Petrelintide Yields Up to 10.7% Weight Loss With Mild GI Effects

Once-weekly petrelintide, an investigational long-acting amylin analog, produced mean body weight reductions of up to 10.7% over 42 weeks in adults with obesity, with gastrointestinal (GI) tolerability that largely resembled placebo apart from mostly mild nausea during dose escalation, according to results of the phase 2 ZUPREME 1 trial (NCT06662539).^1,2

The findings, published in The Lancet Diabetes & Endocrinology and presented at the European Association for the Study of Diabetes (EASD) Annual Meeting in Milan, Italy, add to evidence that amylin-based agents could offer an alternative for patients who struggle to tolerate glucagon-like peptide-1 receptor agonists (GLP-1 RAs).^1,2

Targeting a Tolerability Gap

GI adverse events are a leading driver of GLP-1 RA discontinuation, the investigators noted, with approximately 37% of discontinuations in a cardiovascular outcomes trial of semaglutide attributed to GI effects. Real-world data estimate that up to 75% of individuals stop injectable GLP-1 RA therapy within 12 months, which can lead to weight regain. Amylin, a pancreatic hormone cosecreted with insulin, regulates appetite through mechanisms partly independent of incretin pathways. Petrelintide is a potent agonist of amylin and calcitonin receptors with a half-life of approximately 10 days, supporting once-weekly dosing.¹

Weight Loss Plateaued Above 5 mg

The trial randomly assigned 493 adults without type 2 diabetes who had a BMI of at least 30 kg/m², or at least 27 kg/m² with hypertension or dyslipidemia, across 32 sites in Poland, Romania, and the US; 485 received at least 1 dose. Participants were assigned 5:1 to 1 of 5 petrelintide maintenance doses (1.0 mg to 9.0 mg) or placebo, starting at 0.5 mg with fixed 4-week escalation steps. All received lifestyle counseling targeting a deficit of approximately 500 kcal/day.¹

At week 28, the primary end point, mean weight change, ranged from –7.9% to –9.8% with petrelintide vs –1.7% with placebo (P < .0001 for all comparisons). By week 42, reductions reached –8.7% to –10.7%, while the placebo showed no further change. The 5.0-mg, 7.0-mg, and 9.0-mg doses produced similar results, which the authors said suggests a plateau. At week 42, 34% to 56% of participants receiving petrelintide lost at least 10% of body weight vs 9% with placebo; week 42 end points were exploratory.¹

Nausea Was the Main GI Signal

Nausea occurred in 20% of participants receiving petrelintide vs 6% with placebo; 80% of cases were mild, and 73% occurred during dose escalation. Rates of diarrhea (7% vs 7%) and constipation (7% vs 4%) were low, and vomiting was infrequent overall (3% vs 6%), although the 9.0-mg group reached 9%. Just 1% of participants permanently discontinued petrelintide due to GI events, 2% required dose reductions, and 88% to 98% reached their target maintenance dose.¹

For pharmacists, the profile points to escalation-phase nausea as the key counseling focus. Other signals included anti-petrelintide antibodies in 38% of treated participants, with no apparent effect on weight loss, and alopecia in 5% vs 1% with placebo. Three serious adverse events were considered treatment related: 2 cases of cholelithiasis and 1 of obstructive pancreatitis. No deaths occurred.¹

Cardiometabolic Effects and Limitations

Petrelintide was associated with reductions in high-sensitivity C-reactive protein of up to 41% vs 6% with placebo, systolic blood pressure reductions of 2.8 to 4.0 mm Hg, and greater high-density lipoprotein cholesterol increases. Reductions in triglycerides and low-density lipoprotein cholesterol were largely similar to placebo, and several of these analyses were post hoc. Pulse rate decreased slightly, in contrast to increases typically seen with GLP-1 RAs.¹

The population was 86% White, only 4% had a BMI between 27 and 30 kg/m², and dose groups were not masked from one another. The authors cautioned against cross-trial comparisons, noting that weight loss was similar to the 11.5% reported with cagrilintide after 68 weeks.^1,3

The study authors noted that it remains an open question whether amylin–GLP-1 combinations improve tolerability over GLP-1 monotherapy but wrote that "amylin-based therapies might have a future as individual as well as combination therapies." Petrelintide will advance to phase 3 evaluation.^1,2

REFERENCES

1. Garvey WT, Ard J, Connery L, 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. Published online September 29, 2026. doi:10.1016/S2213-8587(26)00213-5

2. European Association for the Study of Diabetes. New amylin-based obesity drug petrelintide can deliver over 10% weight loss; less than GLP-1 / incretin drugs on average but with far fewer side effects. News release. September 29, 2026.

3. Garvey WT, Blüher M, Osorto Contreras CK, et al; REDEFINE 1 Study Group. Coadministered cagrilintide and semaglutide in adults with overweight or obesity. N Engl J Med. 2025;393:635-647.