ZUPREME-2: Petrelintide Outperforms Placebo for Weight Loss in T2D and Obesity

ZUPREME-2, a phase 2 trial of investigational long-acting human amylin analog petrelintide, has achieved its primary endpoint of superior reductions in body weight among patients with overweight or obesity and type 2 diabetes (T2D) compared to placebo.1

Announced by parent company Zealand Pharma on October 7, 2026, these results are consistent with the prior ZUPREME-1 trial, which established the drug’s efficacy in patients with overweight or obesity without T2D. The full data from ZUPREME-2 are expected to be presented at an upcoming medical conference.1

“These results further support the potential of petrelintide in chronic weight management and, for the first time, demonstrate its promise as a standalone treatment for those living with overweight or obesity and type 2 diabetes,” David Kendall, MD, chief medical officer at Zealand Pharma, said in a statement. “These data confirm the potential for clinically meaningful weight reduction with a promising and favorable tolerability profile.”1

Structuring ZUPREME-2

ZUPREME-2 was a randomized, double-blind, phase 2 trial of petrelintide once weekly in patients with overweight or obesity and T2D. Patients were eligible for inclusion if they had been diagnosed with T2D ≥180 days before screening, had a body mass index (BMI) ≥27 kg/m2, and were receiving treatment with metformin with or without SGLT2 inhibitors. Patients were excluded if they had severe hypoglycemia within 6 months before screening, a self-reported change in body weight >5% within 90 days, or obesity due to endocrine disorder or genetic syndromes, among other criteria.2

The trial included a screening period, a dose escalation period of ≤16 weeks with escalation taking place every fourth week, and a maintenance period until week 28. This was followed by a follow-up period until week 38. The primary endpoint for the study was percentage change in body weight from baseline to week 28. Secondary outcomes included the number of patients achieving ≥5% and ≥10% body weight loss by week 28, change in body weight in kg, change in waist circumference, HbA1c, fasting glucose, and hsCRP, among others.2

Petrelintide’s Outcomes and Efficacy

A total of 220 patients were enrolled in the trial, with a mean baseline BMI of 36.3 kg/m2 and a mean baseline HbA1c of 8%. These patients were then randomized to receive 3 separate doses of either petrelintide or placebo, all of which were administered once weekly and subcutaneously. By week 28, investigators reported that patients receiving petrelintide achieved ≤9.2% mean weight loss from baseline, while the placebo arm saw ≤2% mean weight loss. Additionally, petrelintide demonstrated a substantial reduction in HbA1c across all treatment arms, with a placebo-adjusted HbA1c reduction of 0.61-0.88%.1,2

The investigators also recorded no unexpected safety signals during the trial. Petrelintide demonstrated a favorable tolerability profile, and treatment discontinuation rates due to gastrointestinal adverse events were 1.9% for the petrelintide arm and 1.7% for the placebo arm. Additionally, the majority of adverse events were gastrointestinal, and the vast majority of these were reportedly mild and occurred during the escalation period.1

Zealand Pharma and petrelintide co-developer Roche have already initiated a Phase 3a program for petrelintide, consisting of the ZUPREME-3, ZUPREME-4, and ZUPREME-5 trials. This program plans to evaluate patients with overweight or obesity without T2D, with T2D, and established cardiovascular disease, respectively. Zealand Pharma plans to enroll roughly 7000 patients across all 3 trials.1

“Together with Roche, we look forward to investigating petrelintide in our recently initiated Phase 3 registrational program to address important unmet medical needs in chronic weight management,” Kendall said in a statement.1

References

1. Zealand Pharma. Zealand Pharma announces positive Phase 2 ZUPREME-2 topline results for amylin analog petrelintide in people with overweight or obesity and type 2 diabetes. Globe Newswire. October 7, 2026. Accessed October 7, 2026. https://www.globenewswire.com/news-release/2026/10/07/3376750/0/en/zealand-pharma-announces-positive-phase-2-zupreme-2-topline-results-for-amylin-analog-petrelintide-in-people-with-overweight-or-obesity-and-type-2-diabetes.html

2. Zealand Pharma. Efficacy and Safety of Petrelintide in Participants With Overweight or Obesity and Type 2 Diabetes (ZUPREME 2). ClinicalTrials.gov Identifier: NCT06926842. Updated September 9, 2026. Accessed October 7, 2026. https://clinicaltrials.gov/study/NCT06926842?term=NCT06926842&rank=1