Retatrutide Outperforms Placebo for Weight Loss With and Without Type 2 Diabetes

Two phase 3 trials published September 29 in NEJM and The Lancet found that once-weekly subcutaneous retatrutide (Eli Lilly), an investigational agonist of glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 (GLP-1), and glucagon receptors, produced significantly greater weight reduction than placebo over 80 weeks in adults with obesity, with or without type 2 diabetes (T2D).

Both double-blind trials randomly assigned participants to retatrutide 4mg, 9mg, or 12mg or to placebo. Percent change in body weight with the 9mg and 12mg doses versus placebo was a primary endpoint in each. TRIUMPH-1 enrolled 2,339 adults with obesity without diabetes and also assessed knee osteoarthritis pain and obstructive sleep apnea (OSA). TRIUMPH-2 enrolled 1,152 adults with a BMI of 27 kg/m² or higher and T2D (HbA1c, 6.5%-10.5%) at 92 centers in 8 countries.

In TRIUMPH-1, mean body weight changed by −17.6%, −23.7%, and −25.0% with the 4mg, 9mg, and 12mg doses, respectively, versus −3.9% with placebo (P<0.001 for 9mg and 12mg). In TRIUMPH-2, the corresponding changes were −11.9%, −16.8%, and −18.8% versus −5.1% with placebo, for estimated treatment differences of up to −13.8 percentage points at 12mg (P<0.0001 for all doses). TRIUMPH-2 investigators reported that treatment was also associated with improved glycemic control.

In TRIUMPH-1 subgroups analyzed with a hybrid-treatment estimand, WOMAC pain scores among 574 participants with knee osteoarthritis fell 1.6 to 1.8 points more with 9mg and 12mg than with placebo, and the apnea-hypopnea index among 243 participants with OSA fell by 21.9 to 24.4 more events per hour than with placebo (P<0.001 for all). Gastrointestinal events were the most common adverse events in both trials. In TRIUMPH-2, diarrhea occurred in 34% of participants receiving 9mg or 12mg versus 13% receiving placebo, and nausea occurred in up to 28% versus 8%. Hypotension and dysesthesia were also more frequent with retatrutide. Discontinuation due to adverse events or death occurred in 12% (9mg) and 8% (12mg) of participants versus 5% with placebo.

TRIUMPH-2 investigators concluded that the safety profile was generally consistent with other GLP-1 receptor agonist molecules and that retatrutide might be effective for obesity in people with T2D.

Sources: Jastreboff AM, Kaplan LM, Davies MJ, et al. Retatrutide, a triple hormone receptor agonist, for treatment of obesity. N Engl J Med. Published online September 29, 2026. doi:10.1056/NEJMoa2604169

Bellido V, le Roux CW, Ekinci EI, et al. Retatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2): a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial. Lancet. Published online September 29, 2026. doi:10.1016/S0140-6736(26)01861-1