Hello, I'm Jamie Almendoz, Medical Director for the UT Southwestern Weight Wellness Program in Dallas, and today I'm going to be speaking to you about advanced therapies for obesity beyond lifestyle. Our learning objectives will include outlining the effectiveness of bariatric surgery for managing obesity and cardiometabolic complications, to review the indications, mechanisms, and effectiveness of approved anti-obesity medications, and to discuss treatment of obesity as a chronic disease with potential combinations of lifestyle, medication, and procedures. Here are the criteria for considering bariatric surgery based on the 1991 NIH consensus statement. This suggests that people with a BMI of 35 to 39 with one-weight-related comorbidities such as type 2 diabetes, hypertension, or hyperlipidemia should be considered for bariatric surgery, or those with a BMI of 40 or greater without necessarily having a comorbidity that they should be considered for having bariatric surgery. In spite of the rising prevalence of obesity and complications related to excess adiposity, bariatric surgery is performed in less than 1% of eligible people within the U.S. Due to advances in techniques and training for bariatric surgery, rates of mortality and complications have decreased dramatically over the last several decades. Currently, we often use the analogy that having a bariatric surgery like a sleeve gastrectomy has similar or less risk than having another minor gastrointestinal procedure such as cholecystectomy. In 2019, if you add up the primary revision and endobariatric interventions for treating obesity, we can see that there's close to a quarter million procedures performed annually in the U.S. to treat obesity. In response to the growing body of evidence for the role of metabolic and bariatric surgery in treating obesity and its complications, in late 2022, the American Society for Metabolic and Bariatric Surgery and the International Federation for the Surgery of Obesity and Metabolic Disorders proposed updated guidelines as an adjunct to the 1991 NIH consensus statement. They recommend that bariatric surgery be recommended for those with a BMI of 35 or greater regardless of comorbidities. They also suggest that bariatric surgery be considered for those with a BMI of 30 to 35 with comorbidities, that bariatric surgery should be offered to Asians with a BMI of greater than 27.5, and that BMI thresholds for diagnosing obesity in those of Asian descent be adjusted to those with a BMI of 25 or greater. Bariatric surgery is one of the most effective tools for treating severe obesity and its complications. The magnitude of weight reduction as a result of surgery varies by procedure. If we start on the left-hand side of the slide, we can see that the average weight reduction expected with adjustable gastric banding is approximately 15%. Sleeve gastrectomy is the number one performed procedure in North America and can be expected to result in average weight loss of approximately 21%. Rheumatoid gastric bypass is the second most commonly performed procedure in North America and results in approximately 25% total body weight reduction. Bibipancreatic diversion with juvenile switch is less commonly performed and can be expected to result in approximately 34% body weight reduction. Weight loss after bariatric surgery varies by individual. In the left-hand figure on this slide, we can see that the amount of weight lost as expressed by percent excess body weight loss varies and follows a normal distribution. In the green box, we can see excess body weight loss between 50 and 100%, which in older surgical literature demonstrates a successful surgery. However, we can see that there are a significant proportion of people in the study that lay outside of this green box. On the right-hand side of the slide, we see data from the Swedish obesity study, which follows people out over approximately 20 years. We can see that within the first year after bariatric surgery, there's often rapid weight loss, which is followed by a nadir and then a plateau in body weight with gradual weight recurrence over the next 10 years, which then is followed by what appears to be a period of stabilization with regards to body weight recurrence. Weight loss varies between individuals for any given intervention, but an important question to ask is how much weight does somebody on average need to lose in order to see an improvement in the disease state or to try to induce remission? If we look at data from the LOOKAHEAD trial, where people with type 2 diabetes were randomized to either intensive lifestyle or standard of care, those in the intensive lifestyle group experienced an 8.6% non-sustained body weight reduction at one year. If we look at rates of remission in type 2 diabetes in those in the intensive lifestyle intervention versus standard of care, we can see that at one year, rates of remission for those who lost weight were approximately 11.5% versus 2% in the standard of care group. If we follow that out over four years, those in the intensive lifestyle intervention experienced remission rates of 7.3% relative to 2% in the standard of care group. When they looked overall over 10 years, there was no reduction in cardiovascular death or a composite of cardiovascular endpoints. However, in a post-hoc analysis, participants who lost more than 10% of their body weight experienced a 20% lower composite cardiovascular endpoint and also a 20% lower cardiovascular mortality. So the question is not, is weight loss important, but how can we get our patients to achieve clinically meaningful weight loss with interventions? When we look at diabetes outcomes as a result of the bariatric procedures that we discussed earlier, we can see on the right-hand figure that there are significant improvements in glycated hemoglobin at five years after bariatric surgery, with improvements ranging from between 2% and 2.5% depending on the procedure used, relative to 1.6% or 0.3% with medical therapy alone. If we look at the left-hand figure, we can see diabetes remission rates at five years after bariatric surgery. And these range from about 23% with sleeve gastrectomy, 31% to 37% with rheumatoid gastric bypass, and a 63% rate of remission for those who've undergone biopancreatic diversion. When we follow up people with a history of type 2 diabetes after bariatric surgery even further, we can see that rates of remission at 10 years range between 50% for those who underwent biopancreatic diversion to 25% for those who underwent rheumatoid gastric bypass. In the left-hand figure, we can see the changes in hemoglobin A1c, which started off somewhere between 8% to 9%, and we can see a gradual increase in hemoglobin A1c. But for all the individuals who experienced relapse or recurrence in their type 2 diabetes, we can see that they have very good glycemic control with a mean hemoglobin A1c of about 6.7%. And so while diabetes may not be put into remission forever, diabetes appears to be easier to control. If we look at the figure on the right-hand side of the slide, these are showing the diabetes-related complications at 10 years. The left-hand side of the figure shows those who were in the medical therapy group, and we can see rates of microvascular complications of about 61%, and macrovascular complications about 11%. This contrasts quite sharply to those who underwent bariatric surgery, where we can see microvascular complications of about 5%, and very few macrovascular events over the 10-year period. From several studies, we can identify predictors of diabetes remission after bariatric surgery, and these include shorter duration of diabetes, good preoperative glycemic control, not being on insulin, younger age, smaller waist circumference, and the presence of fatty liver disease. If we look at the figure to the left of the slide, we can see data from the Swedish Obesity Study looking at the rates of diabetes remission stratified by follow-up time in years and also further substratified by the duration of diabetes at the time of surgery. We can see that for those who had diabetes for less than one year at the time of surgery, their rates of diabetes remission were over 90%, relative to rates of remission less than 40% in those who had diabetes for four years or more. This suggests that doing bariatric surgery earlier in the course of diabetes will yield a higher likelihood of remission. Unfortunately, this is the opposite of what occurs typically in clinical practice, where people often wait until advanced diabetes, requirement for insulin, or other complications have developed before considering bariatric surgery. The magnitude of weight reduction after bariatric surgery is also an important predictor of the likelihood of remission of type 2 diabetes. These data from this study would suggest that those who lose 20% or more of their body weight have the highest likelihood of experiencing remission in their type 2 diabetes. In recognition of the benefits of bariatric surgery for people with type 2 diabetes, the ACE Clinical Practice Guideline on Diabetes Maltose Comprehensive Care from 2022 proposed that persons with a BMI of 35 or greater, with one or more severe obesity-related complications such as type 2 diabetes, should be considered for a bariatric procedure. Moreover, persons with a BMI of 30 to 34.9 and type 2 diabetes with inadequate glycemic control should also be considered for bariatric procedure because of the benefits of glycemic reduction and complications related to bariatric surgery in people with diabetes. In this section, we're going to shift focus from type 2 diabetes to the impact of weight loss on helping people with non-alcoholic fatty liver disease. The data on the left-hand side of the slide are from a lifestyle intervention study where weight loss was attempted to help to improve fatty liver. The average weight reduction in the study was quite disappointing, with weight loss of about 3.8%, with less than a third of people losing 5% of their body weight or more. However, if we look to the right-hand side of the slide and stratify the results of the remission in stat of hepatitis by magnitude of weight reduction, we can see that those who lost less than 5% of their body weight experienced only a 10% remission in stat of hepatitis. However, for those who lost greater than 10% of their body weight, 90% of them experienced remission in their stat of hepatitis. This would suggest that shooting for a body weight reduction of 10% or greater for people with fatty liver disease will yield the best clinical outcomes. For those who experienced more significant weight loss through bariatric surgery, there can be significant reductions in non-alcoholic stat of hepatitis. These are data from 180 patients with biopsy proven NASH who underwent bariatric surgery. We can see that on the left-hand side that those who decreased their body mass index by 10 points or greater experienced more than 90% remission in non-alcoholic stat of hepatitis according to biopsy. We can also see significant improvements in fibrosis on the right-hand side of the slide. Data from the Splendor study would suggest that people with NASH who undergo bariatric surgery relative to those who don't undergo bariatric surgery experience an 88% reduction in a composite of adverse liver outcomes that include clinical or histological cirrhosis, development of hepatocellular carcinoma, liver transplantation, or liver-related mortality. The recently published BRAVE study is a randomized controlled trial comparing lifestyle intervention, including medications, to bariatric surgery for treating non-alcoholic stat of hepatitis. We can see that in the middle panel that those who underwent room-wide gastric bypass and sleeve gastrectomy experienced NASH resolution at rates of about 56% to 57% relative to 16% in those in the medical therapy group. If we look at the far right-hand panel, we can see that improvements in at least one stage of fibrosis without worsening of NASH occurred in over a third of people with room-wide gastric bypass or sleeve gastrectomy and in under a quarter of people in the lifestyle modification group. What is noteworthy about this study is that the more severe the NASH and liver fibrosis, the higher proportion of patients who experienced NASH resolution as a result of bariatric surgery. In recognition of the clinical benefits of bariatric surgery for people with NAFLD, the 2022 ACE Clinical Practice Guideline, published in conjunction with the American Association for the Study of Liver Diseases, suggests bariatric surgery for those at all risk levels of fibrosis in those with non-alcoholic fatty liver disease. We can see that for those at the highest risk that they recommend stronger consideration for bariatric surgery to treat steatohepatitis and fibrosis, and the recommendation is also to avoid bariatric surgery in those with decompensated cirrhosis. For all people, they do recommend behavioral modification, counseling, and also consideration for anti-obesity medications with a view to using incretin-based therapies for those with NASH. In this section, we're going to shift focus to reduction in cardiovascular outcomes for people with a history of bariatric surgery. In this slide, we can see the data for all-cause mortality on the left for people with type 2 diabetes who undergo bariatric surgery, and we can see significant reductions in mortality that start to separate out about one year after surgery. On the right-hand side, we can see approximately 40% reduction in composite MACE cardiovascular outcomes, including coronary artery events, cerebrovascular events, heart failure, atrial fibrillation, nephropathy, and all-cause mortality, which separates out, again, almost a year after surgery, suggesting significant improvements in cardiovascular risk for people with type 2 diabetes who undergo bariatric surgery. While we don't have randomized controlled prospective data on which surgery is best for cardiovascular risk reduction in people with type 2 diabetes, these data would suggest that Roux-en-Y gastric bypass, which is the darker of the two solid lines here in the figure, that is associated with greater weight reduction, better glycemic control, and also a lower risk of composite cardiovascular endpoints and nephropathy compared with those who undergo sleeve gastrectomy. Even for people with a history of cardiovascular disease, there can be significant improvements in cardiovascular risk and reductions in cardiovascular events after bariatric surgery. These data from a population-based retrospective cohort study show a 50% reduction in all-cause mortality, 65% reduction in cardiovascular mortality, and also a 63% reduction in heart failure hospitalization for those with a history of cardiovascular disease who undergo bariatric surgery relative to those who don't. Shifting focus from cardiovascular disease to cancer risk, there are data that suggest that people with obesity and type 2 diabetes who undergo bariatric surgery decrease their risk of cancer by approximately 40%. When evaluating larger cohorts who don't necessarily have type 2 diabetes, we can see that bariatric surgery is associated with about a 32% reduction in obesity-associated cancer cases relative to those who don't undergo bariatric surgery. There's a reduction in total cancer cases, so not necessarily obesity-associated cancer risk of about 17%, and what's striking is that there's a reduction in cancer-related mortality of about 50% at 10 years. From the same study, this slide nicely demonstrates the dose-response relationship between body weight reduction and decreased risk of obesity-associated cancers for people after bariatric surgery, with the greatest reduction in cancer risk seen in those who lost 39% or greater of their body weight. Long-term data from the Swedish Obesity Study would suggest that bariatric surgery is associated with a significant reduction in overall mortality, much of which is driven by a reduction in fatal cardiovascular events, which is seen in the right-hand figure. Data from the Swedish Obesity Study suggests that bariatric surgery increases life expectancy. When compared to non-surgical controls with obesity, those who undergo bariatric surgery increase life expectancy by about three years. However, when compared to a non-surgical control group without a history of obesity, those with a history of bariatric surgery still live five and a half years less. So what this means is, while bariatric surgery increases life expectancy for people with obesity, it doesn't normalize it to the same level as those without a history of obesity. In this segment, we're going to shift focus to using anti-obesity medications to treat obesity, and these are indicated for people with a BMI of 30 or more, or those with a BMI of 27 to 30 with one or more weight-related comorbidities. Guidelines suggest that medications for treating obesity should be prescribed as adjuncts for lifestyle interventions, and this diagram on the right suggests some important considerations when selecting anti-obesity medication therapies. These include contraindications and cautions as to why a specific agent should not be used, comorbidities, so for example, if an agent could help a comorbidity while also helping to reduce weight, such as a GLP-1 agent as someone with a history of type 2 diabetes, cues where a patient may describe appetite control symptoms or preferences on a mode of delivery, combinations, using combined therapies for treating obesity the way we would other complex diseases such as hypertension, and lastly, cost and coverage considerations, which can be problematic given the challenges with coverage of anti-obesity medications in the U.S. It's important to note that in spite of advances in anti-obesity medication therapies, medications are still prescribed to less than 3% of eligible people in the U.S. The first agent we're going to discuss today, which is GELSSIS-100, a cellulose citric acid superabsorbent hydrogel, is technically not an anti-obesity medication and is a medical device which absorbs more than 100 times its weight in water when ingested. It's taken before meals with a glass of water and occupies about a quarter of the average stomach volume, simulating about a cup and a half of cooked vegetables. As you can imagine, side effects are typically gastrointestinal in nature, and because this is technically a medical device and not an anti-obesity medication, it can be prescribed in people with a BMI of between 25 and 40. What's interesting to note is that with an average weight loss of 6.4% in the clinical trials, greater weight reduction was seen in people with a history of hyperglycemia. Within the chart, we can also see 5% weight loss outcomes and 10% or greater weight loss outcomes occurring in over a quarter of people treated with GELSIS-100. The average cost per month, this is list price, is approximately $100 for therapy. Oralistat is a gastrointestinal lipase inhibitor that's available in two different strengths, 60 milligrams over the counter or 120 milligrams prescription strength. Oralistat is taken two or three times daily before meals and results in malabsorption of about 30% of dietary fat. As a result of that, you can imagine that side effects are primarily gastrointestinal in nature and consist of things like diarrhea, malabsorption, and there's also an increased risk of nephrolithiasis because of overabsorption of oxalate due to complexing of calcium with fatty acids. There are rare reports of severe liver injury in the literature and the cost ranges between $40 for the over-the-counter strength to about $550 for the prescription strength. Average weight reduction is about 8.8% relative to 5.8% in placebo with close to 39% of people experiencing 10% or greater weight loss. Now while these numbers look quite impressive, in clinical practice it can sometimes be challenging to get patients to take this medication consistently, especially if they experience significant side effects. Naltrexone bupropion extended release is a combination of a frequently used antidepressant medication with a new opioid receptor antagonist. These are given in fixed dose sustained release pills, each containing naltrexone 8 milligrams and bupropion 19 milligrams. The dose is titrated gradually over the course of three weeks to a target of two tablets twice daily. Side effects and considerations for this medication include a combination of factors related to bupropion that can be insomnia, mood changes, tremor or irritability. From the naltrexone component there can be issues with gastrointestinal side effects and also concerns about opioid effectiveness, so making sure that we don't use this in people who need opioids for chronic pain management or those with planned elective procedures upcoming. From a special consideration perspective, bupropion can lower seizure threshold and should not be prescribed to people with a history of seizure disorder. The average list price for this medication is about $230 or so and this does not represent what would be covered by insurance if a patient had coverage for anti-obesity medications. Average weight reduction with this medication is about 6.1% relative to 1.3% with placebo, with approximately 21% of people achieving 10% or greater weight loss with treatment. Denatamine is a stimulant type anti-obesity medication which blocks uptake and increases release of norepinephrine. It's available in multiple doses ranging from 8 milligrams to 37.5 milligrams which can be taken in divided doses throughout the course of the day. As a stimulant, the primary side effects include things such as anxiety, insomnia, tremor, dry mouth, and palpitations. It should be used with caution or not used at all in people with a history of atherosclerotic cardiovascular disease, atrial fibrillation, and uncontrolled hypertension. It needs to be used in caution in people who are currently using monoamine oxidase inhibitors or tricyclic antidepressants for a range of indications. Caution should be used in people with a history of substance abuse or misuse such as methamphetamine and I put hyperthyroidism here because unfortunately it is a somewhat common practice at certain weight loss or weight loss clinics to co-prescribe desiccated thyroid products with fentanyl in an attempt to help people overcome a slow metabolism. The average cost per month is between $10 and $45 per month which is what makes this medication so attractive for prescribing by many providers given the challenges with approval for other more expensive anti-obesity medications. The average weight reduction in 26 weeks is about 6% relative to 1.7% placebo with approximately 1 in 5 people achieving 10% or greater body weight reduction. Centramine to Pyramid Extended Release is more potent for weight reduction than centramine alone. The addition of to Pyramid adds some additional complexity as it is a GABA receptor agonist and also a carbonic anhydrase inhibitor. It has potential teratogenicity and should be used in caution with in women with reproductive potential who should be using ideally two forms of contraception. There's a risk of cleft palate with this medication. There's also dose dependent impacts on paresthesia, word finding, difficulty, memory and fatigue. As it is a carbonic anhydrase inhibitor it does increase the risk of calcium phosphate kidney stones. The average cost per month is about $200 without insurance. Average weight reduction is almost 10% with centramine to Pyramid relative to placebo 1.2% with close to half of people treated with the highest dose which is 15 milligrams of centramine and 92 milligrams to Pyramid achieving 10% or greater body weight reduction. The Ligatide 3 milligrams was the first GLP-1 receptor agonist approved for treating obesity. It's a daily injection and it started at 0.6 milligrams once daily and gradually titrated as tolerated to a target dose of 3 milligrams once daily. The side effects are primarily gastrointestinal in nature, primarily nausea, sometimes constipation or diarrhea. There's a risk of pancreatitis which was seen in 0.2% of study participants and those who were treated with loratatide which is similar to those treated with other GLP-1 agents for obesity. There's a warning with regards to thyroid c-cell tumors and those who are at risk for medullary thyroid cancer who have a history of multiple endocrine neoplasia type 2b as in pre-clinical studies when loratatide was given in high doses to rodents there was an increase in thyroid c-cell tumors because rodent thyroid c-cells contain receptors for GLP-1 whereas there is very little expression of GLP-1 receptors in human thyroid tissue. Weight loss seen on average at one year is approximately 8% with loratatide relative to 2.6% with placebo with close to a third of people achieving 10% or more weight loss. The average list price per month without insurance is about $1,200 putting this in a new category in terms of both class of medication but also cost. Beyond reductions in body weight it's also important to note that anti-obesity medications and in particular incretin-based therapies can also decrease body fat in problematic depots such as the visceral or ectopic fat depot. These data demonstrate the benefits of loratatide 3 milligrams daily versus placebo for decreasing visceral fat in people with obesity. So loratatide 2.4 milligrams once weekly is the most recently approved GLP-1 receptor agonist for treating obesity. It's given as a weekly injection started at 0.25 milligrams once weekly and gradually titrated according to patient tolerance to a target dose of 2.4 milligrams once weekly using a single-use pen. As with other GLP-1 agents the side effects are primarily nausea, diarrhea, and constipation. Average weight reduction with somagetide 2.4 milligrams weekly is approximately 14.9% in people without a history of type 2 diabetes relative to 2.4% weight reduction with placebo. Close to 70% of people achieve 10% or greater body weight reduction and almost a third of people experience 20% or greater body weight reduction which is pretty phenomenal for an anti-obesity medication therapy. We don't yet have the results of the select cardiovascular outcomes trial which is an event-driven trial with people at risk for cardiovascular disease involving 17,500 participants. We're hoping to see the results of that later this year. Given that there are currently two GLP-1 receptor agonists approved for treating obesity people will often ask which one is more effective. The step 8 trial which is a direct head-to-head comparison of loraglitide 3 milligrams daily with somagetide 2.4 milligrams weekly for treating obesity answers this question very nicely. We can see the clinically significant weight loss cut points of 10, 15, and 20% along the x-axis here with the proportion of subjects achieving this magnitude of weight reduction and we can see that for 20% weight loss this was achieved in 39% of people treated with somagetide 2.4 milligrams relative to only 6% of people treated with loraglitide 3 milligrams once daily and while these are both effective agent it appears that somagetide 2.4 milligrams weekly is superior to loraglitide for treating obesity. Anti-obesity medications and in particular GLP-1 receptor agonists can also be very effective for treating excess body weight or weight recurrence after bariatric surgery. These data show that people who were treated with anti-obesity medication regimens which contain GLP-1 lost significantly more weight than those who were treated with anti-obesity medication regimens that do not contain a GLP-1 agent. In the last slide we reviewed that anti-obesity medication regimens which contain GLP-1 agents appear to be more effective for treating post-bariatric weight regain. In this recently published paper the authors compared the effectiveness for loraglitide 3 milligrams which is approved for treating obesity relative to somagetide 1 milligram once weekly, a dose which is not current not approved for treating obesity, in terms of effectiveness for treating post-bariatric weight recurrence and found that somagetide 1 milligram appears to be superior to loraglitide 3 milligrams for treating excess body weight or weight recurrence after bariatric surgery. Terzapotite is a new incretin-based therapy which is a combination of a GLP-1 and GIP receptor agonist. It is not currently approved for treating obesity and these are data from the Surmount-1 trial which were published in the middle of 2022 showing the effectiveness of terzapotite at 5, 10, and 15 milligram weekly doses relative to placebo for treating obesity. Similar to other incretin-based therapies, side effects are primarily gastrointestinal in nature including nausea, vomiting, diarrhea, and constipation. What's impressive is the average weight reduction at 72 weeks of treatment with terzapotite was approximately 22.5 percent with the 15 milligram dose and over 56 percent of people achieved 20 percent or more weight reduction with treatment. So what we see here is quite an effective anti-obesity medication therapy with combined agonism on the GLP-1 and GIP receptors and we're looking forward to more advanced therapies and more effective therapies for treating obesity. I alluded to this in the last slide but the future of incretin-based therapies appears to be multi-receptor agonism. On the left-hand panel we can see a combination of two incretin-based therapies, cagrilliontide plus sonaglutide 2.4 and results from a phase 1b trial showing that at approximately 20 weeks combination of sonaglutide 2.4 milligrams with cagrilliontide 2.4 milligrams which is an analogue resulted in approximately 17 percent body weight reduction. A phase 3 clinical trial of a combination of cagrilliontide plus sonaglutide started in the end of 2024. On the right-hand side we can see some phase 1 results from AMG-133 which is a monthly administered combination of a GLP-1 receptor antagonist plus GLP-1 receptor agonist resulting in significant body weight reduction but impressively there appears to be a durability to the weight reduction from this monthly administered therapy. To summarize the section on anti-obesity medications there are several which are approved by the FDA for treating obesity. If we start in the bottom right-hand corner we have oralistat the gastrointestinal lipase inhibitor, gelosis 100 the super absorbent hydrogel, there's phentermine that can be taken alone or in combination with tipyramid which is in fact the most potent or effective oral anti-obesity medication, there's bupropion naltrexone and then loraglutide and sonaglutide the GLP-1 receptor agonist. In the blue box we can see a variety of different medications that are in the pipeline which are under development or waiting submission for approval and in the gray box outside of the scope of today's talk are a variety of medications that are frequently used off-label for treating obesity including metformin, non-loraglutide, sonaglutide, GLP-1 receptor agonist, SGLT2 inhibitors, tipyramid, bupropion and other stimulants. To put the magnitude of weight reduction with anti-obesity medications into perspective what we have here is in the green bar the anticipated weight reduction seen with lifestyle intervention which is about three to seven percent relative to the anticipated weight reduction with bariatric surgery in the order of twenty to thirty-five percent. We can see older oral anti-obesity medications towards the left that include orlistat, naltrexone, bupropion, phentermine and phentermine tipyramid. Within the incretin-based therapies bar we can see sequential advances from loraglutide, sonaglutide and naltrexone which is not yet approved for treating obesity as we are closing the gap between lifestyle modification and bariatric surgery for treating obesity. It's important to note that anti-obesity medications augment the weight loss which is seen with lifestyle modification. In the red line here we can see intensive behavioral therapy or intensive lifestyle modification with an improvement in weight reduction with the addition of loraglutide in the orange line and then when we include multi-component efforts such as mural placements we can see a further reduction in body weight when combining lifestyle modification with anti-obesity medications. What we need to do is start thinking about obesity like other complex diseases such as hypertension with regards to the integration of pharmacotherapy or other intervention with lifestyle modification and the role of chronic therapies. What I mean by this is if we have a patient who is taking for example losartan for treating their blood pressure when they come back to clinic and their blood pressure is well controlled we don't discontinue the losartan because if we do we know the blood pressure will go up. The challenge is that many people once they achieve significant weight loss or achieve their target weight with anti-obesity medications these medications are discontinued with subsequent weight recurrence which results in not just frustration on the part of the patient and healthcare provider but also recurrence in obesity or adiposity related complications including hypertension diabetes and other risks. One of the challenges is that obesity is not being treated as a chronic disease in the U.S. and these data show that the average duration of a prescription for anti-obesity medications is approximately 81 days and the challenge with this is that we know from the data presented earlier in this talk that the maximal weight loss impact of anti-obesity medications is really not seen within 90 days and it's important to note that when we discontinue medications there's often recurrence in body weight. There's a nice demonstration of recurrence in body weight with cessation of therapy. These are data from the step one extension trial where people were treated with somaglutide 2.4 milligrams for 68 weeks and we can see in the left hand panel that once the medication is discontinued at 68 weeks that there is on average a weight recurrence of about two thirds of the weight lost over the prior 68 weeks over the next year and in the right hand panel we can see the weight recurrence stratified by the amount of weight lost with therapy. So what this really shows us quite nicely is that medications for treating obesity are very effective but that weight recurrence occurs once we stop the effective therapy. In summary what we need to do is start treating obesity like the chronic complex disease that it is. This starts when we have an evaluation with a patient with obesity by excluding secondary causes such as medical problems, medications, behavioral challenges and also environmental issues. When possible we should create an integrated weight and complication management program that includes as a foundation recommendations around nutrition, physical activity and behavioral modification. When appropriate depending on the magnitude of weight reduction needed or the present complications pharmacotherapy or bariatric procedures should be considered but it's important to note that this is not a one-directional treatment algorithm and that those who are started on pharmacotherapy or who undergo bariatric procedures should be looped back into the integrated lifestyle program. It's also important to note that those who do not achieve or maintain significant weight reduction with either pharmacotherapy or bariatric procedures can change and then have the contralateral treatment applied. So for example pharmacotherapy after bariatric surgery can be very effective for treating both weight regain and also inadequate or insufficient weight reduction. It's also important to make sure that when people experience weight recurrence that we screen them for recurrence and complications associated with adiposity. In summary with respect to treating obesity with advanced therapies typically lifestyle modification alone is insufficient for a durable weight loss of 10% or greater and unfortunately currently anti-obesity medications and bariatric surgery are underutilized for treating obesity and its complications. Anti-obesity medications should be considered in people who are eligible and newer incredent-based therapies appear to be superior to older anti-obesity medications for treating obesity in those with and without type 2 diabetes. Bariatric surgery is safe and effective for treating obesity, type 2 diabetes, decreasing cardiometabolic disease burden and it also appears to be effective at decreasing risk of some cancers. What we need to do is treat obesity as a chronic disease to improve not just body weight but also clinical outcomes and the quality of life of our patients. Thank you very much.

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