So, we're going to talk about evidence, we're going to talk about unique populations, we're going to talk about the multiple treatment options. We'll start with the fact that we're all terrible at this. You're terrible at this, we're terrible at this, we're surprisingly terrible at this. Imagine 50% of patients undergoing PCI actually get a lipid profile checked. About 36% of patients that had a PCI actually get a lipid panel within six months. Those numbers are striking, but it's repeatedly demonstrated how poor we are at actually even checking lipid profiles, never mind treating them. We're even worse when it comes to minorities and underserved patient populations. And this is despite having a ton of data and a ton of therapies to treat this. We're going to talk about many of these, believe it or not, in a ten minute talk. But we have so many options and we're just not operationalizing them. Statins work, statins are foundational therapy. We have decades of data, we have tens of trials, we have so much information. And we've proved over and over that the lower the LDL the better. All the way up to recent years where we're starting to push below the 50 mark and demonstrating the best cardiovascular outcomes. Subhash talked a little bit about very high risk ASCVD and we're going to come back to that. But all the guidelines tend to point at this very high risk ASCVD. Pointing for LDL goals under 55, pointing for reductions of greater than 50% from the American College of Cardiology, from the European Societies, the American Diabetic Associations. We should be pushing really, really, really hard in an organized way to get LDLs down. So what is very high risk for future ASCVD events? You can look at having had events or having high risk conditions. Coupling those, whether it's a recent ACS, a recent MI, a recent ischemic stroke or any of these conditions gets you to a very high ASCVD risk. Notice none of this includes genetics like was discussed previously. None of this discusses prior coronary imaging by non-invasive testing as was discussed previously. So we certainly have to further optimize these algorithms. But here's an algorithm we do have. So the 2022 ACC expert algorithm is a very helpful one to use. Imagine taking everyone that has established cardiovascular disease, checking an LDL, getting them in the high intensity statin, rechecking after six weeks. If they're not very high, you shoot for 70. If they're below 70, great, move on. If they're above 70, you're going to be adding Zetia. If they're still not getting there, you're considering adding PCSK9s or alternate therapies. If they are on the very high risk side, you're shooting for less than 55. If you're not less than 55, you're adding PCSK9s. You can think about benbodoic acid or on glycerin or other agents as second line. High intensity statins are real things. You know, there's not some magic in the branding. It's been studied very regularly and closely, percentage reductions you get in LDL. And so we're thinking about atorvastatin 40 or 80 or resuvastatin 20 or 40 when we think about high intensity statin dose. Follow-up labs sounds tedious, but we're just not good at it. So we have to keep reiterating this concept. We need to be checking follow-up fasting lipid profiles 4 to 12 weeks after statin initiation. Just because someone has a mild liver condition doesn't mean you forget about ever putting them on a statin. You can use them, be thoughtful and safe about cautious, careful checking and also figuring out what mild liver condition actually is. Know that if someone has severe statin-associated symptoms, including myalgias, there are other options including benbodoic acid, which we're going to talk about in a little bit with some of the demonstrated really remarkable benefits in terms of cardiovascular outcomes. Some folks use coenzyme Q10, it's class 3, there's not a ton of great data kind of supporting its recommendation to prevent those symptoms. Also know that the routine measurements in everyone on creatinine kinase and transaminase levels probably aren't really helpful. You could do three hours of talks on statin therapy and primary prevention in women, but a couple things just completely beat home. You have to be very aware if you're treating women, which I imagine everyone is, that there are conditions including premature menopause, pregnancy-associated conditions, gestational diabetes, all of these matter when you're starting to think about someone's overall cardiovascular risk over time. Also be extremely thoughtful about women of childbearing age, it doesn't mean you undertreat them at all, but it certainly means that you have to be having discussions about them, about the risks associated with statins, about the fact that they should be off statins one to two months before a planned pregnancy, that they should be on oral contraceptives or have a plan with regards to prevention of pregnancy if they're on statin therapy. I'm the director of the Peripheral Vascular Talk, so I can't throw in a couple hints about critical limb ischemia in patients with vascular disease. PAD patients benefit from statins. They decrease maize, decrease death, decrease amputation. So next, let's take a tour around the liver as we talk about PCSK9s, as we talk about the citrate pathways through cholesterol availability, all leading to that LDL receptor. We'll start just outside of the liver and the gut. So Zetia. So Zetia selectively blocks this NPC1L1 protein in the gut. It inhibits cholesterol reabsorption. By doing so, particularly when added to statins, it significantly reduces your cholesterol levels. Decreases cholesterol, decreases LDL, increases HDL, decreases triglycerides. Improve It was the main trial in 2015 that gave us really good data about both the benefit from a biomarker standpoint, also the three-component maize benefit with reduction in events with addition of Zetia. The question about this is always that it was added to Simvastatin, which isn't exactly a high-potency statin on our list, but nonetheless demonstrated benefit of a PO therapy in addition to statin therapies. PCSK9 inhibitors. Bear with me for some biochemistry, but we'll try to keep it simple. So what does PCSK9 do? PCSK9 is a protein that binds to and marks the LDL receptor on liver cells for degradation. If you do that, you make more LDL bioavailable in the blood. And so what do PCSK9 inhibitors do? They're actually monoclonal antibodies. They bind to and disable PCSK9 protein, thus decreasing LDL. So Evolocumab, Olirocumab, both have been studied in RCTs and combination therapies with statins and Zetia. The two you have to be able to quote is Fourier and Odyssey. So on one side, it's addition to maximal statin and Zetia followed for two years. In Odyssey, it's followed in patients within four weeks, actually, of having a heart attack. So they're on maximal statin and we're adding PCSK9 inhibitors. Both trials demonstrated robust effects in terms of decreasing major adverse cardiovascular outcomes out to three years or even longer on the Odyssey side. We know also from the extended side of Fourier that if you continue to follow these patients here, the patients treated with placebo were crossed over onto PCSK9 inhibition. And we see that once those curves diverge, they continue to stay long over time. The longer your LDL is low, the better your overall outcomes are over the years. So get these folks started on therapy and get them started well. These are huge benefits. These aren't small numbers for additional therapies, 40% to 60% further reduction in LDL atop statin therapy, significant benefits even in the highest risk patient populations, including those PAD patients. You're not only reducing their cardiovascular risk, their major adverse limb events are also going down. So you're saving limbs and you're saving lives. Higher risk patients like that PAD population get an even larger benefit in terms of their cardiovascular risk reduction when you're adding on these therapies. So the EVOLVE-MI trial we're excited to be part of in Central Texas. This is a patient that's also looking at how early can you start. So if someone comes in and they have a heart attack and you get them started on robust LDL reduction, what's going to be our long-term benefit? This is one of the biggest parts of what we're studying going forward in the next decade. Let's swing over to the other side of the liver and think about what's happening with bimbidoic acid. So bimbidoic acid really is a revolution. If you guys are not prescribing bimbidoic acid to your patients who are either statin intolerant or need additional therapy, you really need to be thinking about incorporating. It's kind of game-changing how we practice. So ATP citrate lyase is an enzyme in cholesterol biosynthesis that's what bimbidoic acid actually inhibits. It's a prodrug. It's activated in the liver. It can be added on to statin plus or minus Zetia for maximal therapy with an 18% LDL reduction. If someone's just on Zetia because they didn't tolerate a statin, it's a 25% reduction. Most interestingly, your statin intolerant patients in the CLEAR outcomes trial, which you saw a little bit about, which I'll show you, this is a PO medication for statin intolerant patients that significantly reduces major adverse cardiovascular events. This is the CLEAR outcomes trial, which you heard about earlier. LDL reduction was profound. High-sensitivity CRP reduction was profound. Every cardiovascular outcome, four-component, three-component, fatal or non-fatal MI, need for revascularization, all decreased significantly. And oh, by the way, it also decreases risk of major adverse limb events in patients with peripheral artery disease. Slightly above the PCSK9 pathway is inglycerin. So what does inglycerin do? Remember what PCSK9 does, right? So PCSK9 binds to and marks the LDL receptor on liver cells for degradation. So inglycerin's upstream of your PCSK9 inhibitors. It's actually a small interfering RNA or siRNA. It actually slows down or shuts down the synthesis of PCSK9, thus decreasing your blood circulating LDL. Again, it can be an add-on therapy, again, up to 50% reduction in LDL levels. Approved since February 2021, or December 2021. Remember, this is an injected dose, a dose on day 90, and a dose six months later. This is another therapy that's being studied. What happens if someone hits the door with this STEMI and you give them a shot that treats their LDL for six months? Really, really interesting. We see robust LDL reduction, 50% delta in their LDL scores over time within the Orion 10 data. Orion 4, I think, is actually going to be finishing up in the months to come. So we should start seeing clinical outcomes data coming from inglycerin as well. Several other trials led by Drs. Moran and Bott and others studying the siRNAs. So LP little a, we've talked a little bit about, so I won't dive into it in this kind of whirlwind talk on every way to treat LDL. But we know that LPAs, little a, is independently associated with long-term MACE. For the structural folks who are just dying to talk about valves, we also get some impact, interestingly, from LP little a, which is kind of poorly quantified, but increasingly interesting over time. This is a challenging test. Why? Because it's not reimbursed. We don't really know how to treat it. We don't know how available it is. It's expensive. We're not really sure what to do with it. Interestingly, some of the therapies we already have help it. So PCSK9s and glycerin nicotinic acid, in particular, will decrease your LP little a. And this is a huge target for reduction in upcoming clinical trials. Opaceron, lepidocerone, pelicascarcin, all these therapies are coming down the line as another means of targeting a novel pathway for LDL reduction. So in conclusion, we're terrible at this. Even in the highest risk patients where it's obvious, we're terrible at it. Statins work, but they only work if we prescribe them and only work if we follow them. Adjunctive therapies are helpful. Benbidoic acid is spectacular, especially in statin intolerant patients. We've got a lot of new targets coming down the line. So always remember, 30% of your job is stenting stuff. 70% of your job is preventing stuff from needing to be stented. And keep that in mind as you're going to work. So quick question for you. Your patient has, your patient's on 80 milligrams of Lipitor, their LDL is 90, and this is your patient that you stented. What is your first go-to? Great. So, you know, in the very high risk patients, we start thinking about adjunctive therapy very quickly. Oftentimes, whether that's PCSK9 additions, and glycerin's kind of tough to get to, or, you know, we'll think about Benbidoic acid additions too. Oftentimes, sometimes insurance plays a role, patient's willingness to take an injection plays a role, but we try to get them there quickly. You know, there's this concept of a capture moment, that time when someone just had a heart attack, that's the time where they don't want to have another one again. They're going to cardiac rehab, they're doing all this stuff, you can get them on therapies that can really work.

LDL management

ASCVD patients

LDL-lowering therapies

statin intolerance

cardiovascular outcomes