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GLP-1 has become a popular buzzword in the weight-loss community — but now some are touting “GLP-3s,” claiming they are taking obesity medications to the next level.
GLP-1 (glucagon-like peptide-1) medications work by mimicking a naturally occurring hormone in the body that helps regulate blood sugar and appetite.
The informal term “GLP-3” refers to a new triple-agonist drug that targets three hormones: GLP-1, GIP (glucose-dependent insulinotropic polypeptide, another naturally occurring hormone released by the gut after eating) and glucagon receptors. The most advanced example is retatrutide by Eli Lilly, according to clinical trial outcomes.
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The New England Journal of Medicine published results from a 2023 phase 2 retatrutide trial for obesity, revealing “substantial reductions in body weight” after 48 weeks of treatment.
A 12 mg once-weekly injection led to a 24.2% weight reduction, and participants continued to drop pounds after the 48-week trial period.
Side effects are reportedly similar to GLP-1 medications, most commonly including gastrointestinal complications like nausea, vomiting and diarrhea. Heart rate increases were noted, depending on the dose.
How it’s different
Retatrutide mimics three natural hormones found in the body, compared to GLP-1s that simulate just one hormone, according to a report by GoodRx pharmacists.
GIP and GLP-1 hormones signal the pancreas to release insulin after eating, while slowing digestion to help initiate feelings of fullness.
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These hormones target the area of the brain that regulates appetite and influences food cravings, the report noted.
The third hormone, glucagon, speeds up metabolism and helps the body break down fat cells for energy. That hormone also tells the liver to make new sugar, which is kept in check by GIP and GLP-1 activity, preventing blood sugar spikes.
“This added metabolism boost can add to and complement GIP’s and GLP-1’s actions. And that’s why it seems to provide significant weight loss,” the GoodRx website states. “If approved, retatrutide will be the first in a new class of medications.”
Eli Lilly announced results from its phase 3 trial TRIUMPH-4 in December, testing retatrutide’s effect on weight loss and other health conditions.
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Participants with obesity and knee arthritis who took a 12-mg dose of retatrutide saw an average weight loss of 71.8 lbs (28.7%) at 68 weeks.
The drug also reduced Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores by an average of 75.8%, marking “significant improvements” in comfort level and physical function, according to a press release.
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More than one in eight patients reported being “completely free” from knee pain at the end of the trial.
Seven additional phase 3 trials for retatrutide are expected to wrap up in 2026. The drug could see FDA approval in 2027, according to GoodRx.
“We are encouraged by the results of TRIUMPH-4, which highlight the powerful effect of retatrutide, a first-in-class triple agonist, on body weight, pain and physical function,” Kenneth Custer, Ph.D., executive vice president and president of Lilly Cardiometabolic Health, wrote in a statement.
“With seven additional phase 3 readouts expected in 2026, we believe retatrutide could become an important option for patients with significant weight loss needs and certain complications, including knee osteoarthritis.”
Despite limited data availability on the drug, the medication could also be applied to treat other conditions like type 2 diabetes, kidney disease, cardiovascular risk reduction and metabolic dysfunction, according to GoodRx and other experts.
Fox News senior medical analyst Dr. Marc Siegel noted that Lilly’s Zepbound and Mounjaro already target two metabolic pathways — GLP-1 and GIP — which work together to promote weight loss, reduce hunger and inflammation, improve insulin function and slow digestion.
The doctor confirmed that the new drug, with its third receptor agonist, will further decrease hunger while increasing the feeling of fullness.
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“The weight loss in clinical trials is even more substantial, and the most likely reason that it decreases orthopedic problems is because of the weight loss — less stress on the joints and the decreased inflammation,” Siegel added.
The most common side effect of GLP-3s is gastrointestinal symptoms, the doctor confirmed. Rarer side effects may include pancreatitis, gallstones and heart arrhythmia.
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