Lipid Lowering Agents Beyond Statins: Ezetimibe and PCSK9 Inhibitors

Erin D. Michos, MD, MHS, FACC, FASPC: Let’s dive into these nonstatin therapies. Before we get into some of the fancier tools that we have, Bob will tell us about the role of ezetimibe. Are we still using ezetimibe? Which patients are candidates of ezetimibe? What’s the evidence behind ezetimibe?

Robert Busch, MD: The evidence is the IMPROVE-IT trial, where ezetimibe was added to a statin, simvastatin, which dropped LDL [low-density lipoprotein] about 20% and lowered events, particularly in patients with diabetes. Once that came out, the American College of Endocrinology widely embraced the goal of getting LDL down to 55 mg/dL. We’ve always used 55 mg/dL as the goal in the extreme high-risk patient with diabetes. Ezetimibe is very well tolerated. It’s generic, although it’s not on the $4 list a lot of the time, so sometimes we have to do prior authorizations for generic ezetimibe. But it’s a pill; it works. We explained to the patient that it’s just like your diabetes drugs: metformin works at the liver and another works at the kidney, making urine like an SGLT2. The statin is lowering the liver, making sugar; the ezetimibe is blocking cholesterol absorption; and 2 of those make the liver upregulate and suck up the LDL so that it doesn’t deposit in the blood vessels.

We’re explaining 2 different mechanisms of action, which they already heard with their diabetes drug before, so that makes it a little easier. The PCSK9 are miracle drugs They’re injectable every 2 weeks or every 6 months with inclisiran. Our patients are used to injection; to us, it’s no big deal. In fact, a lot of our cardiologists interestingly refer their patients to us for a PCSK9. We laugh—“Can’t they give a shot every 2 weeks?” But I love making that phone call to a patient when they’re on a PCSK9, telling them that their LDL is 1 digit is lower than their great-grandchild’s LDL.

Erin D. Michos, MD, MHS, FACC, FASPC: Once you’ve reviewed the evidence supporting the PCSK9 inhibitors, can you mention what the guidelines said about which patients to add PCSK9 inhibitors in? and then mentioned what did the guidelines say about which patients to add PCSK9 inhibitors in? Alison, since you were a co-author on the 2018 cholesterol guidelines, can you answer this?

Alison Bailey, MD, FACC: There were 2 large outcomes trials with PCSK9 inhibitors, both of which added to maximally tolerated statins in patients with ASCVD [atherosclerotic cardiovascular disease] or primary hyperlipidemia. We show a significant reduction in events and a significant reduction in LDL cholesterol, upward of 50% to 60%. Those are associated with reduction in cardiovascular event rates. When we discussed these in the guidelines, we talked about the high-risk patient with ASCVD as the primary group. We went in with more than 50% reduction in LDL cholesterol, to a goal of less than 70 mg/dL. With our recent update, it’s less than 55 mg/dL but more into the European guidelines. That’s the perfect patient to add ezetimibe first line and then a PCSK9 inhibitor. Patients who are statin intolerant—Pam mentioned multiple definitions for that—can’t tolerate a hydrostatin or can’t get a statin dose that would get into that guideline-recommended dose reduction.

Erin D. Michos, MD, MHS, FACC, FASPC: Even in patients with familial hypercholesterolemia, for primary prevention, if their LDL remains above 100 mg/dL despite maximally tolerated statin and ezetimibe, there’s a role for PCSK9 because of their high lifetime risk of ASCVD. Even though in the ODYSSEY Outcomes and 4-year trials, there was a 15% reduction in major adverse cardiovascular events. Those trials had 2% absolute reduction. Those trials were only 2 years, but it looks like the curves are widening. If had they been carried on longer, it looks as if there would have been greater reduction. In fact, some of the legacy data following these patients after the trial ended show that they continue to experience further reduction having had that LDL lowering. These are very important things to be thinking about. Pam, do you want to mention inclisiran? What is inclisiran?

Pam Taub, MD, FACC, FASPC: Inclisiran works on the PCSK9 platform. The monoclonal antibodies, like evolocumab and alirocumab, suck up the PCSK9 protein from the circulation. PCSK9 is a bad protein that basically degrades the LDL receptor prematurely. The LDL receptor is our friend; it clears LDL cholesterol. Inclisiran acts upstream to PCSK9 inhibitors, and it works by preventing the synthesis of the PCSK protein on this really important PCSK9 platform. What’s nice about inclisiran is the way it’s dosed. You can give it every 6 months and get a 50% reduction in LDL. That’s important because adherence is very difficult. As Bob mentioned, a lot of his patients with diabetes are having pills for breakfast. If you can give an injection every 6 months, you’re reducing pill burden and ensuring that there’s adherence. It’s a great new tool to our nonstatin therapy.

Alison Bailey, MD, FACC: Erin, 1 of the other things, as Jorge mentioned, there are pleiotropic effects of the statins. We’re learning more that there may be additional effects of that PCSK9 inhibition. A recent trial presented the PACMAN-AMI trial, which looked at plaque composition with PCSK9s added early to statins after a myocardial infarction. We saw a reduction in plaque volume and fortification of the fibrous cap of the plaque. We think that’s the whole concept of vulnerable plaque and upstream risk for acute coronary syndromes.

Jorge Plutzky, MD: Which may ultimately connect to the extent of LDL lowering and the need to get LDL levels down.

Erin D. Michos, MD, MHS, FACC, FASPC: It’s the safety of giving it in the acute setting in the hospital after an MI. We usually consider these starting as outpatient therapies, but in very high-risk patients, initiating in the hospital is shown to have plaque regression. We’re learning more about the importance of LP(a) [lipoprotein(a)]. You mentioned it as a risk enhancing factor. Therefore, the PCSK9 inhibitors do lower LP(a) 20% to 25% and inclisiran to a similar degree. That may be part of the benefit; we don‘t know. It‘s not approved for LP(a) lowering, but if you have a very high-risk patient who needs additional LDL lowering, and they also have elevated LP(a), these agents are particularly attractive if you’re thinking about initiating the PCSK9 even earlier.

We have the ODYSSEY Outcomes data for the PCSK9 monoclonal antibodies evolocumab and alirocumab. But with inclisiran, which is improved for FDA lowering, there’s an ODYSSEY Outcomes trial ongoing. Pam, do you want to say anything more about that trial?

Pam Taub, MD, FACC, FASPC: There are 2 ODYSSEY Outcomes trials, ORION and VICTORION-2 PREVENT, that both Bob and I are involved in. They’re looking at patients with ASCVD and at the impact of inclisiran on outcomes. One thing I want to mention is how well tolerated the PCSK9 inhibitors and inclisiran are. We’re used to patients complaining about statin-related adverse effects. I’ve had about 50 patients already get on inclisiran. I’m surprised that they’re not calling with any adverse effects. There really are none, including for PCSK9 inhibitors. The adverse effect profile is very favorable.

Robert Busch, MD: For our colleagues listening to this, patients might think, “Oh my God, it’s an injectable,” especially the PCSK9 inhibitors they take every 2 weeks. But no one complains about the second injection because the first 1 is so easy. It’s very easy to give. Because they get LDL lowering so robustly and quickly, patients buy into it because it’s success. It’s an A+ from where they were before.

Transcript edited for clarity