Eli Lilly announced on Thursday that its new weight-loss drug, retatrutide, helped participants in a large clinical trial achieve significantly greater weight loss than existing obesity medications, with an average reduction of up to 28.3% of body weight.
Phase 3 Trial Results
The Indiana-based pharmaceutical company reported that retatrutide, a once-weekly triple hormone receptor agonist, led to an average weight loss of 70.3 pounds (28.3%) over 80 weeks among participants receiving the 12mg dose. Notably, 45.3% of those on the highest dose achieved at least 30% weight loss.
In the phase 3 trial, 2,339 adults with obesity or overweight and at least one weight-related comorbidity (excluding diabetes) were randomized to receive retatrutide in doses of 4mg, 9mg, 12mg, or a placebo. Over 80 weeks, participants on the highest doses experienced substantial weight reduction.
- 12mg dose: Average weight loss of 70.3lb (28.3%)
- 9mg dose: Average weight loss of 64.4lb (25.9%)
- 4mg dose: Average weight loss of 47.2lb (19.0%)
Dr. Susan Spratt, an endocrinologist at Duke Health, told NBC News: “This is the largest weight loss I’ve ever seen in any medication trial. This is huge.”
Comparison with Existing Drugs
Retatrutide’s efficacy appears to exceed that of other weight-loss medications, including Eli Lilly’s own Zepbound and Novo Nordisk’s Wegovy. Zepbound users typically lose 15% to 20% of starting body weight over 72 weeks, while Wegovy users lose 14% to 19% over 64 to 72 weeks.
Unlike some oral weight-loss drugs, retatrutide and Zepbound are administered as once-weekly injections with incremental dose escalation.
Mechanism of Action
Retatrutide is a GLP-1 and GIP receptor agonist, similar to Zepbound, but it uniquely includes glucagon, a hormone that raises blood sugar levels to prevent hypoglycemia. The combination of these three hormones helps regulate metabolism, appetite control, and energy balance.
Side Effects
Common side effects associated with retatrutide included nausea, diarrhea, constipation, and vomiting. Nausea occurred in 28.6% (4mg), 38.4% (9mg), and 42.4% (12mg) of participants, compared to 14.8% in the placebo group. Diarrhea affected 25.2%, 34.1%, and 32.0% across doses, versus 13.5% on placebo. Vomiting increased with dose, affecting up to 25% on the highest dose versus 4.8% on placebo. Upper respiratory tract infections were reported in 12-14% of treated patients versus 11.6% on placebo.
Additional Health Benefits
Beyond weight loss, retatrutide showed improvements in cardiovascular risk factors, including HDL cholesterol, triglycerides, and systolic blood pressure. Emerging research suggests GLP-1 receptor agonists may also reduce anxiety, depression, and work absences.
“It was impressive to see that every dose of retatrutide resulted in clinically meaningful weight reduction for nearly all participants,” said Dr. Ania Jastreboff of Yale School of Medicine, the study’s lead author. “Importantly, treatment also resulted in clear improvements in cardio-metabolic health measures.”
