Good morning everyone, thank you for coming this early to this presentation on PCSK9 inhibitors and it's titled Basic Biology to Clinical Outcomes. I am Connie Newman, I'm an endocrinologist and I've been a member of the Endocrine Society for many, many years since I was a fellow and the society has really helped me throughout my career and so I urge everyone here to think about getting more involved in the Endocrine Society. I want to thank the Endocrine Society for inviting me to speak today. My area of expertise is lipids, cholesterol and triglycerides and in particular I am a member of the Cholesterol Treatment Trialist Collaboration which has done and continues to do meta-analyses, patient level meta-analyses of the large statin trials mainly. So, I do not have any disclosures. So this is the barcode that everyone needs to, I don't know, photograph so you can ask questions. No questions right now, okay. Are you set in the room with that? Everyone, and any, okay good. And I guess people who are here virtually, I'm not sure if there are any, have to do this as well. Okay, so I'm gonna start with a patient. This is a 74 year old man who has type two diabetes and hypertension and he's had an MI and he's taking atorvastatin 80 milligrams, ezetimibe 10 milligrams, as well as valsartan, metformin, semaglutide. He also takes vitamin D. And he presents with intermittent chest pain which is associated with nausea and which is intensified by exercise. So in physical exam what's notable is that his BMI is 30 meaning he has obesity. He also has xanthelasma. And when we look at his labs the most interesting finding is the LDL cholesterol is 75 milligrams per deciliter. His HDL is 50, triglycerides 175, a little bit elevated. And his A1C is 7.2%. Okay, so here's my first question which I think is relatively easy. What is the first line medication to be used as adjunct to diet and exercise for lowering LDL cholesterol? So I'm gonna ask you just to write this in. See if we get anything, what we get. Write in the name of the medicine. Because it's not a ABC slide. Good, I see one. I don't know if we'll see more. Okay, so the answer of course is a statin. You know, the class of statins has been around since 1987. And they've been proven in many large term outcomes trials to reduce cardiovascular disease including MI, stroke, and also revascularization procedures. So here's another question. Would you change the patient's lipid lowering regimen? He's a 74 year old man with a history of an MI. His LDL is 75. So yes or no, would you change it? Interesting. Does anyone need more time to vote in the room? Okay, so that's interesting. About 70% said yes and 25% said no. And we're gonna talk about that later after I give you a bit of a background. And this is just an informational question. Have you treated patients with monoclonal antibodies to PCSK9? Oh great, so about half. Oh, a little more than half right now say yes and 40% no, that's good to know. And the next question is, have you treated patients with Inclisiran which is the newest drug we have for lowering LDL cholesterol? Yes or no? Well, it looks like most people here, or 100%, say there might be one person who says yes, but most people say no. So I'm gonna talk a lot about Inclisiran today. And I think this is a really important new medication which could actually change the way we manage cholesterol in the future, especially if the price gets to a reasonable number. Right now it'll be about $6,500 a year after the first year. Okay, so I'm gonna talk a little bit about in the beginning about LDL lowering medications. And what they do is they work by upregulating the LDL receptor. So we have, let's see if I can point. So we have bile acid sequestrants and azetamide that work in the GI tract. Also statins and benpedoic acid which work on the enzymes in the cholesterol synthesis pathway. And then we have the PCSK9 inhibitors. And I'm including Inclisiran in that although it's not really a inhibitor of PCSK9. So that's what I'm gonna focus on today. So what is PCSK9, Proprotein Converte Subtilisin Kexin Type 9? It is a protein which binds to LDL receptors and it escorts the LDL receptors to the lysosome in the liver where the receptor is degraded. So therefore PCSK9 lowers LDL receptors which means the LDL levels would increase. So fewer LDL receptors decrease the clearance thus as I just said increasing the concentrations of LDL. Here is a figure that I have borrowed from a paper by Ogura in Journal of Cardiology. And if you look at the left part of this, oops, sorry, I knew. If you look at this side, what we see is the LDL molecule binding to a receptor and it gets into the lysosome and LDL is degraded to amino acids and cholesterol. And the receptor though is recycled, goes back to the surface of the cell in this instance. And that's the way LDL is metabolized part of the time. But there's also a protein called PCSK9 and what that does, it binds to the LDL receptor and you see the LDL in the little yellow circles in the receptor and then it takes the LDL receptor and the LDL, it takes it to the lysosome and the LDL receptor is degraded. And that is the way we lower LDL receptors can be reduced and this would increase LDL cholesterol. So there are two ways that we can modify what PCSK9 does. The first method was developed many years ago and I think that two drugs were approved in 2015 and these are monoclonal antibodies to PCSK9. They inhibit the binding of PCSK9 to the LDL receptor and this reduces the degradation of the LDL receptor in the liver and it increases the recycling of LDL receptors so we have more receptors, lower LDL levels and now we have a small interfering RNA. It's called an siRNA which was approved in 2021 in the US and prior to that in Europe and this reduces the translation of PCSK9 mRNA. We'll talk about that in a minute. So going back to our first patient, just to remind you, he's a 74-year-old man. He has had an MI, he has type 2 diabetes so he has risk factors for atherosclerotic cardiovascular disease and he's taking atorvastatin 80, he's at MI10 and his LDL is 75 milligrams per deciliter. So I'm showing you the barcode again for anyone who has just come in the room because that way you can answer the polling questions. I'll give everyone a minute. Are you all okay with that? Does anyone need more time? Okay, oh, there's someone new. I guess I'm gonna have to move on because of the time. If you can photograph this barcode quickly, you'll be able to answer the polling questions. So which of the following options that I'm gonna show you is appropriate for this patient who's got type 2 diabetes? This patient whose LDL is 75. And you can choose more than one. And you'll vote on the next slide. Recommend no change in medications. Add benpedoic acid, 180 milligrams daily. Add evolocumab, 140 milligrams subcutaneously every two weeks. Discontinue atorvastatin and start resuvastatin, 20 milligrams a day. Or add Inclisiran, 284 milligrams subcutaneously at first dose. Inclisiran is the small interfering RNA that I spoke about before. So, you can choose A, B, C, D, or E. Okay. Well, this is, I see everything is changing. So, I think most of you have voted to add evolocumab, some to add Inclisiran, and 20% say no change whatsoever. So I'm gonna talk about what I think would be the correct answers. So, I think the answers that are correct would be to add evolocumab, or you could add allorelcumab, or you could add Inclisiran with 284 milligrams for the first dose. It would then have to be given three months later, and then six months after that, and every six months. And it's subcutaneous. So, why are we targeting PCSK9 in this patient who's already on a statin and a Zetimibe? He has a history of recurrent MI, and because of his type two diabetes, his MI, and his new chest pain, he is likely to have another MI. And an LDL of 75 can be further reduced, which would provide additional atherosclerotic cardiovascular disease benefit. And PCSK9 inhibition with evolocumab or allorelcumab, or using Inclisiran to actually catabolize the messenger RNA for PCSK9, would reduce LDL by an additional 50%. So before, does anyone have any questions about that? Okay. I'm looking for questions from virtually. So the two mechanisms of pharmacological inhibition of PCSK9 are the monoclonal antibody, which you all know about and some of you have used, and the small interfering RNA, which directs the catalytic breakdown of the PCSK9 messenger RNA, thus reducing the synthesis of PCSK9. I'm gonna show you a few slides showing some data from the large outcomes trials of evolocumab and allorelcumab, looking at LDL reduction and also cardiovascular event reduction. And this is from the Fourier trial, and we can see there is a mean reduction in LDL, and these are patients that are on statins, of 59%, and the median LDL is 30, which is low, but it's okay. And if you look at the cardiovascular outcomes in this trial, and these were a composite outcome of cardiovascular death, MI stroke, hospitalization for unstable angina, and coronary revascularization in these patients with ASCVD, there was a 15% relative risk reduction in the primary endpoint, and the absolute reduction was 2%, 14.6% to 12.6%. If we look at allorelcumab in the Odyssey outcomes trial, you see again a very large reduction in LDL on top of a statin, and that was about 63% in this trial, and the on-treatment LDL, that means patients who were taking the medication, was 53.3 milligrams per deciliter. And again, there was a statistically significant relative risk reduction in cardiovascular disease with an absolute reduction of 1.6%. So this is a schematic showing Inclisirin. So we see it has two strands, and it's combined with some other amino acids, or it's combined with 3X, Gal-A-N-A-C-N-acetylglucosamine at the sense 3 ending, and this enables hepatic uptake, because that's where Inclisirin works. It works in the liver, and what happens is that the antisense strand separates from the other strand, and it's incorporated into a RNA-induced silencing complex, and this RNA-induced silencing complex catabolizes the messenger RNA for PCSK9. And we do have some data of the effect of Inclisirin on PCSK9 levels and when the dose of 284 milligrams was given at day one and at day 90, three months later, PCSK9 levels were reduced by 75% and 69% at day 120 and day 180. And here's some data from a trial of Inclisiran looking at the effects on LDL cholesterol in patients, let's see if I can use a pointer, in patients with heterozygous familial hypercholesterolemia and we see a 48% reduction in LDL, this is on top of a statin, and in patients with heart disease, a 51% reduction in LDL cholesterol and these are at day 510 and this medication was given at day one, day 90, day 270 and 450, so it was not given very often and these effects are long lasting. So just to summarize, Inclisiran is a small interfering RNA directed to the PCSK9 mRNA, it is indicated, and this is from the FDA label, as an adjunct to diet and maximally tolerated statin therapy for lowering LDL in adults with heterozygous FH or with atherosclerotic cardiovascular disease. Right now we do not know its effect on cardiovascular morbidity and mortality, but our study is ongoing. It reduces total cholesterol, LDL, ApoB and non-HDLs. Cholesterol has a small effect on triglycerides, about 10% and it is dosed on day one at three months, six months later and then every six months. And the most common side effect is injection site reactions and there's no evidence right now for adverse effects on liver or on the kidney or on muscle or on platelet counts but it has not been studied in patients with end stage renal disease or severe liver disease. Just wanted to review something about the pharmacokinetics. With single dose of this, of Inclisiran, plasma concentrations peak at four hours and they're undetectable 24 to 48 hours after the dose. But remember, Inclisiran works in the liver. So this is really not relevant to its action. There's similar findings like that with multiple dosing. Its half-life of elimination is nine hours and it's primarily metabolized by nucleases and it's not a substrate for CYP3A4 or transporters as are many statins. Also, when given to people with mild, moderate or severe kidney disease, there was a two to three-fold increase in area under the curve and also a one to two-fold increase in patients with mild or moderate hepatic impairment. So going back to this patient who now has been started on either Evolacumab or Inclisiran, we wanna know what target you recommend for this patient. Would you recommend less than 100, less than 70, less than 55, or less than 40? So this is another voting question. Is everyone, does anyone need more time? Less than 40. Okay, so I don't know if the person is in the room who said less than 40, do you wanna speak about that? You don't have to. Those who said, 70% said less than 55, which is what I would do, and less than 70, 21%. So does anyone have a comment, wanna comment on their answer or on having this target? Okay, we'll move on. So the answer that I chose was less than 55. I suppose one could be really aggressive and choose the target of below 40. If one wanted to. So I think we know why we're targeting an LDL of less than 55, because this patient really has a very high risk of a recurrent event. And in the European guidelines, they specify an LDL goal of less than 55 for patients with ASCVD who are at high risk of a recurrent event. Here is a chart looking at treatment of high risk groups, looking at what a target LDL could be in adults, and in people who have ASCVD, you could target below 70, but in those who have recurrent events, you could target less than 55. In patients with severe hypercholesterolemia, the target could be less than 55 if they had atherosclerotic cardiovascular disease or other risk factors. And people with diabetes and mellitus who have multiple risk factors, you also could consider a target below 55 milligrams per deciliter. So just to summarize, these are the medications that target PCSK9. I've listed the doses in the third column. And the LDL reduction with these medications is 50% to 60%. There may be less reduction in patients with heterozygous familial hypercholesterolemia. So I'm gonna move to patient two. I don't know the time, because the clock hasn't started. And this patient is a 30-year-old woman, and she presents for cholesterol evaluation and management. And she was diagnosed with hypercholesterolemia 10 years ago when she was 20 years old. And at that time, she had tendon xanthomas, and she had the following laboratory test results. Total cholesterol of 290, an LDL of 220, HDL of 50, and triglycerides of 100. And her mother has high cholesterol and is being treated with medications. And her maternal grandfather had an MI at the age of 45. And she's currently taking resuvastatin, 20 milligrams, ezetimibe, 10 milligrams. So her laboratory tests right now show an LDL of 90 milligrams per deciliter. Her hemoglobin A1C is 4.9%. She has normal creatinine. So this is the first question. What is the diagnosis for this patient? Does she have familial combined hyperlipidemia, heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, polygenic hypercholesterolemia, or type III hyperlipidemia? Okay, 100%, correct. I'm glad to see that, that's great. Okay, so obviously that is the diagnosis for this patient. And I'm just gonna go through the why, because she has a very high LDL, she's a young adult, she has normal HDL, she has normal triglycerides. She has a family history of premature cardiovascular disease and a second degree relative, and that's pretty important in making the diagnosis clinically. And she has a mother with high cholesterol. Now there are various criteria, such as the Simon-Broom Registry, the Dutch Clinic Network criteria and others to make a diagnosis of FH. And sometimes they advocate for genetic testing, but you don't necessarily need genetic testing. So why are the other answers not correct? Well, I think we know that familial combined hyperlipidemia means elevations in both LDL and triglycerides. And homozygous familial hypercholesterolemia, which is a very rare disease, one in a million perhaps, if untreated, these people unfortunately develop MIs in their teens, their LDL is usually above 500. In polygenic hypercholesterolemia, which is the most common form of hypercholesterolemia, the LDL could be as high as in this patient, which was about 220, but it's usually lower. Triglycerides are normal, you can also have tendons and thomas, but a family history of premature CHD is less common, and the young age at presentation in this patient, she presented when she was 20 years old, suggest heterozygous FH. And type 3 hyperlipidemia is something different, also known as dysbeta lipoproteinemia, and there's elevations in total cholesterol triglycerides, LDL, the low HDL levels, and there are changes in the APOE gene. Most people in the APOE3 predominates, and in type 3, APOE2. And people with type 3 also have a high risk of atherosclerotic cardiovascular disease. So I have a few slides on familial hypercholesterolemia, and because of the time, I'm just gonna go through them briefly. Heterozygous FH is a very important disease, which we need to detect, because it often is not detected, and does not get treated properly. We now think that it's present in one in 250 people, while homozygous FH is rare, maybe present in one in a million people. And the LDL in heterozygous FH could be 190, it could go up much higher to 400. And there's one mutant allele for the LDL receptor in the heterozygous form. The mutation usually is in the LDL receptor, but it could be in PCSK9, or in APOEB, and if untreated, people with heterozygous FH do not have a great clinical course, 50% of men have an MI before the age of 50, and in women, 30% have an MI before the age of 60. And we know that in homozygous FH, there are mutations in two alleles encoding the LDL receptor, and if untreated, people can have MIs in their teens and die before the age of 30. Usually it's mutations in the LDL receptor, which could be receptor negative, with less than 2% activity, or the LDL receptor could be defective with some activity, two to 25%. There also could be mutations in PCSK9 and APOEB. See if I can get beyond this. So the clinical features of heterozygous FH are what was basically seen in the patient that I presented. And you can make the diagnosis using MedPed criteria, the UK Simon Broome Register, the Dutch Lipid Clinic Network. And I've talked already about the risk of sudden death or MI in the 30s to 40s if untreated. So there are many medications approved for heterozygous FH. Statins are approved for children and adults. Statins are actually approved for children starting at age eight or starting at age 10, depending on the statin. Alirocumab, Evolocumab, and Eclisarin right now are only approved for adults, as far as I know. Ezetimibe does not have age restrictions, but there isn't much data in children younger than the age of 10. And Colacevulam is also approved for boys and for girls after menarche. For homozygous FH, the total cholesterol is extremely high, over 500. There are Xanthomas, Tuberous Xanthomas, Premature Coronary Disease. And as I said many times, they can have an MI in adolescence. And so there are various medications that can lower LDL in patients with homozygous FH, and on top of apheresis, this can really help our patients. Here you see a statin used first, baseline LDL was 503. Then there was a reduction of 10 to 25% with a statin. With Ezetimibe, another reduction of 10 to 15%. Large reduction with apheresis, about 50% or more. And then finally, in this case, Mipomercin, which is no longer on the market, Lomidipide or Evolocumab were used. And the LDL got down to a very low number, which is 124 to 81 milligrams per deciliter. I don't have a slide on the newest medication, the Angiopoietin-like 3 inhibitor, which is called Evanacumab, which is also, which is just approved for homozygous FH. And it reduces LDL cholesterol, I believe, by about 50%, 40 to 50%. And this, what Angiopoietin type 3 does, is it slows lipoprotein lipase and hepatic lipase. So the inhibitor actually changes that, and so LDL levels are reduced. So what is the next step for cholesterol management in this 30-year-old woman? Because her LDL, I think, was 90, and she's on Rosuvastatin and Ezetimibe, you can see that in the blue box. So should we add Alirocumab or Evolocumab, add Bempidoic acid, discontinue Ezetimibe, add a PCSK9 inhibitor, switch to Rosuvastatin 20 to Atorvastatin 80, and oh, and that was with only four choices. So what do you think? Okay, everyone seems to have the right answer. What I didn't have on here was Inclisiran, you also could have used, oh, 20%, say discontinue Ezetimibe and add a PCSK9 inhibitor. We don't actually need to discontinue Ezetimibe, you can add the PCSK9 inhibitor on top of Ezetimibe. Does anyone have any questions? Okay. Under what circumstances would you want to try to get a breakdown of the LDL profile in terms of particle number, particle size, to in some way guide the treatment decision? Many of us, lipidologists, don't necessarily believe that certainly in these cases we need a breakdown. If a patient has an LDL of 100 and they don't have many risk factors, you might want to look at LDL particles, which could be high, but usually we don't do that. It's not necessary. Okay, let's see if we can move on here. Oh. So. Patient two, did I go to the right way? What is the next step for cholesterol management? I think we've just, oh, that was the answer. Okay, so why add, I think you all know why we want to add something else like a PCS canine inhibitor or Inclisiran, because we need further reduction in LDL to reduce her risk. She has had a lifelong increase in LDL cholesterol, which has affected her coronary arteries. And we expect that her LDL will be reduced by 50%. And palyrocumab and evalocumab are not yet approved for children with heterozygous FH. So, the other choices were to add bempedoic acid, and that reduces LDL only by 17%, and the CV outcomes trial is ongoing. Discontinuing ezetimibe and adding a PCS canine inhibitor, you could do that, but it's not really necessary to discontinue the ezetimibe. And switching risuvastatin 20 to octorvastatin 80 doesn't really do anything. They're both high-intensity statins, unless, so there's really no reason to choose that. Okay, and here's some more data on Inclisiran in patients with heterozygous FH. This is similar, I think it's from the same study I showed before, and you see the change in LDL cholesterol. It was reduced by 48%, and pretty much stayed low for 500 days. Go on to the next slide. And in this study, which is called Orion 9, the attainment of target levels of LDL in these patients are already on statins, as shown here. So 65% achieved an LDL below 100, 48% an LDL below 70, and 19% an LDL below 50 by adding Inclisiran, the newest drug, to a statin. So how effective are statins in familial hypercholesterolemia because we know there are defective LDL receptors. It's actually not, statins work in heterozygous familial hypercholesterolemia, but not as well as they do in other patients because of the LDL receptor mutations. And statins are limited in those with PCSK9 gain-of-function mutations, which enhance LDL receptor degradation. So going back to this 30-year-old woman who is now on, I believe, Alirocumab, she comes back in a year, and her LDL cholesterol is 20 milligrams per deciliter on two measurements. So what do you think should be done? The choices are to do nothing, to continue all her medications, to discontinue ezetimibe, to lower the dose of rosuvastatin, because she's on 20, to lower the dose of the PCSK9 inhibitor, or to stop the PCSK9 inhibitor. So I'll give you a chance to think about that. Well, it's changing a little bit. So I can't really say that the answer that I would choose would be first answer, continue all medications at the current dose. But I cannot fault anyone who would discontinue the ezetimibe or lower the dose of the PCSK9 inhibitor. But really, that is not necessary. And I'm gonna tell you why it's not necessary because basically, the clinical trials of the monoclonal antibodies to PCSK9 have patients whose LDL levels are less than 15 milligrams per deciliter. And there's no evidence that these low levels are harmful. But there's also no evidence that reducing the LDL to below 20 is actually beneficial beyond reducing it to below 50. And this has been discussed in a book that's not quite out yet. The Endocrinology and Metabolism Clinics of North America that I edited along with Alan Chait. And it's in a chapter written by Jonathan Tobert, How Low Can We Go? So we also, just in terms of benefit, I just wanted to mention what's said on the slide that there was a pre-specified analysis of ODYSSEY outcomes and basically, there was no difference in benefit in risk reduction in patients with an LDL below 25 and those with an LDL of 25 to 50. And in terms of safety of levels below 15 milligrams, the data from ODYSSEY outcomes shows that there are 730 patients who were randomized to Alirocumab. Their LDL was less than 15 and there was no evidence of harm. There was no evidence for an increase in diabetes or a change in cognitive function. And that was ODYSSEY outcomes. In the FOREA trial with Evolocumab, 1,330. Five patients had an LDL less than 15 in the Evolocumab group and 504 patients had an LDL below 10 and there was no evidence that these LDL levels were unsafe. And I've asked this question because one of my major interests is in drug safety, specifically safety of lipid-lowering medications. So we have a few minutes and I guess, does anyone have any questions? Okay. I have a question actually. So, other than patient preference and insurance approval, how are you, is there anything else you're going to use to decide between using the monoclonal antibodies with PCSK9 or the ECZone? So, patient? Do you have a patient preference and say that the patient tells you which one to use or the insurance approves because that's why you're gonna be... Well, I think that if you can, that would be a good reason if the insurance approves a monoclonal antibody to use it because if the insurance will not pay for Inclisiran, it's gonna cost about $9,000 the first year and about $6,500 every year after that. But right now, I do not know, other than the fact that it can be given twice a year and Inclisiran can be given twice a year, I don't know of any difference except that there are outcomes, positive outcomes trials with the monoclonal antibodies to PCSK9. Thank you for asking that. So I'm not, I think there is another patient but I'm gonna skip that because I left a few more slides at the end to summarize. And okay, so I just wanted to summarize that to talk about what additional LDL reduction you can achieve on top of a statin in your patients. So a high-intensity statin usually can achieve a 50% reduction. That would be a tour of a statin 80, receive a statin 20 or 40, also a tour of a statin 40 I believe is included in that, though we don't have much data on that. If you add ezetimibe to a high-intensity statin, the reduction could be 65%. If you add a PCSK9 antibody to a high-intensity statin, 75% LDL reduction. And if you add, if you use a high-intensity statin, ezetimibe and a PCSK9 antibody or a small interfering RNA, the reduction can be as great as 85%, which I think is incredible that we have come a long way since I was a fellow in endocrinology when we really, I guess, we didn't even have Mevacor. It was a long time ago. Mevacor was approved in 1987. So I didn't say anything much about safety of the monoclonal antibodies to PCSK9, but basically they are well tolerated. There is some problems in some patients, maybe 10% at the injection site. It could be itchy, it could be painful, you can get some redness. But there is no increase in new onset diabetes to date, which is of interest because you know there's an increase in new onset diabetes, about 2% per year in patients on statins. But the database on the antibodies to PCSK9 is not as large as the statin database, but still right now there's no increase in new onset diabetes. And also there's no data to evaluate safety during pregnancy. In terms of the small interfering RNA in Gleaserin, the benefit, as I said before, is a reduction in LDL of 50 to 60%. We still don't know the cardiovascular outcomes data. And the main safety issues to date are injection site pain and other reactions. And pregnancy, if the patient becomes pregnant, Gleaserin should be discontinued. So this is my last slide before my conclusion. I usually don't talk about medication cost and coverage, but I thought it was pretty important for this topic because these medications, statins are really inexpensive. I think you can get a month of a statin, I don't know if it's for under, for $30 or less. Very great drugs, proven safe and beneficial. But sometimes statins are just not enough and we need to lower LDL more. And if we choose, and these are the best ones we have to add to a statin. But the monoclonal antibodies cost without insurance about $5,800 a year, but they're covered by many Medicare plans and by Medicaid. And they're also covered by some insurance plans. So there is a good chance that the patient can get it without paying the full price. And Gleaserin is new. When that drug was being developed, the company that was developing it was the medicines, I believe it was called the Medicines Agency. And it was supposed to be an inexpensive medication that could change population health. Given twice a year, not costing very much. But then the drug was bought by Novartis and things changed, the prices are higher. So right now, the price in this country is 3,250 per dose. So the first year is close to $10,000 because you need three doses. And every year after that it will be $6,500 annually if not covered. And I'm not sure how much coverage patients can get, but I do know that if you have Medicare Part B and supplemental insurance, you can pay less. And patients with commercial insurance may be eligible for a manufacturer co-pay program. And how do you get this medication to your patients? Well, it's not as simple as writing a prescription and having the patient go to the pharmacy. Some healthcare practitioners, such as some cardiologists, will actually buy Inclisiran with their money and then bill the patient. Also, there are specialty pharmacies that you can send a patient to. And there are alternate injection centers which will give Inclisiran to patients. And I just wanted to mention that in England, where a lot of the work was done for Inclisiran, and which is, and in Oxford, the large outcomes trial is being coordinated. The company has made a deal with the National Health Service, and they think they've given 30,000 to 40,000 doses for a small price to the National Health Service to give to patients. And I hope that there will be a study of that, then we will know the outcomes. Because it's very important to see how, if it's affordable, how many thousands of patients will benefit from Inclisiran. So just to summarize, we know that statins as adjunct to healthy nutrition and physical activity are the foundation of cholesterol management. And statins can be used in conjunction with many non-statin medications. And specifically in people with ASCVD, or high risk of that, who require further LDL cholesterol reduction, medications with the PCSK9 mechanism of action can lower LDL by 50% on top of a statin. And Evalocumab and Elirocumab have outcomes trials showing that they reduce cardiovascular disease risk when given in addition to a statin. And Inclisiran, the small interfering RNA directed to the PCSK9 messenger RNA can be administered eventually after the first year. It can be administered twice a year, reduces LDL by about 50%. And it is hoped that this will increase adherence to lipid lowering therapies. I expect it will, but we really don't have the data yet. And the outcomes trial for Inclisiran is ongoing. So I think we're at the end of time. I'll stay for questions after. And also I just have to acknowledge that I've had a long career, and I am thankful to everyone, to my teachers, to my patients, to my colleagues, but specifically to my family. And I always show this picture of this man in front of an old car, and that's my dad who's a pediatrician who encouraged me to become a doctor even when there were very few women who were doctors. And of course on the other pictures of my family, my children, my two sons, my daughter, my husband Jonathan with the cap on his head who developed the drug Mevacor. And I'm grateful to the Endocrine Society for everything it's done for everyone who's an endocrinologist and for our patients and for inviting me. And also I'm grateful to the American College of Physicians and to the American Medical Women's Association. I'm a past president, so if anyone wants to talk to me about AMWA, please see me afterwards. Now questions, just, oh yes, I have some questions from the audience which I guess I should answer. It says, ebulocumab is improved in children, I don't know. Why is bempidoic acid not a consideration in that patient? Well, because it only lowers, I think I answered that, LDL by 17%. And can the PCSK9 inhibitor be used at a lower dose weekly instead of twice a week? And what's the difference in efficacy? I don't know the data on that, but I mean it's usually administered either every month or every two weeks. Okay, so that's the end of my presentation. I'm gonna go down and talk to anyone who wants to talk to me. So thank you very much for being here.

Connie Newman

endocrinologist

PCSK9 inhibitors

cholesterol management

LDL cholesterol

statins

ezetimibe

LDL reduction