combination of the ATP citrate lyase inhibitor bempedoic acid (Esperion Therapeutics) and ezetimibe (Zetia, Merck/Schering-Plough) substantially lowers low-density-lipoprotein (LDL)-cholesterol levels, even in the presence of statins, a new study suggests.

The study involved more than 300 patients, 65% of whom were already taking a statin at the maximally tolerated dose, randomized to the fixed-dose combination of bempedoic acid and ezetimibe, bempedoic acid alone, ezetimibe alone, or placebo.

Regardless of other lipid-lowering therapy, the fixed-dose combination lowered LDL-cholesterol levels by a significant 36%, or 38% when compared with placebo, versus 23% for ezetimibe alone and 17% for bempedoic acid.

The findings were presented here at the European Atherosclerosis Society 2019 Congress.

Christie M. Ballantyne, MD, Baylor College of Medicine, Houston, who presented the data, said that the magnitude of LDL-cholesterol lowering with the fixed-dose combination "suggests that there are additive benefits of using these agents with different mechanisms of action."

Noting that the combination reduced other lipids and inflammatory markers, such as high-sensitivity C-reactive protein (hsCRP), and was well tolerated, he said that it "may provide a potent and convenient oral therapy complementary to existing lipid-modifying therapy."

The session was chaired by François Mach, MD, PhD, head of cardiology at Geneva University Hospital, and Alexandros D. Tselepis, MD, PhD, director of the Atherothrombosis Research Centre, University of Ioannina, Greece.

Tselepis underlined that, although the current results are encouraging, the impact of the fixed-dose combination on clinical end points needs to be determined.

"For the moment, I think the effects of bempedoic acid are very important concerning the lipid-lowering effects, but it should be translated into clinical end points," he told | Medscape Cardiology. "We give drugs to save lives, so we should wait for that, but, for the moment, the results we have are very promising."

Mach added that, should safety not prove to be an issue, the fixed-dose combination could be important in daily practice "for patients who are so-called statin-intolerant."

"We are facing this more and more, especially women in primary prevention," he explained. "Even if you let them know that they have familial hypercholesterolemia, they are afraid of statins, just the word statins. In the media, everywhere, statins are a problem."

Consequently, Mach said he can see this the fixed-dose combination "in primary prevention, just to replace statins," although it will likely be 3 or 4 years before it will be widely available.

Ballantyne began his presentation by pointing out that may patients who are receiving maximally tolerated statins require further lipid-modifying therapy.

With bempedoic acid acting upstream of 3-hydroxy-3-methylglutaryl–coenzyme A reductase, the target of statins, in the cholesterol–biosynthesis pathway, and ezetimibe inhibiting intestinal cholesterol absorption, their mechanisms of action are complementary to statins, he added.

Previous studies have indicated that, against a background of other lipid-lowering therapy, bempedoic acid achieves an approximate 18% reduction in LDL cholesterol when added to maximally tolerated statins.

A further 11% reduction can be seen when adding the drug to ezetimibe, Ballantyne noted.

To determine the impact of a fixed-dose combination of bempedoic acid 180 mg and ezetimibe 10 mg in the context of maximally tolerated statin therapy, the researchers conducted a phase 3, double-blind, multicenter study.

They recruited patients with atherosclerotic CVD/familial hypercholesterolemia or multiple CVD risk factors, all with elevated LDL-cholesterol levels, and included those who were not receiving statins in the definition of "maximally tolerated."

After screening, 382 patients were randomized in a 2:2:2:1 fashion to the fixed-dose combination (n = 108), bempedoic acid alone (n = 110), ezetimibe alone (n = 109), or placebo (n = 55) for 12 weeks.

After patients who discontinued therapy because of adverse events or other reasons were excluded, the researchers had 86 patients treated with the fixed-dose combination, 88 with bempedoic acid alone, 86 treated with ezetimibe alone, and 41 with placebo for the efficacy analysis.

Only one fixed-dose combination patient was not available for the safety analysis.

The groups were generally balanced in terms of baseline characteristics, although the fixed-dose-combination group were slightly younger than other patients, at an average age of 62 years, versus 65 years.

Moreover, the proportion of women ranged from 50% to 55% in the treatment groups, but was 42% in the placebo group.

More patients had a history of diabetes in the bempedoic-acid-alone and ezetimibe-alone groups, at approximately 50% versus around 41% in the fixed-dose combination and placebo groups.

Notably, there was a substantial proportion of patients across all four groups that was not receiving statin therapy, ranging from 31% in the bempedoic-acid group to 38% in the fixed-dose-combination group.

Significant Reduction

Ballantyne reported that all three treatments groups demonstrated a significant reduction in LDL-cholesterol levels at week 12 versus baseline, at 17.2% for bempedoic acid alone, 23.2% for ezetimibe alone, and 36.2% for the fixed-dose combination.

In patients given placebo, there was a 1.8% increase in LDL-cholesterol levels over the treatment period.

The researchers found that the fixed-dose combination achieved significantly greater reductions in LDL-cholesterol levels compared with all the other groups (P < .001), at a placebo-corrected difference over baseline of 38.0%.

The results also showed that active treatment resulted in decreases in hsCRP levels, at 8.2% with ezetimibe alone, 31.9% with bempedoic acid alone, and 35.1% with the fixed-dose combination.

With placebo patients seeing an increase in hsCRP levels of 21.8% over the 12-week study, the team calculated that the fixed-dose combination was associated with significantly greater reductions in hsCRP versus placebo (P < .001) and versus ezetimibe alone (P < .05).

Similarly, the fixed-dose combination was associated with significantly greater reductions in non-high-density-lipoprotein cholesterol levels, total cholesterol, and apolipoprotein B levels compared with placebo and both treatments alone.

In terms of safety, rates of any treatment-emergent, serious, and drug-related adverse events were broadly comparable between the three treatment groups and, as expected, markedly lower in the placebo group.

The proportion of patients who experienced an adverse event leading to treatment discontinuation was lower with the fixed-dose combination, at 8.2%, versus 10.2% for bempedoic acid alone and 11.6% for ezetimibe alone.

The most common adverse events of special interest with the fixed-dose combination were muscle-related in six (7.1%) patients, alongside new-onset or worsening diabetes in one patient (4.7%), and renal events in one patient.

"Nice Niche"

During the postpresentation discussion, Ballantyne said that the response between patients who were and were not on a statin was "pretty similar," which is in line with what has been seen in previous studies.

Mach asked whether the fixed-dose combination could one day be combined with a statin to create a single pill with all three drugs.

Ballantyne said that it certainly could be done, and "has been looked at," with the cholesterol levels achieved having been "quite robust."

However, that is not on the horizon at the moment as it is felt that the current two-drug combination has a role to play.

"I do think that it would be something that would be appealing, particularly for a lot of our high-risk primary prevention," Ballantyne said. "It's really difficult to get a PCSK9 inhibitor, but we have a lot of people who have high calcium scores or they’re in high-risk primary prevention, and they have difficulty tolerating statins.

"So it would be nice to have something that gives a 40% LDL reduction. I think that could be a very nice niche for the fixed-dose combination," he added.

The study was funded by Esperion Therapeutics. Ballantyne reports relationships with Abbott Diagnostic, Akcea, Amgen, Astra Zeneca, Boehringer Ingelheim, Denis Seine, Eli Lilly, Esperion Therapeutics, Giles, Matinas BioPharma, Merck, Novartis, Novo Nordisk, Regeneron, Roche Diagnostic, Sanofi-Synthelabo, National Institutes of Health, American Heart Association, and American Diabetes Association. Other authors also report numerous relationships.

European Atherosclerosis Society (EAS) 2019 Congress: Abstract EAS19-1133. Presented May 27, 2019.

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