 Welcome everyone to the Texas Art Institute Women's Symposium. It's my honor to present this topic in front of all of you, which is non-statin therapies for LDL cholesterol lowering. How do we rationally use them? These are my sources of support and other disclosures, none of which are related to what we are going to be talking about. So the objectives of the talk are that we want to discuss the recent CV outcomes trials with addition of non-statin medications to statin therapy. We want to discuss how we can identify major groups of patients who have demonstrated a CVD benefit with the use of these non-statin agents. The third is that we want to understand how to rationally use these non-statin therapies as recommended by the 2018 AHA ACC in multi-society cholesterol guidelines. And then I want to spend some time talking about newer therapeutic options, vampidoic acid and inclycerin. And I would like to mention this right now that although vampidoic acid is FDA approved, please note that inclycerin as of yet is not FDA approved. So with that, let's start out with what we know about LDL cholesterol lowering. Of course, this is no new news to any of you that LDL cholesterol lowering reduces ACVD events, whether it's primary prevention or secondary prevention. And these are the data from the very large individual patient level meta-analysis performed by the cholesterol treatment trialists. And what we know is that every millimole, about 39 milligrams per deciliter reduction in LDL cholesterol leads to about 20 to 25% reduction in major cardiovascular endpoints. Note that that is a relative risk reduction. And therefore statins remain the mainstay of therapy when we talk about whether primary prevention patients or secondary prevention patients. But the important thing is that despite treatment with statin therapy, residual risk persists. Statin therapy cuts down about one third of the risk that's there, but almost two thirds of the events continue to happen in these patients despite statin therapy. So statin therapies work, don't get me wrong. They work really well, they cut down quite a few events, but despite that, quite a few events in these patients continue to occur. Now, what could be the reason for that? Of course, there's a very long list of things and I'm not going to talk about residual risk today. So what we're going to basically concentrate on are two major reasons. One is LDL cholesterol goal achieved, but then there could be other risk factors, like other risk factors like hypertension, diabetes or inflammation, or it could be poor lifestyle. But the other thing here is that LDL cholesterol goal may not be achieved despite optimal statin therapy, whether that is because that patient is not a good responder, there are adherence related issues or they started out with a very high LDL cholesterol level. Then of course, then there's other list of triglyceride mediated residual risk, L-pyridylated mediated residual risk, but we are going to be focusing primarily on LDL cholesterol mediated risk today. So let's go back into the recent history and talk a little bit about where we have started out with non-statin therapies. Again, I'm going to take you through this journey for the last 10 years when we've had quite a few non-statin LDL cholesterol lowering that have led to improvement in cardiovascular outcomes. Again, I'm not going to talk about HDL raising therapies or triglyceride lowering therapies or L-pyridylate lowering therapies. Just focus on LDL cholesterol lowering therapies that are non-statins. So the first major study that came out looking at a non-statin was improved study, which looked at the use of isothermide in patients who were already on statin therapy in ACS population. And what we noticed there was at the end of seven years, there was about 14 to 15 milligrams per deciliter reduction in LDL cholesterol, which was associated with a 7% relative risk reduction in major vascular events over that seven-year period in this particular trial in about a 2% absolute risk reduction. So that's what we know about isothermide. The other thing that has happened in the past 15, 20 years is our understanding of the genetics and how they impact lipid lowering therapies and cardiovascular events. So this is one of the very early studies that came out looking at PCSK9 genetic mutations or polymorphisms showing that those patients in this data out of Eric's study, those patients who had no nonsense mutation, i.e., they are regular patients, if you look at their median LDL cholesterol levels and compare it to those who have nonsense mutations in PCSK9, whereby the function of PCSK9 goes down, in those patients who have these nonsense mutations, their LDL cholesterol distribution is shifted to the left. So very low levels of LDL cholesterol compared to the general population, but not just that. They had much more reduction in CHD events, almost 88% reduction in CHD events. And I would like to mention a concept here that's extremely important. If we lead to 10%, 20% LDL cholesterol reduction via a medication versus a mutation or a polymorphism, the risk reduction we get from polymorphism is always higher compared to similar LDL cholesterol reduction by a medication, whether that is statin therapy, whether that is a ZMI or a PCSK9 inhibitor. And that is because when somebody has a genetic polymorphism that is associated with lifelong lowering of LDL cholesterol. So it's the area under the curve that determines that those patients who have these genetic polymorphisms have had low levels of LDL cholesterol throughout their life versus somebody who was started on statin therapy or ZMI or PCSK9 in their middle Asia or even later. In those cases, they may not derive as much benefit. Now with that, what we know is that how PCSK9 works. So let's start out with a regular cycle of how LDL particle enters a hepatocyte and how it's metabolized. We all know that when LDL particle comes on the surface of the hepatocyte, it comes in contact with the LDL receptor. It is endocyte post. And then cholesterol is taken up whereas LDL receptor really goes back to the surface and is recycled. It's a very, very efficient system. And because of this recycling of the LDL receptor, more and more LDL particles are brought inside the hepatocyte. Well, what happens when PCSK9 binds to this complex of LDL receptor as well as LDL particle? If PCSK9 binds to this LDL receptor complex, then rather than LDL receptor being recycled, which is what keeps the system extremely efficient, that LDL receptor is degraded into the lysosome leading to lower levels of LDL receptors on the hepatocyte surface and consequently higher levels of LDL cholesterol in the serum. Of course, if we were to then inhibit PCSK9, whether it is due to genetic polymorphisms that I showed you, or if we give an antibody that binds to PCSK9 outside the hepatocyte surface, it does not allow PCSK9 to bind to the LDL receptor complex. And at that point, again, the LDL receptors are recycled that much more efficiently, leading to a very high LDL receptor density on the surface of the hepatocyte. And consequently, a lot of these LDL particles are brought inside the hepatocyte, leading to lowering of serum cholesterol levels. When we look at the outcome studies of PCSK9 inhibitors, of course, the two major trials that we have right now are the Fourier trial and the Odyssey outcomes trial. And most of you would know that these were patients with secondary prevention in whom PCSK9 inhibitors were used for these outcomes trials. Fourier trial was a trial, a very large trial of almost 28,000 patients with stable established ASCVD. So prior MI, prior stroke, symptomatic peripheral arterial disease, these patients were all on stacking therapy. And if their LDL cholesterol levels are above 70 milligrams per deciliter, or their non-HDL cholesterol levels were above 100 milligrams per deciliter, then they were randomized to either have a look command, one of the PCSK9 inhibitors, or placebo. And then these patients were followed for a median followup of about 2.2 years in this particular trial. What we know is that LDL cholesterol levels were lowered by close to 60%. Absolute reduction in LDL cholesterol of about 56 milligrams per deciliter. Median levels of LDL cholesterol were close to 30 milligrams per deciliter in this trial, one of the lowest we have seen in a randomized control trial of LDL cholesterol lowering. And what we found was that the use of evalucamab in stable but high-risk ACVD patients was associated with a 15% relative risk reduction, about 1.5 to 2% absolute risk reduction in the primary endpoint, which was a larger large endpoint, including CV death, MI stroke, revascularization for unstable angina, as well as hospitalizations for unstable angina. And when you looked at very hard outcomes, which was the CT secondary outcome, which included MI stroke or CV death, removing hospitalization for unstable angina or revascularization, again, what we see is about a 20% risk reduction that was relative and about 2% absolute risk reduction at a median followup of 2.2 years. As I mentioned, that there were quite a few patients who achieved very low levels of LDL cholesterol impact. If you look at the distribution of LDL cholesterol levels in this trial, what you will find is that 10% of patients actually achieved LDL cholesterol levels of 20 milligrams per deciliter or lower. So less than half a million, 10% of the patients, 40% of the patients achieved LDL cholesterol levels of 50 milligrams per deciliter or lower. And what we found in this particular study was that there was a monotonic relationship between achieved LDL cholesterol levels and cardiovascular outcomes. Of course, what you get is less and less as you move more and more down on this line, but the relationship itself is monotonic. With that, there were no safety concerns. Now, one of the concerns in those days was that maybe low levels of LDL cholesterol will lead to neurocognitive side effects. And this was an FDA mandated study. So it's a subgroup of Fourier study, which is known as the Ebbinghaus study, where these patients underwent quite an extensive neuropsychological battery that was done both pre and post, at least at 19 months of follow-up, there did not seem to be any significant impact of the use of Avalocomap or neurocognitive function in these patients. So remember, these were patients with stable ASCVD. Then we had another large outcome trial, Odyssey outcome trial, which was performed in patients with ACS. So now we are looking at patients who are higher risk because they had an acute coronary syndrome event in the last one up to 12 months. And then these patients again were receiving the standard of care at that time, which was marketed to high-intensity statin therapy. In fact, in most patients were on high-intensity and those who were not were on maximally tolerated statin therapy. And then they were randomized to another PCS-canine inhibitor, in this case, alirocuma or placebo. And the median follow-up here was a little bit longer, about 2.8 years. And then 44% of the patients had a follow-up of more than three years. And in these patients, again, the primary outcome was a four-point maze as opposed to five-point maze for the Avalocomap treatment, which was the four-year trial that we just talked about. So again, unstable adrenary coronal hospitalization was part of it, but revascularization was not. And when we look at what happened in this particular study, the use of alirocumap in this particular study was associated with a 60% reduction in LDL cholesterol. As you can see here, of course, there was a titration protocol here. So the achieved LDL cholesterol levels are not as low as what we saw in four-year trial. But again, even in this study, at a median follow-up of 2.8 years, there was a 15% relative risk reduction and 1.7% absolute risk reduction in the primary efficacy endpoint with the use of alirocumap in patients with ACS. Now, I've showed you data for ZMI, but I've showed you data for the two PCS canine inhibitors. But I think there is a lot of learning there that even among these patients who are secondary prevention patients, we can identify patients who are to derive the most benefit from the use of these non-statin therapies on top of statin therapies. So these are data, again, from improved trial. Remember, this is the trial where ZMI was given on top of moderate intensity statin therapy. So what these investigators did was they looked at these nine risk markers or risk indicators, which you can see are all very easily available from any EMR when we're evaluating these patients in our clinic. And if these patients had zero to one of these risk indicators, you will notice that the risk of events was very low at follow-up of seven years. As you accrue more of these, if you had two or more of these risk indicators, your risk of having an event was much higher. If you had three or more, your risk was 34%, which was the average risk in the placebo arm. In fact, if you had five or more of these risk markers, which would not be unusual if you look at these risk indicators, the event rates are close to 69 to 70%. So seven out of 10 patients, if they have more than five of these risk indicators would have a recurrent cardiovascular event, and that's no surprise. But that's not the entire story. When we look at the benefit of ZMI, that was also dependent on these risk markers. So if you had zero to one risk markers, you did not derive any benefit from the use of ZMI. If you had two of these, you derived a 2% absolute risk reduction, which was the average absolute risk reduction in this trial. But if you had three or more of these risk markers, the absolute risk reduction was 6%. So the numbers needed to treat was 16, much lower than 45, what you would need for two of these risk markers. And of course, when you have zero to one of these, there is no benefit. When you look at the same trial and you look at patients who had polyvascular disease, if they had atherosclerosis in more than one bed, they had ACS, but they also had schemic stroke or PAD, look at the event rates. The event rates are much higher, but at the same time, these patients derive a much larger absolute risk reduction with the use of ZMI. Similarly, when we look at Asias with polyvascular disease and diabetes, the event rates are even higher. But again, the absolute risk reduction is also higher and you only need to treat 10 to 11 patients to prevent one major vascular event in these particular patients. So the point being that even amongst these patients who are secondary prevention patients, they're not all created equal. Their risk profile is different and consequently the benefit they derive from the use of non statins is different as well. Similarly, when you look at patients with peripheral arterial disease, you find similar things when you look at the use of PCS-canine inhibitors. So it not only holds true for azatomide, but also for PCS-canine inhibitors. These are data from Fourier study. And when you look at patients with PAD, those patients have a much higher event rate compared to those who do not have PAD along with a Schemic Heart Disease or Schemic Stroke. But importantly, these patients derive a lot more benefit from the use of PCS-canine inhibitors compared to those who do not have peripheral arterial disease. If you look at data again from Fourier trials, patients who had their qualifying MI less than two years before the events, much higher event rates. If you had two or more MI's, much higher event rates. If you had residual multi-vessel CAD, much higher event rates. But at the same time, when you look at absolute risk reduction, much higher in those who had more recent MI, higher number of MI, as well as those who had multi-vessel disease that was present. So we can identify even for PCS-canine inhibitors which patients will derive the most benefit from the use of this class of therapy. You look at data from Odyssey Outcomes. Again, similar story. Look at the event rates in the placebo group, which by the way here is statin arm. Look at the event rates for those who have LDL cholesterol levels at baseline of 100 milligrams per desicc or higher. Much higher event rates compared to those who are below 100, but at the same time, the absolute risk reduction is much higher, 3.4% compared to 1.6%, which was the average absolute risk reduction in this particular trial. And therefore, when we identify these patients, the numbers needed to treat comes down drastically. We can have more impact of our therapies that may not be as easily accessible and maybe in some cases very expensive. So based on all of this, the 2018 AHA-ACC cholesterol guidelines are asking us as clinicians to also perform risk stratification when it comes to our secondary prevention patients. So not just primary prevention, we perform risk stratification, but also in secondary prevention. So they talk about two categories of secondary prevention patients. Patients not at very high risk and ACVD patients who are at high risk. And as you notice here, in both of them, high intensity statin therapy remains our first priority in terms of how we need to treat these patients. But then these guidelines identify a very high risk ACVD group, which again, based on what I just showed you, you can pretty much guess what that group will be. Those are patients who had major ACVD events, that is they had recent ACS, they have history of prior MI in the absence of this ACS event. So if they had multiple ACS events, history of Schemic Stroke, Symptomatic PAD. If these patients had two or more of these ACS events, well, they are very high risk. On the other hand, if they had one of these major ACVD events, and if they have two or more of these high risk conditions, which again would make sense, whether it's age more than or equal to 65, heterozygous FH, history of prior PCI or cabbage, diabetes, hypertension, chronic kidney disease, smoking, high LDL cholesterol, history of heart failure, or again, any of these, if you have those, if you have two of those and you have only one major ACVD event, again, you will fall into this very high risk ACVD group. And those are the patients where after intensifying statin therapy, the guidelines would recommend use of azetamide and sequential use of azetamide followed by PCS canine inhibitors if LDL cholesterol levels remain above 70 milligrams per deciliter, despite the use of statin therapy and azetamide. And of course, one may ask why that's the case. So again, the use of azetamide followed by the use of PCS canine inhibitors. And then the reason for that is if you look at a lot of simulation studies both within and outside, very large healthcare systems like VA, what you will notice is that a large majority of these patients will really drop their LDL cholesterol levels below 70 milligrams per deciliter by the use of high intensity statin therapy combined with azetamide. So as per the guidelines, identifying very high risk ACVD patients, maximizing statin therapy, statin adherence, and then using azetamide followed by PCS canine inhibitors as needed and reserving these therapies for our very high risk ACVD patients. Let's quickly pivot and talk about two other therapies that lower LDL cholesterol. The first one is Bampidioic acid. Now it works on the same pathway as statin but a little bit higher up. But the important thing is that this is a pro drug that has to be converted into an active drug inside the hepatocyte using this enzyme called ACS-VL1. And once that's done, it converts into an active compound. And then that is what actually leads to inhibition of an enzyme called ATP citrate-Liase which is higher up in this cholesterol synthesis. It's in the same pathway as HMG-CoA reductase which is inhibited by statin therapy. So much higher up in the same, but in the same pathway. And it leads to the same effect, increase in LDL receptors because cholesterol level inside the hepatocytes go down. But the important thing is that since ACS-VL1 is only present in the liver, but not in the skeletal muscle, there is this possibility that it will reduce the occurrence of statin associated musculoskeletal side effects that are sometimes very common in some of our patients who are taking statin therapy. Now, if you look at the genetics of ATP citrate-Liase, you will find that even genetics prove towards a possibility theological role of these patients. So genetics are supportive that this lowering LDL cholesterol using this mechanism will likely be beneficial, although we do not have any outcomes trials. If you look at the efficacy program related to bapidioic acid, we've had multiple trials, clear harmony, clear wisdom, clear serenity, clear tranquility. It's all clear and it's all a lot of wisdom and serenity and tranquility. When you look at these trials, what you see is that of course, a lot of high-risk patient populations were enrolled in these trials with a decent follow-up. And when you look at these trials and I'm using clear wisdom as one of the trials here, and as you can see here, clear wisdom is a trial that use patients with ACVD or heterozygous FH who are on maximally tolerated statin therapy overall, there was about a 15% reduction in LDL cholesterol. But as you can imagine, since it works on the same pathway as a statin, you have much larger reduction in LDL cholesterol among patients who are not taking statin therapy. Whereas those who are taking statin therapy, it's much lower reduction in LDL cholesterol, more like 15%. So for bapidioic acid, studies show that it lowers LDL cholesterol about 15 to 25% on a background of statin therapy. And as we discussed, there's higher LDL cholesterol reduction in patients not on statins. Again, there is a medication available that combines bapidioic acid and azetamide that leads to about 35% reduction in LDL cholesterol. As we discussed, it's not active in muscles. And overall, it has good safety profile, except two things that we need to know as clinicians. One is that it leads to uric acid increase. So those patients who have history of hyperuricemia or doubt, we need to follow the uric acid levels. And it has a small but appreciable increase in the incidence of tendon rupture, which needs to be kept in mind when we are treating these patients. We, of course, do not know whether it improves cardiovascular outcomes. We have some genetic data that would seem to point towards that. So there's a large global study right now going on in patients who have CV events or who have very high risk of CVD events who are statin intolerant, who are enrolled in a trial called Clear Outcomes. And this trial will tell us whether the use of bapidioic acid is associated with an improvement in cardiovascular outcomes. So we know that it lowers LDL cholesterol between 15 to 25% whether it improves cardiovascular outcomes we'll find out once the results of Clear Outcomes are out. So then let's talk about another group of medication that is not approved by FDA currently, which is Inclinceran. And that is an SIRNA. It's an RNA inhibition technology whereby you have small interfering RNA. It's a double-stranded RNA, which is delivered to the liver. You give it subcube. It has this gel-nac entity attached to it, which binds specific receptors on the hepatocyte surface. So very much targeting of the drug to the organ where it really needs to work. So it reduces the need to have very large doses which sometimes are required for this small interfering RNA molecules. But by targeting the tissue where it needs to act, it really lowers the dose that needs to be given for this particular drug. It has two strands. Again, it goes into the hepatocyte, binds this risk complex, this RNA complex. And when it binds that, again, the guide strand remains there. The passenger strand, which brings it there, dissociates. And once that happens, then it binds to the messenger RNA in the cytoplasm for PCS canine inhibitor. And once it binds to that messenger RNA, that messenger RNA for PCS canine is again degraded. And just like PCS canine inhibitors, the LDL receptor levels go up. So again, remember PCS canine inhibitors bind here outside the hepatocyte, right? They bind the PCS canine protein. And this SIRNA actually binds to the messenger RNA of PCS canine basically doing the same thing but doing it inside the hepatocyte, allowing you to have very long action, duration of action, allowing you to not give the medication like every two weeks or every four weeks, what we do with the PCS canine inhibitors currently. So when we look at what is the efficacy data that's available for this medication, we have three large trials, Orion 9, 10 and 11. Orion 5 is still ongoing, but then we have data from 9, 10 and 11, which has looked at heterozygous FH patients, second prevention patients, as well as secondary and high risk primary prevention patients. And this medication, the way it is given is that you give the first dose, you give the second dose at 90 days, and then you follow it every six months. So on a stable situation, one would give this drug basically twice every year. So one could potentially tie it with a patient's visit to a primary care or a cardiologist's office and then be done with this, right? So the question is how does it work? When we look at this combined meta-analysis of Orion 9, 10 and 11, what we found was that it lowers LDL cholesterol by about 50%, very similar to PCS canine inhibitors. And again, lowers PCS canine levels by almost 80%. Overall, it seemed to be safe except self-limiting mild to moderate treatment associated adverse events at the injection site and a mild increase in bronchitis. But otherwise, no difference in muscle toxicity, liver toxicity, or hympliological problems in these trials when we combine data from Orion 9, 10 and 11 about 3,600 patients. We again, just like BAMPID-boic acid, there's an outcomes trial called Orion 4-CV outcomes trial that is ongoing with Inclinsterion right now looking at cardiovascular outcomes in patients with stable atherosclerosis. Those with MIFRs show or prefer arterial disease. And we'll see if this medication improves cardiovascular outcomes in addition to a lowering LDL cholesterol, which we know it does at this point. So if I have to look at the great journey of lipid lowering medications in the past three decades, really this is where we are. We started out with statins in 1990s. We of course had quite a few trials done with statin therapy in very many different times of patient populations. We of course on our way had some trials that did not show benefit. We had the trials related to fibroid therapies that did not turn out. We had trials related to HDL raising, aim high that did not work out. And then we have trials that have shown benefit. For example, Fourier and Odyssey outcomes. And now we are in this phase when we're looking at BAMPID-boic acid as well as Inclinsterion. So we have come a long way with a lot of therapeutic options available for clinicians to use on their high-risk patients. So what are our take home messages? Well, high-intensity statin therapy plus lifestyle that is healthy remains the first step in secondary ASCVD prevention. The 2018 AHA ACC multi-society cholesterol guidelines identify a very high-risk ASCVD group among secondary prevention patients. So we need to perform risk stratification even in our secondary prevention patients because these very high-risk ASCVD patients are the patients who have the highest absolute event rate. And therefore, these are the patients who will derive the highest absolute risk reduction with the use of non-statin therapies. For example, is that am I been PCS canine inhibitors? But remember that statin use and emphasis on statin adherence remains the first step before we perform a step-wise addition of ZMI or PCS canine and very high-risk patients. And several newer options may provide clinicians further non-statin options for lowering LDL cholesterol, Bapidioic acid being something that is FDA approved and in glycerin that is not FDA approved. Both of them are undergoing their CV outcomes trials right now. So again, with that, there's a lot of hope in the field of LDL cholesterol loading by non-statins. Thank you for your time. Take care.