Petrelintide users lost about 8% to 10% of body weight in 28 weeks in a phase 2 trial funded by its maker

The weight loss drugs that took over obesity medicine, semaglutide and tirzepatide, work through gut hormones, and they come with a familiar cost in nausea and other stomach trouble. Real-world data suggest that up to 75% of individuals stop injectable drugs of this kind within a year, the authors of a new trial note, and many then regain weight. People stop for many reasons, and stomach side effects are frequently reported as a leading cause.

That trial tested a drug that works another way. Petrelintide is a long-acting copy of amylin, a hormone the pancreas releases alongside insulin. In a randomized trial of 485 adults with obesity, weekly injections led to weight loss of about 8% to 10% after 28 weeks, compared with under 2% on placebo. Nausea was the main side effect and was mostly mild. The results were published in The Lancet Diabetes & Endocrinology and presented at the European Association for the Study of Diabetes meeting in Milan.

The trial was paid for by Zealand Pharma, the manufacturer of petrelintide. It was a phase 2 trial, the stage that settles on a dose before larger testing, and it lasted 42 weeks.

What amylin is and why petrelintide targets it

Amylin is a pancreatic hormone that induces satiety, the feeling of being full, and the pancreas releases it along with insulin. It helps regulate appetite via mechanisms partly independent of glucagon-like peptide-1, or GLP-1, the gut hormone that semaglutide and tirzepatide mimic. Drug companies have built longer-lasting versions of amylin to use as medicines, and petrelintide has a half-life of approximately 10 days, meaning it takes about that long for half a dose to clear, which allows a single injection each week.

The idea is not new. Cagrilintide, a long-acting amylin analogue from Novo Nordisk, cut weight by 6.0% to 10.8% depending on dose over 26 weeks in a 2021 phase 2 trial, against 3.0% on placebo. Several such drugs are now in development. The hope is that they will cause fewer side effects, even if they produce less weight loss than the strongest gut hormone drugs.

How the ZUPREME 1 trial of petrelintide worked

The trial, known as ZUPREME 1, ran at 32 sites (public hospitals and private clinics) in Poland, Romania and the United States. Its 485 participants were adults without type 2 diabetes who had a body mass index of at least 30, or at least 27 along with high blood pressure or high cholesterol. Their average age was 47, 53% were women, the average weight was 107.1 kilograms, about 236 pounds, and 86% were White.

They were assigned at random, five to every one, to one of five weekly doses of petrelintide from 1.0 to 9.0 mg or to a placebo, and injected themselves under the skin. Neither participants nor trial staff knew who was on petrelintide and who was on placebo, which came in identical vials, though the different doses were not hidden from one another. Everyone started at 0.5 mg and moved up in fixed 4-week escalation steps. All participants also received the same advice on diet and activity, aimed at an energy deficit of approximately 500 calories a day.

The main measure was the change in body weight after 28 weeks. The weight figures the paper leads with are what is called an efficacy estimate: they describe the effect in people taking the drug as intended. Estimates that count everyone who started, including those who stopped, tend to be somewhat smaller, a point that matters when trials are compared.

How much weight people lost on petrelintide

At 28 weeks, average weight change ranged from 7.9% to 9.8% lower across the five doses, against 1.7% on placebo. After subtracting the placebo effect, the drug’s own contribution was between 6.2 and 8.1 percentage points, the largest at the middle 5.0 mg dose. For the average participant, a 9.8% loss would mean a little over 10 kilograms, or about 23 pounds.

The loss did not stop there. Body weight continued to decline to week 42, reaching 8.7% to 10.7% on petrelintide while the placebo group stayed put. The three highest doses produced similar results, which the authors read as a plateau, and between 34% and 56% of people on petrelintide lost at least a tenth of their weight by week 42, against 9% on placebo. Those 42-week figures were exploratory, meaning the trial was not designed to test them.

“We are seeing over 10% weight loss with this medication,” said W. Timothy Garvey, an endocrinologist at the University of Alabama at Birmingham and the trial’s lead author, at an American Diabetes Association meeting in June. “I believe the data suggest in this phase 2 trial that this has the potential to be a better tolerated medication than GLP-1 therapy.” Garvey reports financial relationships with many drugmakers, Zealand Pharma among them.

There were modest changes in heart risk markers. A blood marker of inflammation fell by up to 41% on petrelintide and by 6% on placebo, and systolic blood pressure, the top number in a reading, dropped by about 3 to 4 points. Several of these analyses were post hoc, meaning they were decided after the data were in. Most blood fats moved about as much as on placebo.

Nausea and other side effects of petrelintide

The case for petrelintide rests on tolerability. The most common adverse event with petrelintide was nausea, in 79 of 404 people (20%), against 5 of 81 (6%) on placebo. About 80% of nausea cases were mild and 73% happened while the dose was being raised. Vomiting was less common on the drug than on placebo, at 3% versus 6%, though it reached 9% in the highest-dose group. Diarrhea affected 7% in both groups and constipation 7% against 4%.

Few people quit because of stomach trouble. In the authors’ words, the tolerability was “further supported by the low proportion of participants who permanently discontinued petrelintide due to gastrointestinal adverse events”, 1.5%, and between 88% and 98% reached their assigned dose.

Less common problems turned up too. Hair thinning was reported in 5% of people on petrelintide and 1% on placebo. Three serious problems were judged to be related to the drug: two cases of gallstones and one case of obstructive pancreatitis, in which a blocked duct inflames the pancreas. Antibodies against the drug appeared in 38% of treated participants, with no apparent effect on weight loss. No one died during the trial.

How petrelintide compares with semaglutide and other amylin drugs

The weight loss is smaller than with the best-known drug. In the main 68-week trial of semaglutide at the 2.4 mg obesity dose, average weight change was 14.9% in the semaglutide group as compared with 2.4% on placebo, a figure that counted everyone regardless of whether they stopped treatment. Petrelintide’s headline numbers are efficacy estimates, which tend to run higher, so the true gap between the drugs may be somewhat wider than the raw figures suggest. Stomach side effects were common there too, and 4.5% stopped treatment because of them, compared with 0.8% on placebo. The petrelintide authors cautioned against cross-trial comparisons, since trials differ in length, participants and how results were counted.

Within the amylin class, the authors noted, the weight loss was similar to the 11.5% reported with cagrilintide given alone over 68 weeks in a large phase 3 trial. That trial’s main purpose was to test cagrilintide combined with semaglutide, a pairing that produced 20.4% average weight loss over 68 weeks, but with gastrointestinal side effects affecting 79.6% in the combination group and 39.9% in the placebo group.

A 2026 network meta-analysis, which pooled six trials of the newer amylin-based drugs to compare them indirectly, found large weight losses at high doses but also more stomach side effects. Its authors called the evidence sparse and of low certainty, with results that are preliminary and require confirmation in larger trials.

In a commentary published alongside the trial, Sten Madsbad and Jens Holst of the University of Copenhagen pointed to the question that the combination results leave open. “The important open question is whether the side-effect profile of the combination therapies is improved compared with single GLP-1 agonist therapy, which was not evident in the cagrilintide and semaglutide trials,” they wrote. “However, amylin-based therapies might have a future as individual as well as combination therapies.”

What the petrelintide trial leaves untested

A short, early trial. Forty-two weeks of treatment says nothing about what happens over years, or after people stop. Phase 2 trials are built to choose a dose, and petrelintide now moves to phase 3, where it will need to repeat these results in more people.

Who took part. Participants were mostly White, none had diabetes, and only 4% had a body mass index between 27 and 30.

Who paid. Zealand Pharma funded the trial, and the lead author has financial ties to the company. On the other side of the ledger, the trial’s ClinicalTrials.gov record NCT06662539 was first posted in October 2024, before enrollment began in December, and the company did not know who was on which treatment while the trial ran.

The comparison that matters. This trial did not test petrelintide against semaglutide or tirzepatide, so whether it is truly easier to stay on remains a claim drawn from separate trials.

What petrelintide means for people with obesity

Petrelintide is not available outside trials. If later trials confirm these results, it would offer moderate weight loss, smaller on average than the strongest gut hormone drugs. Whether it causes less of the nausea that drives some people to stop would need a head-to-head trial to show. Whether a weight loss medicine suits a particular person is assessed by their doctor. Do not stop or change a prescribed medicine without talking to your doctor.

The authors wrote that the results “support both the effectiveness of this novel amylin agonist” and add to evidence that amylin-based drugs “might substantially improve tolerability and overall patient experience and potentially drive greater treatment adherence”, a hope that only longer, independent and head-to-head trials can test.