Weekly Amylin Drug Achieves Up to 10.7% Weight Loss

A ONCE-WEEKLY investigational amylin analogue produced weight loss of up to 10.7% in adults with overweight or obesity, according to results from the phase 2 ZUPREME 1 trial.

Petrelintide produced significantly greater reductions in body weight than placebo across all five doses tested at 28 weeks, with weight loss continuing through 42 weeks.

Testing an Alternative Weight-Loss Pathway

Petrelintide is a long-acting analogue of amylin, a pancreatic hormone co-secreted with insulin in response to food intake. Amylin signalling contributes to appetite and energy-intake regulation, making the pathway a potential target for obesity treatment

The randomised, double-blind, placebo-controlled ZUPREME 1 trial investigated 485 adults with overweight or obesity without type 2 diabetes. Participants had a mean age of 47 years, mean BMI of 36.7 kg/m² and mean body weight of 107.1 kg; 53% were women.

Participants received once-weekly subcutaneous petrelintide at doses of 1.0 mg, 2.5 mg, 5.0 mg, 7.0 mg or 9.0 mg, or placebo, alongside lifestyle intervention.

Weight Loss Approaches 10% by 28 Weeks

The primary endpoint was percentage change in body weight at Week 28.

Mean weight reductions were 7.9% with both 1.0 mg and 2.5 mg petrelintide, 9.8% with 5.0 mg, 9.3% with 7.0 mg and 9.4% with 9.0 mg, compared with 1.7% with placebo. The greatest placebo-adjusted reduction, 8.1 percentage points, was therefore observed with the 5.0 mg dose.

Weight loss continued beyond the primary endpoint. By Week 42, mean reductions reached 8.7%, 9.2%, 10.7%, 10.5% and 10.2% across the five ascending petrelintide doses, respectively, compared with 1.7% for placebo under the efficacy estimand.

The results suggest that increasing the dose beyond 5.0 mg did not produce substantially greater weight loss in this trial.

Nausea Most Common Adverse Event

Nausea was the most frequently reported adverse event, affecting 79 of 404 participants receiving petrelintide (20%) compared with five of 81 (6%) receiving placebo.

Vomiting occurred in 3% and 6%, respectively, while diarrhoea affected 7% in both groups. Constipation was reported in 7% of petrelintide recipients and 4% receiving placebo.

Overall serious adverse-event rates were similar between groups. However, independent experts highlighted three serious events considered related to petrelintide: two cases of gallstones and one case of obstructive pancreatitis.

Larger Trials Needed

The results support further investigation of amylin-based therapies as another pharmacological approach to chronic weight management.

However, comparisons with established GLP-1 receptor agonists should be made cautiously. ZUPREME 1 did not directly compare petrelintide with a GLP-1-based treatment, meaning the study cannot establish whether petrelintide offers superior tolerability or treatment persistence.

The drug also remains investigational. Larger and longer phase 3 studies will be needed to establish its long-term efficacy and safety and determine how it might fit alongside existing obesity treatments.

Importantly for diabetes specialists, ZUPREME 1 excluded people with type 2 diabetes. Petrelintide is being investigated separately in people with overweight or obesity and type 2 diabetes in the ZUPREME 2 programme.

Reference

Garvey WT et al. Petrelintide, a human amylin analogue for the treatment of obesity (ZUPREME 1): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol. 2026. doi:10.1016/S2213-8587(26)00213-5.