Welcome to The Peptide Podcast. In this episode, we’re unpacking the latest on retatrutide and how it measures up against <a href= "https://pepties.com/differences-between-semaglutide-and-tirzepatide/"> semaglutide and tirzepatide</a>.  If you want to support what we do, head over to our <a href="https://pepties.com/partners/">Partners Page</a>. You'll find some amazing brands we trust—and by checking them out, you're helping us keep the podcast going.  https://pepties.com/partners/ We’ll look closely at what the studies tell us so far — from overall weight loss to reductions in visceral fat and how much <a href= "https://pepties.com/how-wegovy-semaglutide-can-impact-muscle-mass/"> lean muscle mass</a> is preserved. We’ll also talk about where the evidence is solid, where it’s still developing, and why cross-trial comparisons should be made with caution. What is retatrutide? So let’s start with the basics—what is retatrutide? Retatrutide is a new type of weight-loss medication called a triple agonist. That sounds fancy, but what it really means is that it targets three hormone receptors in the gut and pancreas: GLP-1, GIP, and glucagon. Each of these plays a slightly different role in metabolism and appetite regulation. To break it down: GLP-1, which you might already know from drugs like semaglutide, mainly slows digestion, helps you feel full, and <a href= "https://pepties.com/building-an-insulin-sensitive-lifestyle/">improves insulin sensitivity</a>. GIP, which tirzepatide targets along with GLP-1, also helps regulate blood sugar and may improve how the body stores and burns fat. Retatrutide adds glucagon receptor activation on top of that, which seems to further boost fat burning. So how does this compare to semaglutide and tirzepatide? <a href= "https://pepties.com/podcast-episodes/#:~:text=Podcast%2094%3A%20Long%2DTerm%20Health%20Benefits%20of%20Semaglutide%20For%20Weight%20Loss"> Semaglutide</a> is a GLP-1-only drug, so it mainly works by reducing appetite and slowing gastric emptying. Tirzepatide is a dual agonist, hitting GLP-1 and GIP, which gives it a slightly stronger effect on blood sugar control and fat metabolism compared to semaglutide. Retatrutide goes one step further by adding glucagon activity, potentially giving more total fat loss. In other words, you can think of it like a spectrum: semaglutide hits one target, tirzepatide hits two, and retatrutide hits three—each additional receptor seems to enhance metabolic effects and fat loss in clinical trials. That’s why people are excited about retatrutide, though it’s still early, and we’re waiting on larger studies to see exactly how it compares head-to-head with the others. And that’s going to be key, since right now we don’t have direct comparisons to other advanced therapies like semaglutide or tirzepatide in the published Phase 2 data. How does retatrutide compare to semaglutide and tirzepatide? Total body weight loss: Now let’s put these three medications side by side and look at what the trials actually tell us about total body weight loss. Starting with retatrutide: in its <a href= "https://pubmed.ncbi.nlm.nih.gov/40609566/">Phase 2 obesity program</a>, the numbers were unusually large, especially given the relatively short trial window. In the 48-week study, people on the higher doses—8 or 12 milligrams weekly—lost about 22 to 24% of their body weight on average. That’s the result that really made headlines. It’s worth noting that some trials report slightly different averages depending on the group studied—people with obesity but no diabetes versus people with type 2 diabetes—but across the board, that 48-week signal is consistently very strong. For comparison, let’s step back to semaglutide at the 2.4 mg dose, which was tested in the pivotal <a href= "https://www.nejm.org/doi/full/10.1056/NEJMoa2032183">STEP-1 trial</a>. Over 68 weeks, participants lost about 15% of their body weight on average. That was a landmark finding when it was published in the New England Journal of Medicine—it essentially set the modern benchmark for what a GLP-1 monotherapy could do. Then we have tirzepatide, the dual GIP and GLP-1 agonist. The <a href= "https://www.nejm.org/doi/full/10.1056/NEJMoa2206038">SURMOUNT-1 trial</a>, which ran for 72 weeks, showed dose-dependent results: about 15% weight loss at 5 mg, 19.5% at 10 mg, and 20.9% at 15 mg, compared to only around 3% with placebo. Other obesity studies with tirzepatide have backed this up, especially at the higher doses. And in head-to-head comparisons with semaglutide, tirzepatide has consistently come out on top. So if we zoom out: retatrutide’s Phase 2 data suggest the greatest average reductions—over 22%—in less than a year. Tirzepatide follows closely behind with around 21% over 72 weeks. And semaglutide shows very meaningful, but smaller, weight loss of around 15% over a similar time frame. The big caveat here is that these aren’t perfect apples-to-apples comparisons. The trials differed in their length, the types of patients enrolled—some had type 2 diabetes, some did not—their baseline weights, and even the way results were reported. Plus, retatrutide is still in Phase 2 for obesity, whereas semaglutide and tirzepatide already have large Phase 3 programs and real-world data backing them up. Visceral fat reduction: Next, let’s talk about visceral fat reduction—that’s the deep fat that surrounds organs like the liver, pancreas, and intestines. It’s particularly important because high levels of visceral fat are strongly linked to cardiometabolic disease. Starting with retatrutide, one of the <a href= "https://pubmed.ncbi.nlm.nih.gov/40609566/">Phase 2 substudies used DEXA scans</a> to measure body composition in detail. At the higher doses—8 and 12 milligrams per week—participants saw visceral fat drop by about 29 to 31% over 48 weeks. That’s a very large relative reduction in under a year and one of the reasons people are excited about retatrutide’s potential not just for weight loss, but also for improving long-term metabolic health. How does that compare to the other drugs? With semaglutide, we also have DEXA and imaging <a href= "https://pepties.com/why-protein-and-lifting-matter-on-glp-1s/">substudies from the STEP program</a> and follow-up mechanistic work. These consistently show meaningful visceral fat reductions, along with improvements in the ratio of lean to fat mass. The difference is that semaglutide studies typically report VAT changes as “significant and clinically relevant,” but they don’t always publish one clear headline number that’s directly comparable to retatrutide’s ~30%. In other words, semaglutide definitely lowers visceral fat, but depending on the study and population, the exact percentage looks different. For tirzepatide, we also have <a href= "https://pubmed.ncbi.nlm.nih.gov/39996356/">imaging-based data from the SURMOUNT trials</a> and related body-composition studies. These show that the majority of weight lost is fat mass—including a significant portion of visceral fat. Some analyses report reductions on par with what’s seen with GLP-1 therapies, while others suggest tirzepatide may push a bit further. But again, the actual percentages vary depending on whether the study used DEXA, CT, or MRI, and on who was enrolled. The big caveat here is that we don’t yet have a head-to-head imaging study comparing all three drugs in the same population with the same methods. Retatrutide’s ~30% visceral fat drop is certainly eye-catching, but without that kind of standardized comparison, it’s hard to say definitively whether it’s truly better than semaglutide or tirzepatide. Lean muscle mass preservation: Now let’s shift to lean mass preservation, which is just as important as total weight or fat loss. Across all of the modern obesity drug trials, one thing has been consistent: most of the weight people lose is fat, but some lean tissue is lost too. That’s expected whenever you’re in a sustained calorie deficit. The question is how much muscle is preserved, and how the proportions break down. With retatrutide, the DEXA substudy showed something reassuring. Even though people lost a lot of total weight and fat, the proportion of lean mass lost compared to total weight loss was similar to what we see with other therapies. In other words, the drug seems to drive large fat reductions without causing disproportionate muscle loss. Interestingly, the absolute amount of lean tissue lost in kilograms was pretty stable across different doses, even though fat loss varied quite a bit. That suggests the extra weight loss with higher doses is really coming from fat, not muscle. Looking at semaglutide, the STEP trials with DEXA scans reported the same general pattern. People lost more fat than lean mass, and when you adjust for the total weight loss, body composition actually improved. In fact, some analyses showed a slight increase in the percentage of body weight that was lean tissue, even though the absolute lean mass in kilograms went down. So again, it’s not that muscle isn’t affected—it is—but fat loss makes up the majority of the change. For tirzepatide, the SURMOUNT body-composition studies found that about 75% of the weight lost is fat and about 25% is lean mass. That split is very similar to what was seen in the placebo groups, which means the drug isn’t shifting the balance unfavorably. It preferentially reduces fat, while lean mass preservation is in the same ballpark as semaglutide and retatrutide. Now, here’s the important nuance: lean mass on a DEXA scan isn’t just skeletal muscle. It includes water, organ tissue, and other components. So if someone loses 3 or 4 kilograms of “lean mass,” we don’t know how much of that is functional muscle versus water or smaller organ size. That’s why these numbers can be misleading if you take them at face value. And this is where lifestyle comes in. <a href= "https://pepties.com/resistance-training-to-improve-peptide-performance/"> Resistance training</a> and adequate protein intake are critical alongside medication. Lifting weights or doing bodyweight resistance work helps preserve functional muscle, while getting enough <a href= "https://pepties.com/why-protein-and-lifting-matter-on-glp-1s/">protein</a>—typically somewhere in the range of 0.8 to 1 gram per pound per day depending on age and activity—supports muscle repair and maintenance. Every trial we’ve seen shows that the best outcomes, in terms of maintaining strength and function, come from pairing these drugs with exercise and <a href= "https://pepties.com/How-to-Eat-Healthy-While-Taking-Semaglutide/">nutrition</a> strategies. That way, the unavoidable lean mass changes have far less impact on long-term metabolic health and performance. Limitations, biases, and what’s missing (the critical context). <ol> <li dir="ltr" aria-level="1"> No large, peer-reviewed head-to-head trials (yet) comparing retatrutide with semaglutide or tirzepatide for the same endpoints using identical imaging protocols. Most comparisons are cross-trial and therefore imperfect. Retatrutide Phase-2 was often compared to placebo or <a href= "https://trulicity.lilly.com/what-is-trulicity#how-trulicity-works"> dulaglutide</a> (in the T2D DEXA substudy) rather than to semaglutide or tirzepatide. A head-to-head (planned/registered) study vs tirzepatide is listed on ClinicalTrials.gov but results are not published yet. </li> <li dir="ltr" aria-level="1"> Different populations & durations. Some retatrutide data come from cohorts that include people with T2D or NAFLD; semaglutide STEP trials were often in people with obesity (without diabetes) and run longer (68 weeks), while tirzepatide SURMOUNT trials ran to 72 weeks. These differences change the absolute and percent outcomes. </li> <li dir="ltr" aria-level="1"> Funding and reporting bias. Many of the early retatrutide analyses are industry-funded (Eli Lilly), which is standard for drug development, but it requires us to carefully read methods, endpoints, and completeness of reporting. Independent replication and Phase-3 confirmation matter. </li> <li dir="ltr" aria-level="1"> Imaging method variation. VAT reported by DXA vs MRI vs CT are not directly interchangeable. Some trials report VAT area, others percent change; that complicates cross-trial percent comparisons.<a href= "https://pmc.ncbi.nlm.nih.gov/articles/PMC8089287/?utm_source=chatgpt.com"> </a> </li> </ol> Thanks for listening to The Peptide Podcast. If today’s episode resonated, share it with a friend. Until next time, be well, and as always, have a happy, healthy week.

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