Dr. Daniel Einhor n provides a summary of novel therapies related to managing and treating diabetes and cardiovascular disease . Hi everyone, welcome back. I know that was a short break but I am totally excited about this afternoon I think Dr cork and I really set us up for a lot of success this afternoon. We have a great panel of speakers. Uh We've been very very much looking forward to hearing from starting with a very own doctor Daniel Einhorn. I'm not sure if Dr Einhorn is aware of this but he is has become universally there has been universally considered as our go to endocrinologist for our cardiology group here at scripts. Uh He does everything underground diabetes, thyroid disease, osteoporosis, lipid disorders, polycystic ovarian syndrome, adrenal disease, parathyroid disease and diagnostic dilemmas that may have a hormonal origin. But most importantly he really does an amazing job of taking care of our patients with cardiovascular disease and cardiovascular risk. Dr Einhorn serves as the president of the American Association of Clinical Endocrinologists. He's the medical director of the scripts, Whittier diabetes Institute and a clinical professor of medicine at U. C. S. D. He's an editor and contributor to numerous books and articles including publications from the Emma and the Royal Society of Medicine. He also just informed us right right during break that he is actually out in texas at one of the first uh in person multi disciplinary groups. Bring them together guideline writers in cardiology, endocrine um and uh renal disease. Pretty exciting. So uh without further ado I want to introduce Dr Einhorn who's gonna be speaking on cardio, cardio metabolic disease and novel therapies, SGL T two inhibitors and GLP one agonists. So doctor in Home, thank you so much. Sweet introduction. It's uh it's great to be here. You know I love I love this audience. Uh And as you heard from chris um some of the things I'm going to tell you are are so new. They haven't been written down yet. Um But I'm going to go over a lot of stuff that's going to happen quickly. You know that's the way I like to do it. It will be close to three slides a minute. So hang on. But I want to be sure that you get the message loud and clear. I'm just gonna be telling the story. Um Because the message does have some wrinkles. There's a very simple underlying message. But the wrinkles are important. So I hope you get both of those. And then at the end when we have our Q. And A. I'm happy to go back to to anything. Now let's be sure I got this. So those are my disclosures including some fun startups. So I want to start with the punch line. And the punch line comes from the american College of Cardiology 2020 which basically says use SGL T two inhibitors and GLP one receptor agonists in your adults with diabetes and any hint of cardiovascular disease, either risk or actual disease. And that's true. And you start and that's true. Further down the list and now what's being added, we'll get to it. It doesn't matter what they have diabetes or not. These two drugs, S GLT two inhibitors and GLP ones are your drugs, they're cardiology drugs, the cardiovascular drugs. It just so happens that they started off about blood sugar, but the blood sugar part maybe the least interesting part. So they died people in diabetes, we've owned them so far because we developed them. But they are your drugs and I'm waiting for you guys to be the major prescribers of these. A reminder that it's scripts. We were there from the beginning, courtesy of Tom and the rest of you. You really get it as soon as things evolved and changed scripts was there? I'm very proud of everyone. And you basically were there for the evolution from drugs that started off as diabetes drugs. Now their diabetes and heart drugs and now their heart and kidney drugs and they've taught us that the heart, kidney and diabetes metabolism are the same system. It's one system we got trained because geographically these things are different are separated in the body, but they are one system. And so if you're working on the hard part, you're working on the diabetic part and the kidney part and vice versa. So you see something very complicated like this. This is, wow, this is how you treat diabetes, but actually it's very simple. It's the same message, use GLP ones at SGL T two's, use them early, use them first, use them together and then if you still need more things for sugar, here's a whole bunch of other things. Let the endocrinologists and the primary care doctors worry about that. But basically it's the same patients, same approach And it just codified January 2021 it's reinforced. So this is now the consistent message. We're not guessing anymore. We're very confident, very absolute about this. It's clear that blood sugar, although it's a signal that something's arrive metabolically, it's not the main actor in the both acute and long term benefits of these drugs. And just so, you know, established A. S. C. B. D. Is not on the label for these drugs. The clinician decides what it is. Heart failure, whether half past four half breath is not defined in the label. And even chronic kidney disease is not defined. The good part of that is it means you can use your clinical judgment to know who is the right patient. So, for Dan Einhorn, I can't imagine adult but the type two diabetes, who doesn't have risk factors that makes me worry about them as the patient here we're talking about. But it's my judgment that they have the right setting to use these two classes of drugs. So here's a triumvirate. This is probably going to grow over time, but it's certainly very clear from these drugs that the heart, kidney and energy metabolism are inextricably linked. Nothing happens in one of them without it happening in the other. Now, some things are sugar related. So let's not throw them out completely arterial stiffness, some parts of endothelial dysfunction, oxidative stress, plato activation. Some of the inflammatory issues are very glucose sensitive, but most of this is not driven by if the sugar is higher or lower. Okay, that has a small part to play and not zero. But most things are the entire familiar, which the heart and kidney represent along with metabolism. And when there's a disorder of one you'll see disorders of the other. There's almost never an isolated disorder of one that doesn't affect the kidney and affect metabolism because again, they signal to each other all the time and it happens from the very beginning, it happens along the entire continuum of of time and severity. So it's not that there's a threshold point where all of a sudden one affects the other, they're always affecting the other and they're affecting each other, normal physiology to. So as a diabetes guy, I am now acutely aware of the heart and kidney in every action that I make. It happens that deliver could be tossed in at some point. It might be. But certainly the heart and kidney are part of every decision I'm making in my patients with diabetes. And of course a lot of this is driven by obesity and you know, the drivers of obesity, including the hyper Aldo issues, hyperglycemia, all the mechanism that you associate with obesity. You know, drive these three systems in somewhat different ways. But again, they interact with each other and affect how the other responds. And if you just take, let's say the glucose, if you start with the glucose part of things, you know, hyperglycemia, hyper insulin, Neemia, insulin resistance. Well, there's a cascade of consequences of that which again, go there. They are neurologic, their inflammatory vascular but again, it's not hard to see how they would affect the heart and the kidneys. And so the familiar, you know, if you have diabetes the time to first and my first hospitalization for heart failure is a lot different, much greater risk and if you have heart failure, the outcomes are poorer and again, that makes sense, understanding that these are inextricably linked system. So if you started with the heart as may be getting the first insults, well, the heart will then directly reflect what the kidney responds and what the liver and pancreas respond. Because again, it's one system. We have learned this from. The drugs were doing reverse engineering of clinical science. You know, usually it's bench two bedside. This is the opposite. We were quite surprised at what we found clinically and our busy figuring it out why that happens. So just a little bit of history. I was dealing with this earlier today. So I get a little credit for some of this because when I was president of the American College of Endocrinology, the whole Avandia fair came up but there was a fear that Avandia was potentially a dangerous cardiovascular drug. And myself and the American diabetes association managed to save the drug from being pulled from the market, which would have been a disaster for you and me because when you pull a drug from the market, all drugs become suspect to our patients. And so we were really afraid of a real devastating blow for very flimsy data. By the way, this is all blown away. So instead of Avandia was thoroughly exonerated years later. Too late. No one uses it anymore. But so we were able to fight back and say instead of pulling it from the market, why don't you do a rams? Why don't you do surveillance and do studies? So when a diabetes drug comes in, you can prove either that it's safe and you can even prove that it's better. But we never thought that would happen. It was the statisticians kind of built that in because the studies were all about safety. And for the 1st 10 years of these studies here's package that's not even all of them. But a few dozen studies were the result of the FDA mandating safety studies And for 10 years boring, boring boring the drugs were safe but that's all we saw. Um then Things changed September 17, 2015. I've told the story of being there many times. I was in that hotel highly recommend Stockholm in the early fall gorgeous place to be. And they showed this data. As you see now many times if you got em piglet flows in and you are a high risk cardiovascular patient who was already very well treated. My cardiologist. So you had a dramatic improvements in the in the C. V. Death overall mates outcomes and all cause mortality. And so this began the party and began the rethinking this is I showed this data about a month later at scripts and that's when Tom Haywood almost became apoplectic And we have to rescue him. They had to call 911 to the grand rounds room and he survived. And so MPA Guardians got the first indication as a diabetes drug but also to reduce the risk of cardiovascular death. And so we said well maybe it's something unique. Maybe it's a fluke you know because it's so weird we just weren't ready. And then Canada flows in was next this was presented in san Diego. Pretty much the same outcomes for overall cardiovascular events. And so Canada got the indication. You know. Now a few years have gone by you'll notice didn't happen right away. So diabetes drug then Dapa uh came along um farce Iga and the DaPA study included patients who are less high risk. So this was a more real population and at first blush not obvious that it had the same effect. So I got complicated. Oh no. Well, maybe uh you know, it's really not. The next one or two good flows comes along the verges trial and you can see from the lines. Well, it flunked so, you know, MPA worked can work, but the next to not so clear. And so what gradually came along as overall, if you look at the major adverse cardiac event, the drugs were in favour, but it's not homogeneous and it's definitely more impact in patients at greater risk. That that's not a surprise, but overall very much in the right direction. Um And so all of the guidelines from FDA evolved to say these drugs have cardiac benefits. And so, you know, then you break it down. Well, if you look at MPA, the very first one, well for all cause mortality, that was pretty good. A little less dramatic for Canada. And maybe not for Dapa different populations. Cardiovascular death back up. Um Again, um you know, very clear for the first one, MPA not so clear for cardiovascular death. And so so it looks it is in fact had a genius when you look at it that way, where did they all come together? Heart failure? So for heart failure, every single drug in the class, and there's several others are not on the screen, they all do the same thing. So to the extent that heart failure drives what happens with your patients and we're understanding and diabetes, this is becoming much more the issue than um uh Atherosclerotic disease presenting as an M. I. These drugs are all the same when it comes to that. And so when you look at the different ways of understanding these drugs in green or when they clearly had a positive significance. So for heart failure, they all did for cv death really only MPA. And for mace, it was really just those first two MPA and canvas. So we think these are a class if you can only get one and not the other, take what you can get. But there clearly are some differences among them. Now when it comes to heart failure, this class is very homogeneous and it's distinct from other classes of diabetes drugs. So that's never happened before or since. So it's only the STL T two inhibitors. Okay. M. Pecanha and Dapa that are the heart failure of drugs. And I should say anything that says Glenn flows in is a heart failure drug. So, because there's others that are coming along for other reasons now, I told you earlier that what's good for the heart is good for the kidney and vice versa. So every single time you see that the drug is good for the heart, it's good for the kidney. And so in studies are done now to see what's the benefit to the kidney. You get cardiac benefits at the same time, you just can't help it. And that just happens every time. And so for all the things I said that are good about the heart, equally good for the, for the kidney. And now comes Dapa, Hs. So you say, well, you're claiming that the drug is good for heart failure. We'll prove it, do a dedicated study and do it in patients who have diabetes and don't have diabetes. And this was the first, the studies that that showed clearly that you've got heart failure benefits whether or not you have diabetes. And it's a very strikingly uh positive results. And again diabetes, no diabetes didn't matter. And so DaPA now gets this additional indication for um uh I apologize for how chopping some of the slides. Seeing the the response to my finger is a little variable on the platform, forgive me. But so here now is it's good for diabetes. It's good to prevent heart failure in people with diabetes and established heart disease or or just people with multiple risk factors. So that's important. So all of a sudden you move from diabetic control Matter answers. Well, yeah, but not for this drug. Uh It's and it's really about the patient having risk factors for heart failure. And then MPA did the same thing called the MPA reduced trial. Same results. You see these results every single time, whatever the initial study was pegged for and if you see it's good for the heart there it is good for the kidney exactly the same. And that's that's fine. Not an accident is probably not only the same path of physiology but the interaction of the two systems. Um And so here you have now emperor having the very clear indication primary endpoint met and all the secondary endpoints met as well. So good for the heart, good for the kidney. These things travel together for the S. G. L. T. Two S with or without diabetes. You can see it doesn't matter. And for these two drugs, DaPA and MPA doesn't matter the same the same effect. Um Again just so the protocol for Dapa and Dapa did something interesting. It was willing to take patients much earlier on really. Primary prevention and patient could have taken a long time to see a benefit. Well, they saw a kidney benefit that happened fairly quickly, so, uh, well, good for the kidney is going to be good for the heart. Um, and well, you know, there it is um for the composite for renal or cv death. So, and you see these striking p values by the way. The other thing I didn't say, but I've said other talks. But please note these are the only drugs where you see separation of the lines virtually right away at the first measurement time, and then the line separates. So in a short period of time, you see the benefits. Nothing else that we have, and and I believe that's true of statins, and you're Aces and Arbs, nothing works this quickly or separate so quickly and stays separated. Um and again, these are just some of the uh just see if we just jumped here. I apologize for this. Um uh That's Dapa CKD. Alright. We just sort of had a little uh so everything everyone had positive composite outcomes. The only one or two good flows in failed. We don't really know why, but that's the one stld to maybe you don't want to be using unless you absolutely have to a lot of details about the trial. But this is a class more or less a class effect air to being the one the one exception to that. Uh And there's more so we're going to know a lot more about the type of patients. I think really it will be at the time of diagnosis now that we think these drugs will will start to be used. The data says to use them from the outset of treatment. Now, I told you we're doing reverse Science right? We know that the clinically work. Why we're still not exactly sure something. We're pretty sure they're not like BP or diary sis. Um but some things are still likely uh sympathetic nervous system inhibition effect. So in fact that the real effects the sustained natural resource and maybe it's from an interstitial source, we will stay tuned for that. So that's the ScLC two inhibitors. That that's the data. So its use them use them early And let's now switch quickly to the GLP one receptor agonists. These you guys did not use very much because they were injectable. Now there's oral GLP one, it's called rebels is from Novo. So you can do this as an oral agent and when you just look at how GLP ones work they ought to be beneficial for the heart because they work on all the systems. These are all places where your body has receptors for for GLP one and they act in the correct way in type two diabetes. It's as if you had GLP one resistance somewhat akin to insulin resistance. So you, by adding more GLP one, you restore the original physiologic GLP one effect, which is beneficial to the heart, the gut weight, appetite, etcetera. Again, heterogeneous on a molecular level. So you might expect some differences within the group. And there are. Um But by and large, going back now to 2016 17, we already saw that the Victoza, Lizarraga tide had a benefit on mace and death from cardiovascular cause looks a little less striking visually, but definitely they're strong statistics. Um And all cause death again, however you look at it. Um it these are again higher risk cardiac patients. Um And so Victoza was the first GLP one to get the indication. Yeah, it's a diabetes drug but it's also a way to prevent uh major adverse cardiac events in patients who are at at risk. And then the next one online was some magnetite and it clearly showed again the same benefit. So when you have now the SGL the GLP once again they do act as a class albeit with some some some differences that I'll show you in a minute. Generally the GOP one's the big issue is non fatal M. I. And nonfatal stroke there, the major drivers cardiovascular death overall a little less. So. But uh oh XEM picks a magnetized got its indication. So now it's again it's a diabetes drug but it reduces the risk of major adverse events and people with with risk. And here's a drug, Tansy um A big blue tide. You don't see it much. It was pulled off the market in the US but it may come back as it to show the the benefit. Here's one drug that didn't so zenit tied it didn't, it failed. And so you know, there's some heterogeneity. Uh this drug is not used as much as others but we can come back sometimes. It's the only one that's on the formulary. Now here is a very exciting trial. Now doing this is true illicit E and again a significant effect to improve the cardiovascular composite. This major study was was called rewind and whether or not you had prior heart disease. If you're in this risk group, this is prior known heart disease. You got the benefit of the drug regardless of based on a one C maybe if your B. M. I was a little greater, you've got more benefit because these drugs also cause weight loss, Which one of the reasons your patients like it. But what's really cool about the rewind trial is the patient population looks like the kind of people primary care doctors see in practice. So these are not highly enriched, high, high risk cardiovascular patients on 10 different drugs. These are much more of the routine people with with type two and and and a group without. So it's so you didn't have to have severe disease to be able to see the benefit. So here's the indications now it's a diabetes drug, but also it's a drug for people who have multiple risk factors. So now both classes of drugs SGL T two S and GLP ones have evolved to the point where they're beyond glucose beyond diabetes and they're really cardiovascular drugs in these people who are at risk. So, coming to the end, just the last couple of slides again, just to show overall the meta analysis, um, clearly favors, um, the, the GLP ones about how they're studied, but there's some variability within the class. All the ones you're likely to use, which is mainly your true illicit. E or do the blue tide euros, epic. Or some maga tied um, your Victoza or laura tied the ones you're likely to use the most. Are there? Uh, there is still a role for once weekly eggs, any tide. It's the best tolerated of all the GLP ones. It's because of that, that it's still really exists in the world. Um, and again, just different looks, mortality. M I stroke all cause mortality in aggregate. The GLP ones are favorable, favorable, favorable, um, with a little heterogeneity in response, depending on the trial for heart failure. Not so much. So here's cardiovascular mortality and kidney definitely positive. Again, with one exception consistently positive. So are the cardiovascular drugs absolutely that they change the outcome. Are the kidney drugs? I'll show you that absolutely now for heart failure. Um, you know, a little less clear. So uh they they're still positive for heart failure. Not nearly so clear as for the S. G. L. T. Tubes. If it's good for the heart is going to be good for the kidney. Here it is. Um, and there it is. Again, you'll notice that the magnitude of benefit is actually pretty similar heart and kidney. Um, here again, the effect on the kidney, you know, the worse off you are, the more benefits you get. Um and again, it's good for the kidney and it includes improving macro albumin urea. And so the GLP one is clearly just like the S. G. L. T. Two's directly and indirectly. Um will improve kid the outcomes like it improves cardiac outcomes because they're part of the same thing. So now the last slide, the second to the last slide is the other punch line. These drugs are completely different, their mechanism of action is completely different. And even clinically the SGL T two's are really around heart failure and um global cardiovascular risk death. The GLP ones are not around heart failure, they're really around weight loss. Uh And non fatal M. I. Nonfatal stroke. The SGL T two's for example do very little for stroke. The GOP one's do a lot. They really are remarkable a stroke prevention drugs. So these drugs make sense together. Uh ergo the the guidance from the american College of Cardiology, the american diabetes association, the american College of Endocrinology. These are drugs that make sense to use early because we have no other drugs that have these outcome benefits. And remember most of these studies were done on top of everything else you guys know how to do. And on top of all the things we, as endocrinologists, know how to do. The benefits are on top of all that and the early and they're sustained. And by and large, these are very well tolerated drugs that now both available in once a day, oral form, um, and uh, easy to tolerate, easy to live with with just a little education. So, their effects, we think we're sure they're at least additive in studies where they have been added to each other. It's an additive effect. If they're used together from the very beginning, might it be synergistic? Well, maybe why because some of the pathologic mechanisms that affect the kidney, heart metabolism triad may never have a chance to be established. So, as with so many things, the earlier you can intervene, the more you can you can do. So stay tuned. That's about 90 slides in about 28 minutes. So I hope it wasn't too much. But I enjoy doing this. Thank you so much, wow. Dr. Einhorn, thank you very much. You have made me a believer. I think your your your your talk is high energy. I think you were very clear and concise on the benefits and the subtle differences with the meds. I wish we had more time to get more out of you. I mean, I'd love to go over use and how do you know, nuances? Side effects, that kind of stuff. And we'll save that for next year. But looking forward to more to come. So again, thank you very much. Questions are gonna be safe for the end. I appreciate you sticking around for our question and answer.