Phase 3 Trial of Triple Agonist Therapy for Weight Loss in Diabetes

Phase 3 Trial Design and Participant Demographics

The investigational drug retatrutide showed reductions in body weight and blood sugar in adults with type 2 diabetes and overweight or obesity during an 80-week clinical study.

Data presented at the Annual Meeting of the European Association for the Study of Diabetes (EASD) and published in The Lancet evaluated the completed phase 3 trial sponsored by the manufacturer, Eli Lilly. Retatrutide functions as an investigational triple agonist targeting glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors. The trial was conducted across 92 sites in 8 countries, including Argentina, Australia, Brazil, India, Mexico, Romania, Spain, and the United States.

The study enrolled 1,152 randomized adults with a body mass index (BMI) of at least 27 kg/m2 and glycated hemoglobin (HbA1c) between 6.5% and 10.5%. Participants received once-weekly subcutaneous injections of retatrutide at 4 mg, 9 mg, or 12 mg, or a placebo, alongside dietary counseling and guidance on physical activity. At baseline, the mean age was 55.1 years, mean BMI was 38.2 kg/m2, mean HbA1c was 7.71%, and 92% of participants were taking background oral glucose-lowering medications.

Weight Reduction Across the 80-Week Study

Participants assigned to retatrutide experienced dose-dependent weight reductions that reached an average loss of 18.8% of starting body weight at the highest dose.

Over the 80-week trial, mean body weight changed by minus 11.9% in the 4 mg cohort, minus 16.8% in the 9 mg cohort, minus 18.8% in the 12 mg cohort, and minus 5.1% in the placebo group. Estimated treatment differences compared with placebo were minus 6.9% for the 4 mg dose, minus 11.8% for 9 mg, and minus 13.8% for 12 mg. People with type 2 diabetes have historically achieved less weight reduction on obesity pharmacotherapies than people without diabetes.

At the 12 mg dose, 47% of participants lost at least 20% of their starting weight, and 31% lost at least 25%, compared with 6% and 3% in the placebo cohort. A total of 91% of enrolled participants finished the 80-week study period, and 84% completed the trial on their assigned study treatment.

Glycemic Control and Cardiometabolic Markers

Treatment with retatrutide lowered glycated hemoglobin levels and improved secondary markers of cardiovascular risk and systemic inflammation.

Mean HbA1c reductions at Week 80 reached minus 1.38% with the 4 mg dose, minus 1.50% with 9 mg, minus 1.45% with 12 mg, and minus 0.45% with placebo. Among participants receiving the 12 mg weekly dose, 72% achieved an HbA1c target of 6.5% or lower, compared with 29% of participants receiving the placebo.

Investigators also tracked changes in broader cardiometabolic markers across the active treatment groups. Retatrutide administration resulted in reductions in blood pressure and improvements in lipid profiles. The drug also reduced levels of high-sensitivity C-reactive protein (hsCRP), an established blood marker of systemic inflammation.

Adverse Effects and Clinical Caveats

Gastrointestinal events represented the most frequently documented adverse effects during the trial and occurred more often with retatrutide than with placebo.

Diarrhea was documented in 27% to 34% of participants across the retatrutide groups compared with 13% in the placebo cohort. Nausea was reported by 14% to 28% of participants receiving retatrutide compared with 8% of participants receiving the placebo.

Retatrutide remains an investigational therapy that has not received approval from regulatory agencies for clinical use. The study was funded and sponsored by Eli Lilly. The molecule is currently undergoing clinical trials for other conditions, including metabolic liver disease, knee osteoarthritis, chronic low back pain, and obstructive sleep apnea (OSA). Individuals managing blood glucose should discuss currently approved medication options with their clinician.