Novo Nordisk’s Zenagamtide Lowers HbA1c by Up to 1.7% and Delivers 14.6% Weight Loss in Phase 2 Type 2 Diabetes Trial

Novo Nordisk reported positive Phase 2 results showing that once-weekly subcutaneous zenagamtide (amycretin) significantly improved glycemic control and produced up to 14.6% weight loss in adults with type 2 diabetes inadequately controlled on metformin, with or without an SGLT2 inhibitor.

The findings were presented at the 2026 American Diabetes Association (ADA) Scientific Sessions and support advancement into Phase 3 development.

First Dual GLP-1/Amylin Receptor Agonist

Zenagamtide is the first unimolecular peptide engineered to activate both glucagon-like peptide-1 (GLP-1) and amylin receptors. By combining two complementary metabolic pathways in a single molecule, the therapy improves glucose regulation while promoting weight reduction, addressing two major treatment goals in type 2 diabetes management.

Trial Design and Glycemic Outcomes

The randomized, double-blind, placebo-controlled Phase 2 dose-finding study (NCT06542874) enrolled 262 adults with baseline HbA1c levels between 7.0% and 10.0%. Participants received one of six zenagamtide doses ranging from 0.4 mg to 40 mg or placebo for 36 weeks while continuing metformin therapy. Approximately 40% of participants also received an SGLT2 inhibitor. The study used a fixed-dose escalation strategy, with treatment discontinued if participants could not tolerate their assigned target dose.

The trial met its primary endpoint, demonstrating statistically significant HbA1c reductions across all dose levels compared with placebo. At week 36, the highest 40 mg dose achieved a mean HbA1c reduction of 1.71 percentage points from a baseline of 7.8%, corresponding to a treatment difference of 1.56 percentage points versus placebo (p<0.0001).

Glycemic target attainment was notable. Up to 89.1% of participants achieved HbA1c levels below 7%, while 76.2% reached 6.5% or lower. Time spent within the recommended glucose target range of 70–180 mg/dL exceeded 70% across all dose groups and reached 91.4% in the 40 mg cohort.

Durable Weight Reduction

Weight loss was a key supportive secondary outcome. Participants receiving zenagamtide 40 mg experienced a mean body weight reduction of 14.6% from a baseline of 99.2 kg (218.7 lbs), compared with 2.1% for placebo. The reduction was statistically significant versus placebo (p<0.0001). Investigators reported no apparent weight-loss plateau at week 36 among higher-dose groups, suggesting the potential for continued weight reduction beyond the study period.

Safety Profile

Zenagamtide’s safety profile was consistent with other incretin- and amylin-based therapies. Gastrointestinal adverse events were the most commonly reported side effects and were generally mild to moderate in severity. No new safety signals were identified during the study.

Therapeutic Impact and Next Steps

Martin Holst Lange, Executive Vice President and Chief Scientific Officer of Research & Development at Novo Nordisk, said the findings strengthen evidence supporting dual GLP-1 and amylin receptor activation as a potential approach for addressing both hyperglycemia and excess weight while expanding future treatment options for patients with metabolic disease.

Based on the Phase 2 data, Novo Nordisk plans to initiate Phase 3 trials of zenagamtide in adults with type 2 diabetes during the second half of 2026, advancing development of what could become the first dual GLP-1/amylin receptor agonist approved for type 2 diabetes.

Reference

Novo Nordisk’s investigational zenagamtide shows significant HbA1C reductions with up to 14.6% weight loss in adults with type 2 diabetes – presented at ADA 2026