It's a pleasure to be with you here today to discuss this interesting issue about cardiovascular outcomes and atherosclerosis, how do GLP-1 receptor agonists provide benefits? My disclosures are shown here. We face this question because of the success we've had over the last few years in terms of improving cardiovascular outcomes with GLP-1 receptor agonists and this clinical trial data allows us to frame the question and explore why was there benefit? And it is particularly intriguing because within this class we have agents where the primary end point was negative and the benefit was not shown, although safety was established, and other agents in which the primary end point was positive and quite clearly so with Liraglutide in the LEADER Study, sernaglutide in SUSTAIN 6, dulaglutide in REWIND, and then additional data that continues to come out, and this raises the question of what is the basis for this benefit, and I would like to take two broad approaches to this question, first thinking about insights from the clinical trials in terms of understanding why some of the agents didn't work and others did and at least thinking about subgroups and what they might inform us about benefit and mechanisms for benefits and predictors of that. The second approach is a mechanistic one looking at responses that we're seeing on clinical surrogates that we know are very relevant in their own right in terms of cardiovascular risk, issues like blood pressure and hypertension control, and then also looking at the smaller human studies and pre-clinical models for what they might inform us about benefit. Now, as we look at the components of the primary end point as laid out here, we do want to be careful about looking too much into this breakdown. It's the primary end point that was positive. We do see intriguing signals around the potential for effects on stroke as seen in SUSTAIN and REWIND that may point us to additional directions in the future, but the important point is the positive primary end point and we have to keep in mind that there are many different factors that could lead to why there are different results in cardiovascular outcome trials. These are laid out here on the left, the many different components of specific agents related to their pharmacokinetic profiles that could be relevant including how they penetrate the brain, among other tissues, the responses to them, the structure of those drugs, and on right the many different components of the clinical trial in terms of the patients who are studied and the nature of their disease, what therapies they're on, how long the trial was, and on and on could all be influencing the outcomes that we're seeing and raise the possibility that we want to be careful about making conclusions about any one clinical trial. Attention has been paid to the nature of different GLP-1 receptor agonists. We know that there are agents that are built upon a human GLP-1 backbone versus being built on the Exendin-4 backbone and perhaps that might be a difference the Exenatide, Lixisenatide, are based upon Exendin-4. There's also been attention paid to the half-life that perhaps longer acting agents would be accounting for the benefits seen with Dulaglutide and Liraglutide and Albiglutide. Exenatide is available in a long-acting form and so maybe that limits that being a complete explanation, at least on that component of the agents. In terms of the trials themselves, they are always going to be different in terms of the patients being recruited. You can see that laid out here. In general, most of these trials have fairly similar recruitments. There were some differences in terms of their prior cardiovascular disease. They were all in patients who were overweight. The extent of their A1c control prior to the trial was relatively similar and by and large the end points were similar to it's not clear that we are going to get an answer just from the nature of what we can see about the trial at a first pass level, but again each trial is different and that could be relevant. Looking at subgroups we see some intriguing signals that again may help us as we move forward in this field and also try and identify patients who might benefit and thinking about additional populations to study. Here you see in the subgroup the suggestion that those who had higher BMIs and were overweight might have benefitted to a greater extent, and looking beyond that, there are additional aspects of subgroups that could be potentially relevant, you know, one sees a possibility of signals in terms of glucose control with more benefit when the A1c was higher that's intriguing because it returns us to the fact that hyperglycemia may matter, may matter by shifting the background nature of the pathobiology of the atherosclerotic lesion through very subtle things like inflammation and oxidative stress in a given lesion. There are also separations perhaps in terms of the extent of cardiovascular disease that enrollees have and greater, more obvious signals in those who had established disease in the LEADER Trial versus those who didn't have a history of prior disease but had high cardiovascular risk. Now this could simply be a manifestation of the risk and when the events happened in their natural history but it could also have implications as we being looking at these agents for primary prevention and people have not yet had an event as will almost certainly be done. And then also, interesting signals around those who had greater kidney issues as seen in the subgroups in terms of chronic kidney disease. Is that simply the greater risk that those patients have? These agents do have effects on the kidney as we'll touch upon briefly and so that's also of interest, especially the increasing focus on the cardiovascular risk of the patient with chronic kidney disease. As we move beyond the trial analysis, we turn to mechanism and we have to begin by recognizing that we still wrestle with the question of whether atherosclerotic complications in the setting of diabetes are the same or distinct from those patients who don't have diabetes. We know that there are many inputs into atherosclerosis and its complications in the setting of diabetes and that it's not just hyperglycemia but hyperglycemia can matter including more subtle novel pathways like advanced glycation end products, but there are many organs at play in terms of diabetes that are undergoing dysregulation and dysfunction and those different organs input into atherosclerosis and raise the possibility of issues related to complications, be they effects on the pancreas, skeletal muscle, adipose tissue is being very biologically active, the source of mediators that could impact the vasculature and also have effects on the liver, relationships with dyslipidemia and hypercoagulability are all relevant and one notion that's been out there for some time has been that cardiovascular benefit with an agent has to go beyond simple glucose control with and effect on these other pathways so maybe the GLP-1 receptor agonists are having this effect by impacting many of these different target organs. We know that that is plausible given the fact that GLP-1 does signal to these various organs, whether directly through the presence of receptors or indirectly by metabolic changes and those organs are the pancreas, the stomach, gastric entry, emptying and satiety that can have contributing to the weight effects. They can also have effects in terms of the liver and fat tissue, important effects on the brain as a satiety signal and the implications around that become a very active area of research in terms of the central nervous system and more neurologic issues and then of course the heart is what we will discuss more are all potential inputs. I want to spend a little time talking about obesity. We know that adipose tissue is very relevant as a contributor to ultimate cardiovascular risk and that the adipose tissue is a source of mediators that can drive inflammation. Those same mediators can affect the vasculature directly, shifting players in the atherosclerotic process like adhesion molecules that influence inflammatory cell recruitment and effects on the smooth muscle cells as well as inflammatory cells, effects on the liver as mentioned and directly on the vasculature that could impact hypertension among other components of atherosclerosis and cardiovascular risk. Liraglutide and GLP-1 receptor agonists including semaglutide do have effects on adiposity in decreasing body weight and body mass index. In more detailed studies, as shown here, there are effects on adipose depots including the visceral fat, which is considered to be a culprit in terms of cardiovascular risk in particular and these are very intriguing issues, given the fact that Liraglutide at a higher concentration, a higher dose, is already approved for treating obesity and raises questions about whether we could see similar cardiovascular benefits in such patients, given what we see in a patient with diabetes. Semaglutide also has a very significant effect on weight reduction. Here you see the relationship in terms of decreases in body weight and A1c and sustained that raises this possibility and continues this notion and it'll be very exciting to see the results of the SELECT Trial, which is looking at the action of semaglutide on patients who don't have diabetes but have high cardiovascular risk and excess weight. If this is a positive trial, this could have quite a transformative effect on our treatment of obesity which is something we have tended to not pursue, despite the evidence suggesting that it's quite important including among people who don't yet have frank diabetes. In terms of mechanisms, the GLP-1 receptor agonist and the GLP-1 pathway is signaling through various targets that can have an impact ultimately on myocardial metabolism. This can occur through the effects in the GI system, ultimately the heart of course is very dependent upon its energy utilization and treatment with GLP-1 receptor agonists through these actions on the utilization and use of different energy resources may play an important point in shifting the substrate use that could impact myocardial metabolism. Similarly, the effects on the brain can play a role. We know that sympathetic nervous system is very important in terms of fat tissue and its responses and that these ultimately converge upon the heart and myocardial metabolism and taking this a step further is to also think about the heart in different clinical scenarios that could be very relevant in terms of the trials we're seeing. One effect can be just on myocardial metabolism at rest but there are also important questions about effects in the ischemic heart and the adapter responses that the ischemic heart is undergoing during those challenges and then also in the failing heart as it struggles to become more efficient about its use of energy resources. GLP-1 also has an effect on inflammatory cells and I just want to highlight here a nice schematic that emphasizes the vascular effects as seen on the right with action on smooth muscle cells and endothelial cells impacting endothelial function, smooth muscle cell responses that we know are very relevant in terms of plaque stability and vasomotor function that impact blood pressure and also other responses that can affect plaque stability and also data suggesting effects on the coagulation system highlighted here is on platelet aggregation so multiple inputs. One in particular that is intriguing is the effects on inflammation and there has been data in humans and in pre-clinical models pursuing this and there's quite a bit of that. I just want to highlight two studies that have pursued this notion about effects, mechanism of benefit and in particular on inflammation so in this study, a very detailed investigation in both ApoE deficient mice and LDL receptor deficient mice are two classic models of atherosclerosis in response to GLP-1 receptor agonist treatment and those investigators concluded that the benefits seen in reducing atherosclerosis in the model involved changes in inflammation and action also in terms of reduction in, in weight and metabolism, intriguing effects on triglyceride handling which of course is a source of fatty acids and fuel and energy that may have all been drivers of the decrease in atherosclerosis that was seen. And here is a second study that I wanted to highlight because of its performance of global transcriptional analysis of responses and a high fat diet in the absence or presence of Liraglutide and as you see here on the left, this is a transcriptional profiling. Each of these lines reflects a different gene in three samples that were done at baseline on a high fat diet, then after treatment with Liraglutide and if you are not used to looking at these, the red are genes that are-their expression is decreased. The green is increased and vice versa, and what you see here very clearly through this pattern is that in response to high fat diet that Liraglutide completely shifted the red to the green and also the green and black to red, so on the top half there are many genes that were being induced in response to high fat diet that are now repressed and in the bottom half you see many genes that were either neutral or being expressed where the Liraglutide repressed them and this is very supportive of a very broad effect on many different targets in response to these drugs in this preclinical model. The authors ultimately concluded that they thought the action could be through a decrease in inflammation and also another component being added to this study of changes in gut permeability that may impact atherosclerosis and together these effects were results in the improvement in atherosclerosis in this preclinical model. In summary, it's a very exciting time. We stand upon the positive trials we've seen and the data that continues to come out with GLP-1 receptor agonists to now wrestle with why did these agents work and as I've gone through, we can gain insights from looking at the trials and looking for signals and clues about why they've benefitted patients and also which patient populations are most likely to benefit, insights that may inform us as trials continue to go forward, as we await for example in terms of obesity in the SELECT Trial and then also mechanistic studies that point to many different effects but in particular ones on inflammation, adipogenesis, the vasculature, inflammatory cells that could all perhaps contribute to why we've seen positive outcomes and the possibility that maybe it's the intersection of these various effects that's going to help explain the benefits we've seen and it will help inform us as we move forward, trying to harness these benefits in terms of improving outcomes on cardiovascular disease in our patients with diabetes and hopefully beyond. Thank you.

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