The 'Toxic' Peptide That Just Broke Every Obesity Record

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The 'Toxic' Peptide That Just Broke Every Obesity Record

Dr Brad Stanfield 21.04.2026 41 850 просмотров 1 435 лайков

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🩺 Get your personalized health plan: https://drstanfield.com/pages/roadmap 💊 Supplements I Take: https://drstanfield.com/pages/my-supplements 💊MicroVitamin+ (Pro) Powder: https://drstanfield.com/products/microvitamin-plus 💊MicroVitamin Standard Capsules: https://drstanfield.com/products/microvitamin Timestamps: 00:00 Glucagon's Role in Obesity and Diabetes 02:49 The Discovery of GLP-1 and GIP 04:44 Results of the New Retatrutide Trial 06:45 Side Effects of Retatrutide 08:59 The Importance of Protein Intake ✔️ X: https://x.com/BradStanfieldMD ✔️ Patreon: https://www.patreon.com/bradstanfieldmd Here are the links to the research papers referenced in the video: https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average — TRIUMPH-4 press release https://pmc.ncbi.nlm.nih.gov/articles/PMC5805853/ — Glucagon discovery (Peptides 2018) https://journals.lww.com/jodb/fulltext/2023/11001/historical_perspectives_of_glucagon_s_discovery.4.aspx — Glucagon history (JODB 2023) https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.12958 — LY2409021 glucagon antagonist trial https://pmc.ncbi.nlm.nih.gov/articles/PMC4509428/ — GLP-1 receptor agonists review https://www.prnewswire.com/news-releases/novo-nordisk-receives-fda-approval-of-ozempic-semaglutide-injection-for-the-treatment-of-adults-with-type-2-diabetes-300567052.html — Ozempic FDA approval https://www.nejm.org/doi/full/10.1056/NEJMoa2032183 — Semaglutide STEP 1 (NEJM 2021) https://pmc.ncbi.nlm.nih.gov/articles/PMC12507501/ — Tirzepatide dual agonist review https://www.nejm.org/doi/full/10.1056/NEJMoa2206038 — SURMOUNT-1 tirzepatide (NEJM 2022) https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-achieved-157-weight-loss-adults-obesity-or — SURMOUNT-2 press release https://pmc.ncbi.nlm.nih.gov/articles/PMC3609580/ — GLP-1 + glucagon co-infusion https://insights.som.yale.edu/podcasts/health-veritas/ania-jastreboff-treating-obesity-without-shame — Jastreboff Yale podcast https://www.nejm.org/doi/full/10.1056/NEJMoa2301972 — Retatrutide Phase 2 (NEJM 2023) https://www.prnewswire.com/news-releases/lillys-triple-agonist-retatrutide-demonstrated-significant-reductions-in-a1c-and-weight-in-first-phase-3-trial-for-treatment-of-type-2-diabetes-302718589.html — TRANSCEND-T2D-1 press release https://www.reuters.com/business/healthcare-pharmaceuticals/novo-nordisks-obesity-drug-falls-short-against-eli-lillys-copenhagen-trial-2026-02-23/ — Reuters: CagriSema vs Zepbound https://my.clevelandclinic.org/health/symptoms/24989-dysesthesia — Cleveland Clinic: dysesthesia https://www.usatoday.com/story/life/health-wellness/glp-1-cost/88513308007/ — USA Today: GLP-1 drug costs https://www.cbsnews.com/boston/news/blue-cross-blue-shield-massachusetts-weight-loss-glp1/ — BCBS Massachusetts drops GLP-1 coverage https://www.bmj.com/content/392/bmj-2025-085304 — Weight regain after stopping (BMJ 2025) Thumbnail by James Kelly Video edited by Troy Young Script by John Milliken The links above are affiliate links, so I receive a small commission every time you use them to purchase a product. The content contained in this video, and its accompanying description, is not intended to replace viewers’ relationships with their own medical practitioner. Always speak with your doctor regarding the content of this channel, and especially before using any products, services, or devices discussed on this channel.

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Glucagon's Role in Obesity and Diabetes

Patients in a clinical trial are asking to stop their medication, not because of nausea, not because of cost, but because they're losing far too much weight. The average patient in this trial lost 71 lb. Some lost just over 100. 18% of patients on the highest dose, they discontinued partly because they were losing more weight than they had intended. Too effective is now a real clinical problem, but weight loss isn't even the most surprising part of this drug. is how it works because one of the three hormones that this drug activates is a hormone that raises blood sugar levels, increases heart rate, and was literally called the toxic fraction when it was first discovered because it kept killing lab animals. And for 100 years, researchers who touched this hormone, they tried to block it, suppress it, or get rid of it. Then Eli Lilly did the opposite. They turned it on, and the results broke every record in obesity medicine. But there is a catch that the headlines are not mentioning. So to understand why these results are so shocking and how they relate to your health, you need to understand the hormone that made them possible. And to understand that hormone, we have to go back to something unexpected that happened in 1923. Researchers were trying to purify insulin, a brand new miracle drug that was saving diabetic children from death. But every batch that they made, it contained a contaminant, a substance that did the exact opposite of insulin. Instead of lowering blood sugar, it raised it. And instead of helping the lab animals, it made them worse. They called it the toxic fraction, and they spent months trying to get rid of it. And it wasn't properly isolated until 1949 when researchers first encountered this mysterious substance, they named it glucagon from the Greek "lead forth glucose". Its job, as far as anyone could tell at the time, was simple. When blood sugar levels drop too low, glucagon tells the liver to release that stored glucose. It's the emergency backup system, and it's useful when you're starving. It's dangerous when you're not, and that reputation stuck. For decades, glucagon was the hormone that you wanted to suppress. If you had diabetes, glucagon was part of the problem. It was pushing your blood sugar levels too high. If you were obese, glucagon seemed at best and harmful at worst. But in 1957, something strange happened. A researcher named Schulman published a study showing that glucagon reduced appetite and it caused weight loss in humans. But the finding was almost entirely ignored because the logic seemed airtight. A hormone that raises blood sugar levels cannot possibly be useful for combating obesity. End of discussion. By 1960, another researcher named Salter showed that glucagon increased metabolic rate in rodents, but it was also ignored. Multiple pharmaceutical companies over the following decades, they tried building drugs to block glucagon, so glucagon receptor antagonists, and the results, not surprisingly, were disappointing. One trial had to be terminated early because patients' blood pressure rose, signs of fatty liver disease got worse, and patients gained weight. Most concluded that glucagon was a dead end. But in the meantime

The Discovery of GLP-1 and GIP

excitement was building in another corner of diabetes research. So scientists had discovered two other hormones closely linked to blood sugar and metabolism, so GLP-1 and GIP. GLP-1 stimulates insulin release, and it also makes us feel fuller and more satisfied after eating, and it suppresses the appetite. These effects produced powerful weight loss, and it led to the development of semaglutide or Ozempic, which was approved in 2017. Patients on Ozempic, they were losing an incredible 15% of their body weight. Then Eli Lilly added GIP-targeting medications into the mix. So just like GLP-1, GIP, it also stimulates the body to release insulin when we eat. Their drug called tirzepatide pushed weight loss even higher, and in one trial, participants shed an average of 21% of their body weight. But here's the problem. Even with two distinct hormone pathways targeted, patients with type 2 diabetes, they hit a plateau. In the SURMOUNT-2 trial, tirzepatide tested specifically in people with obesity and type 2 diabetes, and the drug reached up to 15. 7% weight loss at the highest dose. It was better than anything that we'd seen before, but for many diabetic patients and morbidly obese patients, it was still not enough. But there was still that third hormone, glucagon. So what had appeared to be a dead end was about to become the new next way forward. So a team of researchers demonstrated something that challenged everything that the field believed about glucagon. They showed that when you infuse glucagon alongside GLP-1, something unexpected happens. The glucagon cranks up the energy expenditure. Your body starts burning more fuel, and the GLP-1 running at the same time, that's the critical point here, blunts the glucose spike that glucagon would normally cause. So that toxic hormone, it wasn't toxic. It was just uncontrolled. If you pair it with the right partner, then it becomes exactly what you want, a metabolic accelerator that burns energy without wrecking your blood sugar. So Eli Lilly

Results of the New Retatrutide Trial

built a drug that turns on all three of these dials at once, so GLP-1, GIP, and glucagon, the hormone that everyone had feared to boost energy expenditure. They called this drug retatrutide. It was the first triple hormone receptor agonist. The phase 2 trial was led by Ania Jastreboff at Yale. So Jastreboff had watched her own father develop diabetes and obesity and the guilt that he carried every time he ate. So she says in her own words, "I never thought it was my father's choice. " She'd spent her career trying to prove that obesity is biology, not just willpower. And now she had 338 patients and a drug that targeted all three hormones at once, and the results were published in the New England Journal of Medicine in 2023, and they were unlike anything that the field had seen. At 48 weeks, patients at the highest dose, they lost an average of 24. 2% of their body weight. But the number that made researchers just stop in their tracks wasn't just the percentage, it was the shape of the curve. So every other obesity drug, be it semaglutide, tirzepatide, all of them, they showed a clear plateau. The weight loss slows, then it flattens, and then stops. Retatrutide's curve, though, was still going down. That had never happened before in the entire history of obesity pharmacology, no plateau. Then the phase 3 trials started to come in, and they confirmed what the phase 2 data had hinted at. The TRAILBLAZER-4 study, which was with patients with obesity and knee osteoarthritis, the average weight loss was 28. 7% of their body weight or 71 lb. That was the largest weight loss ever recorded in an obesity trial, plus a 75% reduction in knee osteoarthritis pain. And in diabetics, where existing drugs deliver about 11 to 15% of weight loss, retatrutide hit 16. 8% in a separate phase 3 trial, still with no plateau. So the hormone that was thrown away in 1923, ignored in 1957, and abandoned by every pharmaceutical company that had tried to use it in the past, just produced the best results in the history of obesity medicine. But there was

Side Effects of Retatrutide

something in the phase 3 data that wasn't in phase 2. So here's the part that the headlines are not covering. In the TRAILBLAZER-4 trial, 20. 9% of patients on the highest dose reported a side effect that has got a clinical name that most people have never heard of, dysesthesia. So this is an abnormal sense of touch where normal sensations feel wrong. Patients describe it as the skin feeling hot or on fire, lightning bolts shooting through the skin, persistent pins and needles, clothing becoming irritating against the skin. One in five patients on the highest dose. And that side effect did not appear in the phase 2 trials. It's new. It's dose-dependent as well. The side effect has not been seen with semaglutide or tirzepatide. It seems specific to retatrutide's third dial. So Lilly explained it as generally mild and said that it really led to discontinuation. Now that may be true for individual patients, but let's do the math here. If this drug reaches a million patients, which it will given the obesity epidemic, that's 200,000 people experiencing abnormal skin sensations. That's not a trivial number, and dysesthesia is not the only concern. With any weight loss strategy, muscle mass is a huge potential downside here. So unless a person on retatrutide performs resistance exercise and make sure that they reach their daily protein targets, they will lose significant amounts of muscle. Then there was a subtle signal of another novel problem. So in an earlier phase 2 trial of retatrutide, there was evidence of elevated heart rate. So whether this issue shows up again in the latest phase 3 trials remains to be seen. The preliminary results so far don't include detailed adverse event information. And finally, there's the discontinuation problem that I mentioned at the start. So 18% of patients at the highest dose, they had to stop taking retatrutide, and some of them stopped because of the side effects, but others stopped because of what the trial reported as perceived excessive weight loss. Patients in the lower BMI range who were losing more weight than their bodies could handle. And even if you're willing to accept the risks, there's one more obstacle. These drugs can cost over $1,000 per month, and insurance companies don't always cover them for weight loss. And the data on what happens when patients stop is ambiguous. Most patients regain the weight that they've lost. So most patients need to stay on these medications lifelong and potentially just at a lower dose. Now I do want to

The Importance of Protein Intake

return to the problem of protein that I mentioned earlier. It's critical that our intake is adequate when we're trying to lose weight. But this has been an area with so much noise on social media. How much protein do we actually need? And does the kind of protein matter? Well, make sure to check out this next video here for a clear view of the research and the intake that I recommend to my patients in the clinic.

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