Mechanism of Action: Bempedoic Acid vs Statins

EP: 1.CLEAR Outocmes Trial Overview: Non-Statin Therapies for Patients with Atherosclerotic Cardiovascular Disease (ASCVD)

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EP: 2.Mechanism of Action: Bempedoic Acid vs Statins

EP: 3.Examining CLEAR Outcomes Trial Structure

EP: 4.Key Data Analysis from CLEAR Outcomes Trial

EP: 5.Adverse Event Profile of Bempedoic Acid

EP: 6.Advantages of Bempedoic Acid in Cardiovascular Disease Treatment Landscape

Seth S. Martin, M.D., M.H.S., FACC, FAHA, FASPC: As we get into the trial itself and the specific intervention used in the trial, it’s important for us to think about and understand how bempedoic acid works, what the mechanism of action is and how this differs from statins. Maybe you can take the lead on that, Leslie.

Leslie Cho, M.D., FACC, FESC, FSCAI: Bempedoic acid is an ATP citrate lyase inhibitor, which prevents cholesterol formation. It works 2 steps above HMGCoA reductase, which is where statins work. But there’s been a hypothesis that because it works, because it’s a prodrug and you need to be activated in the liver and not in the peripheral tissues, perhaps it decreases the myalgia symptoms that are associated with statin intolerance.

Seth S. Martin, M.D., M.H.S., FACC, FAHA, FASPC: That’s a key point about it being a prodrug and not affecting the liver, which is key for this population of patients with statin intolerance or with a history of statin-associated muscle symptoms. It’s quite helpful in that it works similar to our other lipid drugs that we’re comfortable with, in the sense that it upregulates LDL [low-density lipoprotein] receptors and cleans out the LDL garbage.

Leslie Cho, M.D., FACC, FESC, FSCAI: That’s right. As you put it, this was a pragmatic trial design. It was meant to be pragmatic. We included primary and secondary prevention patients. Maybe you can talk about the inclusion criteria of the trial for us.

Seth S. Martin, M.D., M.H.S., FACC, FAHA, FASPC: The key inclusion was a history of statin intolerance, but also the patient could be in the primary or secondary prevention setting. In the subsequent question, we’re going to get into how the characteristics broke down for the groups, but it’s a very important criterion to consider because many trials have been exclusive to the secondary prevention space. Allowing in high-risk primary prevention patients broadened the population and differentiated the trial from other nonstatin trials, such as the IMPROVE-IT trial, which had tested ezetimibe and was a secondary prevention trial. This was an interesting criterion to have that breadth because this is the first oral nonstatin agent being tested with that breadth. Those are the key inclusion criteria. The age went into the 80s, so they included a wide spectrum of ages. Leslie, are there other criteria you’d like to highlight?

Leslie Cho, M.D., FACC, FESC, FSCAI: The most important thing was the consent process. We took 13,790 patients. That’s a lot, and these were patients who could not tolerate statins. Either they couldn’t take the maximum dose of statins to get their LDL down, or they couldn’t take any statins. Sometimes patients can take an intermittent statin or different types of statins. Patients were asked to sign a consent form, which is very unusual. In it they said they understood that statins are a cornerstone therapy and have been shown to decrease heart attack and stroke, and that they understood the benefits but could not take statins. That’s what they were signing up for. The physicians also had to sign. It was an incredibly rigorous way to help patients understand, “Statins are great, and we’d love for you to take statins. But you can be in this trial only if you can’t take statins.”

Seth S. Martin, MD, MHS, FACC, FAHA, FASPC: I loved it, I thought it was a patient-centered approach that made sure that this was being done in the most ethical way, in the way patients were making an informed decision.

Transcript edited for clarity.