Petrelintide, an amylin drug, cut weight ~9% with little extra nausea

Almost every blockbuster weight-loss drug on the market works through the GLP-1 pathway. Petrelintide takes a different route: it is a long-acting analogue of amylin, a hormone the pancreas releases alongside insulin that signals fullness to the brain [s1]. A phase 2 trial called ZUPREME 1 has now reported that the once-weekly injection produced roughly 9% weight loss over 28 weeks — and, notably, caused little more nausea or vomiting than placebo [s1]. That tolerability profile is the result worth watching, because gastrointestinal side-effects are a major reason people abandon GLP-1 drugs.

Amylin is normally co-secreted with insulin after a meal and acts in the brainstem to promote satiety and slow stomach emptying. Interest in copying that signal has grown as researchers look for weight-loss mechanisms that do not rely on the incretin system, either to use on their own or to stack with a GLP-1 drug for larger effects. ZUPREME 1 is the first large randomised test of petrelintide specifically, and so its job is to show whether the approach is worth carrying into late-stage trials [s1].

What the trial did

ZUPREME 1 was a multicentre, randomised, double-blind, placebo-controlled trial at 32 sites in Poland, Romania and the USA, registered as NCT06662539 [s1][s3]. It enrolled adults without type 2 diabetes who had a body-mass index (BMI) of at least 30, or at least 27 with high blood pressure or abnormal blood lipids [s1]. Participants were randomly assigned 5:1 to self-administered once-weekly petrelintide at maintenance doses from 1.0 to 9.0 mg, or to placebo, for 42 weeks including a dose-escalation period [s1]. The primary endpoint was the percentage change in body weight from baseline at 28 weeks [s1].

From Dec 9, 2024, to Feb 25, 2025, 714 people were screened, 493 were randomly assigned and 485 received at least one dose [s1]. The groups were well matched: 255 (53%) were female, mean age was 47 years, mean body weight 107.1 kg and mean BMI 36.7 [s1].

What it found

At 28 weeks, the mean weight loss (efficacy estimand) was -7.9% at both the 1.0-mg and 2.5-mg doses, -9.8% at 5.0 mg, -9.3% at 7.0 mg and -9.4% at 9.0 mg, versus -1.7% with placebo [s1]. The estimated treatment differences versus placebo ranged from -6.2 percentage points at the lowest dose to -8.1 points at 5.0 mg [s1]. Weight continued to fall through week 42, reaching up to -10.7% with petrelintide — a sign the 28-week figure had not yet plateaued [s1].

The tolerability data are the trial's distinctive feature. Nausea was the most common side-effect, in 79 (20%) of 404 petrelintide-treated participants versus five (6%) on placebo, and was described as predominantly mild and concentrated during dose escalation [s1]. Vomiting was infrequent — 12 (3%) with petrelintide versus five (6%) with placebo — and rates of diarrhoea (7% vs 7%) and constipation (7% vs 4%) were close to placebo [s1]. No deaths were reported [s1].

How to read it

The weight loss here is real but should be placed in context. A roughly 9% reduction at 28 weeks is meaningful, yet below the 15-25% seen with the strongest GLP-1 and multi-receptor drugs over longer periods — and this was a shorter trial [s1]. The more interesting claim is mechanistic: because amylin agonism curbs appetite through a different pathway, it may spare patients the heavy gastrointestinal burden of incretin drugs, and it is being explored both alone and in combination with them [s1][s2]. An accompanying commentary frames petrelintide within a growing effort to build obesity treatments around amylin rather than, or in addition to, GLP-1 [s2].

Two cautions apply. This is a phase 2 trial — mid-stage, designed to establish dose and signal, not to confirm benefit — so the findings need replication in larger, longer phase 3 studies [s1]. And it was funded by Zealand Pharma, petrelintide's developer, with several authors employed by the company [s1]; the trial kept participants, staff and the funder masked to treatment assignment, which guards against bias, but the usual reservations about industry-sponsored registration-track trials still apply [s1].

What to watch

The questions ZUPREME 1 cannot answer are the ones phase 3 must: whether the weight loss deepens and holds over a year or more, how petrelintide compares head-to-head with established drugs, and whether its gentler side-effect profile survives at scale [s1]. If it does, an effective weight-loss drug that most people can actually tolerate would matter — because the best drug is of little use to someone who stops taking it.

Sources

• [s1] Petrelintide, a human amylin analogue for the treatment of obesity (ZUPREME 1). The Lancet Diabetes & Endocrinology, 29 September 2026. https://doi.org/10.1016/S2213-8587(26)00213-5
• [s2] Petrelintide and the evolving role of amylin agonism in obesity. The Lancet Diabetes & Endocrinology, 29 September 2026. https://doi.org/10.1016/S2213-8587(26)00216-0
• [s3] Once-weekly Petrelintide Versus Placebo for Obesity or Overweight With Co-morbidities (ZUPREME 1). ClinicalTrials.gov, NCT06662539. https://clinicaltrials.gov/study/NCT06662539