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Should Weight Management Be a Primary Treatment Go ...
Should Weight Management Be a Primary Treatment Go ...
Should Weight Management Be a Primary Treatment Goal for Type 2 Diabetes?
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Good morning, and welcome, everyone, to this morning's debate on the question of should weight management be a primary treatment goal for type 2 diabetes. I'm Jim Gavin, an endocrinologist based here in Atlanta, where I currently serve as chief medical officer for Healing Our Village. I'm honored to serve as moderator for this dynamic and informative debate, I'm sure, on one of the most fluid topics in all of cardiometabolic disease, and that is obesity in type 2 diabetes. It's well known that in the universe of type 2 diabetes, approximately 80% of affected persons are overweight or obese. Obesity is one of the most powerful risk factors for development of those at risk, for development of diabetes in those at risk, and some of the most compelling affirmations of this observation are the outcomes from the Diabetes Prevention Program, whose principal architect and commanding general is with us today. Indeed, in the DPP, lifestyle change with weight loss was able to prevent progression of type 2 by 58% compared to at-risk controls, far exceeding the impact of metformin. Likewise, weight loss has been shown to lead to remission of type 2 diabetes when initiated at early enough periods after diagnosis and when achieving sufficient weight reduction. And there are other findings that confirm the ameliorative effects of weight loss on type 2 diabetes, in part accounting for the concerted focus of attention on weight loss as a major feature of type 2 treatment. However, it is abundantly clear that type 2 diabetes is a highly complex, heterogeneous disease, and its causality and complications are driven by contributions from multiple factors beyond obesity. We are witnessing a huge surge in the incidence of type 2 diabetes and a disconcerting upward trend in obesity, while at the same time we are seeing the emergence of powerful treatment tools that are highly effective for glucose control and weight management in the setting of type 2 diabetes. Now there is uniform guidance across all of the major type 2 treatment guidelines that lifestyle changes should be the initial intervention for treatment with a goal of reducing weight where necessary, and that is almost always, depending on the population. Notable, however, is the fact that the recommendation for intensification of therapy is predicated on the degree of glycemic improvement, not on the percent of weight loss achieved. So an urgent question, given the evidence accumulated on the benefits of weight loss in type 2 diabetes, the complexity of the disease, its spectrum of comorbidities, and the new insights and tools that are emerging to facilitate even more weight loss during treatment, is the question of should weight management be a primary treatment for type 2 diabetes? So today we have two established leaders in endocrinology and metabolism to debate this important question. We welcome Dr. David Nathan, professor of medicine at Harvard University, and one of the leading clinical investigators in diabetes in the world, who currently leads what I believe will be the third decade of follow-up for the Pivotal Diabetes Prevention Program trial, a study with unprecedented clinical impact in type 2 diabetes, and he will argue the con position. Our second luminary, Dr. Ildi Lingve, is a professor of medicine at Southwest Medical Center in Dallas. She is a master clinician in diabetes and thyroid disease. She has a distinguished record of research in areas of metabolic syndrome, obesity, and diabetes. She has served on multiple editorial boards and has received a number of awards and honors for her work as a researcher and mentor. She will argue the affirmative position on the question. Our first position will be Dr. Nathan. Thank you, Jim. I want to thank the organizers for having us today. Those of you at home can't see the size of the audience, but clearly this topic is not as sexy as the last symposium, which was on transgender sports. But thank you all for being here. So my position in this debate is strongly negative. I think that, as I will show you, Dr. Lingve has recently written a review that suggested that we should be using obesity therapy as the primary treatment modality for type 2 diabetes. I think it is both premature and potentially dangerous, as I'll show you in a few minutes. I have no conflicts to disclose. Since I'm the first speaker, I'll just go through what should be obvious to the audience, but I'll go through it nonetheless. And that is that diabetes and obesity, of course, are huge epidemic-level problems. Prevalence of all diabetes in this country reached over 37 million in the most recent CDC accounting, with type 2 being the vast majority of that, of course. Prediabetes another 96 million people, 1.4 million new cases of type 2 diabetes a year. If you look at the total of prediabetes, those at high risk, and with type 2 diabetes, it's an almost unimaginable 130 million people in the U.S. The total cost of this, human cost and financial cost, largely attributed to the complications of diabetes, microvascular and additional cardiovascular risk. And worldwide, it looks pretty much the same, bad. So this is the chronic pandemic of our species. Okay, the effects of obesity, I measured accurately in some ways, is BMI, but here we see data that are quite old, more than 25 years old, from the Nurses' Health Study showing the relationship between BMI on the X axis, and showing that as BMI rises, there's this steep incline in the incidence of type 2 diabetes, no question about it. And the problem here is, of course, is that in the U.S., our population is on the steep part of the curve, okay? So at a BMI greater than 35, the risk is almost 100-fold greater than if your BMI is 22. That's for the development of diabetes. So I will cede without question that increased body mass is the major risk factor for type 2 diabetes, and here's the sad fact of it, is that by 2030, obesity will no longer be at the low 40 percent, but will be almost 50 percent of the country, including the projection is 24 percent of the U.S. population will have a BMI greater than 35, which gives you this enormous increase in risk. So there's also, that's associational data. I'm going to talk a bit about that kind of data later. There is strong support for causal role of obesity as well in type 2 diabetes, which is mostly derived from bariatric surgery, and which loss of the order of 35 to 50 percent of your excess weight ameliorates the majority of patients' diabetes and leads to remission in between 30 and 65 percent, okay? So here we have the course of this chronic disease, type 2 diabetes. We've talked about prevention a little bit, or we're about to talk about prevention, and at the top here, I have the Diabetes Prevention Program logo, and as Jim said, I've had the privilege of leading that for the last 30 years or so, and that has really established that weight loss, as I'll show you, is the primary prevention modality for type 2 diabetes. So in the DPP, we tested a behavioral lifestyle intervention aiming for a 7 percent weight loss or the drug metformin, but here used for prevention instead of treatment, in a very high risk of population of participants with prediabetes. Here you see the weight loss that was achieved with the lifestyle intervention. We did get to the 7 percent increased activity levels as well. Metformin is actually a pretty good weight loss drug. Chronically, still decades later now, those folks weigh less than the original placebo group, and here we see the important thing of the cumulative incidence of developing diabetes. The green line is the placebo, 11 percent per year developed diabetes. The red line is metformin with a 31 percent reduction, and as Jim mentioned, lifestyle was just more powerful, 58 percent reduction with a lifestyle intervention. Okay? We followed this population, as I've said, for decades now, and that was the original 58 percent and 31 percent reduction, but after 10 years, the lifestyle remained at a 34 percent reduction. After 15 years, 27 percent reduction. So still, after 15 years, after the start of this study, still a benefit with regard to diabetes development. So I will concede at the beginning of this debate that weight management or loss is the primary prevention goal for type 2 diabetes, prevention goal, but our question today is not about prevention, it's about treatment. So the question is, is weight management loss the primary treatment goal for type 2 diabetes? And let me just remind you what primary means. It's not a primary, it's the primary. Primary meaning chief importance, principle, main, chief, key, prime, central, foremost. This is it. This is what you're supposed to aim for, and that is what my worthy opponent will argue for. And this is the article that started it. Now, some of you may know that Dr. Lingvay gave a kind of a preview of this debate at the ADA about a week ago, and I purposely didn't listen to that because I thought it might give me some advantage, not that I need one. But I thought it would give me an advantage. But by all reports, she was not only charming and intelligent and had wonderfully colored slides and whatever, but I still, in advance, I want to apologize to you, L.D., okay? So this is from the article that she wrote about it within the past year, and in it, these are all quotes from her. The underlining is mine. Let me just be clear. Weight loss is known to reverse the underlying metabolic abnormalities of type 2 and as such improves glucose control. Loss of 15% or more of body weight can have a disease-modifying effect in people with type 2 diabetes, an outcome that is not attainable by any other glucose-lowering intervention. She goes on to say, further, weight loss in this population exerts benefits that extend beyond glycemic control, blah, blah, blah, blah, and helps a lot of things, makes people better. And the reason that I stress the 15% will do that is that she mentioned 15% in that article, which I did have the advantage of reading before this debate. Mentioned it like 16 times. 15% is the goal for weight loss, the aspirational goal. So let's go back, and we're not going to be finished about prevention, and again, I concede that weight loss is important there, but we're not going to talk about secondary intervention. And for secondary intervention, if we look at my view, the countervailing view to Dr. Lingvay's, and that is glycemic control is what is primary, there are lots of studies, and I've listed here just a few of them. We're all very familiar with the cardiovascular outcome trials that have been published recently, but there are, I have a half a dozen here, an early intervention, and there are many more. Okay? So I'm going to go through some of those. These are studies of glycemia, okay? And again, the reason for these studies was because it was felt, since vascular complications of diabetes are, microvascular complications, are unique to diabetes. People with obesity don't get diabetes complications unless they develop diabetes. So most of these studies were directed at lowering glycemia. And the goal was, the primary goal, should be to decrease morbidity and mortality associated with the disease. I don't think we need to debate that. So the question in this debate is, what is the primary, most important key chief principle management feature of type 2 diabetes treatment? Weight management or something else? I will argue, as I've mentioned, that a glycemic management that is lowering chronic glycemia as represented by the hemoglobin A1C is inarguably the primary treatment goal, with weight management playing a secondary role. So going back to the beginning, there were two studies, the Diabetes Control and Complications Trial, which I've also had the privilege of leading for many decades, and the United Kingdom Prospective Diabetes Study in type 2 diabetes. And these are the data from them. On the left is the use of insulin or sulfonylurea versus a placebo control, or it was actually a diet control. And on the right is the metformin. And these are the microvascular disease complications, which were pretty advanced, by the way. This was, you know, whether you needed photocalculation, or you had hemorrhages in your eyes, or renal failure. So these were pretty advanced complications. And you see that for whichever treatment aimed at lowering A1C from about 9% to about 7%, the lowering of complications was in the range of a 22% to 28% risk reduction that you see here. And that persisted over time. So the benefits of 10 years of therapy with an additional 10 years of follow-up with what has been called by them the legacy or metabolic memory effect basically occurred in the setting of weight gain. So A1C is lowered. And weight gain is occurring at the same time. And yet we see these results. Here we see a number of those other studies that I put on an earlier slide looking at control and complications, glycemic control, not weight control. And here we see that the A1C difference achieved pretty much parallels the reduction in the risk of development or progression of microvascular complications, diabetes-specific complications. At the top, I want to point out, is the DCCT, which is in type 1 diabetes. But all the rest of these are in type 2 diabetes. The greater the A1C lowering, the greater the benefit. And the reduction is largely proportional to the A1C reduction, which is shown here, the DCCT in yellow, where for every 10% decrease in A1C. There's a 43% reduction in risk. This is for retinopathy. For nephropathy, it was like a 40% reduction. And the UKPDS, similarly, had a 37% reduction in risk for every 1% decrease, absolute, in A1C. 10 to 9, 37% reduction. 9 to 8, another 37% reduction, et cetera. So again, lower A1C is better. Well demonstrated. What about cardiovascular disease? Well, here's the UKPDS, looking at myocardial infarction. And here you see insulin on the left. It's about a 20%, 18% reduction, which wasn't seen initially because too few events. But over time, when they looked, with a long enough period of time, we see a significant reduction. And with metformin, the reduction was there probably an extra glycemic effect of metformin. So I showed you the microvascular benefits. Let's turn to cardiovascular benefits. That's in red, appropriately. And here we see those same studies. And you see that the development of MACE or MIs or whatever to the right of the zero. So all with kind of 15%, 20% reductions. These are studies directed at lowering glycemia. All right? The one exception that you guys know about, of course, is the, oh, I'm sorry. Here, the more recent cardiovascular outcome studies probably have extra glycemic effects of these drugs. So their glycemia was not lowered very much, but MACE was. The one exception, though, was the ACCORD study. And MACE events were reduced. Not significantly. It was of borderline significance. But in that study, mortality was increased. And I just want to say that that study is the outlier of all of these. And the reason it was an outlier or exceptional probably was that firstly, they were aiming for an A1C less than 6.1. They used three drugs routinely to lower glycemia and as many as five diabetes drugs. And when it turns out that they looked to see why this mortality was occurring, they couldn't explain it. It wasn't related to the A1C. It wasn't related to hypoglycemia. So here are these studies. The reduction in A1C. These all showed decreases in microvascular disease and for the most part, cardiovascular disease. At the same time, they were gaining weight. These were not weight reduction studies. They weren't aimed for that. And in fact, intensive diabetes control in these populations, DCCT type 1 but all the rest type 2, they actually gained weight. So all of the major clinical trials of metabolic control demonstrating substantial benefits with regard to complications had concurrent weight gain. And here we have this balance of why we do it to reduce complications. And again, intensive therapy lowered risk for complications even with associated weight gain. Are there any long term studies directed at losing weight primarily on weight loss? Which is what Dr. Lingvay is going to argue for, I think, rather than the glycemia. And the answer there is the Lookahead study, which I was one of the principal investigators of that study as well. So as you know, it was the longest duration, largest study looking at weight loss in the setting of type 2 diabetes to see whether it would ameliorate cardiovascular disease. Went on for 10 years. Primary outcome, CBD morbidity and mortality. This shows the weight loss over time. So here on the left is the weight loss. They lost more than they did. This, by the way, was the Diabetes Prevention Program Lifestyle Intervention, but now used in people already with diabetes. They lost substantial weight and then regained it, as we expected. But the main effect was still, over the entire study period, 4 kilogram weight loss. You see A1C on the right. And there they started with pretty good A1C levels. They were close to 7.3 or so. It dropped further in the weight loss group, down to 6.6, and then over time increased. Again, primarily a weight loss modification, not an A1C control study. And so the average A1C was only 0.2. So here we have now Lookahead added to those other studies. The top ones are lowering glycemia. Lookahead is primarily lowering weight. Again, A1C separation rather minor. Weight loss instead of weight gain there. So what were the results? Well, the results were negative. So this study primarily aimed at losing weight. And you see these lines look like a single line because they are a single line. There was no difference between the Intensive Lifestyle Intervention and the control group. So no benefit. So in contrast to the long-term trials of intensive glycemic control, the major study directed primarily at weight management showed no benefit for CVD. Here again is the title of Dr. Lingvay's article. I'm sorry, this is not. This is another paper from the Lookahead study. What about microvascular complications? So here we see microvascular complications. Kidney, now this was not a major goal of the Lookahead study. They didn't have retinal photographs and they didn't really follow microvascular very carefully. But this one study that we published about six years ago or so and looking at different measurements of outcomes and you see the only one that was significant is in the upper left-hand corner here. And that is for advanced CKD, but all of the other outcomes, end-stage renal disease, doubling of serum creatinine, EGFR falling less than 45, all negative. So some modest evidence that maybe this weight loss did have some benefit with kidney disease hasn't been seen otherwise in other complications in that study. The conclusions of those authors, of which I was one, I should point out, was that weight loss should be considered as an adjunct to medical treatment to prevent or delay progression. We could not on the basis of our data support weight loss as a primary outcome. Cardiovascular disease outcomes, negative, no difference. Microvascular, rather minor difference at most. This is now going back to Dr. Lingvay's article, the title at the top, and this is mine now. She didn't write this. Even if we ignore the absence of convincing data to establish weight loss as a primary treatment, is sustained weight loss especially greater than 15%. Again, that's the number that Dr. Lingvay cites as the primary goal of therapy, realistic, realistic. And why the 15%? Because that's the value, I think, that has been expected right here. Dr. Lingvay notes repeatedly that a 15% sustained weight loss is required to achieve desirable benefits in obese type 2. This is a quote. We propose treatment goal of total weight loss of at least 15% with the intention of not merely improving glycemia, but rather as the most effective way to disrupt the core pathophysiology of type 2 diabetes, blah, blah, blah. But as I've showed you, there really are few data, certainly with lifestyle interventions, dietary interventions, that show that there is that benefit compared with the numerous studies supporting that for glycemia. OK, so is sustained weight loss realistic? More bad news from my point of view. In 2010, the NHANES data, based on a large sampling of the US population, showed that only 8.5% of overweight or obese people maintained a 15% weight loss for one year, much less for longer periods of time. And most of the data I'm going to show you are really looking at 10% loss, not 15%, OK? In the paper, again, Dr. Lingvay cited the DIRECT study, which, as you may know, is a primary care-centered study of weight loss in the UK. And she cited this as a way of supporting that weight loss is achievable. But she also noted, all of which is true here, is that the DIRECT study was only able to enroll one out of five of the screen candidates. The attrition was almost a third of the study group. And when it came down to it, only 11% of them lost at least 15% over two years, OK? 11%. So if this is going to be our new direction, again, can we achieve it? These data would suggest we can't. More bad news, OK? I think we're all putting our hope in new drugs, GLP agonists, GIPs, et cetera, to be more effective at getting weight loss down. But these are the data. These are the data from a number of studies. Here, liraglutide, naltrexone bupropion, oralostat. And this is 10% weight loss at one year. That's what most of the data are. And you see here that, if placebo-corrected, it's kind of 15%, 20%. Here, more like 10%, less than 10%. Now, by the way, placebo-corrected is because that's what these were. These were controlled clinical studies, right? But what if we look at the total weight loss? It looks a little bit better. But again, 10% weight loss at one year is still, at best, 20% to 25%. So aiming for this kind of weight loss, 15% as sustained, I would argue, is entirely unrealistic. More bad news. If we do look at what's available for two years, this is with the longest studies with liraglutide, showing that, again, placebo-adjusted is about a 10% weight loss. About 25%, 10%, 25% of the population has a 10% weight loss sustained at two years. If you look at combination drug therapy here, it's even worse. So this is pretty bad. There is a ray of hope, I must say. And this is what I think that obesity physicians and patients aiming at obesity reduction are looking at. Terzapatide, the new combination just approved a month ago of a GIP and a GLP, it looks kind of better. 10% weight loss, I mean, this is at one year again, just one year. But here, 10% weight loss, I mean, it's like a third, even at higher doses, more than a half. If you look at 15% weight loss, which they did report, at one year, much worse. So whether having 15% sustained weight loss is even achievable with medications and diets, et cetera, is really very much in question at this point. All right, what about surgery? Bariatric surgery I mentioned earlier as being the best way of having sustained weight loss, assuming we can get more than the 1% or 2% of people who are eligible for this surgery to get it. That's the percentage that get it currently in the U.S. So I was part of the Diabetes Surgical Symposium or somewhat of the DSS, it was called. And this is the consensus statement that came out, or I am, I'm the second author of it. And in that, we concluded that additional studies are needed to further demonstrate long-term benefits. That was back five, six years ago. So how have we done? Do we have more data with bariatric weight loss surgery to show that there are benefits? Well, these are some of the papers that have come out since then. All of them, without exception, observational, inadequately or poorly controlled studies. So the data remain quite weak, even with metabolic surgery, if you will, okay? The one that is, the biggest one that's gotten a lot of headlines is published in JAMA from the Cleveland Clinic looking at their long-term experience of some of the almost 2,500 patients having surgery compared to 11,000 matched patients who did not. Again, an observational study, inadequately controlled. All right, so the data are really pretty weak when they look at, okay, is microvascular disease reduced, et cetera? No clinical trials, except for one. And the reason that I'm gonna stress the clinical trials is firstly, that's what I do for a living. I do control clinical trials, I have for 40 years now. But the problem with empiricism, associational data, observational science, was kind of put to bed 600 years ago. So this is Francis Bacon, the science philosopher, who said, for what a man had rather were true, he more readily believes. This is where bias comes in so strongly into observations. And in the wake of the death of empiricism, we introduced experimental science, or in other words, controlled clinical trials, which as you all know, of course, is the gold standard against which we measure all other studies, to demonstrate whether there is a causal relationship between the intervention and measuring objectively the benefits and risks of that intervention, okay? So clinical trials, again, now accepted as producing high quality evidence, the only method of scientific inquiry that can prove causality and directly and objectively measure benefits and risks. As Denzel said here, I wish I could do his voice, it's not what you know, it's what you can prove. This is from training day, okay? It's what you can prove. And again, I have argued already, and I'll continue to argue, that what we can prove is that glycemia makes a difference, but weight loss has not risen to that level, okay? So we do finally, after all of my railing against this, we do finally have a long-term controlled clinical trial, published by Mingroni and colleagues, so we finally have a long-term controlled trial, not with the usual dietary and drug intervention, but with a population randomly assigned to bariatric surgery. This was published about eight months ago or so, and the problem with it is that it included 20 patients in a Roux-en-Y group, 20 in a biliary pancreatic diversion, and 20 patients followed in the medical therapy, of whom five were lost to follow-up, didn't complete the study. So the question is, are we really gonna base the future of diabetes care on a surgical trial with fewer than 60 participants? Those are the high-quality data that exist, unless Dr. Lungve has in her back pocket studies of which I'm unaware. So I would say, are there any high-quality data to support weight loss as the primary treatment for type 2 diabetes? And I would answer that with none or very, very little. Again, premature to be thinking about this. Interestingly, this is what the bariatric surgery committed community also says. So this was an editorial written by Phil Schauer and Steve Nissen, and the editorial, this is from less than a year ago. After 70 years, metabolic surgery has earned a cardiovascular outcome trial. So even people within the community continue to ask for this kind of data to be provided. So in summary, numerous high-quality studies have demonstrated benefits of lower glycemia on microvascular disease. And almost certainly in a cardiovascular disease, there are epidemiologic data that suggest that this is having a real impact, reductions in blindness in the setting of diabetes over time, for example. Conversely, limited, if any evidence, high-quality evidence for independent benefits of weight loss on these complications. Therefore, controlling glycemia remains the primary treatment with weight loss an important but adjunct goal. While weight loss for all people with type 2 is an aspirational goal, it is not currently realistic. More importantly, current evidence, meaning high-quality clinical trials, have not demonstrated the same uniform benefits that accrue with intensive glycemia control on morbidity in type 2 diabetes. And with that, case closed, and I thank you for your attention. Thank you. Yes. Thank you. We'll wait for those slides to come up, since I certainly don't want to use your slides. There you go. All right. So my earliest name recognition in the field of diabetes and in my chosen field is that of David Nathan. That's because it seemed like every impactful paper that I've ever read as a fellow, as an early faculty, had David Nathan up and centered there. And that's true, because he participated, as you've heard, in all the landmark studies in the field. DCCT, DPP, Look Ahead Today, GRADE, and lots of the guidelines that I was reading as I was developing my career. So it's no surprise that, in my mind, I created a vision of David Nathan. And that looks like this. So after many years, David Nathan came and visited UT Southwestern. He gave grand rounds and a big lecture. And I have to say that I felt, during this whole visit and day, like I'm a mere mortal at the party of the gods. But you know, you can imagine my consternation and delight when I heard the invitation from Endo Society to debate the great David Nathan. And I thought that all gods must have a weakness. And I thought that the weakness is that, after all, David Nathan is the author on one of the most liberal recommendations of bariatric surgery for type 2 diabetes. He's the number one medical author there. Francesco Rubino is a surgeon. And he boldly stated down here that pretty much a large percentage of patients with diabetes should be treated with bariatric surgery. I have to say that it sounds like we might agree more than we disagree. So let's take the gloves off and see where we can take this. So first, let's define the problem. Obesity does not equal BMI. We have plenty of examples of people like Arnold Schwarzenegger, who have high BMI, but they do not have increase in adiposity. We have plenty of examples otherwise as well. And that's because obesity is a disease of the fat. It's the fat quantity, location, and function that determines obesity. So please, let's stop using BMI as a marker of obesity. I like to call it adiposopathy. You can call it what you want. But as long as you're not calling it by a BMI criteria, we're friends. So complications of adiposopathy are multiple. They are linked to every organ system in the body and range from mechanical to metabolic. And people with obesity suffer many different problems related to morbidity as well as mortality. But in particular, when it comes to diabetes, the two conditions are intricately related. Adiposopathy directly promotes the core defects in diabetes, both insulin resistance as well as beta cell decompensation. But there's a lot of other conjunctural factors around these that really promote each other. So conditions that are related to adiposopathy, like sleep disorders, for example, further promotes diabetes. Also, conditions that are related to diabetes, like medication-induced weight gain or neuropathy, which decreases activity, further promote adiposopathy, causing this vicious cycle that promotes the disease scores. And of course, further aggravated by environmental stimuli like physical and social disparities. The last point I want to make is that diabetes is just one part of this metabolic glycemic continuum. It is interesting how we forget about that. And we forget that the underlying pathophysiology starts well before diabetes. And why is this important is that we like to draw an arbitrary line in the sand, which we usually call it diabetes remission, to measure success, which doesn't make a whole lot of sense. If you have a finishing line, and then you line up your competitors at 100 meters, 400 meters, 5,000 meters, and maybe 50,000 meters, and then you measure success by how many cross the line, you see the problem, right? So you have to think, how far from the line are you setting up your competitor? And perhaps the better measure is not how many cross the line, but it's how far have we gone? And I think I'll show some of that in my presentation. So what I've told you so far is that BMI is a poor measure of individuals' adipose-related disease burden. At the risk of sounding like a real estate agent, it's fat quantity, quality, and location that matters. Adiposity is a key pathogenic driver for many conditions, and it represents a disease continuum, and the goals of treatment should be adjusted accordingly. So I will cover these five questions. And of course, I'll spend most of my time on the why. We've seen a similar slide, and we know that with a diabetes prevention trial for every kilogram lost, there was 16% reduction in diabetes. So this is below that arbitrary line that we're discussing. If we look past that line, we're looking at dietary interventions and type 2 diabetes remission. There are many, many such studies. This is just a small sampling of these studies. But what I want to point out is that pretty much all of these studies are set up to be close to the finishing line, so short duration of diabetes. And indeed, dietary intervention is very successful at diabetes remission. And the more weight loss achieved, you see in those bottom half of my table, the more likely that diabetes remission occurs. So there's a dose response curve. My colleague here already presented and introduced the direct trial, which was a randomized trial of intensive lifestyle of interventions versus usual care. And yes, despite its many problems and problems with retention in the trial, if we look at the results by how much weight the individuals have lost within this trial, irrespective of which group they were on, there is a clear dose response curve between weight loss and diabetes remission. And you see that most patients who lost 10 kilos or more actually had diabetes remission. And the vast majority of those who lost more than 15 kilos had diabetes remission. Lookahead data, we've already heard about it. It's the great David Nathan study. Here as well, if you look by how much weight they've lost, dose response curve with glycemic control. The more weight they lost, the more glycemic improvement. Yes, it's right, Dr. David Nathan. Weight loss, it's hard to achieve with lifestyle interventions. And not only that, but once you achieve weight loss with lifestyle intervention, regain is almost guaranteed because of physiological responses, which increase energy intake and reduce energy expenditure. And that's why we need durable solutions. And the one we've had for many years is bariatric surgery. And you already shown this study from Italy. It's one of several randomized trials in the field, actually. I wish now that I would have picked another one, since you poked a hole in this one. But nevertheless, I think this is a very important study. And like I said, it's one of several that randomized patients with type 2 diabetes. Mind you, about half of these patients were already on insulin treatment at the time of the randomization. And they were randomized to medical treatment, biliopancreatic diversion, or Rheumatoid gastric bypass. You see with both surgical groups, a consistent 30% weight loss over 10 years. I want to point out also that the medical group did not do a bad job either. In fact, if you look at the weight loss in the medical group, this was quite comparable with the intensive arm in the Lookahead study. So about 8% weight loss in the first year, and they maintained the 5% weight loss for 10 years. So not a bad medical treatment at all. And that's reflected in the hemoglobin A1C curves, where they were much reduced and remained at target, below 7% for the entire duration of the study with the surgical groups. And improved initially, but then worsened, and pretty much stayed above goal for the entire duration of the study. But that's not even the full picture. If you look at how many medications it actually took to maintain that glycemic control, the difference becomes even faster. So I mentioned to you that half the patients at baseline were already on insulin. By 10 years in the medical group, 52% were on insulin. 27% were on a GLP-1 injectable therapy. 20% were on oral agents. Those treated with gastric bypass, 5% were on insulin. 25% were on no therapy. And those treated with biliopancreatic diversion, none were on insulin. And in fact, 60% were on no therapy. So you see much better improvement in A1C, but also a lot fewer medications to achieve that improvement. So I think I've shown you that weight loss has a dose response curve, and it does cause glycemic control. The means of inducing weight loss is less important as long as weight loss is sustained. The amount of weight loss, now, it's important because it determines the magnitude of the glycemic effect. The benefits of weight loss are seen no matter where you start. There is a common misconception that weight loss, it's only worth it early in the course of the diabetes. And that's only true if you're thinking of that arbitrary line in the sand of diabetes resolution. But weight loss is beneficial and achieves glycemic control no matter where you started. Even if you started 30 years after diagnosis when your patients are on a lot of insulin, weight loss will still benefit them. No, they will not cross the line, but they will get diabetes improvement, fewer medications, and they will feel much better. So you know how halfway through infomercials you always hear, but wait, if you call in the next five minutes, I'll double your order. Well, wait, if you listen to me for five more minutes, I will give you more amazing data. So yes, we have quite a few studies now in bariatric surgery. Many of them are actually randomized controlled trials. And this one's a recently published one in 2021, a meta-analysis of these studies that showed that microvascular complications are significantly reduced with bariatric surgery. Not only significantly reduced, they are clinically relevantly reduced. Retinopathy is reduced almost in half. Nephropathy is reduced by over 60%, and neuropathy by over 70%. No amount of A1C reduction with our oral glucose-lowering agents or insulin will accomplish this amount of microvascular protection. We also have randomized controlled trials in the bariatric surgery, specifically looking at microvascular complication. This one is a study that randomized patients with BMI of 30 to 35, urinary albumin to creatinine ratio over 30, to either best available medical treatment or Roux-en-Y gastric bypass. Now, this was a really smart study. The surgical group was not allowed to start as GLT2 inhibitors, GLP1 receptor agonists. They were allowed to use standard of care ACE-ARBs for their kidney disease. Statins, metformin, or multivitamins, but no other medications. The medical treatment had to use all available best standard of care, so ACE-ARBs, SGLT2 inhibitors, GLP1s, and then they could have added more medications if needed to control glycemia and their concomitant conditions. Here's the primary endpoint at two years, and mind you, it's an ongoing study. We will see data at five years as well. Remission of urinary albumin to creatinine ratio was 82% in the surgical group versus 55% with the best medical care. Remission of albuminuria with GFR over 60, 82% versus 48%. And yes, Dr. Nathan, it is a randomized study. I also want to point out the micro and macrovascular complications from the Italian randomized study at 10 years, and I think that this graph does the data justice. 72% of patients had macro or micro vascular complications in the medical treatment, and remember, it was darn good medical treatment that they did. Only 5% those with surgical procedures. Furthermore, quality of life was improved in every single domain in those who got periatric surgery versus medical treatment. Have I convinced you, Dr. Nathan? Not yet? All right. Well, let's talk about severe risk factors then. So the Lookahead study also saw the dose response curve between weight loss and systolic blood pressure, diastolic blood pressure, change in triglycerides, improvement in HDL, but I know these don't mean much to you, Dr. Nathan. So I'm gonna show you actually hard outcomes, which are the cardio-renal outcomes. And you see these alligator jaw gaps here? For every single hard endpoint that was evaluated in this really large observational study, there was a major reduction in all-cause mortality, heart failure, coronary artery disease, strokes, nephropathy, AFib. I'll give you more, because I know you're hard to convince. Cancer, this is really fresh out of the oven, was just published a few weeks ago. Obesity-associated cancer cases were significantly reduced, 32% with bariatric surgery versus non-surgical controls, and cancer-related mortality was almost halved. This was irrespective of whether patients had diabetes or not at the time they received bariatric surgery. Furthermore, there's also a dose-dependent defect, which further strengthens the argument. The more weight they lost, the greater the effect on cancer-related mortality. And I know I'll put the last nail in the coffin here for Dr. Nathan, it's all-cause mortality. This was also recently published in Lancet, and it showed that this mortality gap started pretty early after bariatric surgery, and this being a study with 1.2 million patient-year follow-ups, it showed that death was reduced by half in patients who got surgery versus patients in the control group, with a median life expectancy that was increased by 6.1 years. Interestingly, in those who had diabetes at the time of surgery, this effect was even greater. Those with diabetes had a life expectancy increase of 9.3 years. So listen, weight loss is good even in patients with diabetes, not just before diabetes. Those before diabetes had a life expectancy increase of 5.1 years. So I've shown you data that weight loss improves glycemic control, microvascular complications, severe risk factors, CV events, cancer and cancer mortality, quality of life, all-cause mortality. I haven't shown you all the other data where it shows that weight loss improves inflammation, sleep apnea, GERD, NASH, and on and on. But it all comes down to the fact that if you're treating weight loss, you have a holistic approach to the person with diabetes, and you're treating the whole person. It's called an upstream intervention. Glycemic control is too late, Dr. Nathan, because you missed the boat. You missed the upstream intervention that's really at the core of the problem. So I've touched on some of these, but I will briefly go over these remaining points. So how much weight loss? This is one study from the bariatric surgery world that looked at groups of patient by how much weight they lost. And you see them divided by percentage of weight loss, and on the right you see likelihood of diabetes remission. You note that you need to be in that 10 to 15% group to have a significant likelihood of having diabetes remission. But then there's a dose response curve with more weight loss, more likelihood of diabetes remission, which tends to plateau off after that. So somewhere there between 10 and 25% seems to be the sweet spot. And if you look at all the other comorbidities, because really diabetes remission is just one of many beneficial effects that you're gonna have with weight loss. If you look at all the other comorbidities and their relationship with weight loss, really for most of them, you need at least 10% and 20%. The more, the better, up to about 20 to 30% range. So in the middle of this, it's 15%, which is becoming a reasonable target at a population level. And it's something that we can strive for for our patients' benefit. Now, of course, I get it. It has to be individualized. Just like we're individualizing glycemic targets based on many different patient-related factors, we also need to do the same thing for weight. We need to individualize our target to our individual patient and their individual needs and situation. So how? So I think my colleague here painted a pretty bleak picture and I wanna leave you with a more positive note. So yes, lifestyle interventions are hard and hard to sustain, but also bariatric surgery, I think we have been vastly underutilizing a really effective tool in our fight against weight gain. But we have this middle ground of 10 to 20%, which I call the sweet spot for weight loss, where we have many new therapies that are filling this space pretty fast. So one of these is semaglutide, 2.4 milligrams. And we see here for the first time we have almost half the people who lost 10% of body weight, and we have over a quarter who lost 15% body weight. The newest drug-approved terzepatide, the dual-GIP-GLP-1 receptor agonist, at 40 weeks showed 11% average weight loss. And look at the curve, which is still continuing to go down. It has not plateaued yet. At one year, we're almost at 14% average weight loss. And the first obesity study, which was not in patients with diabetes, but it was the longest study that we have, at 72 weeks we've seen 22.5% weight loss, not in diabetes, so probably won't see this much in a diabetic population, but it won't be far from this, and will definitely be above 15% in my opinion. Another one that's not yet available, but in development, is the combination of an amylin agonist with the GLP-1 receptor agonist. Here we have an impressive 17% weight loss just at 20 weeks. And look at that slope of the weight loss, and you can clearly imagine that you would expect weight loss well above 20% with this combination. So yes, we will have, and we already have available options to treat our patients. So that brings up the question of who should we treat? Is it for everybody? And of course it's not for everybody. Type 2 diabetes is a heterogeneous condition. And yes, most patients with diabetes also have adiposopathy, but no, not all of them. How do you know which one are those? Well, you won't know that by the scale or by the BMI. You know that by looking at your patient and actually doing a physical exam. Look at how much fat they have. Where is that fat distributed? Look at their skin. Do they have acanthosis nigricans? Do they have hypertriglyceridemia? Do they have hypertension? If they do, then they have adiposopathy. Then you have people with cardiovascular disease. And if you look at this diagram, you will note that there are roughly three categories in which you can pool your patients with diabetes. Those in whom beta cell dysfunction probably drives the disease pathophysiology where glucocentric approach is very appropriate. You have those who have cardiovascular disease in which medications that are proven to lower cardiovascular events are indicated, so a cardiocentric approach. While in the remaining of your population, which mind you will be, the majority of people you see in clinic, a weight-centric is appropriate. So this is what this would look. Primary physiologic driver for adiposity-related diabetes is insulin resistance. Of course, with beta cell dysfunction, this is the majority of our patients and weight-centric approach should be appropriate with a target of 15%. The target for isolated hyperglycemia, hyperglycemia should remain A1C. And for those with cardiovascular disease, protection with cardiovascular drugs will be the primary goal. And of course, for the reasoning of a good debate, we wanna call things secondary and primary. But in reality, we wanna treat our patient holistically and address all the comorbidities at the same time and make sure that our patients meet all the targets that are appropriate. And lastly, why not Dr. Nathan? So yes, he mentioned, and I'm sure he's gonna mention more about the side effects of weight loss. Gallbladder disease, sarcopenia, bone loss, surgical complications, drug-specific adverse events, cost, distress. Yes, there are lots of complications, but they fade in comparison with the great benefits that you get with weight loss, with weight loss that is meaningful, meaning more than 10%. And for your individual patient, you will have to decide what's the risk-benefit ratio, but don't forget that the benefits of weight loss are far-reaching and go well beyond glycemic control. So, I will leave you with the fact that weight loss is a primary target for the treatment of type 2 diabetes because it treats your patient holistically. Weight loss should be individualized, but an average goal of 15% is quite reasonable. And patient selection should be based on phenotype, not BMI, and should be applied concurrently with all other approaches. And yes, we do have more and more options to treat weight loss. And you already mentioned my paper, and I wanted to shout out to my colleagues who helped me write this paper and acknowledge their contribution. And the main message is that obesity management is the future of diabetes treatment, and in fact, it's the present of diabetes treatment because we can do it right now. With that, I want to thank you, and I want to tell you that I think that Dr. Seuss has quite a few assets up his sleeve, and those are knowledge and wisdom. And he does have a weakness that maybe you don't know about, but it's called hot sauce. He does put hot sauce in everything. Thank you. Thank you. Yeah, I'm going to have you, I'm going to just have you, we're going to do rebuttals from here, okay? Well, the noble combatants have staked out their positions on the question. This is the time that we now move to responses in the form of rebuttals. The first rebuttal will be offered by Professor Nathan, and then I'll turn the microphone over to Professor Lingley again. And let me remind the audience that those of you online, you can submit questions with the designation of either of the two panelists as the respondent for your question or a general question. And those in the audience, there are microphones in the aisles for your questions when we get to that point. David. So is this on? Yes, yes. Is this on? Yes, yes. So I told you she was smart and charming. The goddess of knowledge, I believe, is the goddess Athena, not Zeus. So maybe that's another point in Dr. Lingley's favor. You know, I come back to what, when do we have enough information to substitute the treatment of obesity? I'll call it obesity in shorthand. For the treatment of glycemia. And I'll just come back to that over and over again and say, you know, whether it's not what you know, it's what you can prove or show me the money or something like that, something that's moving. But what you heard from Dr. Lingley is, again, aspirational. The number of long-term controlled studies that have looked at weight loss over time is like almost zero. It's the Mingroni paper. The Chen paper that she showed, I think is mostly a meta-analysis of observational studies, not controlled clinical trials. That figure you showed, which I was straining to see, but I think most of those were observational studies. Again, so there's lots of observational data. Is that, are those enough to turn over what is decades of high-quality controlled clinical trials focusing on glycemia? And, you know, so I say that, and she comes back again with a minion showing, you know, the data, observational, Cleveland Clinic, looking at charts and looking at cancer outcomes. But how do you explain the look-ahead study, which was, you know, large enough and powered enough? And I should point out, by the way, that all of these small studies are all suspect. I mean, when we design these clinical trials, we do it with careful calculations of the power that we have for making comparisons. And you need hundreds and hundreds, if not thousands of patients, to see differences over time. So I just don't get the level of data that Dr. Lingvay has been showing us. Again, it's aspirational. Similarly, for the 15% weight loss, she showed you that, no question, bariatric procedures can get a substantial fraction of people for that 15% weight loss. But as we both know, the percentage of people who are willing to accept it these days is on the order of 1% to 2% of people who would otherwise be eligible for it. So that's just not an answer. I would say that the data, again, are not there to support that it has the benefit. Do I think someday the data could be there? Sure. But before you, in anticipation of those studies, to recommend that we change horses from the A1C horse, if you will, to the weight loss horse, it's just irresponsible to do that. And I would ask as a question to Dr. Lingvay, OK, so if you have someone whose A1C is very high, and you're not sure you can get their weight down, do you not treat them with insulin, which you know is going to increase, lower their A1C for sure, but which will raise their weight? Because what I showed you early on was all of those studies looking at glycemia resulted in weight gain. And the data there for reducing morbidity is far in excess of anything available for weight loss. It is, in terms of controlled clinical trials, high quality data. So would you not treat a person with a drug that you know is going to increase their weight to lower their A1C? That's really, that's the case that exemplifies what we're talking about. Because I suspect, if you're going to be true to what you say, you would want to reduce their weight. But if you can't, doesn't mean you don't lower their A1C, which you know will reduce their morbidity over time. Hallelujah. Dr. Lingvay will now give her rebuttal. And you may answer his question as part of your rebuttal, or you may use your rebuttal time and answer his question as a question. All right. So if I can have slides up, please. All right, there you go. So it is, with two teenage daughters at home, I seldom get the last word in the house. So I am delighted to have the last word in this debate. So I'm going to try to use it wisely. But ultimately, you know, my point is clear that weight loss is for diabetes. So let me answer Dr. Nathan's points. In the Look Ahead study, we talked a lot about how we did not achieve its primary endpoint of cardiovascular benefit. Now the problem with Look Ahead studies, since we're poking holes in different studies, is that weight loss was really pretty minor. By the fourth year, less than 5% weight loss was maintained, but those patients randomized to the intensive group. But there was a very interesting paper from the Lookahead study, which analyzed the data not by intervention, but by how much weight they actually lost. And if they lost more than 10 percent of their body weight, they actually had cardiovascular benefit. They had reduced their MACE, so MI, stroke, cardiovascular mortality, and revascularization. That was the primary endpoint. And they reduced by over 20 percent, and it was significant. So it is the quantity that matters. And yes, 4 or 5 percent is not enough, and 10 percent is more is needed. The second point was about all the studies that showed glycemic benefits and long-term outcomes. Yes, there are a few studies showing that. Many of them have showed microvascular benefits. Very few, and only after you squeeze the data, showed macrovascular benefits. Many of these studies showed significant weight gain. So yes, you might have improved glucose. You might have saved a few nephropathies and retinopathies. But how much other disease have you caused by causing weight gain? How much cirrhosis? How much sleep apnea? How much reflux disease? How much just difficulty with daily living and difficulty in quality of life do we cause by further pushing the weight gain? And lastly, to your point about A1C and would you not lower it quick, of course there are always exceptions to the rule, and you have to treat each patient individually. Yes, if you have Ms. Smith in your office who's going to have a knee replacement in two weeks and her A1C is 13, darn you're going to use insulin. Yes. It's like when you're thinking of the retirement account. You have short-term and long-term investments. Yes, insulin you can get a quick bang for your buck, but it's not a long-term investment. It's very risky and it's going to bite you back. So you want to have that long-term investment portfolio and make sure that weight loss is in there. All right. So my last point here is that, Dr. Nathan, the world has moved along. Exactly a week ago, the ADA has presented the draft guidance of the new ADA ESAD consensus on treatment of diabetes. I'm showing here a couple of the speakers. It's the fantastic Vanita Aroda and the mighty Chantal Mathieu. I'm showing to illustrate two of the graphs which are blurry on purpose. These are drafts and you're not supposed to take a picture of them, and they will be finalized in September. But the point being, the new guidelines recommend four pillars of care. One, glycemic control. Two, weight management. Three, cardiovascular risk mitigation. And four, cardiovascular disease, cardiovascular event treatment. Also when it comes to the algorithm for treatment, weight loss now is a primary goal of treatment along with glucose. So co-primary, and they are stated as co-primaries, and they're side by side as the only treatment algorithm that is now recommended. Third, more intensive treatment up front with medications that do not cause weight gain are recommended from the beginning. So see, lots of changes. And Dr. Nathan, if you don't like them, the comment period is open. There's the website and the email where you can submit them. So with that, I want to thank my support group, who is quite numerous. Some of them are in the audience. They're really fun. It's really fun to be in this field, and a lot of the reason for me enjoying what I'm doing is the camaraderie of the fellows that I'm working with and my colleagues. And we are writing the next chapter in diabetes, and it's going to be called The Rise of the Demigoddesses. Well, these have been compelling positions and really interesting rebuttals. We are now going to field questions, and let me first make sure that the questions that you have, the question that you posed to Ildi was responded to? No, not really, I must say. No, again, the question is whether we sacrifice. So I wasn't at the ADA. I was attending my 51st, actually, delayed by one year college reunion, where I was horrified to see my classmates look so old and so fat. I mean, it was terrible, but they were still alive in their 70s. So I didn't see that. So now it's co-primary. Okay. So the debate, though, was whether it should be the primary or endpoint, and I must say that I still do not understand whether there is the weight of evidence that you suggest there is to defend. Yes, you misread the time. It should be a primary treatment goal. Oh, okay, never mind. Would that change your position? No, no, no, it wouldn't change my position. Primary means primary. I mean, we should be careful about language. Primary means, as I defined earlier, it's the main one, and if it is the primary one, then it supplants A1C, and that was my understanding. So Ildi has suggested that there's a comment period. You probably need to address that with the ADA. I probably do need to get involved. You have a question here at the microphone, Dr. Wilson. Dr. Rosenstock is going to say something. Nathan, you lost this one. Totally lost this one. Thank you, Julio. Julio used to be my friend. Nathan, you lost this one. You're such a Luddite, because, you know. A Luddite? A Luddite. It's not a Luddite. Julio, do you have anything else you'd like to add? Julio, we want to keep the questions and the exchange as civil as possible. Do you have a question, Julio? Yes. The thing is, you play with semantics. You really play with semantics. It is not that you are just treating the obesity or the weight. I mean, we are treating the blood glucose. It's that we now have new tools. We have moved from NPH, sulfonylurea, that we like so much. The truth is that now we have tools. For instance, in the Sermon 1 that was mentioned by Ildi, there were 41% of people who have prediabetes, and 95% of them reverted to normal. And also, when you have type 2 diabetes and you use tercepatide, 55% of those people get down to A1C less than 7%. It's just that we are treating the glucose, but we have tools that lose weight. And it's the combination of both. Julio, I never suggested that we wanted to use tools that purposely have people gain weight. So weight loss, as I said, is an adjunct. So it's just that now we have both. We now have both. We have tools that can treat both. So a debate... You didn't mention that in your study in Look Ahead, it was stopped because of futility. You were not able to conduct a good study where your purpose was to get a 7% weight loss and you did not achieve that. No, no, no. Julio, you may not understand what futility means. Futility is talking to you, I think. But no, the futility of that study was because the primary outcome of cardiovascular disease was not reached at its original stopping point. The study was extended. And after doing the analyses, the blinded or the oversight... Nathan, you need to learn to lose. Julio, Julio. It was stopped not because of weight loss issues. It was stopped because the cardiovascular outcomes... Thank you, Julio, for the question. It was stopped because the premise was to get a weight loss of 7% to reach cardiovascular outcomes. And because you did not reach the 7%, it was not possible to reach cardiovascular outcomes. Your misunderstanding here is beyond... You don't get it. Gentlemen, I shall resume control of this debate. And we have one more question at the microphone. Then I want to address a few of the questions that have come in online. Yes, hello. My name is Giselle. I come from Vanderbilt. Nice to see you, Dr. Limbay. So I guess my question... and Dr. Nathan. But I know her personally. I think all of these new medicines are great for weight loss. But I think the biggest challenge we have in clinic is cost. So any ideas or thoughts on how can we make this more affordable to patients? Sure, let the drug companies drop the prices and not pay Dr. Rosenstock so much to do the studies. I mean, it's a joke, right? Yeah, I mean, it is totally unacceptable. You're absolutely right. And as we all know, insulin... It's generic for decades now. Still being charged enormously. It's going to take legislation, which is ongoing in states. It's ongoing in the government. The Congress may do something if they can get their heads out of their posteriors. But absolutely, it's unacceptable than any of this. And one of the nice things about the bariatric procedure is although it has an initial upfront cost, the cost of it does decrease over time, although continued follow-up medications, vitamin supplementation, all of that does have prolonged costs. So that is a very appealing thing. I'm just waiting for there to be compelling data to show us... I mean, the one thing that Dr. Lingvay didn't talk about is the number of people who go into remission and then come out of remission of their diabetes. Do you want to comment on that a little bit? The number of people who have remission of their diabetes but it lasts for only three to five years? I would love to comment on that, right? Because indeed, they're a third of the patients who have remission and then they, over time, as they slowly gain weight, they will get some diabetes. They do cross the line again, right? But think about it, the lifetime exposure to hyperglycemia and lifestyle exposure, lifelong exposure to the risk factors. These patients still benefited for many years. Not only that, even when they cross back the line, they're still so much closer to the line than where they were 10 years prior. So yes, I will take that any day over not losing weight. All you need to do is prove it, I mean, again. Okay, let's move to a few questions that we have from our listeners online. The first one is to you, David. At the time of the UKPDS and DCCT, patients weren't severely obese. Severe obesity is associated with higher mortality. What does Dr. Nathan say? It sounds like the questioner is interrogating whether or not... Is UKPDS still relevant today is the question? Sure, so it is true that at the time of UKPDS, firstly, the BMI of those patients, I think, was in the average on the high overweight, not even obese. Whereas a decade later, 10 to 15 years later, the DPP with pre-diabetes, their BMI was 34 at baseline. Their average BMI in this pre-diabetic group was in the almost close to that severe obesity, if you will, BMI cut point. And by the way, Dr. Linvey, I agree with you that adisopopathy, if I can pronounce it, is, firstly, more difficult to say than obesity. You know, more syllables. And I would love to abandon it, but so start doing it. Come up with a method of measuring adiposity that is affordable and that actually gives you a better index. But for now, BMI actually does a pretty good job. I mean, it does. All the data that you showed, all the data that I showed, used BMI and they show those relationships. So anyway... All physical exam and clinical evaluation. Physical exam and good luck with that. Okay. Really? I mean, so more beyond weighing the person? Is that what you meant? Caliper measurements? Is that what you meant? It's part of the assessment. Okay. All right. Okay. So again, Jim, what was the question? Oh, so it's whether it's relevant anymore. So, no, it is true that these older studies carefully conducted, the UK PDS by, you know, absolutely an intrepid group of Brits who had very little funding to do it. It seems out of date at this point. I mean, there were no statins, right? So all of their risk was increased for cardiovascular disease. They didn't have statins. ACE inhibitors were just coming into... The paper that we wrote on the DCCT, the same issue was the first study of ACE inhibitors in 1993 that showed how effective they were. So all of these studies do need to be updated, but they do need to be updated. I mean, they need to be done. So I agree in general that some of those older studies were in a different age where overall risk was higher. But your whole premise about glycemic control and its benefits is based on those outdated studies. So the studies that I showed you spanned 20 years, VADT, Accord, et cetera. All of those studies that showed benefit with microvascular disease spanned from the UK PDS, which finished in 1996, I think. I need to remind you that VADT and Accord and all those did not show cardiovascular benefits. They showed microvascular. I was using... And VADT... But the primary endpoint was cardiovascular benefits and they were all negative trials. VADT was positive once they had enough event rate, right? VADT was positive in its long-term follow-up. So it was positive. After they stretched it out a little, yeah. What is stretching out? Primary endpoint. Your trial is... I would rather do... Primary endpoint was negative for all three trials. As was Lookahead. So you're... I mean, Julio got the stopping rules, the futility, wrong. He didn't understand what futility means, apparently. But, you know, Lookahead was a well-controlled, modern day, pretty modern day, long enough, large enough number of patients with a population with typical US type 2 diabetes and it was definitively negative, okay? Now, you would say that's because they didn't lose enough weight. I could agree with that. So show me a data where they lose enough weight in a controlled clinical trial by hook or by crook, medications, lifestyle intervention or surgery where you have a cardiovascular outcome. Show me one. We have several in the bariatric world and there will be ongoing studies in the medical world as well. But why did Phil write that editorial saying six months ago that we need to have a study? Because it wasn't... There are no cardiovascular outcome trials. That's what we were talking about. You were talking about cardiovascular. Okay. That's ongoing right now. So we have no data. Both in the medical world and bariatric world, yes. All right. Let me get one other question in as our time winds down. This one has come in online, Ilya, for you. What are the pros and cons of medical weight loss versus surgical weight loss? You did address that to some extent in your presentation. Yeah. So medication-related side effects are something to consider, like with any medical therapy. Just like insulin and other glucose-lowering medications do have side effects, so do these. Different side effects, but they do have, all of them, side effects. They can be mitigated if you know what you're doing and you're helping your patient through it. But most patients will do quite well on them despite the side effects. As far as bigger problems, it's the cost. We... Thanks, Gisela, for bringing that up. Cost is a problem. That's why we have a study That's why I thought it's so important to make these points in the editorial and make these points in meetings like this and to drive a change in the guidelines because that will drive the change in payers and that will drive a change in how we practice and will eventually lead to us being able to prescribe these medications more commonly to our patients who need them. There are lots of different factors surrounding medical weight loss. One of them is the cost. The cost of medication is a big factor in the cost of medication. The cost of medication is a big factor in the cost of medication. There are different factors surrounding therapy with these medications that we need to consider, but ultimately, when we put in balance the risks and the benefits, I think we will find that as long as the insurance company covers for them, the benefits weigh... outweigh the risks. Okay. We have time for one final brief question. Thank you. Paul Copeland, Boston. Hi, David. Hi, Paul. Nice to meet with you. I asked the question in the chat, but since it doesn't look like there's a question in the chat, I asked the question in the chat, but since it dropped down on the list, I'm going to ask it verbally, and that is, we're all kind of negative about look-ahead, and my question about the look-ahead is twofold. The control group was fairly impressive in terms of its degree of weight loss, not obviously achieving the 7%, but as a control group, lost weight, which isn't the average population of people over that span of over eight years. That's point one. The other, there was a machine learning analysis of look-ahead looking back at who was who, and the people who had a negative cardiovascular outcome were those with A1Cs less than 6.8 and with poor self-reported health at the baseline. Those with A1Cs greater than 6.8 and good self-reported health at the baseline actually had a cardiovascular benefit, so I don't know if you guys are familiar with that machine learning study, but it says look-ahead maybe not even on the cardiovascular front may not be all that negative, not to mention all the other comorbidities that were improved. Secondary point, but my question is about that one study, which I'll show you if you haven't seen it, is the machine learning study showing that if you segregate out the population, it wasn't all that negative amongst certain people in look-ahead. Yeah, so these studies, the NIH-sponsored studies make their data available, so I don't think that was one done by the research group. It was done by somebody who took the data and looked at it, which is perfectly legitimate. You know, I'd just be a little cautious about subgroup analyses. If the main study was powered and stopped for futility because there was no separation in the cardiovascular disease, starting to pick and choose different subgroups is always interesting. It's hypothesis generating, but I'd just be a little cautious about it, but sure, you can pick subgroups in any study who are at the most risk and get the most benefit, but that's not what randomized trials are about. They're supposed to take a group as a whole and see what happens to them, and look ahead was unfortunately. I mean, we were hanging on for years, and we did that study for a long period of time, 9.6 years, and it was only when it was clear that there was never going to be any separation in CVD within our lifetimes that the study was stopped. So, no, I'm not familiar with that machine learning. Yeah, that'd be great. Thank you. Very well. We've come to the end of our session. We'd like to thank the debaters for their contributions for their positions and the insights that they've offered, as is the case with any debate. I'm afraid that we will have to have a moment of truth, and that is the declaration of a winner. All those who think that the winner of this debate on the question of should weight loss, should weight management be a primary treatment goal for type 2 diabetes, all those who think that the yes position was the winner, please acknowledge that by the intensity of your applause. Applause Intensity does not equal duration. Thank you. All those who feel that the con position to this question, Dr. Nathan's position, was the winner of this debate, please do likewise. Applause I should have brought more family. Laughter Well, there you have it. I think Dr. Mingve can... Thank you, Dr. Nathan, for a wonderful debate. And thank you for all your work you've done in the field. It's really impressive to know you and all the legacy that you have. Thank you. Congratulations. It's nice to have love at the end. And thank you all for your questions. Thank you for your attendance. And, Julio, I think you need to wait outside. Okay? Thank you all very much. Enjoy the rest of your evening.
Video Summary
In this video debate, Dr. David Nathan and Dr. Ildiko Lingvay discuss whether weight management should be a primary treatment goal for type 2 diabetes. Dr. Nathan argues against weight management as the primary goal, while Dr. Lingvay argues in favor of it. Dr. Nathan presents evidence from studies like the Diabetes Prevention Program, suggesting that weight loss can prevent the progression of type 2 diabetes. However, he believes that weight management should be a secondary goal compared to glycemic control. On the other hand, Dr. Lingvay emphasizes the benefits of weight loss in type 2 diabetes, citing studies that show reduced complications with bariatric surgery, such as retinopathy, nephropathy, and neuropathy. She advocates for a target of 15% weight loss achievable with medications like semaglutide and terzepatide. Dr. Nathan questions the level of evidence supporting weight loss as the primary goal and expresses concerns about cost and side effects of weight loss medications. The debate concludes with Dr. Lingvay asserting that weight loss is a primary target for holistic treatment, while Dr. Nathan maintains that glycemic control should remain the primary focus but weight management can be a secondary goal. Overall, the debate highlights the need for further research to understand the most effective approaches to treating type 2 diabetes.
Keywords
video debate
weight management
primary treatment goal
type 2 diabetes
Dr. David Nathan
Dr. Ildiko Lingvay
evidence
Diabetes Prevention Program
glycemic control
bariatric surgery
15% weight loss
medications
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