Retatrutide Phase 3 Data Show Weight, A1C Reductions in Obesity and Type 2 Diabetes

Eli Lilly reported new phase 3 data for retatrutide, an investigational once-weekly agonist of glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors, showing reductions in body weight, A1C, knee osteoarthritis pain, and obstructive sleep apnea severity across 2 randomized trials.¹

“Obesity drives more than 200 downstream diseases, yet we have historically treated those conditions one at a time and in silos,” Ania Jastreboff, MD, PhD, professor of medicine and pediatrics at Yale School of Medicine and lead investigator, said in the company announcement.¹ The findings, presented at the American Diabetes Association 86th Scientific Sessions, extend prior phase 2 evidence suggesting retatrutide can produce dose-dependent weight reduction in adults with obesity.²

In TRIUMPH-1 (NCT05929066), an 80-week, randomized, double-blind, placebo-controlled phase 3 master trial, 2339 adults with obesity or overweight were assigned 1:1:1:1 to retatrutide 4 mg, 9 mg, 12 mg, or placebo. The trial included an obesity master trial and 2 nested basket trials evaluating knee osteoarthritis pain and moderate-to-severe obstructive sleep apnea. Participants began retatrutide at 2 mg once weekly, with stepwise dose escalation every 4 weeks to the assigned target dose.¹

According to Lilly, participants receiving retatrutide 9 mg and 12 mg lost a mean 64.4 lb (25.9%) and 70.3 lb (28.3%), respectively, at 80 weeks; those receiving 4 mg lost 47.2 lb (19.0%). Among participants receiving 12 mg, 65.3% achieved a BMI less than 30, and 33.3% achieved a BMI less than 25. In a prespecified 104-week extension among participants with baseline BMI of at least 35 who completed the main trial and tolerated therapy, those continuing retatrutide 12 mg lost a mean 85.0 lb (30.3%).¹

The osteoarthritis and sleep apnea basket trials also met primary end points, Lilly reported. Retatrutide reduced Western Ontario and McMaster Universities Osteoarthritis Index pain subscale scores by up to 4.3 points, a 73.1% reduction from a baseline of 6.0. In participants with moderate-to-severe obstructive sleep apnea, apnea-hypopnea index decreased by up to 36.1 events per hour, a 60.6% reduction from a baseline of 58.6 events per hour.¹

In TRANSCEND-T2D-1 (NCT06354660), a 40-week, randomized, double-blind, placebo-controlled phase 3 trial, 537 adults with type 2 diabetes inadequately controlled with diet and exercise alone were assigned to retatrutide 4 mg, 9 mg, 12 mg, or placebo. Eligible participants had A1C 7.0% to 9.5%, BMI of at least 23, no antidiabetes medication use for at least 90 days before screening, and no insulin exposure except for gestational diabetes.¹

Retatrutide met the primary end point of A1C reduction from baseline at 40 weeks, with reductions of up to 2.0 percentage points from a baseline A1C of 7.9%. Up to 90% of participants achieved A1C less than 7.0%, aligning with the American Diabetes Association’s general glycemic target for many nonpregnant adults, and up to 46% achieved A1C less than 5.7%. Participants receiving 12 mg lost a mean 36.6 lb (16.8%), with weight loss not plateauing at week 40, according to the company.^1,3

The adverse-event profile was consistent with incretin-based therapies, with gastrointestinal events most common. In TRIUMPH-1, nausea occurred in 28.6%, 38.4%, and 42.4% of participants receiving retatrutide 4 mg, 9 mg, and 12 mg, respectively, vs 14.8% with placebo. Discontinuation because of adverse events occurred in 4.1%, 6.9%, and 11.3% of retatrutide groups vs 4.9% with placebo. In TRANSCEND-T2D-1, nausea occurred in 16.4%, 19.5%, and 26.5% of retatrutide groups vs 3.7% with placebo; discontinuation because of adverse events occurred in 2.2%, 4.5%, and 5.1% vs 0% with placebo¹

Retatrutide’s mechanism differentiates it from approved single- and dual-incretin therapies by adding glucagon receptor agonism to GIP and GLP-1 receptor activity. In a phase 2 obesity trial, retatrutide produced mean body weight reductions of up to 24.2% at 48 weeks, with gastrointestinal adverse events reported most frequently.²

For clinicians, the phase 3 results suggest a potential role for retatrutide across obesity and selected obesity-related complications, but interpretation depends on full peer-reviewed reporting of TRIUMPH-1 and longer follow-up from the broader TRIUMPH and TRANSCEND programs. Key unresolved questions include durability after discontinuation, comparative effectiveness against approved antiobesity and diabetes therapies, cardiovascular and renal outcomes, and safety in broader clinical populations. Retatrutide remains investigational and is not approved in any geography.¹

References

1. Eli Lilly and Company. Lilly’s triple agonist, retatrutide, drove substantial improvements in weight, A1C, knee osteoarthritis pain, and obstructive sleep apnea. PR Newswire. June 6, 2026. https://www.prnewswire.com/news-releases/lillys-triple-agonist-retatrutide-drove-substantial-improvements-in-weight-a1c-knee-osteoarthritis-pain-and-obstructive-sleep-apnea-demonstrating-its-remarkable-potential-to-treat-obesity-and-its-complications-302793169.html
2. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity—a phase 2 trial. N Engl J Med. 2023;389(6):514-526. doi:10.1056/NEJMoa2301972
3. American Diabetes Association Professional Practice Committee. Glycemic goals and hypoglycemia: Standards of Care in Diabetes—2025. Diabetes Care. 2025;48(suppl 1):S128-S145.