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NEW ORLEANS — Petrelintide, an investigational drug in the growing field of amylin analogs being studied for long-term obesity treatment, showed significant weight-loss benefits over placebo in people without type 2 diabetes, according to the results of a phase 2 trial. 

Notably, the gastrointestinal (GI) side effect profile of petrelintide seen in the study was mild, suggesting important improvements over glucagon-like peptide 1 (GLP-1) receptor agonists (RAs)

These properties offer the potential for petrelintide and other amylin-based therapies to become both “a first-line medication for obesity and a medication that could improve longer-term medication persistence,” said first study author W. Timothy Garvey, MD, a professor of medicine at the University of Alabama at Birmingham, who presented the findings here at the American Diabetes Association (ADA) 2026 Scientific Sessions.

Amylin, a pancreatic peptide hormone, is involved in the regulation of blood glucose as well as appetite; therefore, long-acting amylin analogs have gained increasing interest as monotherapy, and in combination therapy, as discontinuation rates of GLP-1s remain notably high.

ZUPREME-1 Trial

To further investigate the safety and efficacy of petrelintide, Garvey and colleagues conducted a double-blind, parallel-group, dose-ranging phase 2 trial of petrelintide versus placebo. In the ZUPREME-1 trial, 485 adults were enrolled, 53% female, with a mean BMI of 36.7 kg/m². Participants were randomized to five different dose ranges of weekly subcutaneous injections of petrelintide or placebo.

After dose escalation conducted over 16 weeks, patients were maintained on their assigned dose through week 42. Target doses were achieved by 88%-98% of participants taking petrelintide.

Results showed the mean reduction in body weight from baseline in the petrelintide group was 10.7% versus just 1.7% in the placebo group at week 42 (efficacy estimand; P < .001). 

As with other weight-loss drugs, significant improvements in cardiovascular risk factors were seen, including lipids, blood pressure, and waist circumference.

Low Rates of GI Adverse Events

GI adverse events were mild in more than 75% of patients. Nausea, the leading GI event, was reported among 19.6% of participants taking petrelintide versus 6.2% with placebo.

Of note, reports of vomiting were rare with petrelintide, occurring at rates even lower than placebo, at only 3.0% versus 6.2%, respectively, with rates of diarrhea and constipation under 7.5% in both groups. Just 1.5% of participants discontinued petrelintide due to GI adverse events. 

“These rates are very low,” Garvey noted. Rates of nausea were decreased by half compared with GLP-1s, and rates of vomiting, diarrhea, and constipation were similar to placebo, he added. There were no unexpected safety findings. 

These data suggest petrelintide has the potential to be better tolerated than GLP-1 RAs, he said.

Importantly, weight-loss rates of 10%-15% observed with amylin analogs (as opposed to higher rates with drugs such as tirzepatide) suggest “a safer, slower, and more moderate weight loss that I think most of our patients with obesity require,” Garvey said. This “amount of weight loss is sufficient to improve health and quality of life in many patients.”

Overall, “these findings support the potential of petrelintide as an effective and well-tolerated obesity medication with a distinct mechanism of action,” said Garvey.

He noted that “a lot of patients don’t require the 25%-30% weight loss” that comes with drugs like tirzepatide. With that amount of weight loss, “there is a higher risk of malnutrition, and changes in body composition may be deleterious in some patients,” he explained.

Best-Tolerated Weight-Loss Drug Class? 

Commenting on the study, Marlon Pragnell, PhD, ADA vice president, research & science, said: “We’ve known about amylin for quite some time, but we’re seeing a resurgence now in terms of the potential value of this in the context of weight loss, and there is particular interest in the improved tolerability.” 

“We know that as many as 50% of people stop taking GLP-1s, and with challenges sometimes involving side effects, this could help improve adherence,” he told Medscape Medical News.

Furthermore, “with multiple therapeutic drugs in the pipeline and higher visibility, we can more precisely provide individual care to treat the patient.”

Ultimately, “this field is making a tremendous amount of progress, and it’s an incredibly exciting time,” he said.

Further discussing amylin analogs in a separate symposium at the meeting, Carel le Roux, MBChB, PhD, of University College Dublin and Ulster University, Ireland, agreed that these drugs have a potentially important role in the weight-loss and glucose-control realms.

“Amylin analogs, in my view, will have roles both as monotherapies and combination therapies,” he told symposium attendees.

“This is, to my mind, the best-tolerated [weight-loss drug] class that we have had thus far,” said le Roux, adding that in the future, these drugs may be used for both new and existing patients not yet at their treatment target. 

Of note, he said, “I think what we can see from the emerging data is that there are still a lot of good questions we need to address. But ultimately, I'm confident that this class is going to make a very big impact on your patients and my patients to allow us to achieve sustained health gains.”

The study was sponsored by Roche. 

Garvey has reported relationships with Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pfizer, Fractyl Health, Zealand, Genentech/Roche, Terns Pharmaceuticals, Neurocrine, Keros Therapeutics, Gan & Lee, Corcept, Graviton Bioscience, AbbVie, Madrigal, i2o Therapeutics, and Regeneron. Pragnell has reported no relevant financial relationships. Le Roux has reported relationships with Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pfizer, Fractyl, and Roche.