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A new wave of weight-loss medications dubbed “GLP-3s” is poised to surpass the already popular GLP-1 drugs, potentially offering significantly greater weight reduction benefits for patients with obesity.
While GLP-1 (glucagon-like peptide-1) medications have dominated headlines for their ability to mimic a natural hormone that regulates blood sugar and appetite, the informal term “GLP-3” refers to an advanced triple-agonist drug targeting three hormones simultaneously: GLP-1, GIP (glucose-dependent insulinotropic polypeptide), and glucagon receptors.
Eli Lilly’s retatrutide stands as the most promising example in this new category, according to clinical trial outcomes. In 2023, The New England Journal of Medicine published results from a phase 2 retatrutide trial that demonstrated “substantial reductions in body weight” after 48 weeks of treatment. Participants receiving a 12 mg once-weekly injection achieved a remarkable 24.2% weight reduction, with continued weight loss observed even after the trial period ended.
What makes this new medication different is its multi-targeted approach. Unlike GLP-1 drugs that simulate just one hormone, retatrutide mimics three natural hormones found in the body. GIP and GLP-1 hormones signal the pancreas to release insulin after eating while slowing digestion to promote feelings of fullness. These hormones also target the brain’s appetite regulation centers, influencing food cravings.
The third hormone, glucagon, provides an additional metabolic boost by accelerating metabolism and helping the body break down fat cells for energy. It instructs the liver to produce new sugar, which is balanced by the GIP and GLP-1 activity to prevent 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,” according to information published on the GoodRx website. “If approved, retatrutide will be the first in a new class of medications.”
In December, Eli Lilly announced results from its phase 3 trial TRIUMPH-4, which tested retatrutide’s effect on weight loss and other health conditions. The findings were striking: participants with obesity and knee arthritis who took a 12-mg dose lost an average of 71.8 pounds (28.7%) after 68 weeks.
Beyond weight reduction, the medication also demonstrated significant improvements in pain management. The drug reduced Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores by an average of 75.8%, marking considerable improvements in comfort level and physical function. More than one in eight patients reported being “completely free” from knee pain by the end of the trial.
“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,” said Kenneth Custer, Ph.D., executive vice president and president of Lilly Cardiometabolic Health.
The side effect profile appears similar to that of GLP-1 medications, with gastrointestinal issues like nausea, vomiting, and diarrhea being most common. Some dose-dependent heart rate increases were also noted in trials.
The medication’s potential extends beyond obesity treatment. Experts suggest retatrutide could be applied to treat other conditions such as type 2 diabetes, kidney disease, cardiovascular issues, and metabolic dysfunction.
Dr. Marc Siegel, Fox News senior medical analyst, noted that Eli Lilly’s current dual-target medications, Zepbound and Mounjaro, already work on two metabolic pathways (GLP-1 and GIP) to promote weight loss and improve metabolic health. Adding the third receptor agonist further decreases hunger while increasing satiety, explaining the enhanced weight loss results.
“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 explained.
Seven additional phase 3 trials for retatrutide are expected to conclude in 2026, with potential FDA approval projected for 2027, according to GoodRx.
The development of these triple-agonist medications represents a significant advancement in pharmacological approaches to obesity management, potentially offering more effective options for patients with significant weight-related health complications.
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9 Comments
As someone who has struggled with weight issues, I’m hopeful that these new GLP-3 medications can provide an effective, safe treatment option. The ability to target multiple hormones simultaneously seems like a promising approach, but the long-term impacts will be crucial.
I agree, the prospect of more potent weight loss drugs is exciting, but patient safety has to be the top priority. Careful monitoring of side effects and durability of results will be essential as these GLP-3 medications advance.
This is an interesting development in the ongoing quest for more effective weight loss medications. The triple-action mechanism of GLP-3 drugs like retatrutide is intriguing, but I hope the pharmaceutical companies prioritize rigorous safety assessments before rushing these to market.
The 24% weight loss seen with retatrutide is an impressive result, but I share the concerns about potential risks from simultaneously targeting GLP-1, GIP, and glucagon. Thorough clinical testing will be crucial to establish the long-term safety profile of this new drug class.
The 24% weight reduction achieved with retatrutide in clinical trials is quite remarkable, even if just for a 48-week period. I’m curious to see how these triple-action GLP-3 drugs perform in larger, longer-term studies to evaluate their full potential and any risks.
This new class of weight loss medications is an exciting development, though I have some reservations. Mimicking three hormones simultaneously could have unintended consequences that need to be thoroughly investigated before these drugs are widely adopted.
I agree, the multi-faceted mechanism of action for GLP-3 drugs raises valid concerns about safety that will require careful study. The weight loss benefits are impressive, but patient health must be the top priority.
Interesting development in weight loss medications. The triple-agonist approach targeting GLP-1, GIP, and glucagon sounds promising, especially the 24% weight reduction seen in trials. I wonder how the side effect profile compares to existing GLP-1 drugs.
Safety and long-term efficacy will be key factors to monitor as these new GLP-3 drugs progress. The substantial weight loss results are certainly encouraging, but the multi-target mechanism raises questions about potential risks.