 Thank you Thank you for that kind introduction. It really is That's not true. I'm not really none of it. The truth is that I'm local. I'm from Houston I'm always humbled when I get invited to speak here at Texas Heart and I was on faculty at Baylor and I'm really proud of all you've done for women's health and cardiovascular disease So I may have too many slides, but I'll go through to try and keep us on schedule What what I'd great what I'd like to do today is really describe the important in a relationship between diabetes and cardiovascular risk and Then utilize the ADA guidelines which really have overlap with some of the speakers earlier from dr. Taylor and dr. Varani as far as creating a multifaceted approach to cardiovascular risk in patients and women who have diabetes and Then spend some time about this issue of the new medications and integrating Antidiabetic agents with proven cardiovascular safety and efficacy into the management of the patients who have diabetes Which is really a remarkable step forward compared to where we were four or five years ago We would not say that right because we didn't have a lot of CV safety or efficacy data so we'll hit some of these highlights and go from there, but I thought I would frame it in a case and And then maybe I'll just take a poll and we'll come back to this at the end So this woman is a Margaret I think is the usual name We I had given shown this case before 56 year old woman who presents for routine care She has heart failure with reduced ejection fraction mildly reduce an EF of 40 percent Strong family history of heart disease, but she doesn't have typical obstructive coronary disease her angiogram Showed small vessel disease, but nothing to be fixed He has a ten-year history of type 2 diabetes and you recently started her on a DPP for inhibitor Saxagliptin an oral agent in addition to the metformin that she had been on for years As I mentioned she was diagnosed with heart failure with reduced ejection fraction type 2 diabetes hyperlipidemia and hypertension Which reminds us that type 2 diabetes rarely occurs in isolation. How are we spend a day? We know that there are lots of other Medicines I didn't list all the others for medications are Lysinopyrus 40 pervada law 12 and a half twice a day Metformin 1000 milligrams twice a day Saxagliptin then laxate faxing and atorvastatin at 40 Her exam she has occasional dyspnea with exertion on review of systems and some P. Deledema on occasion. She's 5 6 weighs 185 pounds her BMI is right is near 30 Her blood pressure is 142 over 85 or heart rate 62 exam is essentially unremarkable Lipids are shown there a 1c of 7.8 percent total cholesterol 150 LDL 55 in HDL of 50 in The rest of her labs are normal with an eGFR of 52. So there's a lot of things we could talk about I didn't include triglycerides, which I should have and we'll talk about that a little bit But we'll focus on the glucose issue So the a1c was just about a 7.8 percent So given Cynthia's Cynthia's existing type of diabetes Diagnosis and a diagnosis of reduced left ventricular ejection fraction. What changes would you suggest making on her regimen? Would you leave her alone? No changes. Would you increase the saxagliptin to 5 milligrams daily? Would you change the saxagliptin and replace it with galliburide and sphonia rea? Would you replace the saxagliptin with an sgl2 and hember empirical frozen or replace it with a glp1 receptor agonists? And then finally add insulin to her regimen. We realize that based on all the options we have available I could have made this like 20 20 things sixes enough, huh? Just to show hands anyone with one two three four five six Most people picked four but we had a few hands for almost all of them. We'll come back to that so regardless of how we spend our day job What clinical you know our specialty we know that the problems of diabetes continues to increase seemingly unabated, right? It's estimated that about 30 million or nearly 10 percent of Americans have diabetes It's really important for us to remember from a public health policy as a lot of people still don't Recognize they have diabetes so a large portion of people have unrecognized diabetes and that Knowledge is not shared proportionately among different ethnicities. So we definitely have to work on health disparities And by 2030 this province has continued to rise estimated at 55 million as the population continues to age and as obesity continues to increase We also know that Diabetes the importance of this and I'm probably only talking about type 2 diabetes Is that it's associated with the years of life loss, right? It's shortens life and is associated with increased more morbidity So an average of 50 year old person will live five or six years less if you have diabetes than if you don't have diabetes And we realize despite how we improved diabetes the cardiovascular disease still accounts for most years of life loss in diabetes Which is shown on this slide In the emerging risk factors collaboration paper where we see years of life loss on the y-axis and age on the left For men and for women and vascular deaths is this dark portion And we can still see that vascular deaths account for the majority of premature Years of life lost for both men and women and perhaps even greater in women As dr. Eunice told us and i'll go over in just a minute Now I did mention that we have seen improvements in what we're doing right all this Our efforts to address lifestyle our efforts at um increase awareness of heart disease We are making a difference and here on the left hand side We see patients with type 2 diabetes and we see total mortality as well as cardiovascular mortality We have patients with type 2 diabetes in blue. We have patients um match controls in red This is from a publication last year in the new england journal And we can see that over this time period from 1998 to 2014 that for both groups we're making improvements So this is good But what we see is that we still have this residual risk and this is what we're trying to close that those individuals with Diabetes still have increased risk despite our efforts to implement evidence-based Strategies to reduce their risk But this is a residual risk of diabetes Now diabetes is interesting because of these gender effects that we really don't understand right the impact of diabetes appears to be greater in women We know that in general right being a woman is protective from heart disease before you develop menopause right that there's this lag in the disease Once you in menopause this these numbers quickly catch up And women actually as we've heard before die more of heart disease in men because they quickly catch up And and there's a lot of them to develop heart disease But we've learned that diabetes attenuates this protective effect of female sex Further development of coronary heart disease So if you're a type 2 diabetes diabetic woman that you lose any protection that you had from being a woman And so that's very important lots of studies have shown this framing ham a lot of community studies I just highlight the Rancho Bernardo study which were diabetes had a 2.4 excess risk for coronary heart disease in men, but in women. That's around three and a half fold Mock heart infarction tends to occur earlier in women with diabetes and men with diabetes And as alluded to earlier those women who have diabetes have a higher mortality than men And then the framing ham heart study This is not limited only to the manifestation of coronary artery disease or a heart attack But also extends to different manifestations of cardiovascular disease and heart failure has been an area of a personal interest in as far as Research in diabetes seems to associate with a two-fold greater risk of heart failure in men But this is a five-fold greater risk in women And why this is the case we really don't know So when we see someone with diabetes as we saw our patient Cynthia Or someone who has probably primary prevention what we do We know that we have to be very aggressive about risk factor management in type 2 diabetes Blood pressure control lipid lowering therapy aspirin therapy and glucose control is what i'm going to describe And really focus on cardiovascular outcome studies I'm going to fly through some of this because we've heard about it earlier But they can't stress the importance of blood pressure control as a risk factor to be modified in general and particularly in individuals with diabetes So these are taken from the new ADA guidelines which reflect a little bit of what dr. Taylor said in the overall guidelines They're more harmonized So the guidelines say that we should blood pressure targets should be individualized through a shared decision making process addressing both risk benefits and patient preferences And so this is an important and a new line that was added to the ADA guidelines For individuals who have diabetes and hypertension who have higher cardiovascular risks So not all diabetes is equal when I was finishing my training There was a study from steve hafner from finland that said diabetes with a coronary heart disease risk equivalent Well, that's probably not true, right? There are different flavors of diabetes And depends on what are the risk factors you have and boy if you've had a heart attack or you have heart failure That's a really high risk group So we have so we do have to individualize even among people with type 2 diabetes And this is what dr. Varani was saying earlier is using risk scores or risk tools to help stratify So in people who have either existing atherosclerotic disease who have a 10 year risk greater than 15 percent In general blood pressure target less than 130 over 80 may be appropriate if you can get there safely The data here if you look at the clinical trials is a bit mixed because of the accord blood pressure study which specifically looked at type 2 diabetes and didn't show a statistically significant benefit although the Point estimate the reduction was kind of consistent with brandon's other studies have shown that Indeed, they're not so different. Maybe we can talk about that in Q&A if someone has questions, but and this is what's recommended 130 over 80 And people who are lower risk. We still can keep our goal of 140 overnighting assisted in the third bullet point A reminder that when we take care of patients with diabetes or hypertension in general that when someone comes in And they're really high and i'm sure you do this too as I warn them that the average person to get their Blood pressure control will need between two and three medications to get their blood pressure control Just so they won't get mad at me when I start giving them a bunch of pills If they're really high initiation of two drugs or a single combination pill is recommended if they're greater than 160 over 100 Multidrug therapy is generally required And in patients who have type 2 diabetes and micro ovuminuria, this is where we start thinking well Maybe there is a preference to medicines and an ace or an ARB is recommended as first-line therapy After that we can use size i diuretics or calcium channel blockers And then I think as was mentioned earlier that mineral oil quarter cord receptor antagonists Can be considered in patients not meeting blood pressure targets who are on three anti-hypertensive medications So spironolactone should be a choice if we're having trouble Getting that as long as we are cautious about measuring potassium and their candidates based on their renal function Dr. Rodney talked about this a little bit more, but we remember the atherogenic Dislipidemia of diabetes, which is usually characterized by Relatively normal or maybe mildly increased LDL, but a different type of LDL this small dense LDL, which is more atherogenic This dyslipidemia associated with metabolic syndrome insulin resistance is also characterized by low HDL As well as elevated triglycerides and those really two components are very can be modified with Lifestyle modification diet and exercise We're going to come back to that and really it's again the same issue That we talked about with blood pressure is really focusing on what type of risk that person has and then deciding on How we should treat them Stattons remain the main state of therapy. This is for again from the guidelines and in your handout So they the guidelines survive people into those less than 40 and greater than 40 And those of us again who are taking care of patients realize that we see more and more people who have type 2 diabetes Who are less than 40 or less than 30 and so even now, you know Teenagers so what we do with them is is debated, but again, we use ASCVD risk score If they're high we we uh, it's a statin is um recommended Um, and then a pcsk9 inhibitor if we can't get it less than there If you're over the age of 40, it's considered you could use a moderate dose statin In general, I think um, if you have a one one additional risk factor We should probably be using moderate those statins if you have ASCVD you go high So this is pretty consistent with what the other guidelines say What about the other two components of the of the um Dislipidemia, what about HDL and triglycerides? How aggressive do we treat them beyond lifestyle modification? And what data do we have for that? So for fasting triglycerides that are greater than 500 It's it's recommended and it's pretty clear that we should treat those after we evaluate for secondary causes of hypertricosidemia After we make sure they don't have nephrodic syndrome. They're not They're not hypothyroid ask about alcohol We ruled out secondary causes and they're greater than 500. We should probably treat that to reduce the risk of pancreatitis Below 500 it's sort of a gray zone and the studies which have looked at Adding a phenofibrate on top of a statin and people with diabetes two studies one accord lipid and one the field study Have both shown this adding a phenofibrate on top of a statin did not improve outcomes um in people with diabetes so the cardiovascular outcomes were not Improved so the guidelines suggest we should not be using phenofibrate on top of a statin in that group of people Who have a triglycerides less than 500 if you look at um databases It's used to see fibrates are used a lot in this population There is still a little bit of debate about those people who had high triglycerides in low HDL A value of 204 over 34 in in secondary analysis of those studies which People who enrolled didn't have really high triglycerides at baseline if you did have higher levels in low HDL Maybe there's a signal, but but in general it's not recommended that we do that And then niacin the treat the HDL has been a real disaster on top of adding a statin right niacin has not helped at all And so it has not been shown to prove additional cardiovascular benefit about statin patients don't tolerate it. They become more This uh Glycemic and it's not recommended that we use it. Um in general Aspen how many people prescribe aspen for people with type 2 diabetes? in the clinic The rest of your line I ask this question. I have the pleasure of I have a pleasure of going around the country and I talk with this primate group and I talk to primary care doctors I talk to cardiologists and I ask this question. I want to prescribe aspirin to the um To your type 2 diabetes and all the cardiologists raise their hand But they know the data the data is not good at all for the use of aspirin and people who have type 2 diabetes Clearly aspirin should be used for secondary preventive strategies and those with passive stroke of disease clearly right If you have a q-corner syndrome as dr. Eunice described, we need to have dual anti platelet therapy after a q-corner syndrome or a sense been placed The guidelines say that aspirin may be considered as primary prevention and those who have increased cardiovascular risk after a discussion with the patients on benefits Versus increased risk of bleeding. So to me, this is kind of a wish to wash your statement, right? I'm not sure what to do. I think if someone is high risk for bleeding It's clear in primary prevention. They should not you probably do not need to push the aspirin They have lots of risk factors Maybe maybe and so it really there there probably is A modest benefit related to aspirin and people who have diabetes probably and I say that because there have been about Four randomized controlled trials of which three were neutral and then the last one was positive And so I decided today for Saturday morning. I would show you the positive one, right optimism optimism Optimism right and and so um This is the ascent study that was published at the end of last year It shows the effects of aspirin for primary prevention and people who have diabetes Randomize a lot of people 15,000 individuals to aspirin 100 or placebo All of them for seven and a half years And what's shown on the right hand side of the slide are the events that happen So there were serious vascular events that occurred in 8.5 of those who randomized to aspirin Versus 9.6 on placebo so we can see that there was about a 1 percent difference at about seven and a half years Major bleeding occurred major bleeding in 4.1 percent in aspirin and 3.2 percent in uh control So about a 1 percent difference 0.9 percent difference Over seven and a half years the number needed to treat is 91 to avoid a vascular event in 112 to cause a major bleeding event So it is this really this balance that exists Between the two and when they try to look at risk within this study higher risk lower risk It didn't really pan out that you could identify that individual who would benefit from aspirin based on risks alone but I think in general All right, we cardiologists love our aspirin and and I despite showing this everyone will use it but in general I think If someone has bleeding risk or has had a bleed I would not push it in primary prevention If someone has lots of risk factors, I might use The data would suggest that I'm a bit off so In the next 10 minutes or so, I'm going to show you a lot of data And really this idea data on glycemic therapy because I really think the last Five six years we've entered this new era Where we move beyond hemoglobin a1c to one of cardiovascular safety efficacy Um in choosing which diabetic medication we're going to use and these are going to be reflected in the guidelines Right before we just thought about a1c We had some data on safety But now we have outcome data and it wasn't until 2008 a little over 11 years ago that the fda mandated that when we Developed new diabetic medications that we prove that they're safe and people have diabetes first and foremost We didn't used to do that right they have to be safe And then wouldn't it be good if they were effective and there are lots of stories where there were medicines that had been developed that Could lower a1c That had some safety concerns And then even worse they may have had increased cardiovascular events and that was a story of rosy glideson Which was later exonerated and randomized controlled trials But because this was such high stakes so many people with diabetes We're treating so many people it was so costly We needed more information and the last several years We've had several randomized controlled trials that have been published I'm going to focus on the new medications that are available who have randomized controlled trial And I'm going to focus on the incretin Therapies and then the sgl-2 inhibitors So just for review the incretin signaling or the intricate effect Means that more insulin secreted after glucose is provided orally than intravenously. So if I eat a sandwich my My insulin will increase for the same amount of glucose that if I took at IV And this is a result of the gi hormones glp1 as well as gip equivalent like peptide 1 Which stimulate insulin release following food intake in type 2 diabetes. This incretin effect is reduced And so it is an early hallmark of the disease these These glp1 and glp they're rapidly degraded by an enzyme called dpp4 So to take advantage pharmacologic advantage of this system you had to either inhibit the enzyme that broke them down Or make the glp1 resistant to degradation. So they're the glp1 Receptor analogs that are resistant or the dpp4 inhibitors In addition to the incretin effect affecting glucose, there's a variety of other effects They're cns effects where it promotes satiety and reduction of appetite as well as delayed gastric emptying So it's associated with modest weight loss or sometimes significant weight loss there's decrease Gluconeogenesis within the liver. So a variety of effects that may Be beneficial beyond just glucose and the the glp1 receptors ubiquitous So there are some some data in animal studies, which I wouldn't show Which suggests that it may have some hemorrhagic effects It's there may be some off-target effects as well in the vasculature and in the heart So today we'll start with the dpp4 inhibitors They have been four studies that have been published with the dpp4 oral inhibitors like our patient Who was on saxaglyptin, right? These are the four studies The first one was saxaglyptin and saber to me 53 Examine alaglyptin ticos citaglyptin and carmelina, which was just published at the end of last year the very end I think is online right now And we can see that these are a wash right that for the dpp4 inhibitors neither were they safe Um, no, I take that back. They were safe for their primary outcome. So they didn't increase the hazard ratio So there's important safety study first They had to meet a non-imperiality margin of 1.3 and they all met their non-imperiality margin So they were a safe medication in general with regard to the mace outcome But we can see that it didn't really improve things So it's a good it's a medicine you can use for people with diabetes an oral pill well tolerated Not going to reduce cardiovascular risk and in general it didn't include mace But one thing that came out within the study Is that there was some heterogeneity with regard to the effects on heart failure So that there's been this difference that we've seen in the first study Saxaglyptin showed an increased risk for the development of heart failure With saxaglyptin compared to placebo So our woman who had any ejection fraction of 40 who had some volume retention We might be careful about using this medication Examine and alaglyptin also went on the sit side of not being good for heart failure events So these two caught the attention of the FDA who then put a warning on both of those agencies They should be Used with caution and people at risk for heart failure and maybe should be withdrawn and people who have a symptomatic heart failure The next study said aglyptin Which was a bigger study didn't show any risk and the last study also didn't show any risk of heart failure But the FDA I think had enough and I think that's probably unfair for the last two agents But they put that warning on the class So that we just have to be careful with dpp4 inhibitors and people who have heart failure Knowing that the studies are a bit header. There's heterogeneity within them According to the glp1 receptor agonist, we realize that we have lots of choices from which to choose from Often driven by what the What's the right term the pharmacy or their healthcare plan? formulary tells us it's on the formulary that we can prescribe but Really what the difference is in large part has to do with their half-life beginning with exenotide twice daily Which is a short-acting one Extending all the way down to exenotide once weekly as well as these other agents that are are given once weekly Aragotide as well as once a day. This is probably the weakest of the glp1 receptor agonist And uh, although listed once daily probably is a twice daily medication But we can see that in general that's the main difference. There is some difference as well as the chemical structure and whether it's an human based modification of a human based glp1 or whether it's based on exenotide So to date there are five five studies with glp1 receptor agonist and they are shown on this slide And so this is a little more tricky because within the studies themselves There's a little bit of again some heterogeneity as far as the outcome of the mace outcome, right? Very importantly some studies have shown benefit and have showed significant benefit So elixir the first study that was published Was neutral and that's a shorter acting medication. So I don't think anyone uses this one. So we'll skip that Somagotide showed benefit Leader which was a first study to show To show benefit for a glp1 receptor agonist is here excel favored treatment And then there was a most recently harmony Abiglutide which is not commercially available the company stopped The development of this medication but they did finish the trial and they may bring it back Because they did signal but you get a feeling that beyond the first one They all seem to trend in the right direction for these medications which is important Just spending a little time on some of these because loraglutide leader has an FDA indication for the reduction of Cardiovascular disease and people who have type 2 diabetes. These are the data Which showed the primary outcome was reduced by 13 percent Not only was a primary outcome reduced, but we see the mortality remember CV mortality was a big black part of Years of life lost on the first slide or second slide I showed but accounts for the majority of death was reduced by 22 percent and total mortality was also reduced with loraglutide excel is the once weekly form of Exenotide by durian. This is the name and so I was a us coordinator for this study This was showed again that there was a trend in the right direction. The hazard ratio was 0.91 favoring exenotide Because it didn't meet its superiority outcome everything after that is sort of hypothesis generating But if you look at total mortality, we see that it's very similar to loraglutide And the total mortality would have the same hazard ratio As loraglutide so again a signal that This medication may be beneficial So far for the glp1 receptor agonist all trials have met their primary goals showing that there's no increased risk of atherosclerotic cvd Leaders are saying six in harmony have all demonstrated a benefit on mace and mortality and loraglutide Has this fda indication Not for treating glycemia right for the reduction of cardiovascular disease and people who have type 2 diabetes But let me turn now to the sgl2 inhibitors again as a review the sgl2 inhibitors in the proximal 2 build a kidney and they're responsible for glucose Reabsorption 90 percent of the glucose reabsorption is for the sgl2 receptor So if you block the sgl2 Reabsorption you have glucose geria And so you have spilling of the glucose in the urine a relatively I think simple mechanism action if you think about it Um, but when I asked when I say that we'll show why do they have cardiovascular benefit? Because a relatively simple mechanism of action associated with a hemoglobin a1c of a fall of a Point seven percent modest effects on blood pressure Modest weight loss in a weak diuretic that after time is probably not that strong of a diuretic Lots of excitement with this class of medications right lots and lots of excitement So these are the completed cardiovascular outcomes of the sgl2 inhibitor studies there have been Three of them empa canvas and declare They're all shown here declare the last study that was published in the new england journal At the beginning of this year a release at the aha It had two primary endpoints. It had a traditional mace Endpoint as well as a cardiovascular death and heart failure endpoint They changed that endpoint during the middle of the study when they started to see benefits in the other studies of the splitter But when we see this for empirical frozen and people who had established cardiovascular disease We saw that there was a benefit And the study canvas chemical frozen was associated with the benefit in the reduction of cardiovascular disease For mace in this study. It did not reach statistical significant This study is a little bit different and it has implications on how we practice This study had a larger proportion of people who had primary prevention Some of the two first studies They were mostly people who had a heart attack who had heart disease who were high risk The apical frozen specifically had a group of people who were lower risk And some people think well, maybe that's why we didn't see this difference When we look at cardiovascular death and heart failure is a combined endpoint We did see that there was a benefit associated with apical frozen Again, what's remarkable at these studies and I spend a lot of my time talking about heart failure In my previous life and about medications that increase your risk for heart failure They're associated with greater rates of heart failure like the tzds Insulin whether probably just a maybe a mark of disease severity But also associated with greater heart failure events. So we spent a lot of time talking about How medications and people who had heart failure for diabetes were maybe bad, right? And so we in the how they might cause heart failure and a lot of this so that when we saw this, this is remarkable Here we have a class of medications that seem to prevent heart failure This is what's shown on this slide. We have um, empirical frozen mechanical frozen and apical frozen And we can see that the the hazard ratio is pretty similar across the group of medications. So a very exciting um finding We look at emper reg empirical frozen was associated with mark reductions in cardiovascular mortality is shown here Has a ratio of 0.62 Heart failure shown here empirical frozen versus placebo and we can see that these survival curves begin to For a heart failure begin to split very early and remain separated throughout the study The one question that comes up is that what's going on? Why does the medicine that makes you spill blood sugar in your urine, right? How does it make you have less Chance of dying from heart disease, right? And so that's an area of intense interest You know, if you go back a term we call reverse translation a finding that we're happy to see but we don't completely understand What happens and so lots of mechanisms have been proposed Some people say well, maybe it's the effects on the blood sugar or weight But to date we didn't see really any studies that have shown Reducing blood sugar a strategy of being intensive with blood sugar improves events. So I don't think that's really it Perhaps some vascular effects. I think Stephanie culture has been studying this a little bit Perhaps it's its diuretic effect that's associated with reduction in events Well, that may be true for heart failure But we know that from cardiology that diuretics don't really make people live longer They keep them out of the hospital Maybe not live longer So there's a lot of interest on perhaps other off-target effects and this is moving forward I think probably one of the most important things is that there's also been this reduction in Renal disease seen with these agents and there's this cardiorenal access that there's a renal protection associated with stl2 inhibitors On the way, um, these affect the hemodynamics within the glomerulus Perhaps this is what we're seeing and we definitely see across the board for empirical frozen and the emperor regalcom study mechanical frozen in the Canvas and apical frozen in the recent timmy study and we can see that for all of them There's a reduction in cardio and renal events in addition to the cardiovascular events on that But so far all trials have met their primary goals showing there's no increased risk of a scvd Emperor rag and canvas demonstrated a benefit in mace and mortality with empirical frozen as well as hospitalization of heart failure I didn't talk about this mechanical frozen in that study was associated with a slight increased risk in amputation As I'm sure you may have heard before the numbers are very small Why that's the case? We don't know whether it doesn't necessarily seem to be a class effect from some of the large studies But when emperor regalcom was started, they weren't really looking at this closely We're looking at that really closely now and really the great thing about these studies is because they're large and they're high risk patients We didn't have this data before so we can really begin to look in different studies and see these Unexpected signals and see if they're real so that we don't expose our patients to increased risk Both empirical frozen and mechanical frozen have an fda indication for type 2 diabetes and ethosclerotic Very important apical frozen probably we'll get one too So I'm going to finish up here with a couple of comments more related to cardiologist So we started with these blood glucose medications that were used to treat blood glucose that we're trying to show We're safe and effective and we end up with benefit benefits It's very welcome benefit that we hope for benefit. It's a little hard to explain and we're working on that So now there are several studies for example in the sgl2 inhibitors looking at not the reduction as far as In people who have diabetes But reduct using these medicines not as glucose lowering medications But as heart medications the card like good cardiologists. We try and take everything over And so the question is this is not not a diabetic medicine, but it's actually a cardiac medication So right now there are several ongoing studies at least four that I know of and probably more looking at the effect of sgl2 inhibitors to prevent heart failure events and people with heart failure Kind of irrespective of whether they have diabetes or not and that's what's shown on this study Oh, I better go fast. So I'm going to just um Just show the recent guidelines Here which have now incorporate this information. This is from the late last year the A combined report from both the american guidelines and the european guidelines and echoed and the recent ada guidelines Which are really a change right what they recommend is that we still use metformin And this is if hyperglycemia and people who have atherosclerotic disease or heart failure or ckd But those are the predominant comorbid conditions knowing that There are many comorbid conditions or many things that are involved And once we use metformin and lifestyle that we choose A glp1 receptor if atherosclerotic if a scvd risk is the predominant comorbidity that we're worried about That we either choose a glp1 receptor agonist with proven benefit Or we choose an sgl2 inhibitor with proven benefit as our second therapy And people in which heart failure or chronic kidney disease are the predominant feature that we're the patient may have It's preferred that we use an sgl2 inhibitor with evidence of reducing heart failure or ckd Progression and if not then we can go to the glp1 receptor agonist If it's above target then we can start adding the other medications that are listed on the slide Just to quickly go through the guidelines also suggest that if you in different groups This is just in your handout if you need to minimize hyperglycemia There's an important motion the second line. Maybe are these medications? If weight loss is your main concern Then a glp1 receptor agonist or an sgl2 inhibitor may be your first line after metformin And then finally the issue of cost right these medicines are costly And so cost is the main thing that sometimes we're just limited to the old medicines So funny rear tzds, but we have to be careful with those medicines and our patients who are high risk for scvd So in our woman Cynthia Who had type 2 diabetes and a diagnosed to reduce ejection fraction? I think that you could go I think that increasing sex eglipsum probably wouldn't be my first choice Just because of the fact that it has been associated with greater heart failure events since he has some edema I probably would not choose gliburide And I don't think many people are these days unless cost was really an issue But you'd have to be concerned about the risk of hypoglycemia already She's overweight obese And so associated with weight gain. So I might not choose that. I think you could go with either Four or five. I think the guidelines would suggest that we should try empa first But again, if weight loss is an issue then sometimes we can use the lagrotide or a glp1 receptor agonist And I would probably hold on insulin But I agree that with most people that we probably wouldn't leave her alone Hemoglobin 7.8. We would probably want to get that closer to seven Last comment is what Stephanie said she needed game going into this Is that what is so now that we have a medication that's associated with cardiovascular disease reduction Right now the cardiovascular disease is one of the main things that we use to guide to help decide what our second late Agent is for the treatment of diabetes What is the cardiologist's responsibility in the treatment of diabetes? We sort of take over for hypertension. I mean we have to take over we share right a piece I know that we but we feel comfortable managing that that's I guess the right word We feel comfortable managing lipids. Should we feel comfortable managing diabetes if we don't start A medication that's been associated with cardiovascular reduction and cardiovascular mortality and someone's who's high risk Should we is that our responsibility? And so that is really a big question And so a recent acc panel try to address it. They said a cardiologist a minimum Needs a screen for diabetes and those who uh with or high risk for cvd We have to treat risk factors And then we do have to incorporate the data for newer anti aproposemic agents in the routine practice. This is recommended And whether that's increasing shared decision increasing awareness, it is not not clear yet, but this is a Paper that just published from um From my old institution partners and Stephanie cultures as well in boston Just looking at the prescription patterns of sgl2 inhibitors within that healthcare organization And so we have a data 2013 up to 2017 and we have different people here We have pcp internal medicine and gray We have endocrinologists and red and we have cardiology here in this deep purple And it's just the absolute number of prescriptions by quarter And on the top we have can the fda approval for the different medications When the study came out for embryo outcomes showing that there was benefit Uh, kennecophosicin and the variety of different things. Um, and what we can see is that Cardiologists aren't really prescribing these medications. So they account for about five percent We can see that endocrinologists are really are doing a fair amount But within the system even pcps were less So I think that as we move forward we have to begin to ask these questions of how we're going to incorporate In them into our patients who are high risk So in conclusion patients with type 2 diabetes are at high risk for cardiovascular events We require a multifaceted approach to treat these individuals larygotide, endocrinophosin and kennecophosin are now fda indication Indicated for the reduction of adverse cardiovascular events in patients with type 2 diabetes and ascvd Um, both endocrinophosin and kennecophosin have shown reductions in heart failure as well as dappical frozen And future studies are underway to test the sgel 2 inhibitors in patients beyond just diabetes. So stay tuned Thank you very much