Lilly’s Retatrutide Doubles Ozempic’s Weight Loss in First Phase 3 Head-to-Head Trial

Eli Lilly and Company’s investigational triple hormone receptor agonist retatrutide produced greater blood sugar reductions and more than twice the weight loss of semaglutide (Ozempic) 2 mg in adults with type 2 diabetes, according to topline results from the phase 3 TRANSCEND-T2D-2 trial announced October 28, 2026.¹ It is the first phase 3 trial to compare retatrutide head-to-head with another incretin medicine.¹

“Head-to-head trials show patients and physicians how a potential new medicine compares with treatments that are available and reimbursed today,” said Kenneth Custer, PhD, executive vice president and president of Lilly Cardiometabolic Health.¹

How does retatrutide work?

Retatrutide is a once-weekly agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors.² Phase 2 trials published in 2023 evaluated it in people with type 2 diabetes and in people with obesity.²,³ In the type 2 diabetes study, the 12 mg escalation group lowered HbA1c by 2.16% and body weight by 16.94% at 36 weeks, compared with 1.36% and 2.02% with dulaglutide 1.5 mg.² Semaglutide, the comparator in TRANSCEND-T2D-2, is a once-weekly GLP-1 analog.⁴

The molecule’s structure has also put it at the center of a regulatory dispute. As BioPharm International® has reported, whether retatrutide is classified as a biologic or a drug depends on whether its amino acid count falls above or below the 40-amino-acid threshold, which affects market exclusivity and competitor entry.

What did TRANSCEND-T2D-2 show?

The randomized, open-label trial (NCT06260722) enrolled 1,298 adults with type 2 diabetes inadequately controlled on metformin, with or without an SGLT2 inhibitor.¹ Participants were randomized 2:2:1 to retatrutide 9 mg, retatrutide 12 mg, or Ozempic 2 mg for 80 weeks.¹ Ozempic 2 mg was approved by FDA in 2022 as the highest of Ozempic’s three doses for type 2 diabetes.⁴ Baseline A1C averaged 8.3%.¹

Using the efficacy estimand, A1C fell by 2.2% with both retatrutide doses, compared with 1.8% with Ozempic.¹ Participants lost 19.5% of body weight on retatrutide 9 mg and 20.9% on 12 mg, compared with 9.4% on Ozempic.¹ Retatrutide 9 mg met the A1C noninferiority criterion, and both doses showed superiority on A1C and weight at nominal p<0.001.¹

Type 2 diabetes accounts for about 90% to 95% of diagnosed diabetes in the United States, where more than 40 million people have diabetes.⁵

How do the results fit with other phase 3 data?

TRANSCEND-T2D-2 follows two published placebo-controlled phase 3 trials. In TRANSCEND-T2D-1, 537 adults with type 2 diabetes managed with diet and exercise lost 11.5% to 15.3% of body weight over 40 weeks on retatrutide, compared with 2.6% on placebo.⁶ In TRIUMPH-2, which enrolled 1,152 adults with obesity and type 2 diabetes, weight fell 18.8% with retatrutide 12 mg at 80 weeks, compared with 5.1% with placebo, using the treatment-regimen estimand.⁷

What were the safety findings?

Gastrointestinal events were most common in TRANSCEND-T2D-2. Diarrhea occurred in 28.3% and 32.7% of participants on retatrutide 9 mg and 12 mg, compared with 26.4% on Ozempic, and nausea in 21.2%, 23.8%, and 21.3%, respectively.¹ Discontinuation due to adverse events was 4.8% and 7.9% with retatrutide, compared with 2.7% with Ozempic.¹ In TRIUMPH-2, discontinuation due to adverse events or death ranged from 4% to 12% across retatrutide doses, compared with 5% with placebo.⁷

What happens next?

Retatrutide is not approved by FDA or any other regulator.¹ Lilly said detailed TRANSCEND-T2D-2 results will be presented at a future medical meeting, and it is comparing retatrutide head-to-head with tirzepatide in the ongoing phase 3 TRIUMPH-5 trial.¹ The readout follows Novo Nordisk’s report in September that its CagriSema produced greater weight loss than tirzepatide in a phase 3 trial.

“Based on these results and those from across our phase 3 program, we believe retatrutide, if approved, could shift the treatment paradigm for people living with type 2 diabetes, obesity and related cardiometabolic conditions,” Custer said.¹

References

1. Eli Lilly and Company. Lilly’s retatrutide delivered greater A1C reduction and more than double the weight loss of Ozempic’s highest approved dose in head-to-head trial. Press release. Published October 28, 2026. Accessed October 29, 2026.
2. Rosenstock J, Frias J, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet. Published online June 26, 2023.
3. Jastreboff AM, et al. Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial. N Engl J Med. 2023;389(6):514-526.
4. Managed Healthcare Executive. FDA Approves Higher Dose of Ozempic. Published March 29, 2022. Accessed October 29, 2026.
5. Centers for Disease Control and Prevention. Diabetes Quick Facts. Accessed October 2026.
6. Bajaj HS, Welch M, Shah P, et al. Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial. Lancet. Published online June 6, 2026.
7. 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.