The Role of Combination Therapy in Hypercholesterolemia

Erin D. Michos, MD, MHS, FACC, FASPC: Ezetimibe, unfortunately, is not the most potent LDL [low-density lipoprotein]-lowering medication. It’s only around 18% or so LDL-lowering but in combination with bempedoic acid, you can get up to 40%. Then, with the other PCSK9 inhibitors, you can get 50% to 60% LDL-lowering. While we usually try ezetimibe in these very high-risk patients, we often need more, which is why I want to get back to what you brought up earlier: blood pressure. Somebody comes in and their blood pressure is above 160, you’re thinking combination therapy from the get-go. In clinical practice, we waste a lot of time starting with these low doses. Patients come back in 6 months, in a year. If they’re lucky, they get their dose increased; there’s a lot of inertia. In the GOULD registry that Alison had referred to, over these patients with ASCVD [atherosclerotic cardiovascular disease], these high-risk patients, over a 2-year period, only 17% actually have their lipid-lowering therapy intensified. Tell us about the approach for combination therapy. When should we be thinking about combination therapy? What do the guidelines say about combination therapy for lipids?

Jorge Plutzky, MD: The broad message is to push on and to achieve the numbers that we need to achieve in patients, using the tools available and at our disposal. For many patients, that will be combination therapy. The ezetimibe trial is to show someone over 2-4 weeks that, “Yes, you’re not reacting.” We almost never do that in secondary prevention when the risk is higher. Even primary prevention in high-risk, we’ll say, “Well, we don’t want to spend that time waiting.” We’re really pushing on to additional therapies, using combination therapy, and doing it earlier especially in patients at very high risk; we’re going right to combination therapy, especially when patients start off with much higher LDL levels. We have a very low threshold for starting those agents, especially attending on inpatients services. If someone’s having a recurrent event on a statin alone, they need to aggressively move on, and to tailor that to the given patient using the tools you have available with these adjunctive medicines. We do that very early and aggressively, and after having established the rationale for the patient. I think anyone who practices prevention ends up doing motivational interviewing. When someone said to me, “Oh, that’s interesting. You’re really into motivational interviewing,” for the first time, I said, “Well, what is that?” I went back and then realized, well, gosh, this what we’ve been practicing for a very long time, creating a construct where you’re recognizing what the patient is bringing to the discussion. One of those fundamental tenets is that no patient is trying to hurt themselves. No one’s saying, “I was really hoping for a heart attack. I was really hoping you would place a stent.” They’re coming to this point where there may be a wrestling with a question about LDL lowering. Not because they want to harm themselves, but because they don’t fully understand the data, the evidence, and the options for pushing on and tailoring that to the patient. Explaining why they need combination therapy in the context of, “Well, then consider the alternative. If you’re having an event, to not being around. Or being compromised, or being on even more medicines, or having an interventional surgery.” I think that context really says, “Of course, I’ll take 2 medicines, because I need to do this, because the alternative is really dangerous.”

Erin D. Michos, MD, MHS, FACC, FASPC: Thinking about combination therapy very early, in these very high-risk patients; to be intensifying therapy rapidly every 4-12 weeks, if they’re not at goal, to be intensifying to help overcome some of this inertia.

Transcript edited for clarity