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How Retatrutide Compares to Semaglutide and Tirzepatide

How Retatrutide Compares to Semaglutide and Tirzepatide

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 Welcome to The Peptide Podcast. In this episode, we’re unpacking the latest on retatrutide and how it measures up against semaglutide and tirzepatide. If you want to support what we do, head over to our Partners Page. 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 lean muscle mass 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 improves insulin sensitivity. 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? Semaglutide 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 Phase 2 obesity program, 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 STEP-1 trial. 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 SURMOUNT-1 trial, 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 ...
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