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Evolving Strategies for Cholesterol Management and Atherosclerotic Cardiovascular Disease Risk Reduction - Episode 9

Lipid Lowering Agents Beyond Statins: Bempedoic Acid

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A panel of experts discusses use of bempedoic acid to manage hypercholesterolemia and data with bempedoic acid in combination with other lipid-lowering agents.

Erin D. Michos, MD, MHS, FACC, FASPC: These are definitely important tools. But as mentioned, PCSK9 inhibitors, both the monoclonal antibodies and inclisiran, are injectable. There’s still a role for additional oral agents, particularly in lower-risk patients. We have a new oral agent that’s FDA approved, bempedoic acid. I’m hoping Jorge can explain what it is, how it works, and the evidence behind it from trials.

Jorge Plutzky, MD: It’s been an exciting advance. It’s another chapter in which we say, “Aren’t we done?” No, here’s another chapter, another opportunity to improve outcomes. Bempedoic acid is very encouraging as a therapeutic strategy because you’re into the same pathways and statins, but they’re acting upstream. Bempedoic acid isn’t an active drug. It becomes activated in the liver. The concept, and 1 of the strategies around it, is that it won’t be as active in the muscle because it’s getting activated in liver. You’re giving a prodrug that becomes activated in the liver. You may be able to avoid muscle, which shows in people who complained of myalgias. You’re in the same pathway as the statins.

The LDL [low-density lipoprotein] lowering with bempedoic acid can occur and may not have other issues. It has a significant effect on LDL lowering. Hopefully, we’ll get a chance later on to put this in the context of the other agents. Bempedoic acid is quite effective when used in combination with ezetimibe, and you can achieve significant LDL lowering with that drug. We’ve been using it in the lipid clinic at the Brigham [and Women’s Hospital]. In patients who have statin intolerance, it’s particularly appealing. Patients are in need of additional LDL lowering. But it’s an oral agent. Even though we have great success with the PCSK9 inhibitors and inclisiran for some patients, it makes more sense for them as an adjunctive therapy that’s an oral agent, that can allow you to get down to lower LDL levels. In the patient who’s having issues with myalgias, that may be as a strategy to get around that issue.

Pam Taub, MD, FACC, FASPC: It’s another drug that amazes me because patients don’t have adverse effects. Speaking of pleiotropic effects with statins, bempedoic acid also has some interesting pleiotropic effects. It lowers high-sensitivity CRP [C-reactive protein]. We all know that that’s a marker of inflammation, and inflammation is a big substrate and driver of atherosclerotic cardiovascular disease; that’s very encouraging. Some of the glycemic effects are also very interesting. We don’t see any elevations in blood sugars with bempedoic acid, and with some statins, especially high-intensity ones, they can elevate blood sugars.

Robert Busch, MD: In their ODYSSEY Outcomes study, they’re specifically studying patients with prediabetes to see if it will lower prediabetes going on to diabetes, unlike statins that make patients worry it’s going to raise their blood sugar. As we’ve all mentioned, pill burden is a big deal for patients. Bempedoic acid comes combined with ezetimibe. If they’re on ezetimibe already, it’s an easy change for the patient to say, “I can get you another 20%.” Guess what? You’re going to eliminate the ezetimibe, and the cost might be less than your ezetimibe alone because the company that makes it, with commercial insurance, has vouchers that make it relatively affordable.

Jorge Plutzky, MD: That’s the exact progression. In clinic, if the patient has just had statin intolerance, that’s a scenario in which we feel comfortable. But they’ll often end up on ezetimibe as a nonstatin. They shouldn’t be having the same muscle issues. Then the switch from ezetimibe to bempedoic acid plus ezetimibe becomes easy. One point to make for those who are following closely on this very exciting, evolving science is a very specific target. ACLY, ATP citric lyase, is this enzyme in the same way that we’re targeting HMG-CoA reductase further down the pathways. You’re going upstream to inhibit ACLY when you give bempedoic acid, and the ezetimibe is another separate component that works elsewhere.

Erin D. Michos, MD, MHS, FACC, FASPC: We’ve talked about the LDL lowering 50% to 60% with the PCSK9 inhibitors and inclisiran. With bempedoic acid as a single agent, it’s around 18% to 25% LDL lowering. Combined with ezetimibe, it seems to work better together, about 38% lowering in LDL. That’s almost in the range we get with moderate- to high-intensity statins. Bempedoic acid is available as a single agent and in combination with ezetimibe. It’s been FDA-approved for patients who need additional LDL lowering. We’re still waiting on the Outcomes trial. Maybe Pam can tell us a little about the trial design, which patients were enrolled, and when we might hear results from that.

Pam Taub, MD, FACC, FASPC: The outcome trial is called CLEAR Outcomes. They enrolled a large number of patients who are statin intolerant and a very high percentage of women—almost half the participants are women. The trial has a lot of important future ramifications, including what Bob mentioned about looking at the change in the blood sugar. It’s a global study. We should expect the results by the end of this year. They will hopefully be presented at ACC [American College of Cardiology Scientific Session] in 2023. It’s going to be a landmark study of a nonstatin agent with pleiotropic effects. What I’m really excited about is that it will be 1 of the few studies that has close to 50% women.

Erin D. Michos, MD, MHS, FACC, FASPC: That’s near and dear to my heart. I’m excited to see the results. Will the reduction of major adverse cardiovascular events will be in line with the LDL lowering? Or will there be a greater reduction than just the LDL? How much is the reduction in CRP, and how much is it contributing to events or the reduction in diabetes?

Transcript edited for clarity