We are going to start our session. Our first speaker is Dr. Michael Linkoff. He really does not need any introduction. He is the select, as you recall, the select trial investigator and wrote the seminal paper on the semaglutide and cardiovascular outcomes. He's going to be talking about the obesity and cardiometabolic health from clinical trials and available guidelines to patient care. Mike. Thank you. Okay. Click on your talk. Click on my talk. Yeah, and then start, yeah. All right. So, it's my pleasure to be here this evening and I'm, as soon as we get this to move. There you go. There we go. All right. So, my relationships with industry are shown here. Here again is your barcode to participate for the couple of questions. So, the triad of diabetes, obesity, and cardiovascular disease is growing recognition. We've known for years and appreciated for years the very high prevalence of diabetes among patients with cardiovascular disease and the impact of cardiovascular disease on patients with diabetes, that over 50% die of their vascular disease. And we've appreciated for quite a while that a very high proportion of patients with diabetes have overweight or obesity and vice versa. But I think it's relatively recently that there's been an appreciation that obesity and overweight represent an independent risk factor for cardiovascular disease, for both progression, incidence, and adverse outcomes. And greater than two-thirds of the deaths related to overweight and obesity have been estimated to be due to cardiovascular disease. Now, there are multiple potential mechanisms by which obesity may influence cardiovascular. Of course, there are the intermediate risk factors that are promoted by overweight and obesity, dyslipidemia, hyperglycemia, hypertension, other factors. But there's also growing evidence that there are direct effects of dysfunctional visceral and ectopic fat on vascular tissue, on metabolic milieu, with production of adipokines and pro-inflammatory cytokines. And it's for this reason that in 2023, the AHA Presidential Advisory pointed to the central causative role of overweight and obesity in the development of the metabolic risk factors, which lead to subclinical and then clinical cardiovascular, heart failure, renovascular, and arrhythmogenic complications. And so, pointing out the very importance of treating cardiovascular disease by treating proximally in patients who have overweight and obesity. The GLP-1s have revolutionized the management of both diabetes, but of course, also overweight, particularly in overweight and obesity, given the lack of other effective therapies. Secreted at the enteroendocrine cells in response to meals, they influence glycemic regulation through pancreatic beta cell secretion and preservation of beta cells through effects on gastric emptying, and effects of glucose uptake in liver, muscle, adipose tissue. But they also have direct effects, central effects on the hypothalamus and other areas of the brain that influence satiety and appetite, and have other effects directly on vascular tissue or on inflammation. Now, originally, these drugs were proposed and developed for glycemic control, for the management of patients with overweight and obesity. Semaglutide is perhaps the most potent of the single GLP-1, the single agonists, and in the trials of this agent focused on hyperglycemia in patients with diabetes, that influence on reductions in A1C in the range of 1.5 to as much as almost 2%, so very potent. And in the trials, the large-scale trials of GLP-1s in patients with type 2 diabetes, there emerged evidence, first with the LEADER trial, but then thereafter, of a cardiovascular risk reduction, this being only the second after SGLT2 inhibitors, which came out right shortly before the LEADER trial, only the second class of drugs that modify hyperglycemia that also influence the most common and the most important mortal and morbid complication of diabetes, that is cardiovascular disease, with an estimated risk reduction for the overall meta-analysis of 0.86 or a 14% relative risk reduction. But of course, these drugs do more, and in addition to the glycemic control, and this is for semaglutide in trial testing, two different, sustained two different doses, there's also substantial reduction in weight. Now, that weight reduction varies from agent to agent, and of the GLP-1 agonists, the single-receptor agonists, it's most potent with semaglutide. And in this trial, this was with the lower doses, the doses for diabetes, weight reductions were seen that were quite clear, but it's clearly dose-related as well, and the higher dose, which is used for weight management, is associated with 10 to 15% reductions in body weight. So, for my first ARS question, the question for you is, for what indications have you personally prescribed GLP-1 receptor agonists in your practice? So, for patients with type 2 diabetes, for patients with overweight, or both, or you've not prescribed a GLP-1 receptor agonist? So, what, oh, I'm sorry. How do I move this up? I thought we were gonna have... Yeah, exactly. All right. Here, so you can see the answers, and then I'll move down. Okay, so most for both. I would, you know, I would, it's interesting for me from the cardiovascular specialist standpoint that in many cases the obesity indication is easier than type 2 diabetes indication, in part because we don't have to deal with the interactions with other medications. And so I think in many ways this provides a first entree for cardiovascular specialists that may then get better, more comfortable with the class of drugs. So based upon the results with the trials in diabetes with GOP-run receptor agonists, the select trial was carried out to identify whether or not the cardiovascular benefit of these agents would extend to patients with overweight and obesity who did not have diabetes. So in this trial, patients who had established cardiovascular disease but did not have prior diabetes and overweight or obesity body mass index greater than 27 were randomized to receive the weight management dose, the 2.4 milligrams subcutaneously once weekly of semaglutide versus placebo. So 17,000 patients enrolled in 804 clinical sites followed for a median, a mean of 39.8 months with the primary, the hard clinical endpoint, the triple endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke. And that endpoint was reduced. It was reduced by 20% with the treatment effect evident very early on after initiation of treatment with divergence of the survival curves virtually as early as they could be measured. A highly significant reduction of a 20% reduction in risk. Overall mortality, there was association of reduction in all-cause mortality with contributions both from cardiovascular death as well as noncardiovascular death. Speaking to the multiple actions of these class of drugs and in particular, this was conducted during the COVID era, there was a reduction in infection associated and COVID associated mortality. Other endpoints, ischemic endpoints within that were substantial effects on nonfatal myocardial infarction and coronary vascularization. We also looked at other cardiometabolic, cardio-kidney outcomes including the renal outcomes. These were patients who were not selected for renal disease but they had a significant reduction in a five-component kidney endpoint which was driven primarily by prevention of macroalbuminuria but also trends toward reduction in the reduction of EGFR. And in a much more definitive trial, the FLOW trial, which did focus on patients with carotid kidney disease as well as type 2 diabetes, there was a definitive reduction in a kidney composite endpoint as well as a substantial reduction in the slope of deterioration of EGFR with GLP-1 with semaglutide in this trial. Now, of course, there's a lot of public concern about what are the risks associated with these agents. In this trial of 17,000 patients, there were no increase in serious adverse events. There was a higher rate of discontinuation of study drug as expected primarily due to GI intolerance, usually in the dose titration period early on. But the gastrointestinal serious adverse events were not increased. And importantly, we adjudicated and looked carefully for pancreatitis and there was no increase in the risk of pancreatitis or any other major adverse event. So then the question is, what is the mechanism of benefit? And that's not only important for speculation but also important for design of other drugs or how we use these drugs. Is it the weight loss, the magnitude of weight loss? Is it the glycemic control? Two-thirds of the patients in the trial, although not without diabetes, had prediabetes. Is it the anti-inflammatory effect? There was a 35% reduction in CRP despite almost all of these patients being on statins or other direct or indirect actions. And the answer is we don't know. We've looked. There was a substantial reduction in weight, approximately placebo-corrected approximately 9% reduction, 9% to 10% over the course of the trial and maintained throughout the trial. And yet the measures of baseline adiposity, be they weight or waist circumference or ratios, there was no heterogeneity in the treatment effect in patients who, by the severity of their adiposity or their overweight or obesity. Moreover, in a much more difficult post-talk, it's post-randomization analysis of whether or not the magnitude of weight loss influenced the magnitude of treatment effect. We could not discern that. So whether or not patients had a body, there was no clear association between the magnitude of weight loss and the reduction in body weight, and the reduction in cardiovascular events. Now it looks like there may be a trend here in the force plot, but that's driven primarily by the fact that the placebo patients who lost a lot of weight had the worst outcome. So there's a link to the post-randomization concerns with why did patients in the placebo group use a lot of weight, what else was happening to them. But perhaps most importantly, the patients in the somaglutide group who lost 5% or more or less than 5% had virtually identical cardiovascular outcomes. So very difficult to link the magnitude of MACE effect with the magnitude of weight loss. What about glycemic control? There was a marked reduction in the progression, the biochemical progression of diabetes, almost a 75% risk, and a marked reduction in the third of patients who didn't have pre-diabetes to pre-diabetes, almost a 67% risk. And among those who did have pre-diabetes, the two-thirds of the patients in the trial, two-thirds of them regressed to pre-diabetes in the somaglutide arm, whereas that number was much smaller in the placebo arm. So this is an effect on glycemia, even in patients who didn't have diabetes. And yet, as with weight, there was no heterogeneity in the level of baseline hemoglobin A1C and no association between the cardiovascular benefit and the magnitude of reduction in hemoglobin A1C as measured after randomization or over the course of the trial. What about inflammation? That's very difficult to sort out. We've got a paper that's submitted and hopefully will be in press soon. But the bottom line is that the effect of somaglutide on the cardiovascular outcome was very similar regardless of the level of inflammation in these patients. So CRP did predict outcome, as we've known from numerous studies over the years. But for any strata of CRP, there was the same magnitude of treatment effect with somaglutide in terms of the benefit on cardiovascular. And of course, it gets more complicated, because there are a number of gut hormones, which are targets or potential targets for the newer classes, the newer generations of incretin analogs. There's GLP-1, of course, there's glucagon, there's GYP, and there's amylin. And of course, the most prominent of those right now is the GYP, which is the target of terzepatide, the dual GLP-1 and GYP agonist. This drug is approved and, of course, is associated with even greater magnitude of weight loss and glycemic control than is somaglutide, up to 20% and higher magnitudes of weight loss in their trials. And so it brings to the next question, what best describes your approach to choosing between somaglutide and terzepatide for patients with overweight and obesity and established cardiovascular disease? So I prefer terzepatide due to its greater effect on weight loss and glycemic control. I prefer somaglutide due to its proven effect on CV outcomes. I prefer the one that, in my experience, has had a better adverse profile. Or I base the decision entirely or primarily on which has the best coverage or is less costly for my patient. Okay, I think very pragmatic approach, the majority basing on the coverage. I think that speaks to a good degree of equipoise or expectation that perhaps we'll see similar outcomes. And, of course, that's the question. And I think we all suspect we will, that terzepatide, with its at least equivalent and greater magnitude of weight loss effect and glycemic effect, will have the same effect on cardiovascular outcomes. But aside from the summit trial, which was a heart failure trial, we don't yet have randomized trial data for cardiovascular outcomes with terzepatide, neither for diabetes, although that trial will be done shortly, or in the case of overweight and obesity, the Surmount MMO trial, which is slated for completion in 2027. Again, we expect a benefit, but seeing the independence of weight loss or the magnitude of weight loss and the independence of glycemic control with the magnitude of treatment effect, I think certainly for the time being, we need to say we don't know and that it needs to be proven agent by agent. And of course, the prospects for newer agents and for other targets is virtually limitless. The success with these agents has spawned a number of new development programs. This is only a small proportion of them that most act on multiple receptors. Of course, there's the development of oral agents, and you heard today the SOL trial with the oral semaglutide trial, and even those that are aiming at preventing the muscle loss or the sarcopenia, and you'll hear from Dr. Taub on some of that topic as well. So it's a very interesting and stimulating and exciting time to come. So who does this apply to? Well, there's been a number of studies, but I think one of the best of them was in the Haines Survey publication, which suggested that on the basis of the SELECT trial, an additional 4.3 million people, beyond those who already had an indication for weight management or for treatment of diabetes, would be indicated. Of course, then the question becomes who would have coverage and what are the financial aspects of that? And that's very complex. But I will say that in the cost-effectiveness analysis that we recently published from the SELECT trial, the cost-effectiveness ratio is in a range that is considered an intermediate value at the full price, but at the average United States discount, which is at 48 percent, it lands in an area that is considered in the margin between high and moderate value. So depending a lot upon the individual negotiations, these could be very effective. So from my standpoint, the effects of semaglutide and, more broadly, GLP-1, in this kidney cardiovascular metabolic syndrome, clearly reduced risk of adverse ischemic cardiovascular events, death, myocardial infarction, stroke, and all-cause mortality across a broad spectrum of patients with CKM, those with overweight and obesity, with or without type 2 diabetes, of course those with type 2 diabetes, with chronic kidney disease and obesity or type 2 diabetes, and my colleague Dr. Vest will speak on the heart failure data. There's also reduced risk of important kidney outcomes in patients with CKD and diabetes or CKD and obesity. And of course, the next generation of increase in analogs hold promise, but their clinical benefits remain to be proven in outcome trials. Thank you very much. Thank you.

obesity

cardiometabolic health

GLP-1 receptor agonists

semaglutide

cardiovascular risk reduction