Petrelintide trial reports nearly 10 percent weight loss with nausea as the main side effect

A phase 2 petrelintide trial found that adults with obesity lost up to 9.8% of their body weight in 28 weeks, against 1.7% on placebo. The paper in The Lancet Diabetes and Endocrinology names nausea as the main side effect of the weekly amylin analogue. Medical News Today revisited the results on October 24. The study, called ZUPREME 1, was funded by the developer, Zealand Pharma. It compared petrelintide only with placebo, so claims that it is easier to tolerate than GLP 1 drugs remain untested.

What the ZUPREME 1 study tested

The petrelintide trial enrolled adults without type 2 diabetes who had a body mass index of at least 30, or at least 27 with high blood pressure, abnormal blood lipids or both. It ran at 32 public hospitals and private clinics in Poland, Romania and the United States, according to the paper. Investigators screened 714 people between December 9, 2024 and February 25, 2025, randomised 493 and gave at least one dose to 485. Participants injected petrelintide or placebo under the skin once a week for 42 weeks, a period that included a stepwise dose escalation. Five petrelintide groups each moved up to a different maintenance level, and five people received the drug for every one who received placebo.

The primary endpoint was the percentage change in body weight from the start of the study to week 28. Participants and staff did not know who received the drug, because petrelintide and placebo came in identical vials, but they did know the dose level. The group was 53% female, with a mean age of 47 years, a mean weight of 107.1 kilograms and a mean body mass index of 36.7. Most participants, 86%, were White, which limits what the results say about other groups. The study is listed as NCT06662539 in the US trial registry, which records it as completed on March 7, 2026. Zealand Pharma, which developed petrelintide, paid for the study.

Weight loss at 28 and 42 weeks

Every petrelintide group lost more weight than the placebo group by the 28 week mark. Mean weight change was minus 7.9% in the two lowest dose groups, minus 9.8% in the middle group, and minus 9.3% and minus 9.4% in the two highest groups, the paper reports. The placebo group lost 1.7%. Measured against placebo, the estimated treatment differences ran from 6.2 to 8.1 percentage points. These figures use the efficacy estimand, which estimates the effect in people who kept taking the drug as planned. Weight kept falling after the primary endpoint, and the authors report losses of up to 10.7% by week 42, when treatment ended.

Weight kept falling after the primary endpoint, and the authors report losses of up to 10.7% by week 42, when treatment ended.

The response flattened above the middle level. The three highest groups landed within half a percentage point of each other, so stepping up the dose added little extra weight loss in this study. That pattern will shape the choice of doses for later trials, since a higher level that adds side effects without more benefit offers patients nothing. The trial was also shorter than the phase 3 studies behind approved incretin drugs, and it enrolled a different population, so its numbers cannot be set side by side with theirs. The full results, with confidence intervals for each group, are in the published trial report00213-5/fulltext). The table below summarises the primary endpoint.

Nausea and other gastrointestinal side effects

Nausea was the most common adverse event with petrelintide, reported by 79 of the 404 treated participants, or 20%, against 6% of the placebo group. The authors describe it as mostly mild and concentrated in the dose escalation phase. Other gastrointestinal side effects were less frequent. Vomiting affected 3% of people on petrelintide and 6% on placebo, diarrhoea 7% in both groups, and constipation 7% against 4%. No deaths were reported. In a linked comment in the same journal, Sten Madsbad and Jens Juul Holst noted that only six of the 404 people given petrelintide stopped treatment because of stomach and bowel events. The paper concludes that tolerability was similar to placebo apart from nausea.

The idea that petrelintide causes fewer stomach problems than GLP 1 drugs goes further than this study can. The petrelintide trial had no GLP 1 comparison group, and no semaglutide or tirzepatide arm. The two commentators wrote that it is "also unclear" whether gastrointestinal effects would occur in the same people who cannot tolerate GLP 1 based therapies. Clare Thompson, a general practitioner interviewed by Medical News Today, said more data and a phase 3 trial are needed before patients can draw conclusions about choosing an amylin product instead of a GLP 1. Only larger and longer trials, ideally with a direct comparison, could settle the tolerability question.

Amylin analogues and what comes next

Amylin is a hormone released together with insulin from the pancreas after meals. It slows stomach emptying, lowers glucagon after eating and probably acts as a fullness signal, Madsbad and Holst wrote, through pathways that partly complement those of GLP 1. Petrelintide is a long acting amylin analogue built for once weekly injection. Several companies are now testing such molecules on their own and in pairs with incretin drugs. In October, Lilly reported that eloralintide combined with tirzepatide produced more weight loss than tirzepatide alone in a phase 2b study. Novo Nordisk pairs its own amylin analogue, cagrilintide, with semaglutide in CagriSema.

Zealand Pharma agreed in 2025 to develop and sell petrelintide jointly with Roche, a deal covered in our report on Roche and amylin. On October 7, Zealand reported topline results from a second phase 2 study, ZUPREME 2, in 220 adults with overweight or obesity and type 2 diabetes. Weight fell by up to 9.2% at 28 weeks, against 2.0% on placebo, the company said. The partners have started a phase 3a program of three trials expected to enroll about 7,000 people. An Indian expert committee has also recommended permission for three Roche phase 3 trials of the drug. Petrelintide remains investigational and is not approved anywhere.

Conclusion

The ZUPREME 1 petrelintide trial offers the clearest look so far at a weekly amylin analogue used on its own. Weight loss reached 9.8% at 28 weeks in the best performing group, and nausea, mostly mild and early, was the main side effect. The study did not test petrelintide against any GLP 1 drug, so a tolerability advantage over that class is not proven. The phase 3a program run with Roche will show whether the results hold. This report is research news, not medical advice.