EASD 2026: Amylin agonist delivers weight loss with fewer GI side effects

Clinical takeaway: Consider amylin-based therapies as an emerging option in obesity management. In phase 2 testing, weekly petrelintide produced about 9% to 11% weight loss over 42 weeks while showing low rates of treatment-limiting GI adverse events.

Although GLP-1 and related incretin therapies have transformed obesity treatment, GI side effects remain a major contributor to treatment discontinuation. Amylin agonists target appetite regulation through a different pathway and may help address the need for effective, better-tolerated long-term weight management options.

In the phase 2 ZUPREME 1 trial, investigators randomized 485 adults with obesity and without type 2 diabetes to once-weekly petrelintide (1.0-9.0 mg) or placebo for 42 weeks, alongside lifestyle counseling. Participants had a mean age of 47 years, mean BMI of 36.7 kg/m², and mean body weight of 107 kg.

At week 42, mean weight loss ranged from 8.7% to 10.7% across petrelintide dose groups, compared with 1.7% for placebo. The greatest reductions were seen with the 5.0-, 7.0-, and 9.0-mg maintenance doses, which all achieved roughly 10% weight loss. More than half of participants receiving these higher doses achieved at least 10% weight loss, versus 9% of those given placebo. Absolute weight reductions reached approximately 11 kg, while waist circumference fell by as much as 10.8 cm.

Petrelintide was also associated with reductions in blood pressure, inflammatory marker hsCRP, and fasting insulin levels. GI tolerability appeared favorable: nausea occurred in 20% of treated participants, but vomiting, diarrhea, and constipation each occurred in 7% or fewer. Just 1% permanently discontinued therapy because of GI adverse events, and 88% to 98% successfully escalated to the target maintenance doses. Serious adverse event rates were comparable between petrelintide and placebo, and no deaths were reported.

The findings were presented at the 2026 EASD Annual Meeting and published simultaneously in The Lancet Diabetes & Endocrinology. Study authors wrote: “If reproduced in confirmatory phase 3 trials, this therapy could be suitable for many individuals seeking double-digit percentage weight loss without significant, treatment-limiting, gastrointestinal adverse events.”

Source: Garvey WT, et al. (2026 Sep 29) Lancet Diabetes Endocrinol. Petrelintide, a human amylin analogue for the treatment of obesity (ZUPREME 1): a randomized, double-blind, placebo-controlled, phase 2 trial