GLP-3s: A new generation of weight-loss drugs with three key ingredients

GLP-3s are triple-agonist drugs that target GLP-1, GIP and glucagon receptors; early trials of retatrutide reported substantial average weight losses. Reported side effects are mainly gastrointestinal, with some cardiovascular and rarer risks noted.

GLP-3s are being discussed as a next step after GLP-1 medications because they act on three hormonal pathways instead of one. Retatrutide, developed by Eli Lilly, is the most advanced example and has been the subject of recent clinical reports. Clinicians have also noted psychological and social challenges for some people who experience rapid weight change. Trial results and company statements have driven interest and scrutiny. Key facts: - GLP-3s are described as triple-agonists that target GLP-1, GIP and glucagon receptors, while GLP-1 drugs act primarily on the GLP-1 pathway. - A 2023 phase 2 retatrutide trial reported a 24.2% average weight reduction after 48 weeks with a 12 mg once-weekly dose, as published in the New England Journal of Medicine. - Eli Lilly reported in its phase 3 TRIUMPH-4 trial that participants with obesity and knee arthritis taking 12 mg of retatrutide lost an average 71.8 lbs (28.7%) at 68 weeks and showed large reductions in WOMAC pain scores, according to a company press release. - Reported side effects are similar to GLP-1 drugs and most commonly include gastrointestinal symptoms such as nausea, vomiting and diarrhea; dose-related heart rate increases and rarer events such as pancreatitis, gallstones and heart arrhythmia have also been noted. - Sources cited in the article note potential broader applications under study, including effects on type 2 diabetes, kidney disease and cardiovascular risk, and report that seven additional phase 3 trials are expected to report readouts in 2026 with possible regulatory review thereafter. Summary: GLP-3s combine effects on appetite, insulin signaling and metabolism and have produced larger average weight losses in published trials and company reports than earlier agents, according to the cited sources. Reported adverse effects to date are mainly gastrointestinal, with some cardiovascular observations and occasional rarer events. Multiple phase 3 readouts are expected in 2026, and reporting has suggested a potential regulatory timeline beyond those results. Undetermined at this time.