Lilly's amylin-tirzepatide combo outperforms retatrutide in diabetes weight loss trials

Key points

• EloraTZP, combining eloralintide and tirzepatide, yielded 23.3% average weight loss in 367 adults with obesity and type 2 diabetes over 48 weeks.
• The highest dose (9 mg eloralintide and 15 mg tirzepatide) resulted in a 54.1-pound weight loss, exceeding the 34.4-pound loss seen with tirzepatide alone.
• A1C levels dropped by an average of 2.9% in the combination group, compared to 2.4% for tirzepatide alone and 1.4% for eloralintide alone.
• Discontinuation rates due to adverse events ranged from 10.8% to 27% for the combination, compared to 2.9% for tirzepatide alone, primarily due to gastrointestinal issues.
• Lilly intends to start Phase 3 trials in Q4 2026, including a co-formulation that would require only one injection, with optimized titration schedules to address tolerability.

Background

This development follows recent reports on Lilly’s retatrutide, which showed 25% weight loss in obesity patients but 23% in those with type 2 diabetes, making eloraTZP the more effective option for the latter group. The company also filed for FDA approval of retatrutide as a biologic to extend exclusivity. Meanwhile, competitors like Novo Nordisk are developing similar combinations, such as CagriSema, which combines an amylin analog with semaglutide, though it recently missed a key endpoint in a Phase 3 trial.

How outlets are covering it

Citi analysts noted that the 23.3% weight loss in diabetic patients is comparable to tirzepatide results in non-diabetic populations, highlighting the efficacy attenuation typically seen with diabetes. However, they raised concerns about the high discontinuation rates, suggesting that simultaneous initiation of both drugs may amplify side effects, though they believe optimized Phase 3 titration could improve adherence. Ken Custer, president of Lilly Cardiometabolic Health, argued that the discontinuation rates in Phase 2 are not definitive indicators of long-term tolerability, citing similar high rates in earlier tirzepatide trials. He emphasized that the combination approach is 'physiological,' lightly engaging three hormone systems rather than blasting one, and could become a 'winning approach' for patients who do not respond to current GLP-1 therapies. Leerink Partners analyst David Risinger described the potential for eloralintide as a 'mega-blockbuster,' noting millions of patients who failed or could not tolerate existing treatments.

Why it matters

The results suggest a potential new standard of care for patients with comorbid obesity and type 2 diabetes, a population that often struggles with weight loss on existing GLP-1 therapies. If Phase 3 trials confirm efficacy with improved tolerability, eloraTZP could expand Lilly’s market share in the growing obesity and diabetes drug sector, potentially rivaling or surpassing competitors like Novo Nordisk’s CagriSema. The move to a co-formulation also addresses patient convenience, a key factor in long-term adherence.

What to watch

Lilly will initiate Phase 3 trials for eloraTZP in the fourth quarter of 2026, including a co-formulation product. The company also expects to file for FDA approval of retatrutide before March 2027. Further data on retatrutide’s effectiveness for obstructive sleep apnea is expected at a future medical meeting.