 Good afternoon. It's a real pleasure to be here for the 11th Annual Women's Heart and Vascular Symposium to speak on Update of Diabetes Treatment. Greetings from Kentucky. I miss all my friends and colleagues in Houston. It's a real pleasure to be part of this. And as I've started before, I just want to take a moment to congratulate Stephanie Coulter and her team on this successful symposium for 11 years and all her tireless efforts to improve awareness and reduce the cardiovascular burden of disease, heart disease and women. So congratulations to Stephanie and her team. So what I'd like to do over the next 30 minutes is to review recent epidemiologic trends in diabetes and cardiovascular disease that exists. I want to then identify and present recent cardiovascular outcome trials in individuals with type two diabetes and review safety and efficacy profile, particularly relates to cardiovascular disease of the anti-hyperglycemic medications. And then I'll finish by reviewing the American Diabetes Association practice guidelines regarding glucose lowering medications. So before we get started, I'd like to begin with a case, like a Margaret. So this is the case we might see in clinic on a given day when we're not here on a Saturday. And Margaret is a 68-year-old woman who presents for follow-up after recent hospitalization. She was hospitalized a few weeks ago after she developed approximately one week history of progressive disney on exertion, lower extremity edema, orthopnea, elevated blood pressure and was admitted with an elevated anti-propium P. Shortly after admission, she had an echo, which demonstrated mild concentric Lv were modeling with low normal to modeling depressed left ventricular ejection fraction and ejection fraction that was estimated between 50 and 55%. She had mild left atrial dilatation as well as diastolic premise, which was suggestive increased left ventricular filling pressures. So in total, really a picture of heart failure would preserve the app. She also underwent a nuclear stress test, which showed no evidence of ischemia and again confirmed her low normal ejection fraction. Given her constellations of symptoms and signs, she was diagnosed with heart failure with preserved ejection fraction and was treated with diuretics as well as blood pressure control. Relating to her diabetes, she has a 10-year history of type 2 diabetes and is on a DPP4 inhibitor, Saxagliptin, as well as Metformin. Like many of our patients that we see, she had several comorbidate conditions. Margaret had coronary artery disease and undergone a percutaneous coronary intervention approximately three years ago that otherwise been stable. She'd had type 2 diabetes that was diagnosed 10 years ago, hyperlipidemia for three years, hypertension and obstructive sleep apnea. Her medications when we see her after her hospitalization included aspirin, 81 milligrams daily, lysine or pro 40 milligrams daily, carvetal law 12 and a half twice daily, sprun or lactone 25 milligrams daily, atorvacatin 80 milligrams daily and furosamine 40 milligrams daily. Margaret's on Metformin 1000 milligrams BID and Saxagliptin 2.5 milligrams daily. Since her hospitalization, she feels improved, although she does still have some dyspnea with exertion. Her physical exam is generally unremarkable. She does have a BMI of 30.7. Her blood pressure is not perfect 130 over 85. So maybe just at the upper limit, a heart rate of 62. And in general, she appeared in no acute distress, really no evidence of significant volume overload on exam. Her labs are presented here for hemoglobin A1c was 7.2%. Her total cholesterol was 150. Her LDL was 55. Her HDL was 50 and her triglycerides were normal. It lists those. Her blood count was normal. Her basic metabolic panel was also within normal limits, with the exception that her EGFR was slightly reduced at 52. And her antiprobium P was still slightly elevated at 425. And I remind you of her medicines here on the right hand side. So the question is, is given Cynthia's existing type two diabetes and her comorbid conditions, which include hypertension, coronary artery disease, heart failure with preserved EF, obesity, obstructive sleep apnea. What changes would you suggest to make to her regimen? No changes are necessary. Increase saccagliptin, a DPP4 inhibitor to five milligrams daily. Replace the saccagliptin with gliburide, encephalne urea. Replace saccagliptin with an SGLT2 inhibitor. Here we have empirical flosin. Replace saccagliptin with a GLP1 receptor agonist, laryngotide, or add insulin to her regimen. So we're going to use this case to frame the discussion today as we go back and forth. And I want to think, you know, a few things is one, what would I do? And then who should do this and why? And so we're going to move forward in just a bit. Normally, I would ask you to raise your hands or vote. But since we're virtual, we're going to skip that part. But I do miss our in-person lectures. So regardless of what we do in our day to day life, whether we're a nurse, a physician, a researcher, an administrator within the health system, we know that the prevalence of type 2 diabetes is increasing, seemingly unabated in the US. These are data that are shown on the right from a recent publication in JAMA just a couple of months ago looking at NHANES data. And we can see that in 1976 to 1980, the prevalence of type 2 diabetes was approximately 5.3%. If we fast forward to 2011, 2014, that increased to around 11.5%. And in its last assessment in 2018, that rate had increased to 14.3%. So really a dramatic increase that we've seen in the prevalence of type 2 diabetes. We hope that these curves are somewhat plateauing over recent years, but still it's quite dramatic when you take a step back. In total, if we think 14% of people adults have type 2 diabetes, we realize that that accounts for almost 37 million Americans who are living with diabetes in the US. Diabetes is and has been and unfortunately will be until we get better at how what we do is a leading cause of disability and mortality. And in as much as a very costly disorder, the total costs in 2017 of diabetes was estimated at 327 billion, which represent which approximately a quarter of that was actually which represented approximately 24% of health care care costs. Now I had spent the last year before moving to Kentucky working at the UT School of Public Health and the Department of Epidemiology. So we spent a fair amount of time looking at trends and trying to understand public health in the population. And so this slide just shows what I had discussed previously. The rates of diabetes within the US from 1999 to 2018 in the in Hanes data and you can see this increase in diabetes. But while I wanted to show this slide is because if you look at below the total number in orange and in blue, we can see that over this period that we did a better job of diagnosing diabetes. But there still remains a significant proportion of individuals who are undiagnosed. And so in total, there are about a quarter 23% of individuals who have diabetes if we surveyed a population who remain undiagnosed. This is really a call out to the public health system about how can we reach these individuals because not only are they undiagnosed, but they remain untreated and everything we talk about from lipid control blood pressure control and diabetes treatment are under treated or untreated. So a significant opportunity to improve health and preserve health. So I'm not going to spend a whole lot of time talking about trends and epidemiology, but I do want to just make a couple of points. And I was most taken aback by this study, which looks at the prevalence of type two diabetes and adolescents. So as many of you know, we would call type two diabetes about onset diabetes. But indeed, we see that younger and younger individuals are being diagnosed with diabetes. And these are data that are from a survey. Looking at the prevalence of type two diabetes and adolescents and actually was recently updated in the trends are similar, but I like this graphic, which shown on the slide are the prevalence of type two diabetes in all individuals in the survey age 10 and 19 here in purple, as well as broken down by different ethnic groups. And one can see that over this time period, there's been a gradual increase in this purple line. But what's most remarkable is how disparate this rate of change has occurred in the different populations. That if we look at Native American adolescents in red, that we can see a remarkable increase. The same thing, excuse me, I'll go back the same thing holds true for black adolescents, as well as less so but still increasing for Hispanics. So significant disparities that exist. And we'll come back to that because one of the greatest risk factors or predictors for cardiovascular complications and microvascular complications is duration of diabetes. So if someone gets diabetes at age 18 or 20, you know, when they're 40, they may have had diabetes for 20 years. So this is really important. The scale is not very high as far as the incidence, but a disturbing trend that I think we need to be aware. So we've also known that cardiovascular disease is the leading cause of death in patients with diabetes. This has been this way for many years and still remains. And it really affects all manifestations of cardiovascular disease as shown on the slide. The diabetes is associated with a twofold increased risk for coronary heart disease, increased risk of heart failure, perhaps greater in women than men when we think about the relative risk associated with that. Diabetes is associated with stroke before arterial disease. And most studies have shown that cardiovascular death may be increased by about 50%. And these are real years of life lost when we look at the studies. And it's estimated that the lifespan in adults over the age of 50 are reduced by approximately seven and a half years in men and by about 8.2 years in women. So it has a remarkable burden on health and it's predominantly driven by cardiovascular disease. So if we're going to change these trajectories, we really have to begin to lower this burden of cardiovascular disease. Now, I want to spend just a few moments talking about some of the sex specific associations between diabetes and cardiovascular disease and the difference that we may see in men and women. So we know that in general, generally speaking, the coronary heart disease in women may lag behind that of men by about 10 years before menopause. So when men tend to get the disease earlier. So the presence of diabetes seems to attenuate this protective female effect. Why that's the case where it's not completely clear, but it does in multiple studies show to attenuate that effect. Several studies have also shown that the relative risk of coronary heart disease is higher in women than in men. So if you compare a woman who has diabetes to someone who doesn't have diabetes and then look at a man with diabetes compared to those who don't, the relative risk is higher in women than in men. This may have in part related to the background risk in women without diabetes and it's lower. But nonetheless, diabetes changes the trajectory. Myocardial infarction often occurs earlier in women with diabetes and men with diabetes. And when they do have a myocardial infarction, the mortality is often greater. In the Framingham Heart study, again, when we look at diabetes and the impact on other cardiovascular diseases such as heart failure, there was a twofold greater heart failure risk in men and a fivefold higher in women when we compared women with diabetes and without diabetes. The figure on the right just shows a recent publication which tried to bring in multiple studies and look at cardiovascular mortality and diabetes, comparing the relative risk that exists, comparing men and women. And we can see that there are differences for cardiovascular mortality, particularly seen in young women. So here we see that the relative risk of cardiovascular mortality was approximately sixfold. A woman with a five and a half fold, a woman with diabetes compared to those without diabetes. And then we compare that to a man where the relative risk was 2.30. We can see is that as the background risk of the population increases, as people age, that that magnitude of difference becomes somewhat attenuated. But we still see that women in general tend to have a higher relative risk of cardiovascular mortality associated with diabetes than someone without that issue. The other thing that I think is important to notice, again, when we put on our public health hats and we start looking at populations, it's really the issue that what is happening now. We've known that in the 90s and the early 2000s that we made dramatic improvements in the rates of cardiovascular disease, cardiovascular mortality and myocardial infarction, both in a general population, as well as for individuals with diabetes. But when we can see that over the last between decade, and here I show data between 2010 and 2015, that that momentum that we had may be lost, that we've sort of plateaued in our improvement. And indeed, we see begin to see some more worrisome trends in the population. This slide, again, published a couple of years ago now looks at a variety of complications, myocardial infarction, stroke, lower extremity, amputation, hyperglycemia. And what we can see here, I'll start on the right, is that from 1995 to 2015, these curves tend to go down. But then between 2010 and 2015, they're relatively plateaued. So despite our efforts to try and improve these outcomes, they've sort of plateaued in that older group. When we start to look at younger groups, we see that, in fact, some of these are really going the wrong way. Between 45 and 64 years old, we can see that these areas of these curves begin to increase. And this is particularly true in individuals who are younger. That the rates are a bit of a little bit lower. But the trends, the number of events really seems to be increased. And this is most marked here for lower extremity amputation. Dr. Salim Barani, who's part of this program, has shown us that in younger adults, they're often less likely to be treated with aggressive therapies, or maybe they may have a tendency to be less compliant with the medications. But we do see some worrisome trends, particularly as we put this in the context of the total burden of disease, the earlier onset of disease that we have. Again, a call for public health initiatives to help lower this risk. And then my final slide as it relates to public health in ways that we might be able to improve our care of individuals with diabetes really speaks to how we control risk factors. Again, we've known for a while that aggressive risk factor control is very important and that multifaceted risk factors are approaching. Targeting each one becomes very important to lower risk. This was shown in a study of Steno many years ago, where if you could target all the risk factors and achieve success, you could improve mortality. This was a publication last month in the New England Journal looking at NHANES data and looking at how we were doing in our pace, our individuals with diabetes within the U.S. as it relates to cardiovascular risk factor. On the side are three risk factors, glycemic control, blood pressure control, and lipid control. This is non-HDL cholesterol, but for LDL cholesterol, it's very similar. And what we can see that over between 1999 and 2018, that we have made some improvements in how we've treated, for example, glycemic control, that we went from 44% of a hemoglobin A1c of less than 7% to about 50%. In fact, these numbers are a little bit lower over recent years. This may have to do with what we'll talk about a little bit that maybe we can not be as aggressive at targeting an A1c, but if we move over to blood pressure control, again, we can see that we haven't made much improvement over the last few years and 70% have a blood pressure of less than 140 over 90, and less than half have a blood pressure of less than 130 over 80, less than just a little over half meet criteria for HDL cholesterol. And probably what's most sobering in areas for improvement really is when we look at all risk factors controlled, if we look at those three risk factors and say, how are we doing in a multi risk factor control, we can see that we only are not even reaching 25% of our patients. So we can definitely improve there. So let's go back to our patient and come back now to more glucose related medications and what we might do. So again, as a reminder, since you have diabetes with comorbidities, and the first question is, should we do anything or any changes necessary? Now in the past, we would often look at the A1c and decide what to do based on the glucose level. And the glucose level is still important. Her level is 7.2%, so modestly controlled. Reason why I think with her comorbidities, these guidelines, these are from the American Diabetes Association guidelines as well as from the endocrine guidelines, showing what current recommendations are for hemoglobin A1c goals. And so what we can see is that in general, less than 7% is considered a reasonable goal for most individuals who are not pregnant. Based on many of the studies which have compared intensive glycemic control versus standard therapy, we've learned that in patients with established cardiovascular disease, with lots of complications, driving it lower, while perhaps improving microvascular events really doesn't improve mortality or seving mortality. But if you can get there in people who may have newer onset diabetes, less complications, and perhaps it is reasonable to have a more, a tighter control, less than 6.5% if it can be achieved without substantial hypoglycemia or adverse event. And people who have multiple comorbid conditions to our life expectancy, lots of comorbid conditions, heart failure, people who are having lots of hypoglycemic episodes, perhaps less stringent is appropriate, so these are where we are now. So I think that in general our patient is just slightly above her target and be reasonable to get her lower if we could do it safely, but she's close. But I would argue that we're moving now from an era where when we think about cardiovascular risk reduction and we're thinking about how to choose medication and what medication to add, we're really moving beyond an era of hemoglobin A1C and begin to really incorporate safety, efficacy and cardiovascular impact of these medications to help us decide from a slew of drugs. So our patient is on a DPP4 inhibitor. What do we know about DPP4 inhibitors in cardiovascular disease? Well, this slide highlights four clinical trials of DPP4 inhibitors. Data shows that DPP4 inhibitors are commonly used beyond metformin for the treatment of patients with cardiovascular disease. But in general, when we look at the trials comparing placebo and DPP4 inhibitors, we see that they're relatively neutral as far as meeting their primary efficacy compared to placebo. They don't improve cardiovascular events. This is MACE on the slide, but they don't seem to increase risk of cardiovascular disease. So if you need it, you could use it, but it's really not beneficial for the reduction of cardiovascular disease. And indeed, we have to be careful with heart failure and particularly in our patient. These are slides showing that amongst the DPP4 inhibitors, there is heterogeneity with heart failure risk and some of the DPP4 inhibitors have been associated with increased heart failure risk, particularly sex eglipton in Savor Timmy 53. So in our patient who was recently hospitalized by with heart failure, we would consider discontinuing that medicine or stopping unless there's a clear reason to continue it. And indeed, this is a warning on the labeling for sex eglipton. This wasn't seen in the other ones, but again, no real benefit for cardiovascular risk reduction, modest benefit in glucose control, and use it if you have to or you need to and that's your option, but not in people with heart failure that's decompensated. So if we turn to the second class of medicines that have had lots of new information and have been on my list for her treatment options are the GLP1 receptor agonists. There have been at least, I have six or actually been seven studies looking at GLP1 receptor agonists. And amongst those studies, there has been some heterogeneity, but in general, the GLP1 receptor agonists have been shown to reduce a major adverse cardiovascular effect, but it has been dependent on the GLP1 agonist use. So in leader with laryngotide, somagotide and sustained six, and delagotide and rewind, as well as a recent study with epiglinotide have all been shown to reduce cardiovascular mortality. So if we remember that there were some, we do have to be pay attention to which medication has been involved like lixicenotide or xenotide once weekly. We remember that these medications, some of them haven't been shown the effect and pick one with proven cardiovascular safety. It is a regional option in patients with cardiovascular disease. Again, these medications are subcutaneously injected. So there is that issue that they're being used with injection. They do have some side effects related to nausea and vomiting. But when we look at the patient and these medications have been associated with significant weight loss, the GLP1 receptor agonist may be a good choice to help lower cardiovascular risk and maybe address some of the issues as it relates to obesity. Oral somagotide is the only GLP1 receptor agonist. It's oral. It has had some interesting features in its cardiovascular trial where it did not meet its primary endpoint but was associated with reduction in cardiovascular mortality and all cause death. Since it didn't meet its primary endpoint, this is more hypothesis generating and an area of interest that we should pay attention to. If we look at further data in SGLT2 inhibitors, we indeed see that there is a large growing body of evidence suggesting that these also can reduce major adverse cardiovascular events. There have been multiple studies. I show here four clinical trials which have been performed in people with either established cardiovascular disease or high risk for cardiovascular disease. There have been also studies in people with chronic kidney disease which I haven't included. But we have the Emporeg with Empoclethosin, Cannagalphosin and Canvas, Dapagalphosin and Erticalphosin. And in these studies, in Emporeg and Canvas, we had a 14% reduction in MACE and a reduction in cardiovascular mortality. In this study, the MACE was not significant, but it was an interesting study and had two primary endpoints and the secondary primary endpoint which included cardiovascular death and heart failure hospitalization was reduced by 17%. But what's clear in all these studies is there does seem to be something special as it relates to SGLT2 inhibitors and their prevention of heart failure and people who have diabetes and either established cardiovascular disease or high CV risk. And these are shown on the next slides. Here, I'll just show the meta-analysis. Again, looking at GLP1 receptor agonist and SGLT2 inhibitors. And in general, we can see if we look, knowing that some heterogeneities, so I don't think we can say it's a class effect. But in general, there's a 12% reduction in the hazard for MACE with GLP1 receptor agonist and a similar reduction in the hazard with the SGLT2 inhibitors. So for MACE, I think we have a choice in either one and may pick one based on its effects and patient preference. When we think about heart failure prevention, we have seen that again, there seems to be this special place for SGLT2 inhibitors as shown on the meta-analysis. GLP1 receptor agonist, if we put the totality of the data, favors some modest improvement, but reaches hazard ratio one, so it doesn't meet statistical significance. But if we look at SGLT2 inhibitor, that rate is reduced by approximately 30%. And indeed, this is a whole new era, what was unexpected in these diabetes trials has led to the idea that perhaps an SGLT2 inhibitor is not a diabetic medication, but a heart failure medication. Those studies were for prevention of heart failure in people who maybe 20% may have had established heart failure, but led to the hypothesis that this could improve heart failure outcomes. And there are now four clinical trials which have looked specifically in patients with heart failure. All have shown improvements, and I'm sure we'll hear some of this in our heart failure lecture. This includes the DAPA study, the DAPA heart failure. I have it here on the next slide. DAPA heart failure, emperor reduced, emperor preserved, and then the soda-gluflosin study. What's notable is for these three studies that it didn't matter if you had diabetes or no diabetes. It's only approximately 40 to 50% had diabetes in the study. DAPA heart failure and emperor reduced, looked at heart failure with reduced CF, emperor reserved, had heart failure with preserved CF. The soda-gluflosin study looked at patients with diabetes but who were recently hospitalized. But they were all remarkable and they all met their primary endpoint for a reduction of cardiovascular death or heart failure hospitalization as shown on the slide. So this summarizes those findings. So heart failure hospitalization and CV death were reduced by anywhere between 20 and 29%. This was predominantly driven by reductions in heart failure hospitalization but DAPA-gluflosin and DAPA heart failure also had a reduction in cardiovascular death. So really changed the way we think of these medications have changed the way we're going to treat care or heart failure patients and again speaks to the importance of these medications if heart failure is a comorbidity. So again, we come back to our case, what would we do? So I think we should discontinue the sex eglipton for certain. Again, there would be no benefit from a DPP4 inhibitor and in fact, because of the risk of heart failure we should discontinue it. And I think today with current data if she has no contraindications to an SGLT to inhibitor that would be our answer. I think previously we would, before the Emperor Preserve study with heart failure with preserved EF we might consider loragelotide in general because of weight loss. But once she has heart failure and all this study I think SGLT2 inhibitors would be most appropriate. And finally, I'll end with this slide which is just showing the ADA recommendations for the treatment or our patients with diabetes. And so what I wanna start is the first line therapy is excuse me Metformin in comprehensive lifestyle modification but then the next step is not really looking at the A1C but it's rather to look at indicators of high risk or established cardiovascular disease, CKD or heart failure. If the answer is yes, then consider independently of baseline A1C and independent of the baseline C or the A1 target or Metformin use begin to think about cardiovascular risk. So independent of that if they have an ASCVD indicators of high risk we could use a GLP1 receptor agonist or an SGLT2 inhibitor. If they have heart failure, particularly heart failure with reduced EF and SGLT2 inhibitor and then the presence of chronic coroner excuse me chronic kidney disease will again encourage you to add these medications because of their renal protective effects. So in conclusion, our take home points are the specific anti-hyperglycemic medications, SGLT2 inhibitors and certain GLP1 receptor agonists should be started to lower cardiovascular risk a decision that's independent of glycemic control and really based on comorbid conditions and potential contraindications to the medications. SGLT2 inhibitors have been shown to improve heart failure outcomes in patients with diabetes and now without diabetes, irrespective of LVEF. Despite the advancements we've made by learning from these cardiovascular outcome trials want to remind you that there are large opportunities for improvement in traditional cardiovascular risk factors and this will take some, I think some imagination and some innovation to help change how we deliver care and improve adherence to our medications and that public health measures are so critically needed to reduce the burden of diabetes and cardiovascular disease in our population. So with that, I'd like to thank you for your attention. Again, thank you to the organizers for the opportunity to present.