Dr. Salvatore Carbone describes how lifestyle intervention can be effective managing weight-loss.
Salvatore Carbone, PhD, FHFSA, FASPEN
Well, good morning everyone. It's a pleasure to be back here. And uh uh I'm excited to discuss such an important topic and timely topic of obesity. And today we will discuss really the role of lifestyle intervention as well as pharmacotherapy. We will now discuss the role of surgical bariatric surgery. These are my disclosures and so these are, these are the three main uh topics that we will talk about today and particularly we will briefly discuss the prevalence of obesity in the United States. Uh Then we will talk about how weight loss can be achieved with lifestyle intervention, with diet with and without exercise. And then finally, we will uh talk about the new pharmacotherapy uh available and the FDA approved medications for the treatment of weight loss, which I think it's what is particularly novel and exciting uh within the last couple of years. So what is the definition of obesity? Really, I don't think to describe discuss this in uh in details to this audience, but the who over 20 years ago really described obesity as a chronic disease that is characterized by an abnormal or excessive fat accumulation that impairs health and really the focus is on adiposity is not just on increased body weight because we know that an individual can have an elevated BM I but still present a low adiposity uh at the general population level. However, we know that an elevated BM I usually uh uh correlates with an increased amount of adipose tissue which eventually will increase the risk for the development of uh chronic diseases. Uh both from an endocrine uh ability of adipose tissue to produce uh negative uh cytokines and negative adipokines. But also there is a mechanical stress of adipose tissue place that the adipose tissue place in our body and eventually can cause uh chronic diseases such as for instance, as obstructive sleep apnea. Uh we use BM I as we all know for the diagnosis of obesity. Uh No, it's not ideal but uh this is what usually commonly used and anything above 30 kg per meter squared diagnosis, obesity and every five points increase in the BM IC. Uh classify a different class of obesity when BM I is 40 or greater than we talked about. Um obese class three, obesity or severe obesity. Why do we care about BMIs? Because we know well that any increase in body mass index, there is an increased risk for cardiovascular disease and an increase for all cause mortality. With the sweet spot being between 24 and 25. With the uh data present showing that the that BM I level is associated with the lower risk for cardiovascular disease and all cause of mortality. Something to keep in mind is that in older adults, the ideal BM I is shifted toward right toward the right by one or two points. So in older adults, the uh BM I associated with the lower risk for cardiovascular disease tends to be a little bit higher, closer to 26 or 27. Where, where are we at? In the, in the United States? We're not doing too well. And the prevalence of obesity. The most recent data shows that the prevalence of obesity is uh about 42%. So 42% of the uni individuals in the United States have obesity and about 70 to 75% of individuals in the United States that they have overweight or obesity. Uh Not only that I think something very important to keep into consideration as you can see in the bottom right of this table. Uh There are, there are some major racial disparities with regards to obesity, for instance, in women. Uh when you look at different races and ethnicity, there are uh the prevalence of obesity in individuals who self identify a non Hispanic black is 58%. Uh and individuals who are non Hispanic Asian is 14%. So there are major differences uh between different races that I think we need to consider in uh take into consideration. Uh the, the uh we are uh plan pro prospect the perspection is that there is going to be near nearly half of Americans are projected to have uh obesity by 2030. Uh So that's really problematic. But what really the problem is that we really don't understand what causes obesity and what are, what do we know so far and what are the major uh theory or hypothesis that might explain why this, the there is an increase mic of obesity in the United States. And so the most common uh model that really shows what causes obesity is the energy balance model. It's not new. And we know that if you have a chronic positive energy balance with energy intake being higher than energy expenditure over time, we increase, we accumulate weight in the form of a post tissue particularly. And on the other hand, if we have a negative energy balance where energy expenditure is higher than energy intake, we will uh we will have weight loss, energy expenditure. Remember when we think about energy expenditure, we of often just think about exercise and physical activity. In reality, we have to remember that 60 to 70 per 60 to 75% of energy expenditure is resulting from resting metabolic rate. So the calories that we just burn by resting um and then uh percentage of calories coming from energy expenditure derived from physical activity. And ultimately, a small percentage, 5 to 10% comes from diet in used homogenesis. So the amount of calories that our body uses to digest nutrients, to absorb, to digest uh uh food, absorb nutrients and utilize them. Um And for the metabolism, overall, there are several factors that are involved in food intake. And the energy balance model suggests that we really have four strategies to reduce weight over time and to induce an energy balance that will cause weight loss. One is by increasing energy expenditure and this can be done with by increasing physical activity or exercise training. From a pharmacologic perspective, we really don't have anything that increases energy expenditure as we know there's been some attempts, for instance, over 100 years ago with T hormones and we know that that didn't go too well with the uh resulting in weight loss but also an increased risk of arrhythmia and death. So definitely not something we would want for our patients. Uh And then we have another strategy which is the one to reduce energy absorption in the intestine. And one way to do it is by using or that which is a lipase inhibitor FDA approved for the treatment of obesity, which has however, several uh side effects which are not desirable in our population, typical of uh side effects that are typical of any really mal absorption. And then more recently, we have SGLT one sodium glucose co transporter, one and sodium glucose co transporter two inhibitors which are not FDA approved for the treatment of obesity, but they are approved for the treatment of type two diabetes. And they also induce weight loss by increasing the excretion of glucose for uh SGLT one and SGLT two inhibitors and STLT one. They also located in the gut and they reduce the absorption also of glucose within the intestine. And finally, we have the most powerful uh uh strategies to reduce uh weight, body weight. And this is through by reducing energy intake. One by reducing uh by inducing energy restriction with nutrition. And one using pharmacologic therapies which we will also discuss. Today, lifestyle remained a a first line therapy for patients with obesity. And this usually includes a reduction in energy intake. So, caloric restriction as well as increasing energy expenditure through physical activity. And this is what we're going to discuss for the next 10 minutes. So does lifestyle intervention really work? Uh We often we always recommend lifestyle intervention to our patients with overweight and obesity. But do we really have the evidence that this may actually result in meaningful clinical uh improvements? And the initial data really comes from the diabetes prevention program, the DPP published over 20 years ago in the United States where we, they've shown that individuals who have a BM I of approximate 34 to begin with and they randomized to either Placebo Metformin of lifestyle intervention, which includes caloric restriction and uh increased physical activity. Patients randomized to the lifestyle intervention lose more weight than what patients lose with Metformin alone. And they increased their level of physical activity to a greater magnitude. But most importantly, when they looked at the prevalence, the incidence of diabetes, lifestyle intervention was the most powerful intervention to reduce the risk of developing diabetes. And in fact, there was almost 60% lower relative risk reduction for the development of diabetes for lifestyle compared to placebo or control group. And also 27% lower risk to develop diabetes compared to Metformin with a number needed to treat of 7/3 years. So a number needed to treat very uh low. Uh So something that we should really encourage our patients to do, particularly for the prevention of type two diabetes. But what about cardiovascular events? Uh do we really have solid data to show that weight loss reduces uh cardiovascular end points such as M I stroke and cardiovascular death? Uh The data that we have come from the Luca head trial, which is the largest, uh one of the largest lifestyle intervention uh studies ever done was an NIH funded study looking at intensive lifestyle intervention in patients with type two diabetes. Uh was a very long term study. As you can see here, up to 10 years, the data were presented 10 years ago at the American Art Association. I can still remember the day that the data were uh presented and uh they show that essentially lifestyle intervention is uh efficacious in improving most cardio metabolic risk factors. After 10 years, patients who were randomized to the lifestyle intervention, uh had approximately a body weight that was uh less than about uh lowered by about 4 kg and increase in physical fitness. Uh a reduction in waist circumference as well as a reduction hemoglobin A one C with the main effect of 0.2% as you can appreciate. However, there are definitely some great benefit at one year and then some of the weight loss is regained uh similar for waist circumference as well as hemoglobin A one C. And so this is definitely a problem that we will discuss in a minute. So cardio metabolic risk factors overall were improved, although the results were not overwhelming, but what happened to cardiovascular events. And so when you look at cardiovascular events, there were no benefit in terms of uh hard outcomes. And so this was one of the most disappointing uh frustrating uh results uh of the last probably of the last 20 years uh where we always started by just losing weight to reduce cardiovascular events. And at least the magnitude of achieved in the overall sample of the Luca ahead trial did not show that. Um But why is it? Um well, probably is a problem with adherence. Uh Really the look ahead brought up the problem of long term sustainability when patients are not able to sustain for the rest of their life, a lifestyle intervention, that's probably not going to be as effective as we would like. Uh and this is important because when they do the post analysis of the look ahead uh published a few years ago in the Lancet Lancet diabetes endocrinology, they actually found that in patients who lost more than 10% of their body weight within their first year of the intervention, they did present a reduction in cardiovascular events. So there was about a 21 to 24% lower risk for cardiovascular events. So the recommendation is really to try to achieve a 10% of weight loss within the first year. Uh from the intervention. Now, does it really matter? Uh if we reduce calorie by approximately 500 calories per day, which is typically what's recommended to lose weight? Does it really matter if these calories are coming from fat from protein for carbohydrates? Uh or as far as we achieve the same caloric restriction, we will achieve the same weight loss. And so there, this uh this question was partially answered in early 2000. Uh this was the direct study randomized control trial published in the New England journal of medicine where patients with overweight and obesity were randomized to a low fat diet. A Mediterranean diet in orange and then uh a low carb high fat diet here in uh in uh purple. And what they found by the end of the study is that the three group, they achieved the same degree of caloric restriction. So they were eating the same amount of calories. However, in the higher fat groups diet. So, in the Mediterranean diet and the low carb diet, there was a significantly uh, uh greater weight loss, uh, compared to the low fat diet, suggesting that the higher fat diet, usually it's beneficial with regards to weight loss. However, we also need to take into consideration that weight loss is not the only cardiometabolic risk factor that we should look at and this is a cardiovascular cardiology ground rounds. So I don't need to tell you how important LDL cholesterol or glucose and other uh risk factors uh um uh are. And in fact, in the same study, even if the two high fat diet achieved a similar uh weight loss, the Mediterranean diet was really the ones that showed the most benefit on glucose. There was a reduction in about 30 33 mg per deciliter, particularly in patients with diabetes that was not uh shown in the uh low carb haa diet. And it was also a reduction in fasting insulin with the Mediterranean diet that was not reported in the uh low carb uh haa diet. Not only that uh the quality of diet can also negatively impact cardio metabolic risk factors. And this is a clear example of what we see in patients undergoing ketogenic diet. Uh ketogenic diet is often recommended for weight loss. But what happens to um cardiometabolic risk factors and particularly what happens to LDL cholesterol. This was a case series just published last year in the American Journal Preventive cardiology showing that in 17 subjects undergoing ketogenic diet, there was a dramatic increase in LDL cholesterol. And then when the ketogenic diet was stopped, the LDL cholesterol dropped back to baseline. So definitely uh something to consider. Um however, this was an observational study. What happens in randomized control trials. This was a study published in nutrients a couple of years ago where women were provided with meals. So this was a randomized control feeding trial where the study team was providing meals to the uh to the uh to the to the participants of the study. And for four weeks of these women were following a ketogenic diet. And then for four weeks, they were uh receiving just what was considered to be a healthy diet. And among these 24 women, all 24 actually had an increase in LDL cholesterol on the ketogenic diet. And on average, there was an increase in 70 mg per deciliter in LDL cholesterol. Uh So this is definitely uh and, and the fact that we do not wish for our patients to have. And so that is why the ketogenic diet should not be recommended uh because of these negative effects on cardio metabolic risk factors unless there are some special indication of extremely short term. Although uh what was remarkable of this study here, the randomized control trial, this was only a four week long study and within four weeks, we already saw an increase in 70 mg per deciliter of LDR cholesterol. So we can do very good with diet, but we can also worsen cardio metabolic risk factors even if a patient is losing weight. Something that has also been uh particularly interesting in the last uh I would say 5 to 10 years was the role of nutrition within the circadian rhythm and how nutrition can influence circadian rhythm. Particularly there's been interest in intermediate fasting as a way to lose weight. Uh And however, I would just wanted to point out that intermediate fasting is just a uh a big term that includes three main components. Uh complete alternate day fast and modified, alternate day fast and then a time restricted eating, which we often the fine as intermittent fasting. In reality, there are uh you know, tre or time restricted eating is just a type of intermittent fasting. And the idea of time restricted eating is that if we eat uh uh as much as we want over uh 6 to 10 hours a day, we might be able to lose weight more than with the general uh caloric restriction. And the initial data were very promising showing that uh when you compare it to no intervention at all time, restricted eating is efficacious in reducing energy intake and weight loss. Uh But what happens when you compare it with just a daily general, daily color of restriction, we recommend with our patients this question was answered in the immunogen medicine a couple of years ago. Now, where daily caloric restriction DC R was compared to time restricted eating. And as you can see here, there were really no differences uh between the two groups showing that as far as you achieve a caloric restriction of approximately 300 to 500 calories per day, uh, you will lose the same amount of weight no matter whether you do it over the course of 12 hours a day, 14 hours a day or six or eight hours a day. Uh Also here in the bottom, uh, table figure, you can see that the prevalence of the uh amount of participants that achieve uh more than 5% of weight loss over the course of the study, which was a one year, uh, study was similar about 60% in both groups, randomized control trials in uh with time restricted eating. However, I've shown that patients who were randomized to time restricted eating, uh typically present worse, uh sleep, they tend to slept to sleep a little bit less and their sleep efficiency, which essentially measures the amount of time that patients actually sleep while they're in bed is also lower. So something to consider. And this was also confirmed in the treat randomized control trial where they show that uh patients undergoing time restricted eating, they tended to be awake for a longer period of time and they also present a less spontaneous low level of physical activity as well as a trend toward lower mass or mass. So also something to consider with regard to the potential negative effects of time restricted eating overall. However, we do recommend that in some patients who cannot stick to a daily caloric restriction. And so having the time after which patients should not eat anything during the day can be beneficial for some patients to achieve caloric restriction. So in summary, uh really any type of energy restriction to the magnitude of 300 to 500 calories per day will result in a weight loss. Uh Diet quality is also important uh because uh there are some cardio metabolic risk factor that will be influenced differently based on water. We eating a Mediterranean diet or a low carb diet. And really the Mediterranean diet seems to be the ones that associated with the most favorable effect of cardio metabolic risk factors. What about exercise? We often recommend, we always, we always recommend exercise uh to our patients. Uh but sometimes patients come back and do not necessarily lose weight. And so what do we do with that? Uh And so the question that we often get asked is uh does exercise without energy restriction induce weight loss? So, exercise alone and the answer is no or very little. This was a randomized control trial showing that when you uh have patients who are randomized to a control group, exercise group diet or diet and exercise group, the control group uh really doesn't lose any weight. And when you look at the effect of exercise training on weight loss, there's really a minimal exercise. Uh uh there's minimal weight loss with exercise training alone in the Black Triangle. Uh However, when you have diet caloric restriction or diet with exercise, you do have uh a nice weight loss of approximately can be achieved up to 10% up to one year. Uh And so this is something important when a patients come back and said, I did not lose weight. That is really what is expected for somebody who just does exercise alone. Uh does that mean that exercise is not good for our patients? Absolutely not. All patients should under should uh undergo exercise training. And this is because exercise will improve exercise capacity will improve cardiorespiratory fitness and the peak oxygen consumption. In fact, there's an additive effect with diet and exercise when you combine them. And so really important that even if patient is not losing weight while exer doing exercise training, there are still benefit on exercise capacity. And patients usually they improve their quality of life and they do feel better overall. So weight should not be the only measure that we have, but why patients do not lose significant uh uh weight with exercise alone. And the reason, the main reason are 21 is that the amount of exercise that is required to induce a deficit of 500 calories is usually higher than was what most people can achieve, at least than what I achieve every single day. And two, it's been shown, this is over 30 years ago study showing that there is a compensatory food intake after, uh an individual starts exercising. And this was a study done, uh, like I said, in 1991 showing that, uh, as soon as patients, it starts exercising, they increase their caloric intake by approximately 100 calories per day. Uh And so this is something also to consider uh that might contribute to reducing the effect of weight loss of uh exercise training. And so this is a summary. Uh really of what should we do in our, with our patients with obesity with regards to lifestyle intervention. Because before moving to a pharmacologic approach, uh approaches first energy restriction that remain the gold standard. But how many calories should we reduce our diet of, of uh in our patients? Ideally, if you have a registered dietitian in your team, uh the dietician will assess the energy requirements and determine whether patient needs 1719 102,000 calories, 1200 calories in absence of a nutrition specialist. The most gui most uh recent guidelines suggests really to use a 1200 to 1500 calories per day in women and 15 to 1800 K CAL uh diet in uh uh men. And uh um really the micronutrient composition should be based on patient's preference and the uh comorbidities that patients have, uh there is, there should be always an increased uh recommendation of physical activity and ideally behavioral therapy associated with it where I think we really don't do a very good job. And this is usually because there's just not enough provider for all the patients with obesity is that the, the guidelines recommend at least 14 in person counseling session within the first six months of treatment. And this rarely happens. I would say almost never happens because uh we just don't have enough uh providers to see all this patient as often as we would like. And then remember to target comorbidities if a patient has this lipidemia, uh you know, Mediterranean diet is associated with lower cholesterol level. If a patient has hypertension dash diet usually is associated with lower blood pressure. And now, uh you know, the last part of the uh of today's presentation which is related to the pharmacotherapy, the newer pharmacotherapy and weight loss. And my disclosure here is that I do not prescribe medication. I do research with medication. I don't ha I don't deal with the uh uh pre approval or uh uh issues with the uh uh with patients not being able to really get that medication. So what I'm going to present right now, it's really related to just the clinical trial that has been published. Uh And uh um we can discuss that a little bit more later first, of all who is uh who's, who can get, who has an indication for anti obesity medication or A OM. These are patients who have either a BM I or 30 or higher. So that's a clear indication of obesity or BM I 27 in the presence of a weight related comorbidity. And this can be hypertension, hyper epidemic, uh obstructive sleep apnea type two diabetes or really any cardiovascular disease. So even an individual with a BM I 27 weight loss medication can be prescribed. And uh uh the regulatory agency, the FDA really uh considers a medication to be effective and really they can receive an indication for obesity when there is a 5% of main difference of body weight between the active product, product and the control. And this has to be a statistically difference, particularly significant difference or there is a, a more than 35% of patients lose at least 5% of body weight. And so these are two requirements that a medication needs to have to receive an indication for uh for obesity. So in 2018, we were asked with uh Dave Dixon who's a professor in the School of Pharmacy at bu a close colleague uh to uh write uh a, a mini review on what we knew about medications for weight loss. And at the time, we were very excited to have at least one GRP one receptor agonist, lyra glut of up to 3 mg per day. In addition to older agents such as aristate l caine buPROPion, naltrexone and phentermine to Pyramid, which were approved for long term for the long term use in patients with obesity. In addition to a phentermine, they can still be used for up to 12 weeks max. So it's only approved for a short term period uh at the time really, um Lyra Gluta was the only GRP one receptor agonist. And uh uh this under goes under the brand name of Saxenda for the treatment of obesity and under the name of Victoza for the treatment of type two diabetes at the lower dose of 1.2 mill 1.8 mg per day at the time. However, the prescribing patterns for an diabetes medication were extremely low. Uh Here in this figure, you can see that in red, these are the patients that would actually qualify for a treatment of obesity, uh pharmacological treatment and this is the actual patient that are treated with pharmacological therapies. And this is the same comparison with type two diabetes where most patients with type two diabetes would actually receive at least one medication for their disease. Um And why that really happens, many patients with obesity should be treated pharmacologically, but they're not treated pharmacologically. Why? And one of the main reason is safety, you know, providers are uh really worried about safety of these agents over the last 50 years. We've had several weight loss medication that have resulted in worsening cardiovascular disease, um uh neurological neurological issues. And so really, we, that's uh something that uh to consider and also one of the other main issues is that we didn't have enough efficacy data, not only on weight loss, but really on hard end points, uh such as improvement in cardiovascular events and type two diabetes prevention. And so, looking again at the uh energy balance model of obesity, you really start thinking that reducing energy intake, it is the strongest tool that we have for weight loss and what can we and what we can achieve with medications. Now, it's really uh remarkable and I will show you the data in, in a minute. First of all, A G LP one, we always talk about G LP one, but how do they work? What are, what are they? And so the first discovery of G LP one comes from the eighties where uh patients receiving oral, were receiving intravenous glucose in a wide circle here or uh receiving glucose by mouth, uh different doses, dosages 25 g, 50 or 100 g of glucose. They presented a different insulin response and uh um no, no, no matter what was the amount of glucose that you give intravenously, the amount of insulin that you produce is not increased. However, when you give glucose orally, you do have a significant insulin response. And this extra effect of insulin produced by oral glucose was called the incretin effect. And by from there, now we call incretin hormones such as the G LP one receptor agonist. This uh extra effect on insulin secretion was caused by two main hormones. The glu the glucose dependent insulinotropic peptide G IP and the G LP one, which were those dependent with carbohydrates. So, the higher the amount of carbohydrates that you eat, the higher is the response of G LP one in uh from the uh um intestinal cells, the higher will be the insulin response. And so initially, G LP one was really discovered as a treatment for diabetes. Just because by increasing G LP one, you increase insulin secretion and you improve uh glucose. Uh uh you improve glycemia in the 1996. Uh preclinical studies have shown that in mice, uh actually G LP one receptor agonist could not just be treatment of diabetes but also treatment of obesity. Uh mice, they were receiving uh glu uh G LP one in interest interest in with the intracerebral injection, they reduce their food intake. Uh And this was only happening when actually mice were wild type for the G LP one receptor. If you give a uh G LP one in a G LP one receptor knockout mouse, you don't really see the effects. And this really showed that if you uh the reduction in food intake in use by G LP one is mediated by its own receptor and it's not an indirect effect mediated by other metabolic pathways. So it's not new. We knew that G LP one would reduce food intake. We also know that G LP one reduced cardiovascular events. Uh These are, this is a meta analysis of a randomized control trial over the years. There is a consistent reduction in cardiovascular in the three point maze by approximately 14%. The reduction in cardiovascular death reduction in all cause mortality as well as small but statistically significant reduction hospitalization for heart failure. However, these are data for type two diabetes. What is the evidence related to the FDA approved G LP one receptor agonist for obesity? And so right now, now we will discuss the three FDA approved medications for obesity uh that are part of the GL pr one class. So we will not discuss the or uh um older agents such as or list that for instance. So the first one is lyra glutted. This is, it was approved a few years ago already. Um and this is present in two formulations like I said up to two, up to 1.8 mg for the treatment of type two diabetes under the brand name of Vitos. And then up to 3 mg for the treatment of obesity. Under the brand name of uh Saana, it's a daily injection and uh uh this is essentially the same active ingredients are different doses. And based on the indication that the provider want is using the medication for should use. Uh either the big dosa or saana. This was based on the results of the uh scale trial showing that the Lyra Glu tide was associated with uh uh 8% weight loss reduction compared to baseline and uh 5.4% weight loss reduction compared to placebo at the time, we were very excited when this data was published in 2015. Uh However, this is now we know that this is not really as overwhelming as the newer agents. Importantly, however, in patients with obesity treated with lelu tide, there was a significant lower risk for the development of diabetes. So this is something that we often forget is that patients with obesity, the majority of patients with obesity will develop diabetes. And these agents really uh allow to prevent the development of diabetes in the first place, more recent approval only last year semaglutide. So this is one of the most confusing um uh agents that you could find with regards to weight loss and type two diabetes. Just because the same active ingredients can be uh um used as a uh different formulations. Uh in the if you're using a weekly semaglutide, which is a weekly injection for the treatment of type two diabetes. This is up to 2 mg per day and this goes under the brand name of Ozempic if you're using up to 2.4 mg for the treatment of obesity. So the indication the prescription is for the treatment of obesity. It goes under the brand name of Wigo. And then we also have an oral G LP one receptor agonist, which is a daily uh um daily medication that goes up to 14 mg per day for the treatment of type two diabetes. And this goes under the brand name of Rebels. So over the last couple of years, a lot of us have heard in the main in the media about Ozempic for weight loss. But in reality, they're using Ozempic. It's the indication is for type two diabetes, not for, for obesity. Um And so this is I think very important and why is sema why, how was semaglutide approved for the treatment of obesity? Which is what we will discuss. Uh right now was based on the step trial in the strep trial. As you can see in the uh top left uh panel of the slide, uh the step trial really showed that semaglutide at the dose of 2.4 mg, uh reduce weight loss, body weight by approximately 15% compared to baseline. And uh with a mean difference from placebo of 12.4%. What is particularly important also in the lower panel is that more than 85 85% of patients will lose at least 5% of their body weight and more, almost 70% of patients will lose at least 10% of body weight. So, really remarkable effects with semaglutide. Not only that a couple of months ago at the um at the American Art Association conference, the select trial was published showing that the dose uh the semi glutted dose of 2.4 mg per day. So the FDA approved dose for obesity also reduced cardiovascular events. There was a reduction in the uh primary composite cardiovascular endpoint, uh numerically lower cardiovascular death, uh significantly lower composite heart failure endpoint, which was a composite of cardiovascular death and heart failure specialization and then a lower risk for all cause mortality. Uh So, really remarkable data, not only on weight loss, but also on cardiovascular events. And importantly, as you can see here in the select trial, there was an early separation of the curves suggesting a weight loss alone is not the main cause for a reduction in cardiovascular events because patients start separate the curves are separating even before weight loss is achieved. Nevertheless, this is for the the first time in history uh where a weight loss medication uh that has an indication for obesity reduces cardiovascular events. So really exciting times. Uh semaglutide was also tested in patients with HEF path or failure with preserved ejection fraction. Also data published last year in the neural medicine showing that uh semaglutide induces about a 13% of weight loss in patients with HEF path. And this is associated with the significant improvement in the uh Kansas City Cardiomyopathy questionnaire, which is a KCCQ, which is a measure of quality allows to measure quality of life in this population. And uh in this patients also, this uh weight loss was asso greater weight loss was associated with greater improvements in the KCCQ. And greater weight loss was associated with a greater reduction in uh c reactive protein. So, a measure of inflammation with approximately every 10% reduction in body weight associated with almost a 30%. Uh in CRP. The third medication that is approved for the treatment of obesity and this belongs to the uh G LP one receptor agonist family is tide. Uh Ter ZPA is a dual uh G IP G LP one receptor agonist is also weekly and it's present in two different formulation. Uh they're both up to 50 mg. So it's really the same active ingredient, the same dose except different indication uh for the treatment of diabetes. Ter ZPA goes under the name of Munro 43 of obesity. This was just approved a few weeks ago. Uh The zide goes under the name of Z bound. Uh and this was based on the result of the sermon one trial showing that the zat is even more powerful effect than uh semaglutide with 21% of weight loss of one year. So we're really talking about remarkable effect on body weight with the difference between placebo of approximately 18%. So really uh uh uh important effects when you look at the prevalence of patients that achieve uh uh a magnitude of weight loss of more than 5% on the right panel here, you can see that uh more than 90% of patients achieve more than 5% of body weight with the uh um 15 mg of their zip T but more than 80% achieve more than 10% of body weight of one year. So remember that 10% is really that uh magic number that is associated with lower cardiovascular events and 80 more than 80% of patients will achieve that number in uh with their zip. And so compared to where we were in 2018, where we wrote this piece with Dave, uh we now have some updates. Uh Lord King is no longer available. This was because in the Camellia Timi study, Lord King was associated with the greater risk for cancer. And we now have two new agents semaglutide under the brand name of Wigo and Zepa under the name of the bound. And uh here we uh I just included some of the um basic information on how to prescribe it for semaglutide. Uh There is an initial injection of 0.25 mg once weekly for for weeks. And then uh the aging can be increased until 2.4 mg is reached. And remember the advantage now of these agents is that there are prefilled syringes. Uh The patient doesn't have to manually dose their syringes, they're prefilled and there's no adjustment for renal or hepatic function and then through zip aide or Z bound. Um as uh the initial um injection is a 2.5 mg once weekly for four weeks and then increasing 2.5 mg increments once weekly. And the maintenance doses are dosages are 5, 10 and 15 mg uh once weekly. And also it's uh it has prefilled syringes which is uh definitely very convenient for for patients uh for semaglutide, we have cardiovascular benefit. In select for obesity, we have cardiovascular benefit for the uh diabetes formulation in sustained six with semaglutide 0.5 to 1 mg and in uh with the oral with pioneer six. And then for teret, we only have really cardiovascular safety study ongoing, which is the surpass cardiovascular outcome trial where TER ZPA is being compared with dulaglutide, which goes under the name of Trulicity. Uh And now for the last few minutes, I wanted to show you uh a new kid on the block. This is a re a tru tide. This is a tri triple G IP G LP one Glucagon receptor agonist. This was also just published a few months ago in the New England Journal of Medicine and the effects are even more powerful than the zat. Uh We have a weight loss of uh 24% on average with the higher dose of retta tru tide. Uh So extremely impressive data and what really shocks me every time I see this data is that 100% of patients with the higher doses of retta ru tide will lose at least 5% of body weight. So there's really no, there are no known responders to to these agents at the higher doses with regards to a 5% of body weight. When uh uh a sub analysis of male and female works conducted in this study, this was a phase two trial, a female lost even more weight than males. Uh at the higher dose of a tattoo tide of 12 mg. Uh women lost on average 28% of body weight. So you have a even you can have in some patients an even greater uh weight loss uh than you would expect from baseline. Today, we only discuss semaglutide, lera glut through ZPA tide and retta tru tide. But there are so many other agents. Now in the pipeline, clinical trials are ongoing with the um also with oral G LP one receptor agonists as well as there is an interest also in amylin receptor agonist and combine and combination of Amylin receptor agonist with G LP one receptor agonist. So really exciting time for the field of obesity um that I think we uh really uh will it change? I think the way we treat our patients. Now, a question that we often get asked is, are these agents curing obesity? So what happens when these agents are stopped? Uh does the weight loss continue or is there a way to regain and in both the step trial and surmount trial with, uh, step one with the semaglutide and surmount trial with the zide. The studies were done. And unfortunately, what you see is that, uh, when the medication semaglutide is interrupted, weight gain occurs, weight regain occurs. And so these are chronic treatments as a treatment for hypertension for this lipidemia or diabetes, uh, when medications are stopped weight regain, uh, is present. This is similar data also with their Zaide, uh patients were randomized to the ZEPPA for 36 weeks. Uh And then after 36 weeks, uh they were again randomized to either placebo and their zat. And when you can see that the patient on the placebo uh on the top, right, they regained, they eventually regained weight. So these are chronic treatments and then the last couple of minutes I wanted to spend on population that we might have to be a little more careful about using these agents. Uh There's been uh uh such a big uh advertisement from the media also that people think that we should use these agents in every patients that we, that we can. That with obesity. In reality, the safety data in patients with advanced heart failure are not as good as we think. And so definitely the recommendation is to use as much as possible in patients with obesity. There are data also in patients with half path. But in patients, we have R and advanced heart failure the data are just not as strong I would say. And this comes uh from two main clinical trials, the PHI trial published in 2016 in Jama showing that uh Leo Glu Tide was associated with the greater uh um time to death or hospitalization for heart failure. And this did not reach statistical significance. And then when they looked at patients with and without diabetes on the uh bottom left here, you can see that in patients with diabetes, uh there was a uh you know, a numerically higher uh risk of uh the death of rehospitalization for heart failure in patients with the wire glut. And then in the live trial, which was also a half ref study, uh was a small study showing that there were no effects of the glut on LVEF. However, they were uh numerically higher and significantly higher uh serious adverse events, particularly greater risk for arrhythmias uh in uh in this population. So I think the advanced are failure paid population is something population. We need to be a little more cautious in using these agents. Um One of the potential reasons for this to happen is that GRP one receptor agonist consistently increase heart rate by 3 to 5 bits per minute. Uh in uh pretty much all populations that have been tested in. Uh And so we know that in patients with heart failure, we reduce ejection fraction. We try to keep heart rate actually as low as possible. Uh And so this might be one of the reason why in this population, um there is an increased risk of uh uh arrhythmia. Uh This was uh a recent uh document published by some heart failure expert really all around the world really recommending to avoid GRP one receptor agonist in patients with HEF ref uh while they should be using patients with HEP to reduce aosa cardiovascular disease as well as to improve quality of life as shown in the he uh in the step he PF trial. And so, in conclusion, uh obesity remains highly prevalent in the United States. Uh Lifestyle intervention is effective in reducing body weight. Uh However, long term sustainability remains a major barrier and a barrier. And so that's where I think pharmacologic therapies uh comes very handy and important and should be used in our patients. Exercise, improve exercise capacity and should be recommended even in absence of weight loss. So please uh if you see a patient that is not losing weight but feeling better because they're exercising, they should continue exercise training. Uh G LP one receptor agonists are powerful weight loss agents that have been recently approved by the FDA. And in addition to weight loss, uh they present cardiovascular benefit. Uh chronic treatment is necessary. In fact, we regain after interruption occurs in most patients. We have had patients who did not regain the weight, but those are really the patients who are extremely motivated. They completely change their lifestyle. So the majority of patients will need to be on these agents for uh chronically. And then, and then finally, while in HEF path GRP one receptor agonist is associated with improved quality of life. Uh I think caution should be placed in using these agents in fr particularly in the more advanced uh uh he uh patients. So thank you very much and uh these are just thank thanking all our friends and collaborators and uh I'm happy to take any questions.
