Case-Based Evidence for Cardiovascular Risk Reduction - Episode 11
Deepak Bhatt, MD, MPH: Let’s move on to discuss the future, specifically what may be coming down the pike in terms of emerging therapies? Jamie, perhaps we can start with you and the recent approval for bempedoic acid as monotherapy and combination therapy with ezetimibe? What is the future for statin-intolerant patients?
James A. Underberg, MD: I want to echo your comments from a couple of years ago. Rumor had it that lipidology and cardiovascular disease prevention were dead. There were no treatments available that were going to be new and helping us. You all probably remember what was going on. Look at where we are now. There are new treatments available all the time for us to utilize when we try to take care of patients at high risk for recurrent cardiovascular events or even initial events.
Bempedoic acid is newly available, but unlike icosapent ethyl, we do not yet have any outcome data accessible regarding its effect on heart attack, stroke rates, or cardiovascular end points. It is an ATP citrate lyse inhibitor that inhibits the cholesterol synthesis pathway. Bempedoic acid is 2 steps higher from the rate-limiting enzyme—HMG coenzyme, a reductase that we all know and remember as the target for statins. Because it’s not the rate-limiting step in cholesterol synthesis, inhibiting it doesn’t have the same robust effect on LDL [low-density lipoprotein] lowering that we see with statins.
When used as monotherapy, it lowers LDL cholesterol about 17%. When used in combination with ezetimibe, because there was a fixed-dose combination product available with bempedoic acid and ezetimibe, it does lower LDL cholesterol about 38%, which is a slightly more robust reduction in LDL cholesterol. However, some of that is from the ezetimibe, much like combining statins and ezetimibe. What is unique about bempedoic acid is that when it’s delivered, it’s delivered in an inactive form. Bempedoic acid is converted to its active form by an enzyme specific to the liver but not found in the muscle.
Unlike statins that are taken up and active in both the muscle and the liver, bempedoic acid is active only in the liver. Whether that ascribes to it a better muscle-related adverse-effect profile is unclear. In its clinical trial data, it seems to be well tolerated from a muscle-related adverse-effect perspective, but there are no head-to-head data with statins as monotherapy. In most of the trials it was given on top of statin therapy. It is indicated to be given in patients only with either ASCVD [atherosclerotic cardiovascular disease] or familial hypercholesterolemia or on optimal statin therapy, which could be 0 mg a day of a statin if they can’t take any.
Also, it is used to lower LDL cholesterol, which is the indication it has right now. It’s not outlined as an option in the guidelines because it wasn’t available to us when the guidelines were written; they’re very evidence-based in utilizing medications in the guidelines. If someone is going to use it now, you’re using it based on the FDA indication for the medication, and I believe its role is to be later on down the pathway after many of the medications we’ve spoken about for which we do have the data regarding cardiovascular risk reduction.
Deepak Bhatt, MD, MPH: That’s terrific. Any specific comments about outcomes studies and when they might come and how that might influence this discussion?
James A. Underberg, MD: There is an outcome study being done right now. It’s interesting because it’s being done in high-risk patients, mostly patients with ASCVD who are statin intolerant. Although the drug is not as robust as some of our other lipid-lowering agents, it’s being compared in many cases with placebo. As a result, there is a good chance that we may see a positive outcome in this trial. However, while the result is 3 or 4 years away, it is close to being fully enrolled. We will have that data, but it will not be available for several years.
Deepak Bhatt, MD, MPH: That’s good stuff on bempedoic acid.
Transcript Edited for Clarity