 All right, hello, and thanks so much for the invitation. As many of you may recall, or some of you may not, I was invited to come and do this in January and had to cancel on the same day, so very appreciative for re-extending the invitation to come and talk to you about diabetes and cardiovascular disease, and just a few disclaimers before I get started. So, first and foremost, I'm a cardiologist, I'm not an endocrinologist, and that will be evident through the whole talk. I think I have one slide that mentions hemoglobin A1C. So, we're not gonna be talking about the management of hyperglycemia, we'll be talking about cardiovascular outcomes. Second, everything I'll talk about is related to type 2 diabetes, nothing at all today's relevant for type 1 diabetes. And then the third caveat as a CME program, virtually the entire presentation is off-label. Up until two years ago, we had no diabetes therapy that had a claim or indication for cardiovascular risk mitigation. We now have two medications, I'll go through some of those data. But what I'm gonna talk about is the cardiovascular clinical trials that we've been doing now for just over 10 years in response to regulatory requirements to do cardiovascular assessment of anti-hybrid glycemic therapies. So, this is an extensive slide. I have relationships with virtually every company in the world that makes a diabetes product. I don't do promotional speaking, and I don't promote products. I help drug companies design their clinical trials, and then once they come to fruition, I actually operationalize, they execute the trials internationally. So on the left are companies for whom I've consulted in the execution of large-scale randomized outcomes trials, almost all of them in the space of type 2 diabetes. And on the right are ongoing consultancies I have with helping design the next phase of trials where we'll be looking at novel compounds or novel indications for existing compounds, and we'll talk a little bit about that. So to know where we are and why I'm at a cardiology grand rounds talking about diabetes medicines, I think it's important to understand how we got to this place. And one of the striking things was up until 2008 to get a drug to market for the treatment of hyperglycemia, you simply had to show in 1,500 patients, pharmacokinetic and pharmacodynamic data, and only have to treat three to 600 for six months and only 100 patients to be exposed for a year of a glucose lowering medication. Now, this is a medication intended for use for patients with a lifetime disease. And so we were bringing drugs regularly to market with as little as 250 patient years of observation. So not only does that limit the ability to test important clinical outcomes with such a little patient year exposure, but it also impedes the ability to detect important safety signals. Important, maybe even rare, but serious adverse complications that may be caused by the drug related to or unrelated to their intended mechanism of action. So what you have on this slide, the International Council of Harmonization, the ICH, this was a group of regulatory bodies from around the world that convened in the late 1980s as the internet was coming online and communications were expanding across the globe, the world was becoming flatter and the regulatory bodies wanted to be able to use each other's data to consider new therapeutic options. And so the FDA wanted to be able to consider data from Europe and Australia and Southeast Asia and vice versa so that we could consider each other's data so we didn't have to reproduce it in every domain. And what that meant is we had to generate a common set of playing rules for the registration research of humans for therapies. And so all these regulatory agencies came together and developed International Council of Harmonization guidelines for conduct of this research. And this is the prescription on the slide for non-infectious chronic diseases not otherwise specified. So for cardiovascular disease, for example, everyone agreed we needed to look at cardiovascular outcomes as the primary assessment of efficacy. But for all of these other diseases, there was very little data required. So we brought drugs to market regularly with very little data or knowing very little about them. Fast forward to December of 2008 and then simultaneously between the US FDA and the European Medicines Agency in December of 2008, the regulatory bodies came to agreement and provided new guidance to industry that from this day forward, every new anti-hyperglycemic is required to demonstrate cardiovascular safety. And what that means is those words demonstrate cardiovascular safety effectively means you have to prove through non-inferiority trials, non-inferiority testing that your drug is not worse than a comparator for cardiovascular outcomes. As I mentioned, since no medication in the field of diabetes had cardiovascular indication, what that meant is we would embark on placebo-controlled non-inferiority trials and as a cardiologist that's off-putting that we're going to do a 15,000 patient trial to prove that the drug is not worse than a placebo. But we have to remember this is on the backdrop of these drugs regulating blood glucose. Hyperglycemia continues to be a risk and a target for therapy for microvascular disease risk reduction. So as we're attending to the microvascular disease risk by managing hyperglycemia, at a minimum we need to be sure that we're not harming the cardiovascular system. And for cardiologists, I try to use the analogy as like a cancer chemotherapeutic. We don't expect cancer chemotherapies to improve cardiovascular outcomes, although there may be some that will. We need to know while we're treating the cancer we're not harming the cardiovascular and so that's kind of the diabetes in two different disease state comparison. So this sets the stage. We now have to do large-scale randomized clinical trials and it moves the needle from 250 patient years required of exposure to 15,000 patient years of exposure before you can get a drug permanently approved for use in humans. That's a 70-fold increase in the effort that's required to get drugs to market and with this resource utilization goes money. This is a very expensive proposition. And of course a lot of people cried foul that there's no way we would be able to afford these trials and even if we can afford them we're never gonna find enough patients to properly the trials. And now with the luxury of hindsight at almost our 10-year anniversary of this guidance we know for sure that we haven't halted cardiovascular research and diabetes and we have easily been able to find these patients by rapid enrollment on all of the trials since. Now a lot of people misunderstand that that regulatory guidance change was due because Rosyglutazone had a signal of possibly increasing risk for myocardial infarction. But it goes back a long time before the Rosyglutazone problem. So we were having meetings with the FDA even when I was a fellow with my mentor Rob Califf and other experts from the FDA, from the NIH, from industry science and experts around the world trying to nudge for a decade before this trying to nudge the FDA to change the rules that we needed to know better what these drugs were doing. And that was driven I think by the kind of a perfect storm for regulatory guidance. One was the increasing prevalence of type 2 diabetes. So in 1990 when the ICH put forth those requirements the prevalence of diabetes in the US was about 2%. And it's now in excess of a 12% if you count the patients who are undiagnosed in the United States. So we have a public health epidemic. And so as we have a chronic morbid and mortal disease like type 2 diabetes, we must know how to treat these patients and know that what we're doing to them is actually making their lives better either by improving morbidity and or mortality. Second, there's a growing awareness across the last two decades of the cardiovascular consequences of diabetes as I went through training we learned only about microvascular disease risk. We rarely have ever talked about atherosclerotic vascular disease risk, heart failure, atrial fibrillation. And so as I got interested as a second year resident one of the reasons I got interested in this domain is we really weren't interested as a cardiology community and we really had no data. So I set out and went to learn how to do outcomes trials and have spent my two decades since on that singular mission. Third, because we're bringing drugs to market with only 250 patient years or so of exposure, it's no surprise that we're finding in a post-marketing environment unexpected adverse effects of these drugs either on target like hypoglycemia glycometabolic effects, hypoglycemia increased appetite, weight gain, other things like that but often completely unanticipated and often completely lack of understanding of off target effects like liver failure or macular edema or bone fracture or heart failure or myocardial infarction. So a lot of these drugs have had post-marketing labeling changes or even some drugs removed from the market as we've in a post-marketing environment seen side effects we never intended and often didn't even have a signal in the pre-marketing data that this would happen and I'll show you a few of those examples. And finally and perhaps most importantly the proliferation of medicines as I went through residency in the mid 1990s we only had two therapeutic options. We had insulin and we had sulfonylureas. And so in 1995 Metformin came on board and soon thereafter the thiozolidine diones. So we started to increase the number of medications and I think for cardiologists this tells the story very well. So my friend, Sylvia and Zuki and endocrinologists at Yale put this together. What you see in the blue are a drug classes for the treatment of hypertension and in the red drug classes for the treatment of hypoglycemia and type two diabetes. And from 1950 to near present day what you can see in the anti-hypertensives about once every five years we got a new class of medications so that by present day we have 11 classes of medications approved for hypertension. Look at this therapeutic desert from 1950 all the way to 1995 we had two agents available insulin sulfonylureas. The dotted lines in the middle represent can you see my pointer yeah represent Finformin that was on the market for 17 years before it was withdrawn because of lactic acidemia. So it was only in 1995 we got Metformin and then we got Acrobos, glucose absorption inhibitor in the intestines, the thizolidine diones, this is pyoglyzone and rosiglidazone, myglidonides. And then finally what we're calling now the novel anti-hyperglycemic the GLP1 receptor agonist I'll spend most of this talk talking about just two classes of medicines the one at the top here SGLT2 inhibitors and the GLP1 receptor agonist and a little bit of data on the DPP4 inhibitors. These are the three classes of medication since 2008 where we have generated large scale randomized clinical outcomes data for cardiovascular outcomes. So we'll start with the incretin modulator. So when you ingest carbohydrates and it's delivered to the distal intestine there's a hormonal system that's activated called the incretin system and cells in the distal ilium released into the bloodstream hormones called incretins and most commonly glucagon like peptide I and gastric inhibitory polypeptide. So GLP1 acts on the pancreas augmenting glucose appropriate insulin secretion and by glucose appropriate meaning as your glucose normalizes the augmentation of insulin secretion stops unlike a sulfonioria which just constitutively increases glucose secretion. So these have the advantage of low risk of hypoglycemia and so it was a very exciting proposition to modulate the incretin system. We can do that by the DPP4 inhibitors at the top so dipeptidil peptidase four circulates and cleaves at a very rapid pace cleaves circulating incretins. And so the incretins come out and then DPP4 clears it so you have a very rapid postprandial response that's immediately cleared by an endogenous protease the dipeptidil peptidase four. That can be inhibited by these once daily tablet medications for which are available for use in the U.S. citagliptin, saxagliptin, alloglyptin and lineagliptin. Alternatively, you can augment the endogenous system by administering subcutaneously glucagon-like peptide one receptor agonist, GLP one receptor agonist. This is like giving insulin we're just giving a hormone agonist basically through an injection. So there's the twice daily exenotide once daily laryngotide and lixicenotide and then four therapies that are approved once weekly injections for the treatment of hypoglycemia and we have some data for a few of these from the cardiovascular outcomes trials. So here are the data for the reported DPP4 inhibitor trials and I summarized them all on one single slide because it's a pretty ho-hum result. This is about 100,000 patient years of observation probably six to $700 million spent on these three trials combined. So the SAVR trial evaluated saxagliptin versus placebo patients all of these trials enrolled patients with type two diabetes with prevalent atherosclerotic vascular disease or in the case of SAVR, high risk for high risk primary prevention with type two diabetes. And so while you're looking at here, we collected 1,200, over 1,200 primary cardiovascular outcome events cardiovascular death, MI and stroke. So these all represent the point estimates all represent the effect on our traditional gold standard three point MACE event. So cardiovascular death, MI and stroke. So what you see from SAVR after over 12,000 events were accumulated we have a point estimate of 1.0 exactly where we started. So we proved unequivocally that saxagliptin is a placebo when it comes to cardiovascular risk reduction. So if you're a pessimist you'll say well this trial failed because we didn't improve outcomes. But if you're an optimist and you understand how these trials were designed primarily to prove non inferiority or safety saxagliptin met that target. The upper confidence limit is 1.12. So the regulatory agencies require that upper confidence limit to be less than 1.3 at which time you can claim safety. And so saxagliptin is safe but not incrementally efficacious. Similarly, allagliptin once daily a tablet in post acute coronary syndrome patients almost exactly the same result. And then citagliptin with over 1,400 primary outcome events exactly the same result. And so what you see here is complete neutrality. And in fact we've proven equivalency to placebo with cardiovascular outcomes and remembering that this is proof of safety but not proof of incremental efficacy. And although people want to complain about the fact that we're not moving the needle forward. Remember this is the first time in the field of type two diabetes that we have confidence that what we're doing to the patients to treat their hyperglycemia is not harming them from a cardiovascular perspective. And as I said people started complaining. And so as Dr. Willerson mentioned I'm deputy editor of circulation and I have the privilege in that role of commissioning content. So when I see something hot or contentious or exciting I can reach out to an expert in the field and say can you please give me a little paper on that help our readers understand. And so Gabriel Steg we presented the heart failure outcomes from citagliptin at the European Society of Cardiology and that analysis that I led. And Gabriel Steg who's a good friend of mine and is an associate editor at circulation was the discussant and he was wildly critical of our approach. He just said we're wasting our money we got to do it differently although he didn't have any alternative solutions. So I invited him to write a paper that I completely disagree with but they're very thoughtful. They're very thoughtful folks. So Gabriel and his endocrine colleague Runeon Rousseau published a paper criticizing the way that we were doing cardiovascular outcomes research and diabetes. And similarly and published about the same time in diabetes care. These three authors Smith Goldfein and Hayat actually hadn't been involved in the development of the guidance to do these cardiovascular outcomes. And now six years later they're coming out and criticizing it publicly that we're wasting our money and we're wasting our time. But I think these folks fail to realize a few things. One is proving safety is a good step forward. We're not sprinting yet but it's an important step forward. We have to walk before we run. And what they also fail to acknowledge is the power of these trials to detect non cardiovascular safety signals. So when you do a 15,000 patient year observation and you're looking at primary outcomes for cardiovascular disease you're also surveying throughout the study all of the adverse events that are accumulating and see if there's an imbalance between one or the other. I was on the executive committee of all three of these development programs and we halted all three of these programs in the middle of the development program because of unexpected adverse signals that we saw in the large scale cardiovascular outcomes trials that we would have never seen had we brought the drugs to market with such little requirement as before 2008. So Taspoglutide this is a once weekly injectable GLP1 receptor agonist. After about 600 patient years of observation in the Temerge-8 trial and the overall program NAWSI is a common side effect. We expected that vomiting is a common side effect in this class of medicines, we expected that. Never expected 50%, 50%, 50% of patients exposed to compounds developed neutralizing antibodies and we had some cases of anaphylaxis and anaphylactoid reactions. Never anticipated that it hasn't been seen in any of the other compounds in the class so this probably has to do with the formulation of the incipient and not the drug itself but regardless we stopped the program and never exposed the patient population to this dangerous drug. We would have not seen that in the prior days. Alleglitizar we did a post acute coronary syndrome patient trial of patients with type two diabetes of a dual P part alpha gamma agonist a once daily tablet that mimics the effects of a fibric acid, the P part alpha agonist and a TZD a P part gamma agonist. Lower glucose, lower triglycerides raises HDL. All seems like a good idea. Because it has a TZD effect, we expected heart failure. It was manageable. We expected to decline in EGFR. This is an effect of the P part alpha and it's a hemodynamic effect that it resolves after stopping study drug. We never expected bone fracture but that wasn't prohibitive but we had to stop the program because this drug caused a 40% statistically significant increased risk for upper GI bleeding. Now we have no idea how a dual P part alpha gamma agonist will cause an upper GI bleed but it did and the signal was consistent and continued to diverge and we stopped the program before this drug came to market, abandoned the compound. Finally a novel therapeutic target GPR 40. So G coupled protein receptor 40 is on the pancreatic beta cell and agonizing that increases glucose appropriate insulin secretion. So this once daily tablet, vasiglophilm after 2000 patient years had prohibitive hepatotoxicity. Stopped the trial and prevented it from coming to market and exposing patients to this hepatotoxic risk. So there are examples from these trials where we are getting something for our money. It's not good for the companies and it's not good for the compounds but it's certainly good for our patients that we're not having to remove these drugs from the market 10 years after they've been exposed to millions of people and all of these adverse cardiovascular consequences. So bringing this back full circle to cardiology. So I was on the executive committee of the SAVR TEMI 53 trial with Saxagliptin. Never did we anticipate that Saxagliptin would cause heart failure but we are completely convinced that this is a real finding. Remember Saxagliptin was the 16,000 patient trial with Saxagliptin versus placebo. Complete neutrality for cardiovascular death, myocardial infarction and stroke but a 27% increased risk for hospitalization for heart failure. Now these heart failure events were not part of the primary analysis but fortunately every one of these trials I've worked on, the companies have spent the extra money to prospectively capture heart failure hospitalizations, collect the information and centrally adjudicate it just like we do in heart failure trials. So these are bona fide centrally adjudication confirmed heart failure events and it's an increased risk of 27%. If you turn this absolute risk increment of 0.7% into an annualized risk increment is 0.35% and that's exactly the same risk we see with pyoglidazone. So the same heart failure concern we've had with the Thazolidine Dione medications and specifically with pyoglidazone is reproduced almost exactly quantitatively with Saxagliptin. And here's a meta analysis across the field. So the data I just showed you in the top with Saver Timmy 53, a 27% statistically significant increased risk for heart failure. In the exam and trial with Allagliptin post-acute coronary syndrome, the point estimate looks more similar to than different from the Saver experience. So it looks like Allagliptin may have a heart failure problem too. We were conducting the TECOS trial as these signals emerged and so we were able in the TECOS trial before we locked the database and unblinded that we were able to develop a prospective statistical analysis plan. So a little bit more rigorous than the previous trials that did all of these analyses post-hoc and we were able to show that with Citagliptin absolutely no signal whatsoever, suggesting some heterogeneity across the class with regards to the heart failure signal. We published this meta analysis plot in the primary publication from the TECOS trial looking at heart failure risk. And our conclusion is there looks to be a difference between the compounds. The FDA at the time agreed and product label modified Allagliptin and Saxagliptin inserting in their product labels a risk for heart failure did not apply to Citagliptin but about one year ago with no new data at all, the FDA required that product label to be modified with Citagliptin and also with Linagliptin. So in the product label of those two drugs it says this class of medications has been associated with heart failure like Saxagliptin and Allagliptin. Be careful with this one, which makes no sense at all because we've shown clearly with robust data. We've just completed the trial on the study co-chair for the Carmelina trial of Linagliptin will be presenting that at the EASD meeting in about three weeks. So we have the fourth agent now with cardiovascular outcomes data. I can't share those with you but of course we were very interested in heart failure in that trial as well and we'll be presenting the heart failure data at the AHA. So that's kind of the downer part of the talk. Now there are real exciting stuff where we actually have moved the needle for with cardiovascular efficacy and so I'll talk a little bit about the data we have in hand for the SGLT2 antagonists. So these are once daily tablets that inhibit the re-uptake of glucose from the filtered urine. So these drugs are glucose uric agents. They cause you to, they increase urinary glucose excretion and by doing so lower blood glucose. But by excreting glucose in the urine you're also excreting calories. And so these drugs are all associated with important weight loss up to 10 to 12 pounds over a year to two period of time. So that's an important side effect. It's a little bit of a diuretic and it also is a vasoactive secondary vasoactivity that I'll go through. So these drugs lower blood pressure. So there's all these favorable effects. Very little risk of hypoglycemia in fact no risk of hypoglycemia when the drugs are used alone and again weight loss. And so with insulin and sulfoniorias we have this problem with weight gain because insulin increases appetite and we also have hypoglycemia. So the GLP1 receptor agonist, the DPP4 inhibitors and these SGLT2 antagonists have almost no incremental risk for hypoglycemia and important move forward for the patients. So in September of 2015 at the European Association for the Study of Diabetes the MPREG outcome primary results were reported. And this was the first time in the history of diabetes research whether it's type one or type two that a clinical trial was positive for an important clinical outcome. So all of the type one diabetes data on hypoglycemia management is all based on intermediate markers of disease like photographs of retina, albumin in the urine, change in GFR, amputations are not counted most of the time. And so we have intermediate biomarkers. These are legitimate clinical outcomes that patients experience. So cardiovascular death, MI and stroke and within pagliflows in the SGLT2 inhibitor you see a point estimate of 14% relative risk reduction statistically significant. So a lot of cardiologists will say well 14% relative risk reduction. That's not very much. These drugs are pretty expensive. I don't know if this is really worth the money but remember, this is the first move forward of the efficacy needle. And so this was an important observation. More stunningly in that trial was the effect on cardiovascular death. The entire effect on the three point composite outcome was driven by the effect on cardiovascular death at 38% reduction in cardiovascular death. We don't have a single agent in the entire cardiology arsenal that reduces cardiovascular death risk by 38%. Because there's no precedent for it and we didn't expect this drug to save lives nobody believed these data when they first came out. There has to be something wrong here but these data have been put through the ringer for statistical rigor. And I think the whole field now acknowledges that this is a real finding. And in fact, the FDA granted a product label indication. The first drug in the history of diabetes to have in the label an indication to reduce clinical risk. So every drug in the field has an indication to reduce hyperglycemia in patients with diabetes. There's no clinical indication. So in the impagliflozin label I apologize for the use of a trade name. It will be the only one you see here but I just copied this from the press release. This is impagliflozin. Once a daily now with an FDA approved and around the world now, regulatory approved indication for reduction of cardiovascular risk, cardiovascular death risk in patients with atherosclerotic vascular disease. And it's important to realize that indication has nothing to do with blood glucose. Nowhere in the indication the product label is anything to do with blood glucose. This is a cardiovascular risk mitigating drug with an indication. As I mentioned before we didn't prospectively plan in any of the trials I'm talking about because the regulators didn't require it. We didn't prospectively include heart failure in the primary outcome. But what you'll see here is heart failure represents probably twice as many hospitalizations as does acute coronary syndromes. And so this is an important mediator. This is women with diabetes on the left, men with diabetes on the right in time from 1998 to 2014. And what you see at the top these are heart failure hospitalizations. And of course they're going down. We're doing better and better every day but there's this gradient of risk where heart failure still drives the morbidity of these patients with diabetes. So heart failure is a critically important outcome. And in the infrared outcome trial similar in timing and similar in magnitude heart failure hospitalization was reduced with impagliflowsen by 35%. So again, this is a primary risk population for heart failure. This isn't treating heart failure. This is preventing its hospitalization mostly in patients without prior heart failure. So again, a statistically significant improvement. Now this wasn't part of the primary analysis plan. So this is not get into the product labels. So these drugs are not indicated yet to prevent heart failure but I'll see how they're, I'll show you how they're entering our guidelines independent of the product labels. What we always like in science is, is verification, replication. So here's replication of the cardiovascular outcomes findings from the impagliflowsen trial program in this case with cannibal flows in a second SGLT2 inhibitor. Again, in one daily tablet, two different trials were combined for a primary analysis of pooled data from two different trials. This is cannibal flows in versus placebo in patients at high risk for cardiovascular disease. And here's the primary result on cardiovascular death, myocardial infarction and stroke. And what you see here is exactly the same to the 1,000th decimal point, the effect on three point cardiovascular outcomes cardiovascular death and mind stroke and to the 1,000th decimal point, the confidence intervals. So this is precise replication of the impagliflowsen data. So this is nice to see it amplifies the likelihood of these signals being real. Now here's a point estimate plot putting in blue the cannibal flows in data and in red the comparable data from impreg outcome with impagliflowsen. And again, what I showed you, the cardiovascular death in mind stroke exactly the same primary result. What you see though is with cannibal flows and there's a little more consistency across each of the three components of the outcome. So cardiovascular death, EMI and stroke all went in the same direction but none of them importantly were statistically significant. Specifically cardiovascular death was not reduced statistically significantly with cannibal flows in contrast with the impagliflowsen data I just showed you. So there is an apparent difference between these drugs whether that's real or spurious, it remains unclear. And again, the heart failure hospitalization almost exactly the same 35 or so percent reduction. So this looks like a real effect of this class of compounds. Unfortunately for the Canvas program there was a signal completely unexpected and continues to be unexplained of amputation risk. And so cannibal flows was associated with a doubling of risk for amputation. Now the absolute risk increment here is about 0.3% meaning you have to treat about 350 patients to have this adverse effect if this is a precise estimate. But this is a signal that has not been seen with the other SGLT2 inhibitors and so it remains a concern with cannibal flows and then a product label caution in that regard. Now you'll hear possibly a lot, well these are just small amputations well as a small amputation for me is a bad event but it's not just small amputations you look about 1.3 of these amputations were at the ankle or above in the same point estimate. So this may be a real finding I think as the data are coming forward it looks like there may be some compromise of defense against soft tissue infections. There's been a recent observation of a few extra cases of 4NAs gain green with SGLT2 inhibitors. Again, not a prohibitive safety signal but a commonality between gain green and amputation these may be somehow compromising defense mechanisms and not necessarily being a vascular phenomenon as people thought initially. So let's talk about a little why we think these drugs are improving cardiovascular outcomes. It's clearly not due to hyperglycemia management. These event differences are emerging immediately after initiation of the trial long before hyperglycemia management could impact clinical events. And here you see sub-analysis post-talk sub-analysis from the MPREG outcome trial. On the top line you see the point estimate from the overall trial result on the composite outcome of heart failure or cardiovascular death a 30, 34% relative risk reduction. What you see below here is the A1C stratified by the baseline value at entry. So no matter how well or poorly your glucose controlled when you got into the trial you had a continuous benefit across the strata based on hyperglycemia severity at baseline. And these are the data of achieved hemoglobin A1C. So during the trial what you see again at the top the primary result from the overall study cardiovascular death a 38% relative risk reduction which is what I showed you before. So if you stratified the cohort by patients in the trial who had any reduction from baseline versus those who had no reduction even the patients with no change at all during the trial under A1C they had the same magnitude of benefit on heart failure hospitalization reduction. Similarly if you stratified by people who had more than a 3% drop, 0.3% drop versus not similar consistency. And so this clearly at least epidemiologically disconnects glucose effects from cardiovascular effects. And I think that's an important message for we cardiologists to take home to our clinical practice. These drugs all lower blood pressure. They do so three to five millimeters of mercury systolic pressure. This is consistent across the class. This magnitude of blood pressure reduction in huge populations may be expected to reduce cardiovascular risk a little bit especially heart failure risk a little bit but not by 38%. We've done blood pressure trials for decades and we've never seen this magnitude of risk reduction even with 10 and 12 millimeters of mercury reduction with some of the therapy. Blood pressure is favorable but it's not the explanation. This is what I think is the explanation and it's really exciting field understanding how the kidney is regulating these outcomes. So this is a cartoon of a angry diabetic glomerulus and this is I'm gonna give credit to David Churny a brilliant renal physiologist at University of Toronto who's taught me everything I probably learned once and forgot about this mechanism and the glomerular impact of these medications. So what you see here is a widely dilated arterial glomerulus disruption of capillary basement membranes and then enlarge glomerulus with glomerular hypertension. And what you see in the lumen here of the nephron is very little sodium. These little icons represent sodium. Very little sodium is making it to the macula densa. You may remember the macula densa is in the juxtaglomerular apparatus and it tastes the urine to see how salty it is and the saltier it is the more it impacts the tone of the afferent arterial and it's reflecting intravascular volume status at the kidney level. So when it's getting very little sodium delivered it perceives hypovolemia increases arterial dimension afferent arterial which increases glomerular pressure. That makes sense. So if you probe, if you drug these targets the STLT co-transporters what you do is prevent the resorption of glucose but because they're sodium glucose co-transporters you're also reducing proximal sodium reclamation. So that results in increased sodium delivery and chloride delivery to the macula densa and you restore to glomerular feedback. And so the macula densa now becomes happy system is now perceived as uvolemic. It feeds forward on the afferent arterial restoring its tone. Immediately, and this has been shown with single nephron studies immediately with a single dose of this medication. Does this happen? So you shut down glomerular hypertension and what happens when you measure the creatinine the next day it's increased just like it is with ACE inhibitors. It's not a kidney injury phenomenon it's thought to be purely hemodynamic. So we're altering glomerular transglomerular pressures. GFR goes down acutely and now that the kidney's perceiving uvolemia there's attenuation of the stimulation of the renin angiotensin aldosterone system and attenuation of stimulation of the sympathetic nervous system. And when you do that it's a little bit pharmacologically like giving an acern arb, a mineralic corticord antagonist and a beta blocker all at once. So if you think about that physiologically it may come as less of a surprise that these drugs are reducing cardiovascular death and reducing heart failure. Now this is all pie in the sky in a hand drawn cartoon and maybe or maybe not that it's real but I think this is a really compelling hypothesis as being explored as we speak seems to have locked up. Maybe that's what I need to do. All right, so again as a deviantor of circulation we reach out to the experts in the field when we see signals that we need to understand better. And so we reached out to Professor Tachmeier to help us understand an observation that was perceived with this class of medications. So one of the things we've seen with these medications is there's an increase in fasting beta hydroxybutyrate, a ketone body. Beta hydroxybutyrate is what we monitor when we do urine ketone testing or point of care finger stick testing is what we follow as the marker of diabetic ketoacidosis but in physiologic concentrations this is a highly efficient metabolic substrate and our brains and our hearts can do substrate shifting to metabolize beta hydroxybutyrate in preference to glucose. And so that's a highly efficient metabolic substrate and if you think about it it decreases myocardial oxygen demand, right? And so you're more efficiently generating ATP. These are data with impagliflozin and what you see in the blue are concentrations on the vertical axis of circulating beta hydroxybutyrate. So in the fasting state three hours before a mixed meal test there's a certain level of beta hydroxybutyrate and then postprandially it's appropriately suppressed physiologically. A single dose in the red of impagliflozin does very little to that maybe a little bit of a postprandial excursion but not making much of that. But after 12 weeks on impagliflozin these are the baseline levels. There's more than a doubling of fasting beta hydroxybutyrate and it goes up almost threefold in the immediate postprandial state. So there's more. This is well within the physiologic range and about one-tenth of what we see with diabetic ketoacidosis. So physiologically this could be favorably affecting myocardial metabolism and understanding all of these patients had atherosclerotic vascular disease. So they had vulnerable myocardium some with a burden of ischemia and whatnot. And so favorably affecting myocardial metabolism may favorably affect cardiovascular death risk and also heart failure. So that's myocardial oxygen demand. And so these drugs are diuretics they decrease plasma volume in diastolic volumes are a little bit reduced and that decreases trans myocardial pressure gradients which directly relates to myocardial oxygen demand. So by reducing plasma volume by increasing provision of metabolic substrate and also by lowering blood pressure and thereby lowering afterload three different effects that will favorably affect myocardial oxygen consumption. Here's a way that we may be favorably affecting myocardial oxygen delivery. So these are data from the MPREG outcome trial where impagla flows in each of the two doses studied increased circulating hematocrut by almost 4%. And people look at this and say, well the diuretics this is just hemoconcentration. There is no diuretic that increases your circulating hematocrit by 4%. This is a unit of blood transfusion, right? This is what athletes do for competitive advantage. And then the setting of ischemic heart disease these patients may be markedly benefiting from the increased oxygen supply of increased red cell mass. So there's a lot of exploration going on to look at what part of this is hemoconcentration and what part of this may be expansion of red cell mass. These are some fairly compelling data with Dapagliflozin suggesting that there's a resetting of the erythropoietin set point for a given hematocrit. So what you see in the top is the baseline hematocrit and the change over a 12 week period of time. And on the bottom, the change in circulating erythropoietin. So what you see here, and this has a diuretic control in this study. So what you see here with the placebo there's no change over 12 weeks in hematocrit. With hydrochlorothiazide there's no change in hematocrit measurable across the 12 weeks. With Dapagliflozin beginning at week two continuing all the way up to a new steady state at week eight and then plateauing is the effect on hematocrit. So this drug is increasing hematocrit. If you look at the bottom, erythropoietin doesn't change with placebo nor with HTTZ but there's an acute rise even within one week of circulating erythropoietin and by two weeks it's increased by three fold. And then it goes back to its baseline but understand it's back to its baseline at a new hematocrit. So I think this is pretty potent indirect evidence of expansion of red cell mass through stimulation of erythropoiesis. And again a very exciting field that's going on. The bringing these observations all together there's a lot of smoke and mirrors here a lot of hand drawn cartoons and great ideas on the back of napkins and it will be interesting to continue to explore this scientifically how these drugs may be benefiting. But for my 20 years in the field of diabetes we really have focused on atherosclerotic vascular disease and we focus on metabolic dyslipidemia and hyperglycemia and blood pressure and all of these ASCVD risk factors but we're now expanding our domain of understanding the connection between diabetes and cardiovascular disease to understand the hemodynamic and the intravascular volume influence that diabetes has on these patients and all of these feeding together not just for MI stroke and peripheral arterial disease but also heart failure and importantly kidney disease. And these are all coming together with honestly with the kidney at the center of much of this hypothesis. The shifting gears I'll spend just a little bit of time on the GLP1 receptor agonist. Remember these are the injectable agonist of the GLP1 receptor. We now have four trials on the left and on the far right are two trials that failed to achieve efficacy with GLP1 receptor agonist but importantly in the middle laryngotide with once daily dosing and semaglotide with once weekly dosing both had a statistically significant favorable effect on three point MACE outcomes. So subsequent to this laryngotide becomes the second and we only have two drugs. The second drug to have an FDA product label to reduce cardiovascular risk independent of blood glucose in patients with type two diabetes and prevalent atherosclerosis. So now these drugs have entered our cardiology guidelines. And again it's one thing when they're in the endocrine guidelines but now as cardiology guidelines often being listed as a level one A indication we must address these as clinicians. And again not that we're embarking on management of hyperglycemia we're using drugs that independent of hyperglycemia in given patients at given risk these drugs are mitigating cardiovascular events. So 2016 both the heart failure and the prevention guidelines from the ESC endorsed use of impagliflozin and specifically or SGLT2 inhibitors generally to prevent heart failure and reduce risk for death. The ADA has come full circle from focusing completely on blood glucose to in 2017 they recommended these two proven effective therapies for patients with type two diabetes but they kept in here suboptimally controlled and they actually removed the suboptimally controlled in 2018. So the ADA has even disconnected glucose management from the cardiovascular benefits of these drugs and endorsing them in their guidelines. I'm gonna skip some of these slides so we'll have some time for questions and just go straight to where I think so the guidelines I just showed you is where we are today these are in the guidelines today and we as a cardiology community have to understand how to apply them. And again whether or not you want to manage glucose is up to you but you can use these drugs without embarking on glucose management. So the ADA has actually been fairly receptive to conversations around this proposal. So I propose that once you have diabetes, type two diabetes and atherosclerotic vascular disease you just stop everything the patient is on and you start one of these two proven therapies independent of blood glucose don't even measure the A1C I would propose. That gets a little bit uncomfortable for some people but that's where I think we are. Once the patient is on one of these two therapies and stable and tolerating it I propose we add the second one. The mechanisms of the benefit appear to be very different whether they're truly additive we haven't studied yet but there's no reason to believe there won't be incremental benefit and these drugs are both approved for use with the other. And so this is within the product label to use them together. Then I propose again not checking A1C we've got two drugs on board. I propose thinking about a third drug pioglitazine and one staley tablet thysyloblindione. This drug has been thrown the baby out with the bath water because rosiclitazine's effect on myocardial infarction. Pioglitazine has point estimates toward efficacy and a recent post stroke trial that proves 24% relative risk reduction with pioglitazine. So I think it still should be considered whether or not you wanna use it. It's not in most of the guidelines but I think we have to continue to talk about it. Once on two or three medications and stable then I think we can check a hemoglobin A1C and whether you wanna do that or let the primary care or the endocrinologist do that is up to you. If for that patient they're not at that patient's A1C target then I would propose you can start any one of these five medications including but not prioritizing Metformin. Metformin has less data than any one of these compounds recently combined. So Metformin remains pretty certainly safe probably minimally beneficial. We don't know its effects. Hopefully we'll do a trial about that that we have four other classes of medicine with proven efficacy, I mean proven safety without incremental efficacy. And I'll just finish with this algorithm. It's provocative, it's disruptive and it's meant to be and this is a CME program and I'm not proposing you start applying this today but I think this is likely where we're going in the next five years. Patients with reduced ejection fraction heart failure that is the basis of much of this institution. There are some safety signals with the GLP1 receptor agonist. I would discourage their use in patients with advanced systolic heart failure. This is evidence-based but not financially-based. Each of these medications are around four to $500 a month. So we have to figure out how to get those costs down and how to get these medications to the patients for the cardiovascular efficacy. And I'll re-acknowledge I've conflicted I've been involved in the development of all of these compounds that I'm endorsing in a disruptive fashion and just understand that we're working together and we're working with the agency, the associations to bring these observations into the academic domain. And I think it's time as cardiologists that we stop using subfinerias and even short-acting insulin in type 2 diabetes. We have a plethora of options with cardiovascular safety and some with efficacy proven. So I'll just finish. I've commissioned two primers for kind of the use of these medications for dummies. How do we cardiologists go into the clinic and prescribe an SGLT2 inhibitor? A very short 1200 word primer on how to do that published in circulation, David Churny and Jay Houdel from Toronto. And similarly, we've now published a primer on how to prescribe GLP1 receptor agonist in the cardiology clinic if you want to embark on injection teaching and starting these medications. So I'll finish there. I'll be happy to try to answer any questions. We certainly didn't shut down clinical research when the regulatory guidance changed. We have five trials with five compounds proving unequivocally safety with regards to three-point MACE outcomes. A little bit of heterogeneity in the DPP4 inhibitors with regards to heart failure, I think it's important to pay attention to. But fortunately, we now have four drugs. I will tell you in the next six weeks we will be presenting results from three additional large-scale randomized trials. So Lyna-glyptin, albiglotide and Dapagliflosing results will all be available presented two at the EASD and then one at the AHA. And so we'll have three more trials to deal with just in the next six weeks. All right, thank you for your attention. I'll be happy to try to answer any questions. Thank you very much. Direct motion.