 It's a real pleasure for me to be here and I want to extend Dr. Hernandez's congratulations on this conference for the eighth year in a row in everyone's attendance. Such an important issue, the issue of women in cardiovascular disease has been highlighted before. So congratulations again and I'm always humbled to be here truthfully. So today I'm going to talk a little bit about diabetes, combination regimens, what's in the mixed bag for women. So I take some liberty with combination and I'm really going to talk more about what's in the bag for women and what's in the bag that you reach for. I'm going to briefly describe the interrelationship between diabetes and cardiovascular disease both in men and women. Then utilized briefly focused on some of the ADA guidelines to create a combined or multifaceted approach to CV risk reduction in patients with diabetes. But we'll spend the most of my time is really to integrate new information that we've learned over the last five to six years about anti-diabetic agents with proven CV safety and efficacy in the management of our patients with diabetes. So now we're running a little over but I'm going to throw it out a little bit because I know people here are clinicians. So I'm going to start with two clinical cases and maybe just take a poll by raise of hands. So the first patient is Catherine. She's a 61-year-old woman who has stable coronary artery disease, five-year history of uncontrolled diabetes, and a two-year history of chronic kidney disease with an EGFR of 45. Our BMI is 31 despite attempts to make behavioral changes. She's being treated with maximum doses of metformin and gliburide. So not too in common from what we use. Given her history and comorbidities, which of the following agents or approaches to her diabetes regimen would you provide would provide cardiovascular effects and reduce her cardiovascular risk? One, keep the course. No changes necessary. Two, stop the gliburide and initiate insulin. Three, add a DPP4 inhibitor, citagliptin. Four, add empagliflosesin and then SGL2 inhibitor. And five, add laryngotide, a GOP1 receptor agonist. So lots of agent, lots of things to choose from. Just quick hands. So one, anyone? Two, three, four, five. Okay. So kind of a mix in the group and we'll come back to that in a minute. Second case is something that I've been interested in. A 55-year-old woman with a history of heart failure with reduced rejection fraction has a history of hypertension and a five-year history of uncontrolled diabetes who's on metformin. Many of us are PCPs, many of us are cardiologists, but you've been consulted to talk about cardiovascular risk. And would you change any of the medications based on her cardiac history? One, no changes are necessary. Two, discontinue metformin and initiate insulin. Three, add citagliptin, a DPP4 inhibitor. Four, add empagliflosesin and SGL2 inhibitor, or five, add laryngotide. And again, just briefly, one, two, three, okay, a handful, four, okay, and five. Great. So a little spun. So we're going to go through this because the bag that we have now is quite large, right? And that's just a few choices. I could have made the list even longer. So how do we decide when we're taking care of patients and how do we integrate the new information? So as we know and as Stephanie alluded to, the problems of diabetes continues to grow. Despite whatever we do on our regular day, if we're clinicians, researchers, we know that this prevalence continues to increase. It's estimated that 30 million Americans are living with diabetes, again, of which 7.2 million have undiagnosed diabetes. And we know that this prevalence is increasing in certain subgroups, particularly ethnic minority women, that they're driving some of this increase that we see in largely dovetails of rates of obesity. By 2030, if this is unchecked, the prevalence is estimated to rise to about 54.9 million. And despite how we treat diabetes, despite the improvements we made in blood pressure control and cholesterol control, it still is associated with reduced survival, years of life lost. And this is shown on this slide, both for men and women, that the presence of diabetes shifts the curve leftward and downward so that you lose life if you have diabetes. So it's not a benign condition despite our improvements in how we care for it. And this is the challenge. And again, when we think specifically about what's driving these future years of life lost to diabetes, it's cardiovascular disease. It has been and it remains cardiovascular disease. And this is shown here on this slide, both for men as well as for women. And you can see that it lists vascular deaths, cancer deaths, non-cancer deaths, a variety of deaths here. And we can see that indeed, vascular deaths account for the majority of years lost. And this is greater in women. So the impact of diabetes in women seems to be higher than men. And at least it takes away any protective effect women have against cardiovascular disease. It sort of mitigates that benefit. So when we talk about how do we manage this or how do we reduce this risk with cardiovascular disease, it really does take a multifaceted approach. Again, this idea of a combination. It's not just glucose, it's everything. And it's what we've heard in the last two excellent lectures. One has to do with blood pressure control, make sure we treat it and we treat it appropriately. Recent guidelines at the ADA say less than 140 over 80. There's some controversy, 130 over 80. And the new guidelines have been suggestive and this may be appropriate in people with diabetes. Lipid therapy, we've heard the first talk, high-dose statin if you have cardiovascular disease, moderate to high-dose statin with you have other risk factors. So we need to be aggressive. Aspirin always complicates and very excellently described earlier when appropriate. And then glucose control. Glucose control is important. Guidelines say that hemoglobin A1C should be less than 7% for most adults. If you can get lower, easier in people who have a shorter duration of diabetes, who aren't on multiple medicines and don't have multiple comorbidities, maybe it's appropriate. If people have lots of comorbid conditions, if they are on lots of medicines, they're having hypoglycemia, we probably should not be very aggressive with them and less stringent goals of less than 8% may be appropriate in that group. So we've known this and we've known this for a while and we're doing better but we still have a lot of room to improve. What's shown on here are data from the in-hane study over a 20-year period from 1988 to 2010. And there are different targets here. So we have A1C on the left, less than 7%, less than 8%. We have two blood pressure categories, LDL on statin. And what we can see over this temporal period is color-coded that we've improved. We've done a better job. We continue to do a better job in lots of systems approaches. But we still could do a lot better. For example, if we look at statin here in 2010, we're only at 50% to 60%. And then when we think about what's been shown to improve outcomes and we think about this multifaceted approach that is not one target but really it's all of them, we look down at people who have all these targets controlled, we see we have a lot of room for improvement. Again, this probably will take systems approaches. Patients are part of this, compliance with medications, but it definitely opens this room that we know kind of what to do, but we have to be able to implement this and becomes very important. So I'm going to switch gears. There we go. Yeah. Switch here is a little bit and now really turn to the newer medicines and what I like to call driving forces in how we treat patients today. I had a nice cup of coffee with one of the doctors from Fort Worth who's been practicing for 40 years outside and loves it. Thank you for that. And you know, over that time period, we've had an explosion of new medications that are available for treatment of diabetes in this bag, if you will. For the longest time, from 1920 up until the 90s, the mid 90s, we had insulin and we had sulfonylureas and we had a by Gwanai, we had Phenformin come in and then met pulled off the market and then met Formin come in. So we were relatively flat, you know, two to four medications. But over this time period, there's been an explosion in the class of medicines that are available. And within each class, we know there are four or five different types of medicines. So we have lots and lots of choices over this time period for the treatment of diabetes. So how do we choose? I'm having a little trouble moving forward. There we go. So in part, we're now choosing, again, based in part on new information we're learning from cardiovascular outcome trials. You know, in the past, we would choose often based on side effects of medications on, you know, how they may influence surrogate outcomes, which one was stronger for A1C. But in 2008, almost a decade ago, it was in the fall of 2008, the FDA said that from now on, as we get these new medications, as we have these all these data available that we as clinicians would need more information in order to treat patients. So the FDA in 2008 said, you can't just lower blood glucose alone. You have to show that these medicines are safe in people who have high cardiovascular risk, you know, not just lower risk people, just lowering glucose isn't enough. It has to be safe in real people who are at risk for heart disease. And even better, wouldn't it be good if it lowered heart disease? But at a minimum to bring a drug to market today, it had to be safe. And it said certain requirements. You couldn't have an increased hazard ratio. You had to follow them for at least two years. A variety of things that industry was mandated to bring people for trial. And it was in this setting that every new drug that was brought to market now had a new cardiovascular outcome trial. So again, up until 2018, we have one or two studies. But after 2008, when the FDA mandated that we had this explosion of trials that became available with over 200,000 participants enrolled in the study, not to lower blood glucose, not to take a drug and lower blood glucose, but to take a drug and see is it safe and can it lower cardiovascular disease? Diabetes, cardiovascular disease, not diabetes, glucose. And so we've had an explosion of those studies. And it really ushered in this new era where could we move beyond management of diabetes or in just lowering A1C alone? Could we lower CVD risk with these medications? So today, there have been nine, nine CV outcome trials. And I'm briefly going to go over on nine and they'll give me that luxury, but sort of in the classes. And the first group of medicines that I'm going to describe are the medicines that are the incretins. And these are DPP4 inhibitors or GLP1 agonists. What incretin means is just a review is that when you are more insulin is secreted after glucose is provided orally than intravenously. So if I eat a sandwich, my more insulin is secreted than if I were to take a glucose shot. And that's in part related to the incretin hormones in the gut, predominantly GLP1 and GIP, which stimulate insulin release after a food intake. Now these hormones in the gut are rapidly degraded. So to take advantage of that pharmacologically, they created analogs of resistant to degradation or inhibit the enzyme which degrades at the DPP4 enzyme. These are associated with other effects, early satiety, which make promote weight loss. There are different GLP1 receptors in the body. So maybe some pleotropic effects. In general, these medicines are well tolerated, particularly as monotherapy. There's a low risk for hypoglycemia. The GLP1 receptor agonists, the injectables are associated with weight loss as well as mod reductions in blood pressure. In general, the GLP1 receptor agonists can have some adverse effects, GI effects and nausea, which can be mitigated with some patient instructions as far as monitoring what they eat particularly early on and avoiding large meals. So let me show you the three studies that have been published for the DPP4 inhibitors. Very popular medicines, very popular. I imagine it was choice three on our question, right? Or two, I can't remember. So for the DPP4 inhibitors, there was three studies, the Saber Timmy study examined anticos. And so all these studies are kind of similar. I think what you need to know is they were high risk groups, either people who had cardiovascular disease or who had an acute coronary event, but they were high risk so that you could get the events. So when you think about how this applies to my low risk patients, you want to be careful as we think about the applicability. But for each DPP4 inhibitor, we can see that the primary outcome, which was a combined outcome of stroke, MI, or cardiovascular death, was neutral, as shown here, shown on this on the hazard line. So it was one. So they all met their non-inferiority endpoint. They were as good as placebo, but they weren't superior. When you looked at different outcomes, there was some heterogeneity that is practicing doctors. I think we have to be aware that they weren't all the same, particularly for the outcome of heart failure, that in the Saber study that Saxagliptin was associated with increased heart failure events. In the examined study, Alec Lipton had a slight increased risk as well as shown on this slide. This is an unexpected finding and an unexplained finding. But nonetheless, the FDA in 2016 said we need to be aware of this and they added a warning to the label that said heart failure risk was increased with Saxagliptin and Alec Lipton, particularly in people who had a history of heart failure or chronic kidney disease. So if you're taking care of someone and they have heart failure and you're using Saxagliptin and they have decompensation, you probably want to switch that medicine. So moving on from the DPP4 inhibitors to the GLP1 agonist, we know that there are many of these on the market. They predominantly vary in their half-life and their pharmaconetics, and I've listed them here. There are some that are dose twice daily, like the original biota, exenitide, and then going down to weekly, for example, exenitide weekly or bi-dureum, which is shown here. For the GLP1 agonist, there have been four studies that have been published to date. So remember the DPP4 inhibitors? They were neutral and had some heart failure signal. With GLP1 agonist, there is some excitement, and I'm going to go into these a little bit in more detail, but there are four studies, again in the same manner, listed here on the slide. But what we see here is that two of the studies were actually positive, which is really exciting, that they actually lowered cardiovascular disease, and that was a sustained sixth study with semaglutide and larygulotide, the leader study. And I'm going to just show a little bit more on larygulotide, because this is what's available, and it has now, I'll show you an FDA approval. Larygulotide, this study included nearly 10,000 individuals who had cardiovascular disease, and what we can see here is the primary outcome was reduced, and people who were randomized to larygulotide compared to placebo, with a 13% reduction in the primary outcome. In addition to that primary outcome, we saw the cardiovascular-related death, as well as death from any cause was reduced. So this is interesting. Right now, a diabetes medicine is associated with improved outcomes, again, not for diabetes, but for cardiovascular disease. Also with larygulotide, and I think as we think about these new agents, is this whole story that's coming about on renal protection, but not only are they associated with cardiovascular benefits, but they also seem to be associated with renal protection. This is from the leader study looking at the effects of larygulotide on the composite renal outcome compared to placebo, and in part may be related to some of the cardiovascular effects that we're seeing. And again, larygulotide now, like, now has an FDA indication for reducing the risk of myocardial infarction, stroke, and CV death in adults with type 2 diabetes who have established cardiovascular disease. So very similar to the population that was in leader, that the medicine is now improved for this cardiovascular indication. Excel is another study that was probably the most recently, the most recent of all the CV outcome trials published. This was a study looking at the once weekly formation of exenitide. I don't know how many of you use that. It is commercially available. It showed that the outcome was non-inferior. The primary outcome was, the hazard ratio was 0.91 as shown on the slide. It almost meant superiority, but it didn't come quite close. But kind of interesting, if you go over to the, so that was a primary outcome. It's non-inferior, not superior, but if you look over to the right upper quadrant, you can see that death from any cause was actually reduced with exenitide compared to placebo. This should be considered, because the primary endpoint wasn't met. This is really exploratory, but kind of interesting because it goes along with what was seen in laryngotide. And if you know the study, I was one of the U.S. national coordinators for it. There was a high dropout rate. 40% of people stopped the medicine. So it's remarkable that we saw that signal in this trial, and I think it's just something we keep in the back of our mind. So in summary for the GLP-1, all the trials have met their primary goals showing there's no increased risk of CVD. Leader and sustained six actually demonstrated benefit on MACE as well as mortality with laryngotide. I'm going to finish here, and I'm just going to go over the last class of medications, which are the SGL-2 inhibitors. Remember, these are the medicines that inhibit the SGL-2 receptor, which is in the kidney, so they promote glucoseuria, they inhibit glucose reabsorption. They're associated with modest effects on A1C, modest effects on blood pressure, and modest effects on plasma volume. And probably the study that got the most excitement was this study called EMPA-REG, looking at EMPA glyphosin, which looked at 7,000 individuals with cardiovascular disease, and this is a primary outcome which showed that that medicine was associated with significantly reduced events in the primary MACE outcome over the study. And really interesting as we think about mechanisms is if you look at the Kaplan-Meier curves, they begin to separate pretty early, you know, different than what we would normally see, for example, with statins. So the mechanisms are still being worked out on why these curves seem to separate early, but they did. Cardiovascular death was also reduced in EMPA-REG with EMPA glyphosin, and then finally, and I think very important, is heart failure was significantly reduced with EMPA glyphosin versus placebo with a hazard ratio of 0.65. So this was, again, I think somewhat unexpected from this drug class, because we weren't really sure about the mechanisms. Similar to laryngotide and similar to other medicines in this class, kidney disease was reduced with EMPA glyphosin compared to placebo. And again, this idea that, like we think about ACE inhibitors, that there may be a special place for these medicines in renal protection. So just like laryngotide, so laryngotide has an FDA indication, EMPA glyphosin also has an FDA indication, slightly different, because it was, EMPA was approved for reducing the risk of cardiovascular death and adults with people with type 2 diabetes and CBD. So cardiovascular death, which is a really, again, a big deal when you think about how we treat diabetes. So finally, the last study that was published, you know, the issue with that was that was somewhat unexpected. And was it a class effect? Was it real? Is when we heard this new study, which is called CANVAS, which looked at the same medication, the same class of medication called cannibalphosin. And we looked at the outcomes in that group of patients, and we saw that similarly to the EMPA study that the primary outcome was reduced with cannibalphosin compared to placebo. Death and cardiovascular causes was not statistically significant, but if we look at the far right, we can see that hospitalization for heart failure was also reduced in this group of individuals. So kind of in line with the EMPA story, that these medicines seem to have some beneficial effect on the primary base outcomes, as well as maybe a special role in heart failure prevention. Again, renal effects were lower in that group as well. So there's no free lunch, right? We've learned in diabetes that we always have to be careful of the side effects. And so in cannibalphosin, one of the sort of in CANVAS, one of the unexpected findings too, was that there was a slight increased risk of amputations that was seen and it's gotten a fair amount of publicity. Again, whether this is a chance finding is unclear, the mechanisms are not known, it wasn't a large percentage, but definitely is something we would need to keep an eye on as we take care of patients. So so far, all trials have met their primary goals showing there's no increased risk of cardiovascular disease. Emporeg with empicalphosin and canvass with cannibalphosin demonstrated a benefit in MACE and mortality as well as hospitalization for heart failure. And there are further studies that are going. So I'm going to conclude here, it's a lot of information that we've learned over these last years, a lot of information I know. And I think the main points is that a multifaceted approach is needed for patients who have type 2 diabetes who are high risk for cardiovascular events. Recent cardiovascular outcome trials of these diabetic medications have provided much needed information on safety and efficacy. Leraglotide, empicalphosin and cannibalphosin have been positive, have been beneficial in patients with CBD and type 2 diabetes. And we need to keep a look out. I just showed 9, there are I think 22 in the pipeline and many patients coming. So we're going to get a lot more data. And so one of the challenges for us will be how do we incorporate all this data into practically taking care of patients? How do we reach for certain agents for each individual patient? So thank you for your attention.