Dr. Daniel Einhorn reviews the most current treatment options for patients with type 2 diabetes who are also afflicted with cardiac or renal disease and how these co-morbidities are often linked.
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So our next speaker is Dr Daniel Einhorn. Um He is the medical director of the scripts, wittier diabetes institute in a clinical professor of medicine at U. C. S. D. He's an editor and contributor to numerous publications throughout the course of his career. Um And has been a teacher in G. M. E. Here at scripts at UCSD and throughout the world. We're very lucky to have him here today, but also just in clinical practice. He's been a great wealth of knowledge for us in our cardiology practice um here at scripts and um you know is more we're learning more and more about the overlap between um cardiology and cardiovascular disease as it relates to the metabolism and endocrine logic diseases. Um There's there's so much more of an interplay here between our specialties and what we're learning is that maybe at some point we may need a cardio metabolic clinic or something like that. Um So um with that I'd like to welcome dr Einhorn, thank you very much for joining us today. All right, thank you so much. It's a it's great to be back here. I really enjoy cardiology conferences and as you say, the the overlap is such that I'm going to uh taco halfway through about a way that scripts may actually be one of the national leaders in executing exactly what you were saying. So, Tom asked me to deal with cardiovascular disease and heart failure, not just heart failure and not a with me as I'm going to take this as a chance to give you some insight what your endocrinology colleagues are doing as they co manage the same patients with you. And as you pointed out, where do we find the line between us? So, there's just some of my disclosures and diabetes has just been an extraordinary time. Those of us in it feel very, very lucky, especially the last five years and some really interesting startups happening in SAn Diego. So stay, stay tuned. I want to remind the group that tom tom Haywood got it right away. I mean, I heard I was there for the very first presentation of the splc to data in uh september 2015. I gave grand rounds at scripts two months later Tom was there would be joked, we saw his pupils dilating from the back of the room and he immediately got it. He saw nobody was applying just a cardiology quite yet, but tom realized it right away and within a few months convened the whole department, the rest of us, those of us who write guidelines. It actually took us a few years to to be confident enough debate the data into a guideline. So it's 2018 before the american college guidelines. Got it and applied what I'm going to talk about in 2019. Before the guidelines look like they do today. I'll talk about that in a moment. So, you know the joke and uh you know, Stockholm, cardiologist, endocrinologist, and a real doctor walk into a bar. But anyway, I want to start with the punch line. Uh and by the way, a little disclaimer, since I can't see or hear you guys in the audience, I'm going to save my uh my new cartoons for next year. Hopefully worth waiting for. So, the punch line is if you're an endocrinologist and you're treating diabetes, you know, lifestyle and Metformin are still first. But then please please please use an SDLP too, especially if there's any risk of heart failure or kidney or use a GLP one. If it's more the established heart disease patients, um neither of which, by the way, are defined in the package insert you, the clinician, make that definition. Um And if you're not using an SD LT two first using a GLP one, well then the next drug is the other one. So please always use SGL T to always use GLP one. We'll talk about the individual drugs in a bit and only if you've exhausted your med foreman SdlP to GLP one. Do you think of doing anything else in diabetes? So so so we get it. Um And what's changed? I'm sure the evolution in the moment. So first it was all about heart failure and the kidney. We got that 2019. And then as we got further along, it came to prevention of heart failure and heart disease. And We realize it has nothing to do with the a. one c. So independent of a one c. and now independent of diabetes at all. Um as you heard earlier this morning, you know the the S. G. L. T. To have a special place in the heart failure. But the GLP ones belong in cardiovascular disease as well. But the issue in diabetes is whatever the sugar is And whatever else is going on. GLP one s. GLT two. And in particular, if there's also a real issue, anything I'll say about the heart applies to the kidney perhaps even more so. So this seemingly complicated slide. All it says is what I've just said use GLP wanted SGL t to um the bay of other considerations. However cost, weight loss, avoiding hippos. And so the rest of the algorithm is really if you must there are other agents for diabetes but they really are secondary or tertiary. And at the end I'm going to try to argue to not use some of them at all. Now, some caveats nowhere in the label does it say what heart disease or heart failure? Uh, I mean, hey, these are all for the clinician to decide. And we've certainly come now clinically to call the multiple risk factor patient, heart disease patient and primary prevention as perhaps more important than secondary prevention. Recalling that most of the beneficiaries in the diabetes trials who benefited from the heart failure outcome didn't know they had heart failure going into the study. Okay, that was not the case report form. Similarly, chronic kidney disease was not defined, but we'll do that separately. So just to give you a feel now as an endocrinologist, I don't look at a one C very much anymore. How about that? I don't look at individual sugars very much anymore. When I see my patients, I get a report that looks more like this, which looks a little dizzying at first. But let me just break it down. So the top um, will be this colored bar and the green is the person is in range, yellow and orange too high, red and dark red too low. And time and range is a very critical metric. That turns out to be more valuable than a one C, which after all, is just an average. So, you know, if you're low half the time and high after time, on average, you look normal even though you're not so time and range is the new metric. That's important. Um The other metric that's on this, if you can see it in the lower left hand corner on the box is variability. I'll talk about that. But glucose variability Should be less than 30%. The higher the variability, the more there's a complication rate from micro to macro vascular disease, the more there's hypoglycemia and the more the person doesn't feel well And they don't even realize that not feeling well sometimes until you correct it. So variability, but here you see almost 50 on this patient ought to be less than 30 and we'll come back to that. So here is my Holter monitor. This is two weeks of data on on a patient going left to right. It's a 24 hour day and left parties overnight and then the morning, then the afternoon and then the evening and the range of 70 to 1 80 between the green lines is for this patient at the time and rain. The acceptable range and you see this patient goes low overnight, shoots up after breakfast, spends most of the day to high, shoots up after supper, goes down again to low overnight. So this patient is a mess. But at least you know why you can see where the problem is. If all you had was a high A. One C. You might not know where to start to fix it. Um ideally after the right medication and some lifestyle changes when patients see this on themselves, they will often self correct. You know that certainly the dietary issues, you know, the breakfast cereal in a box is one of the greatest hoax has ever inflicted on the american public. If you have diabetes and you measure glucose, you realize that dry cereal in a box which lasts forever on refrigerated. That's not really a food, that's something else. But anyway, this is a more acceptable two weeks of the data, much less variability by the way the line is the mean and the shades of gray are the variability and then last but not least if I need to get granular. I took it okay. There was a saturday night that that was a big night, whatever was going on that I'm saying goodbye pointer here a little bit um and just sort of point out and really isolate you know what went on, you know that looks that you have some evening highs, you know what's going on with those and just as a matter of being able to be very, very specific, giving patients a chance to self correct and targeting your therapy much more specifically, A one C misses all of this and sporadic glucose monitoring, misses all of this. So now we try as much as possible to these periodically have some continuous glucose monitoring and be able to do the job much much better. There is a correlation between time and range and outcome Over the next 10 years, um 5 to 10 years and now. Is that because everything else is being done right? Or is it something about the glucose itself? We don't know. But time and range correlates with outcomes. And variability is a new metric that we could only get since we started continuous monitoring. And it turns out also to be a major independent predictive factor for adverse events. Here's one of the more recent studies with acute coronary syndrome. Because of all I want to cover. I'm not going to get to granular that I'm happy to come back in the Q and A. And there is a relationship between a variability and major adverse cardiac event. Now again, chicken and egg not always clear is that is this this patient who because of cardiac risk has more variability? Or does the variability give them more risk? And that's that's to be worked out. But there's clearly a relationship between hypo glossy mia and bad cardiovascular outcomes. And the relationship between variability and hypoglycemia. And so again, using drugs that help you with variability are important. And hypo and variability do a lot to rever this uh anti or I should say, this hyper koa global state, this afra genic state, this pro inflammatory state and by multiple mechanisms. So there's a plausible connection between hypoglycemia variability etcetera beyond high glucose alone. So that's why we're getting away from a one C as a metric. It still has helped us along the way. I'll come back to it. But the endocrinologist can do a much better job. I'll let you know what's really going on with the patient and the two darlings of diabetes and our cardiology SGL T two's and GLP ones reduce by seeming variability quite significantly and maybe that's part of the secret sauce that makes them so good for our patients. Now, just in a moment, we as endocrinologist, please excuse us. We had to play catch up all before 2015. I didn't know anything about heart failure in diabetes. It just wasn't apparent to me in practice. Now I understand it's the most important, the largest excess risk compared to the non the non diabetic. Maybe it's because there's much more renal disease in people with diabetes. But nevertheless we're now learning this. We understand it's a potent predictor. Our patients are the ones much more likely to get heart failure um and to have symptomatic heart failure and hospitalizations. So we honestly and ambulatory end up in practice. That was just not very obvious. And these numbers of uh you know, 2.5 times more likely to have heart failure than those of our patients without diabetes. We didn't know that. So please forgive us. Were relatively quick learners. But this is all stuff really. The last few years and the last couple of years for many of my colleagues um there is a relationship between glycemic control and incident heart failure. Again. Is that the sugar or sugar the victim? But it turns out for about every 1% increase in a one C. There's an 8% increased risk of of heart failure. Um And this over a very long period of time. So uh there's something about the people with diabetes and I thought this was interesting um going from a normal A. One C. And blue and then prediabetes and red and diabetes. And on the X axis is degrees of impairment of ejection fraction. The worst the ejection fraction the greater is the impact of having diabetes for whatever reason glucose or otherwise. So the way the endocrinologist looks at the story of heart failure over on the left side is where we think we should live. Which is really the early detection and hopefully the prevention based on dealing with all the risk factors at some point around here as a patient comes symptomatic ought to be our handoff to you in cardiology so hopefully you can keep the patient up here and then prevent the deterioration. Um But this kind of juxtaposition. This unity point is where I think we're gonna need that special specialist or that department that you mentioned just just before. So let's get into this uh where do we treat the same patients? Same patients? But we don't want to do each other specialties. And frankly we don't get to talk with each other about each patient. That's just not the way the world is today. Um We're not always sure how our therapies are drugs affect your therapies drugs, but, you know, patients and families ask us about each other's treatments. Um and so we want to see some some division of labor, at least as things are constituted now. So for the last five years there's been an avalanche of data. I think we know what to do in the cardio metabolic space in terms of using the right drugs, looking for the right metrics handing off to each other. But since none of us is trained to handle the whole continuum, you know what how do we deal with this? So one you sort of suggested, how about a new medical specialty? This is an honest to goodness effort in several circles to create an endo cardio renal specialist where we die Vitalogy, non invasive cardiology, non dialysis, nephrology, obesity management. And you have that primary care in there and this specialist may emerge one of the major medical schools. In the next few years. We imagine that person is heading up. A team of professionals will be the one to kind of manage the multiple, noninvasive or minimally invasive tests and labs and we'll do clinical trials, population research administration and teach. So we think there's a legitimate uh call for this cross trained individual. In the meantime, maybe we're going to have a new kind of medical department and scripts. Maybe one of the national leaders in an alliance of medical centers that are essentially establishing cardio endo cardio renal metabolic centers. Usually it's di pathology and our cardiology that that headed up. But it could be primary care, whoever is the champion locally. Uh My good friend and colleague Miquel Costa Borough do I'm sure is known to you. Cardiologist is the first one spearheading it at ST loops in the in Kansas city and hopefully with scripts also on the board and leading it, um we'll have kind of a virtual department where there are pathways when the patient enters our system at scripts. And hopefully we will draw patients into the system for this. They'll have a team that's automatically set up to think about their kidneys and their heart and their metabolic control and their liver and their weight, uh etcetera etcetera. Um and uh there are ways, especially as we get into being at risk for a population where this might be the most important thing that we can do along with oncology and perhaps, you know, vaccines, the most important thing we can do for our population for their health and also for the economics of being at risk for a population. And to go along with this. A number of us are writing a new type of guideline which is now independent of any medical society. Hopefully it'll be endorsed by the society but it's it's multi specialty and so we can you know we understand accessibility and complexity but we're gonna do this based on expert opinion and experience will have multiple sponsors to avoid even the appearance of conflicts of interest. And actually I get to be one of the ones who makes the forward looking statements. I think this is going to be medical care in the future. I think we're going to practice together more and more. I think it's going to be fun and I think our patients are going to be very grateful for what we do. So just to slide back to the monday and I can't have this talk without mentioning just you know some of the data. So the S. G. L. T. To, this is the three studies that started the whole story uh MPA Canha and capital flows in uh in each case having a major impact on heart failure outcomes. Every single SGL T two has done this. So when you hear about a failure of a trial or this or that this has never failed. Always always SGL T two's have this positive impact on heart failure. Whether the people going into the study knew they had a heart failure or not. Um We didn't jump in 2015. In terms of the guidelines, we waited a year and something so that we saw that now to S. C. L. T. Two's gave us the same kind of data and that's what we needed to see. It looked the same. So now we are confident. Now we began to rewrite the guidelines and then the third S CLT to data came out again always in the same direction for heart failure and basically for cardiovascular outcomes. So now we are often running and we became very clear that this must be used. That's the standard of care and it must be used before. Um Other drugs and the only reason do not use it as accessibility or intolerance. And we get that too. Um And here's a story whether or not you have a history of heart failure that doesn't matter. The outcomes were valuable regardless whether you knew you were going to benefit or not. And again the article flows in the Virgin Studies. Sometimes said to be failed studies for the mace outcome, Major adverse cardiac event. But when but for congestive heart failure, always always along with the others. All the STL T two's and and the fifth one I mentioned just a moment show the same impact. So there's not much question. But now some dedicated heart failure studies. This is when the studies where the first one that showed there really doesn't matter. There's no difference if you have diabetes or not, you get the heart failure benefit. Um And since we in endocrinology are just not great at physical exams anymore. Um you know, learning how to use Pro BMP is going to be something maybe you'll help us with. We may sometimes not know how to interpret the results. Maybe they will come up in the Q. And A. And again some uh you know, dedicated heart failure studies is with MPA the emperor study again showing the same thing. It's really again and again. And the P values are always very striking. So this is very strong data and it's never been in the other direction. The fifth SLT two is so tickle flows have not yet released in the US. But it's studies clearly had the heart failure benefit. For whatever reason. The company was looking to do something else with this drug is looking for a type one and other types of patients. But they could have gotten the chf indication it was right. The FDA basically invited them to do it but just know that there's no no wiggle room in the data on SCL tts. It's all the same. Um So is it a class effect? I think so. I think that the language of the approvals just have to have the studies were done. The FDA definitely sees each molecule as different. Uh And that's why, you know, something quote unquote failed are not getting the monitor. But if a formulary forces you to uh S. C. L. T. To that quote unquote failed in the clinical trials, it did not fail. If what you're using it for is heart failure to this moment. We don't know. This slide hasn't changed in a couple of years because we don't know what it is. But my good friend and colleague who we all learned from every year and I love this talk this morning christian Mendy uh mentioned something else I haven't thought about that. Unlike uh let's say loop diuretics. Matthias. It's S. C. L. T. To take fluid from the interstitial space preferentially and produce a primarily water diaries. Is though there's some sodium as well. And so that maybe some of the secret sauce that that that we have to explore. But we're all united. You know the cardiology um renal and endocrinology. And so that's that chapter. Now the GLP ones you haven't talked about as much because right now the GLP ones mean injectable And so I get it. So this is a doula sema and lira glue tied or to elicit EOS M pick and Victoza. Um Did they have FDA approval for cardiovascular disease prevention? The wording is different just depending on how the studies were done. But these are three drugs with cardiovascular labels that the FDA gave them after they were approved for diabetes. And there's going to be an oral version of some magnetite ore is m picked. The oral version is called Rebel sis. I'm in the midst of working on that trial is called the Soul Trial S. O. U. L. For uh And we'll have I think a couple more years before we report. But then you in cardiology will have an oral agent that you can prescribe as a cardiovascular drug. So Rebel says R. Y. B. E. L. S. U. S. I thought not to use it here because it's not indicated in cardiovascular disease yet. I don't want people to be confused but it's oral so magnetite and I have every reason to think it will have beneficial cardiac outcomes and it makes sense. The GOP one's, you know, analog of a natural hormone work everywhere. You would want a molecule to work whether it's on coagulation, on inflammation, a natural rhesus on postprandial lipids and the heart has GLP one receptors. Um We know that they lower glucose, they also lower weight and they also lower blood pressure. And so there's any one of a number of mechanisms where the GLP ones can work but they do work and if someone needs more weight loss or more glucose control, an endocrinologist will go at the GLP ones first because of all the other benefits. And there's again different studies at different endpoints. Sometimes was composite mace. Sometimes it was see the death. Sometimes it was all cause mortality or some combination. I see it mainly as how the studies were done. But these are the three GLP one. The GLP one may sort of had this complexity. I try to make it simple but not every GLP one is the same as every other. But if you can remember laura magnetite, some magnetite do the glue tied or Victoza. Those epic and treeless city. Um Those are the ones that are going to be cardiovascular drugs are really our cardiovascular drugs. Excuse me. And the oral version I think you'll find very, very acceptable. Um every time you look um they have the benefits. So for these three drugs very, very consistent. The reason you perhaps have not been so interested is their impact on heart failure is man. So, um, no impact on on heart failure. And so, uh but it's a cardiovascular drug. So it is in this talk. Um now this is interesting just published this week, um comparing um, the SCL T two's and the GLP ones for cardiovascular medical and cost dot coms. And uh it looks like a reason to be done study. And so I didn't have all the print out yet, but basically no difference. So I know you love the SGL T two. So they already came up earlier today. But the GLP ones we'll warm your heart as well, especially when it's oral, oral is already available. Already, many of my patients are are on it. Those who prefer oral to a once a week injectable. It's an aesthetic choice. And I have no reason to think that it won't have a beneficial cardiovascular outcome is to say molecule but not indicated yet. So I left it off the slide. Um the guidelines are keeping right up with this. No longer are we printing guidelines once a year guidelines and diabetes are now considered living documents which are online and can change at any time and they've had to change. There's been many midyear changes. So if you're reaching for a printed diabetes guideline, it's already out of date. So you go online if you want to use the guidelines now, just the last minute or two since I want to be complete, Metformin is still there and it's not going to be gotten rid of any time soon. And so don't cringe. There are, there's always, you know, uh Tempest in a teapot arguments to get rid of Metformin as first line and just go directly to S. G. L. T. Two S. And GLP ones. But for the time being I think for years we'll have Metformin And that's okay. You can tell your patients is literally something that comes out of nature. You know, french lilac go through were used for a couple of 100 years. We understand this molecule. And to the extent that there's data I won't go through while I showed you a couple of years ago. But every time you look at it, the data looks good for Metformin and it's never in the other direction. So um you know what that that's uh here's a hard mortality and the reach registry every single time it's positive and remember whatever you know and I know it? S A L. T. Two's and GLP one is on a backbone of Metformin because virtually all patients, the vast majority coming into studies, we're already on Metformin and every time it's looked at the registries for heart and kidney, it's beneficial in no time is it negative for the heart? It's a well tolerated safe drug, weight neutral, but a safe drug, it's going to be there And we'll have an outcome trial in 2024, it'll report. So it will be a bit more specific. I have to mention pie, a glitch zone because although it's a heart failure conference, for God's sakes, you stop by a glitter zone when the patient develops heart failure. But you know, we don't have a lot of drugs that do all these good things. And all these different is what happens when you have an anti insulin resistance drug. And I remind you in the heart failure studies if there was fluid retention piled medicine is not associated with excess death. So it's still a real drug and the risk benefit is for PAHO psychlo set. Why am I mentioning cyclo set? Because this is a really cool drug. Um, we don't use it much in for glucose, but it's revealing the mechanism for circadian rhythm and the sympathetic nervous system. So Romo Christine may be very important in our thinking. Now, a couple of drugs we urge people not to use the DPP four remain among the most popular drugs in diabetes. And I don't know why they don't work nearly as well for anything and they have no cardiovascular benefits. So, and they're expensive like any other branded drug. So we try to stop using these drugs unless the needs in glucose control. So, finally, areas for this population that we're talking about, they should not be used as people get older as they have heart and kidney disease. You should not you saw finally areas remember by case study my poor patients silka older people are not protected who overnight hypo and this is miserable for their dementia and everything else in frailty etcetera. The A one c of course will miss this completely. But so funny areas we consider their books. Um and so just based on on the data SGL t two s GLP ones, diabetes has gotten a lot better. The improvements are going to be mainly in ease of use and potency. Um and one other thing just conceptually in a couple of days, I'm going to chair an ad board on the extent to which hyper cortisol is um maybe like hyper Aldo. Austrian is um as a unifying additional mechanism where it's a total body effect. That's safer ff and so stay tuned. Hyper cortisol is um may have therapy is just like hyper Aldo as therapies. We didn't appreciate hyper Aldo for a while. Well ST stay tuned and the lessons from covid are only going to end with this. Um Covid does not make you, sorry, diabetes does not make you more susceptible to covid. It just makes covid worse when you get it and its glycemic variability. Perhaps more than glucose. High glucose is a bad prognostic feature. However, often it's not about diabetes, it's glucose as an acute phase reactant. And the whole experience with covid this past year has taught us that remote glucose monitoring can be done in the ICU and we do remote glucose monitoring the way you do remote chf monitoring. So thank you all very much. Got it in 90 slides, 30 minutes. Got it done.
