 Stephanie, thank you for inviting me again, for giving me a shorter slot for such an important topic, and a little late, and the slot before break. But I will take one minute to congratulate Stephanie and her colleagues for this symposium. And for 10 years of this, and 10 years of advocacy for women's health, particularly as it relates to cardiovascular disease, many people come to this conference and realize that this is just one aspect of what she has done. There's public education on the web. There's community outreach programs to help the underserved, particularly women. And then there's issues with advocacy. So 10 years of that, Stephanie, is wonderful. So now I only have... Now, I've got to cut the applause short, because now I only have 14 minutes, because I'm with the break. So I do think this is an interesting topic, and as Stephanie was introducing me, she said cardiologists enrolled with diabetes treatment, and I've really come to think of this different. Cardiologists should be involved with cardiovascular risk reduction. And so how you do that, let's call it whatever we want to call it. And there's this debate about diabetes, no diabetes, but what I'm going to try and convince you now is that this is an issue of cardiovascular disease, cardiovascular mortality, and these diabetic drugs are treating cardiovascular disease and not necessarily diabetes. So we'll go from there. So just sort of as an objective, we're really going to use this to help identify which medications we use to treat our patients who have cardiovascular disease. And this is really based on the data regarding cardiovascular safety and efficacy profile of the agents, as well combining that with the patient's individual cardiovascular history and their comorbid conditions. So I'm going to center this around a case, and we'll keep coming back to this. And this is Cynthia. Cynthia is a 56-year-old woman who presents for routine care. She has heart failure with reduced ejection fraction, an EF of 40%, as Jerry said, maybe mid-range, low, right at the top of that, right at the bottom thing. A strong family history of heart disease, but she herself does not have obstructive coronary artery disease. She was cath and had small vessel disease. She has a long-standing history of type 2 diabetes on the DP-P4 inhibitor to sacsagliptin and metformin. The medical history is here on the left, as we'd seen multiple comorbidities that we often find, hypertension, hyperlipidemia. And her medications here on the right include Lysinopril, Carvetalol, metformin, 1,000 milligrams twice daily, sacsagliptin, 2.5 milligrams daily that was recently started, maybe three months ago. Vynlaxifine and Atorvastatin. When you talk to her, she's doing well, other than occasionally describing disney on exertion, as well as pediladema. The exam is here. Her BMI is 29.9, blood pressure 142 over 85, heart rate of 60. 5, heart rate of 62. Exam is really unremarkable. A1C, 7.8%. Lipid panel is okay. Her electrolytes are reasonable. And her EGFR is 52. So some degree of kidney disease. So the question is, is you're busy in clinic? Given Cynthia's existing type 2 diabetes and a diagnosis of reduced left ventricular systolic function, what changes would you suggest making to her regimen? A1, let her go. Doing okay. We'll just go with that. 2, increase sexagliptin to 5 milligrams daily. A DPP4 inhibitor. 3, replace sexagliptin with Gliberide, esophaneurea. Replace sexagliptin with an SGLT2 inhibitor. Empagliflozin. Replace sexagliptin with laryngotide. Or add insulin now to her regimen because she has kidney disease. The list can be really long, right? So let's go through this just a little bit. I won't spend too much time on this. We know that the prevalence of type 2 diabetes continues to increase. Nearly 30 million Americans have diabetes of which about 7 million are undiagnosed despite our efforts at increasing awareness and to make the diagnosis. And this rate is going to increase in conjunction with the rates of obesity as well as the aging nature of our population. We also know that we've made substantial improvements in how we treat diabetes and that the burden of cardiovascular disease in general has reduced over the last two decades. But cardiovascular disease still remains the leading cause of death in patients with type 2 diabetes. It increases the risk of stroke, increases the risk of coronary heart disease, rates of heart failure. Jerry's lecture was wonderful. We know for a long time that diabetes amplifies the risk for heart failure, it's a risk of cardiovascular mortality, as well as increasing the risk of total mortality. Simply said, diabetes is associated with reduction in the life of a year's life. When that diagnosis is made, your life is shortened for both men as well as women. Now women, the conference is really focused on women. Women share I don't know, disproportionate burden. A special relationship would probably be. And not a good one with diabetes as far as the risk factor to diabetes plays for women. Prior to menopause, we've learned that generally coronary heart disease lags by about 10 years. There's this protection that women have before they hit menopause. But if you have type 2 diabetes, and a young woman like we're seeing more and more of, we realize that this protection is lost, that it's attenuated. When we look at studies and we look at relative risk, we see that women than in men. Several studies, this is from the Rancho Bernardo study where men had a two-fold increased risk for coronary heart disease while women had a three-and-a-half increased risk for coronary heart disease compared to their non-diabetic counterparts. When women do develop diabetes, when they do develop cardiovascular disease, their outcomes tend to be worse in those with diabetes, diabetic women compared to diabetic men counterparts. MI may occur earlier in women with diabetes than in men. And if when they have an MI, the mortality may be higher. Mechanism behind this are unclear. We're hoping that we're closing treatment gaps that have occurred. The institution of evidence-based medicine, but we still see that there's a residual risk. And in heart failure, it's an important complication associated with increased morbidity as well as mortality. And the Framingham Heart Study showed us that the relative risk associated with diabetes is higher in women compared to men. Now another thing and busy slide is just that we don't see diabetes in isolation, right? And particularly when people have cardiovascular disease, we realize that there's this multi-morbidity that's associated with diabetes. And this is what this slide is really trying to show. Here we see these dashed lines, and it has three comorbid conditions. Type II diabetes, MI, and stroke. And here on the bottom line are survival curves or estimated life of years of life lost for diabetes alone, stroke alone, or myocardone farsion. When we can see as these start to add up, you know, as we see our patient, Cynthia, that the risk increases, which makes sense, but by age 60, which should be right today, midlife, I guess we'd call it, that it's not midlife for someone who's had a stroke or MI, their life is shortened substantially. That a history of any of these two conditions is associated with 12 years of reduced life expectancy. The history of all three is associated with 15 years of reduced life expectancy. So let's go back to our case and go to how do we take care of our patient with diabetes. So A1C is important. A1C we can't ignore. Many of my cardiologists want to say let's forget about it, but it does it is important for micro vascular disease, retinopathy, nephropathy. And so these are the recommended goals that the ADA as well as the American Association of Endocrinologists propose. And we can see that these goals are individualized depending on comorbid conditions, duration of diabetes, how well people are tolerating medications without side effects. But in general a goal of seven has been recommended and people with advanced disease we may be less stringent. But I would imagine that most of us would consider treating Cynthia a little more aggressively at 7.8. She's doing well in general and hasn't had many complications. But we have a lot of choices now, right? Of diabetic drugs, tons of choices. 2p4 inhibitors, sulfonorrhea insulin, the whole work. So with so many drugs to choose from, how do we decide? When I like to spend the rest of the talk is really describing the evidence that we've entered a new era of diabetes management which shows safety and efficacy and cardiovascular impact well beyond an independent I'm going to say of lowering A1C. So let's come back to that in a minute. The ADA and the EACD suggested when we're looking for what medicines we're going to choose with Cynthia that we consider a variety of factors. Hypoglycemic risk. What is the risk of hypoglycemia? What are the implications of an episode in someone who's sick? Need for weight loss? Chronic kidney disease? Cost effectiveness? What can people afford? And then we have in blue here cardiovascular disease, heart failure and ASCVD. And really this portion of heart failure and ASCVD is the decision tree when you're trying to decide on what agent to treat someone with. Chronic kidney disease, I need to fix my slide, should be on it but should probably come into that group as well. And so previously to 2008 we had very little evidence to help us decide how to treat people but in 2008 I won't get into too much, the FDA said it's no longer adequate or appropriate to approve drugs just based on glycemic control that the medicines we're going to use to treat diabetes to lower A1C have to be safe in people who have risk. This can be a medicine just to lower A1C, they have to be safe. And so they require that all new agents undergo cardiovascular safety testing and a cardiovascular outcome trial. And so over the last 12 years we've had nearly 200 thousand participants participating in diabetes trials aimed at cardiovascular risk reduction. They're non-inferior studies, are they safe? And then if they're safe, test for superiority. Nothing to do with A1C efficacy, right? No A1C, no diabetes sort of an issue here. These are all cardiovascular outcome trials. And so I'm going to talk about these trials and sort of big sweeps, lots of data and we'll come back as it helps us treat Cynthia. And I'm going to start with the incretin memetics, so the DPP4 inhibitors and the GLP1 receptor agonist and then I'll end with the SGLT2 inhibitors and sort of sweep it big and try and go quickly. There are four trials with DPP4 inhibitors. Our patient was on Saxagliptin, so is that a good medicine or not? So when we look at the cardiovascular outcome trials that are here, compared to placebo, we can see in the four studies that have been done, each with an individual agent, when we compare it to placebo it was as good as placebo. So it could lower A1C and it didn't cause harm. So all the studies met primary end points showing no increased cardiovascular risk. So another agent we can use to treat people if we need it for glycemic control. But a bit of caution from the studies was that when you looked at the secondary outcome, so those outcomes are what we call major adverse cardiovascular events, cardiovascular mortality, non-fatal MI and stroke pretty much. One of them had hospitalization for unstable angina. A secondary endpoint at the point at the time which was kind of relegated to secondary but become more and more important as we think about it was heart failure. And we saw early on that within the DP4 class there was heterogeneity in heart failure. So the first study that looked at Saxagliptin, which Cynthia's on showed that the rates of heart failure were a little bit higher compared to placebo. The second study with Allagliptin in an exam and patients who had acute coronary syndrome also trended in that direction. So in that setting the FDA put a warning on all DP4 inhibitors that we have to be cautious and maybe avoided in people who have worsening heart failure even though that's probably unfair for the last two for citagliptin and linagliptin. So if I made that, if I had any financial stake I'd probably be mad about that. But that being said for Cynthia, Saxagliptin probably not the best choice. So probably not the best choice. So let's move forward to the GLP1 receptor agonist what do we have from these data. So we have some exciting and promising data and we'll go over how they fit into the guidelines. There have been six studies published today about GLP1 receptor agonist sort of grouped them with three on the left here leader with larygolotide somagolotide sustained six and dilagolotide rewind which have all shown benefits for reduction in the MACE cardiovascular outcome. And this is what's shown here. Dilagolotide is a little bit different. This rewind is a slightly different study because a lot of patients in this one didn't have established cardiovascular disease they were just high risk. So I think it was around 60%. And these two these are people who had most almost all of them had cardiovascular disease. Larygolotide also had a 22% reduction in cardiovascular mortality as well as a 15% reduction in all-cost death. Somagolotide when we looked at their secondary endpoints what really stood out with some effects it had on stroke for both of these agents. So here are the three that have shown benefit these three on the right have not shown they have shown that they are non-inferior to placebo and trends that are in the right direction not for lixicinotide but for Excel there were some trends that went in the right direction for long-acting xenotide or by durian. And then I'll just point out this last publication that was last year it was an oral GLP1 agonist so it was an oral somagolotide we know that the rest of them were all injectables this was an oral pill and so it compared to placebo in a smaller study and it was non-inferior to placebo it missed superiority testing so non-inferior but what we saw was that there was some interesting findings as far as reduction in cardiovascular death as well as all-cost death that once you don't meet and statistically if you don't meet that first threshold of superiority the rest is just hypothesis generating the study included about 3,300 people so it was half the size of some of the other ones so it's so questionable what that means but again for patients who don't want to take injectables it may be an option from the GLP1 receptor agonist I definitely won't go over this too much but these are just something to keep in mind when we're dosing these medicines and all the medicines have to do with the renal dosing and GLP1 receptor agonist particularly related to laryngotide as well as somaglotide and dilaglotide can be used in people who have more advanced kidney disease so this might be helpful for our patients with advanced CKD where we've been limited in the past so turning to the SGLT2 inhibitors lots of excitement with the SGLT2 inhibitors and deservedly so three studies have been published to date one's the EMPA reg outcome study one's the canvas study and the others declared CIMI58 I'll start with the first two because they were more similar people who mostly had cardiovascular disease and we can see that for the primary MACE outcome there was almost identical reduction in the hazard ratio compared to placebo in the impaglophosism there was a statistically significant and pretty marked reduction in cardiovascular mortality trended in the right direction with canvas but wasn't statistically significant but again looking good and then what was most remarkable was we found with heart failure hospitalization only about 10% of people had heart failure so this is really prevention of heart failure hospitalization and so we can see that there was about a third reduction in heart failure hospitalization and Jerry will know Jerry wrote a paper with me and I forgot many years ago about when we talked about diabetes and heart failure we always talked about harm we talked about TZDs causing volume retention and we talked about hypoglycemia and then all of a sudden the signal comes up well this isn't harm right this is benefit so it was a really different I mean that's really different than what we had talked about 10 years ago when the conferences first started the next study that we have here is Declarer 58 it's a dappaglophosin and this is slightly different because what they did was they rather than use a common endpoint that everyone else said they split their endpoint into two they said we're going to look at heart failure really closely so we're going to look at both MACE outcome and heart failure CV death heart failure hospitalization and it also included about 60% of people who did not have established cardiovascular disease so I was looking at the high risk group but didn't have an event yet and what they found was that for their MACE it was not statistically lower but for the composite of CV death and heart failure hospitalization there was this effect even in a lower risk population so lots of lots of excitement coming back to our woman with an EGFR a 52 I think I said can we use it? the answer is yes but we do have to be aware of renal dosing there's a slight discrepancy between what the ADA recommends and what the FDA recommends at this point as far as their labeling I listed the ADA and took out my FDA slide in general the ADA is pushing further down the spectrum of advanced chronic kidney disease particularly because these agents have shown to have renal protector effect I didn't show a study called Credence of a kidney disease looking at cannagal flows in reducing cardiovascular outcomes with an EGFR down to 30 as well as improving renal outcomes so this is again we need to be careful careful I don't know if we need to be careful so the glycemic effect is much lower it becomes less effective at lowering A when C down at this lower spectrum but it doesn't seem to be less effective at reducing cardiovascular disease this excitement has led to the question earlier that how are these things working which could be another good talk and the answer is we're not 100% certain but the idea that they can prevent heart failure and can work for prevention and then in the small sorts of people who have heart failure could these medicines not be diabetic medicines at all but could they just be cardiovascular medications with some glycemic effects and so this has led to this hypothesis looking at these medications in patients with heart failure in the absence of diabetes and there are several large outcomes studies that are going on I included a couple of functional studies here and we're going to get a lot of information but we were fortunate enough to hear about the first one at the end of last year and that was called DAPA heart failure which was a study with DAPA glyphosin and over 4,000 patients who had heart failure with reduced CF less than 40 randomized to DAPA glyphosin versus placebo on good medical therapy maybe some of them weren't on interest though but it was still good for the time it was started with a primary outcome again cardiovascular outcome of hospitalization for heart failure or death from cardiovascular cause followed for an average about 18 months and what was seen was that there was a 26% reduction in the primary outcome as well as a 17% reduction from death from any cause 60% of patients in the study did not have diabetes 40% did and there was no heterogeneity of effect really across any subgroup there was some signal that maybe was a little bit more beneficial in those who had a lower New York Heart Association class compared to a higher one but this was not statistically significant and I don't think that portrays very well but these are just the outcomes again just so you can see the event curves they begin to split early quite early in the study so the benefit was seen at 18 months without the primary outcome heart failure hospitalization seen here death from cardiovascular causes with the hazard ratio of 0.82 and death from any cause with the hazard ratio of 0.83 so a remarkable push forward of taking the medicine from diabetes and moving into the cardiovascular world as far as and seeing benefits that I think will be incorporated into the next algorithm of our algorithm as Jerry has at Cleveland of how we treat our patients I was reminded that if my kids saw this slide they would be mad at me too they would they'd say dad what are you doing but I just wanted to show that these are the 2020 guidelines just published last month at the standard secure ADA and we're going to come to this section here on the right ASVD in a better slide but what it shows is that first-line therapy still is metformin 70% of patients in all these cardiovascular studies were on metformin to begin with it still remains first-line agent even though the body evidence behind it is not super strong it's still there the next decision tree here in red is indicators of high risk or established ASVD chronic kidney disease or heart failure if no then you come here and we go to hypoglycemia weight loss cost if yes you come to this category which we'll come to but what's new in the guidelines and kind of slipped through people who don't read them obsessively or is that this is consider independently of baseline A1C or individualized A1C target that is different than any other guideline that had been published before where it was if needed therapy beyond metformin to get to glycemic control reach for these agents this says that we don't care about A1C right just treat and so this is it looking at it metformin and lifestyle if you have ASVD risk a GLP1 receptor agonist would prove and benefit so that means you have to know the slight differences in the study or an SGLT2 inhibitor with proven benefit if the EGFR is adequate and then if A1C above the target we have other options if heart failure or chronic kidney disease exists then we should there's preferential recommendation to an SGLT2 inhibitor as long as the EGFR is acceptable to use it so that's what I wanted to talk about these are some take home points just as far as the antireminder that the antidiabetes agents with proven cardiovascular benefits include the SGLT2 inhibitors empagliflozin cannagliflozin endapagliflozin so this is what we have so far there are more coming the FDA has approved these medications and you can look for a reduction of cardiovascular events treat diabetic kidney disease none of these indications by the FDA have anything to do with A1C like the cardiovascular indications and then GLP1 receptor agonist laryngotide has an FDA indication for reduction of adverse cardiovascular events in patients with cardiovascular disease I want to thank you for your attention and let's you get to your break