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Welcome back to the Evidence Pulse Translating obesity Science. My name is Doctor Patrice Forner. I'm an endocrinologist and today I'll be presenting the highlights from ADA 2026. This program is intended for primary care providers who provide care for patients with obesity and the learning objectives are outlined on this slide. These are my disclosures. This program's been accredited for physicians, pharmacists and nurses, and you can claim your credits at the end of the presentation. Now just to note that this presentation will discuss agents that are not currently FDA or TGA approved, so please keep that in mind, we are discussing the results of clinical trials and not necessarily what we do in clinical practice. So let's get into the updates from ADA. There's been a lot of discussion lately about retatratide, now this is Triumph one. It evaluated retatratide, which is a triple agonist, so GIP, GLP-1, and glucagon receptor agonist in adults with obesity. Uh, this was a randomized double-blind phase 3 trial comparing weekly retatratide with placebo. Now the study enrolled 2,339 adults with a BMI of greater than 30 or greater than 27 with at least one obesity-related complication, which is our standard obesity enrollment, uh, and the primary endpoint was the percent change in weight at week 80 with retatratide 9 or 12 mg. The secondary end points included percent change in weight with the retatratide 4 mg and the proportion of participants achieving weight reduction thresholds. The graph shows observed percent weight change over 80 weeks across treatment groups, and at 80 weeks, retatratide produced unprecedented weight loss in a dose-dependent fashion. Under the efficacy estimate, participants achieved mean weight reductions of 19, 25.9, and 28.3 with the 49 and 12 mg doses respectively. And even using the more conservative treatment regimen estimates, so that includes the effect of treatment discontinuation, the average weight loss remained 17.6, 23.7, and 25%. Now these are among the largest weight loss effects ever reported in a phase 3 obesity pharmacotherapy trial. Now retatratide produced substantial reductions in weight but also clinically meaningful improvements in health outcomes. You can see that a higher proportion of participants achieved clinically relevant weight loss thresholds at week 80, so that's in the graph on the left, and more participants receiving retatratide achieved BMI targets compared with placebo and that's on the right. But we know that it's not just about weight loss, so retatratide produced significantly greater improvements in BP, lipids, high sensitivity CRP and reversion to normal glycemia versus placebo, and significant improvements were also seen in physical function and psychosocial quality of life measures. Moving on to evodatide, so that's a GLP-1 and glucagon agonist, so this is synchronized one, it evaluated savodatide in people with obesity without diabetes, and you can clearly see that 6 mg of savoditide in the purple reduced body weight by 16.6% at week 76. 38% of participants achieved at least 20% weight loss, and this is efficacy estimate data. Adverse events were reported in 96.9% of the savodatide treated participants, but it also occurred in 86% of those in the placebo group. Gastrointestinal adverse events leading to discontinuation occurred in 19% in the savoditide group and 2.9% in placebo, and serious adverse events occurred in 8.3% in the savoditide group and 6.2 in placebo. Savoditide at 6 mg reduced waist circumference by 14.6 centimeters at week 76, and on the right you can see MRI analysis demonstrated improvements in body composition and liver fat content, and importantly body weight reduction was driven predominantly by loss of adipose tissue. Savoditide demonstrated a safety profile that was consistent with other GLP-1 receptor agonist based therapies and no safety findings were attributed to glucagon receptor agonism. The reduction in visceral and liver fat highlight the broader metabolic effects of treatment with savoditide. Petralintide is a human amylin analog and it's being developed for long-term obesity management, and it's mechanism of action is distinct from existing obesity treatments and may support improved tolerability and sustained use. Supreme One was a phase 2 randomized double-blind multinational dose finding trial. Adults received once weekly subcutaneous petrolintide or placebo. Doses were escalated for up to 16 weeks before continuing at a maintenance dose through to week 42. This graph shows estimated changes in body weight at week 42 across treatment groups, and you can see the petrolintide demonstrated statistically significant and clinically meaningful weight reduction across all doses from week 28 through week 42. The rates of GI adverse events and serious adverse events were generally similar to placebo, and most of the GI adverse events were mild or moderate in severity. Petrolintide was considered well tolerated across dose groups and the investigators concluded that perolintide has the potential to be an effective and well tolerated obesity treatment and phase 3 studies are planned. I'm sure we've all had patients who haven't responded to treatment, so this study sought to address the challenge of identifying non-responders early in obesity management. The investigators compared baseline profiling with early weight loss markers as predictors of outcomes. So this is a retrospective cohort analysis of 8450 adults with obesity, prescribed a Mediterranean diet and they modeled them for 24 months. They used models comparing baseline characteristics with one month weight loss velocity. And a clinical decision rule was validated in an independent cohort of 128 participants. They set a weight loss velocity threshold of 1.5% per month to distinguish high risk non-responders from responders. They found that baseline profiling showed poor predictive accuracy, however, the one month weight loss velocity achieved high accuracy. Participants with less than 1.5% weight loss per month in the early treatment period were classified as high risk non-responders, and this group benefited significantly from rescue treatment. So they proposed a protocol, which is on the right there, that recommends calculating monthly weight loss velocity at the first follow-up visit. Individuals below that threshold may be considered for escalation to interventions. Such as a very low calorie ketogenic diet or incretin-based pharmacotherapy, and the investigators concluded that baseline profiles are insufficient for predicting dietary success, but physiological response at one month effectively predicted longer term outcomes. They suggest that dynamic monitoring may actually help to identify patients who would benefit from earlier treatment escalation. Now what does this mean for primary care? We have emerging therapies with distinct mechanisms that broaden obesity treatment possibilities. So in Triumph One and Synchronize One, retatratide and savodatide delivered substantial weight reduction, and civodatide reduced liver fat content by up to 63%, so future therapeutic options may change the way we treat our patients. In Supreme one, petrolintide achieved clinically meaningful weight loss and low discontinuation rates and a GI tolerability profile that was again similar to placebo. So these agents again may change the way we treat our patients. We can use early response to guide reassessment and escalation of therapy. Weight loss velocity can predict long-term response, so we need to monitor treatment response and modify plans early. And finally, we need to assess outcomes beyond weight reduction alone. So Triumph One and Synchronize One demonstrated improvements in cardio metabolic measures, body composition and patient reported outcomes, and we should be using these measures to evaluate treatment success. This brings me to our first poll. Based on the Congress data presented, which finding is most likely to change your current and future approach to obesity management in primary care? Is it A the magnitude of weight reduction achieved with emerging therapies, B, the potential to improve obesity-related complications including cardio metabolic risk and liver fat? C, the potential to use early treatment response to guide reassessment and escalation decisions, or D, the growing emphasis on assessing treatment success using outcomes beyond weight loss alone. Now meet Christopher. Christopher's a 47-year-old architect. He has a BMI of 32 and a waist circumference of 108 centimeters. He has pre-diabetes with a HbA1c of 6%, and he has hypertension that's currently controlled with medication. He does have a family history of type 2 diabetes and he has no established cardiovascular disease. He's been following a lifestyle program for weight loss with good adherence and has lost 2.2% of body weight in two months, and he's concerned about his future risk of type two.