Amycretin: Novo Nordisk's GLP-1 + Amylin Drug With 22% Weight Loss

Most obesity drugs in late-stage development chase a single headline: how much weight can one molecule strip off. Amycretin is interesting for a second reason. Novo Nordisk built it as one peptide that activates two appetite pathways — the GLP-1 receptor and the amylin receptor — and then engineered it in two forms at once: a subcutaneous injection and a daily oral tablet. In its phase 1b/2a injectable trial, amycretin produced up to 22% mean body weight reduction over 36 weeks, and the weight-loss curve had not flattened by the end of the study.

That number lands amycretin in the same efficacy tier as retatrutide and tirzepatide, but the dual-formulation strategy and the unusually short timeline behind the 22% figure make it a distinct candidate worth understanding on its own terms. Here is what the published evidence actually shows, where the caveats sit, and how to read the trial readouts coming over the next few years.

What Amycretin Is

Amycretin is a unimolecular GLP-1 and amylin receptor co-agonist — a single engineered peptide that switches on both receptors rather than combining two separate drugs in one syringe. That distinction matters, and it separates amycretin from the other amylin-based approach in late development.

The logic comes from how amylin works. Amylin is a hormone co-secreted with insulin from pancreatic beta cells. It suppresses appetite, slows gastric emptying, and signals satiety through the brainstem and hypothalamus — pathways that overlap with but are not identical to GLP-1 signaling. Combining the two produces additive, sometimes synergistic, appetite suppression.

Evidence: "Amylin, which suppresses appetite and slows gastric emptying, enhances the effects of GLP-1-based therapies when used in combination." — Dahl K, et al. Lancet. 2025. 10.1016/S0140-6736(25)01185-7

Novo Nordisk's other amylin candidate, the cagrilintide-plus-semaglutide combination, pairs two distinct molecules. Amycretin folds both activities into one peptide, which simplifies manufacturing and dosing and is part of why the company could pursue an oral version.

The Injectable Data: Where the 22% Comes From

The pivotal early readout was a phase 1b/2a randomised, placebo-controlled trial run at a single research center in San Antonio, Texas, published in The Lancet in 2025. It enrolled 125 adults with overweight or obesity — 101 randomised to subcutaneous amycretin and 24 to placebo — across three dose cohorts with different treatment durations.

Dose-Dependent Weight Loss

Dose	Duration	Mean weight change	Placebo
1.25 mg	20 weeks	−9.7%	+1.9%
5 mg	28 weeks	−16.2%	+2.3%
20 mg	36 weeks	−22.0%	+2.0%

Two features of the curve are as notable as the headline.

1. No plateau. At every dose, weight was still trending downward when the trial ended. Most GLP-1 monotherapy curves flatten by week 40–60; amycretin's 22% was reached in 36 weeks and had not leveled off.
2. Placebo gained weight. The comparison group put on roughly 2% over the same windows, which widens the placebo-adjusted difference further.

Evidence: "Estimated body weight loss of 9.7% on 1.25 mg, 16.2% on 5 mg, and 22.0% on 20 mg, over treatment durations of 20, 28, and 36 weeks respectively, while placebo participants gained weight." — Dahl K, et al. Lancet. 2025. 10.1016/S0140-6736(25)01185-7

The Tolerability Cost

The efficacy came with a substantial gastrointestinal burden in this dose-escalation setting. Nausea affected 82% of treated participants, vomiting 53%, and diarrhea 41%, with rates rising at higher doses. A dysaesthesia signal (altered skin sensation) appeared in 18–29% of participants, and there was one case of mild gallstone pancreatitis.

Those numbers read high, but context matters: phase 1b/2a trials push doses aggressively to find ceilings, and titration schedules in larger trials are designed to blunt GI effects. Whether a phase 3 titration tames tolerability the way it did for semaglutide and tirzepatide is one of the open questions.

The Oral Data: A Pill That Works Like an Injection

The harder engineering problem was the tablet. Peptides are notoriously difficult to deliver orally — they degrade in the gut and absorb poorly, which is why oral semaglutide requires an absorption enhancer and strict fasting conditions. Amycretin's first-in-human oral trial, published alongside the injectable study, tested whether the molecule could survive that route.

It enrolled 144 adults with overweight or obesity and no diabetes, dosed across single- and multiple-ascending-dose cohorts over up to 12 weeks.

Oral regimen	Duration	Mean weight change	Placebo
50 mg once daily	12 weeks	−10.4%	~−1.1%
2 × 50 mg once daily	12 weeks	−13.1%	~−1.1%

A 13.1% reduction from a daily pill in just 12 weeks is striking — it approaches what injectable semaglutide achieves over 68 weeks. Adverse events were again predominantly gastrointestinal, all mild to moderate, and dose-dependent.

Evidence: "Across parts A–D, there were 364 treatment-emergent adverse events in 89 (62%) of 144 participants, all mild or moderate in severity; the most common were gastrointestinal." — Gasiorek A, et al. Lancet. 2025. 10.1016/S0140-6736(25)01176-6

For patients who prefer not to inject, a pill in this efficacy range would be a meaningful shift. The closest current oral competitor in development is orforglipron, a small-molecule GLP-1 agonist — but orforglipron hits only the GLP-1 receptor, while oral amycretin carries the dual mechanism into tablet form.

How Amycretin Compares to Approved and Pipeline Drugs

Cross-trial comparisons are unreliable — different populations, durations, and titration schemes mean these numbers should be read as ranges, not a leaderboard. With that caution, here is the landscape amycretin is entering.

Drug	Mechanism	Form	Peak weight loss	Trial length
Semaglutide (Wegovy)	GLP-1	Weekly injection	~14.9%	68 weeks
Tirzepatide (Zepbound)	GLP-1 / GIP	Weekly injection	~20.9%	72 weeks
Retatrutide	GLP-1 / GIP / glucagon	Weekly injection	~24.2%	48 weeks
Amycretin (SC)	GLP-1 / amylin	Weekly injection	~22.0%	36 weeks
Amycretin (oral)	GLP-1 / amylin	Daily pill	~13.1%	12 weeks

The amycretin figures stand out partly because they were achieved in shorter trials. A drug that reaches 22% in 36 weeks without plateauing could, in principle, push higher over a full 68- to 72-week course — but that is an extrapolation, not a result. Only phase 3 will show whether the trajectory holds, and how amycretin stacks up against tirzepatide and semaglutide when tested over comparable durations. For the established head-to-head between the two market leaders, see our breakdown of tirzepatide versus semaglutide.

Evidence: "Tirzepatide once weekly produced mean weight reductions of 15.0%, 19.5%, and 20.9% at the 5-mg, 10-mg, and 15-mg doses over 72 weeks." — Jastreboff AM, et al. NEJM. 2022. 10.1056/NEJMoa2206038

Beyond Weight: The Diabetes Signal

A separate phase 2 trial in adults with inadequately controlled type 2 diabetes reported dose-dependent HbA1c reductions of up to 1.8% by week 36, alongside meaningful weight loss. That positions amycretin as a dual obesity-and-diabetes candidate, the same commercial path semaglutide and tirzepatide took.

What Happens Next

Based on the early-phase results and regulatory feedback, Novo Nordisk has moved both the subcutaneous and oral formulations directly into phase 3 development for weight management — bypassing additional phase 2 dose-finding. The subcutaneous data were presented at the American Diabetes Association's 85th Scientific Sessions in June 2025.

Direct-to-phase-3 is an aggressive move that signals confidence, but it raises the stakes. Phase 3 must answer the questions a 125-person, single-site study cannot:

• Does the efficacy replicate at scale, across diverse populations and longer durations?
• Can titration control the GI burden seen in the dose-escalation trials?
• What is the safety profile over a year or more, including the dysaesthesia and pancreatitis signals?
• How durable is the weight loss after stopping, given what we know about weight regain after GLP-1 discontinuation?

Key Takeaways

• Amycretin is a single-peptide GLP-1 and amylin receptor co-agonist from Novo Nordisk, developed as both a weekly subcutaneous injection and a daily oral tablet.
• The injectable phase 1b/2a trial reported up to 22% mean weight loss over 36 weeks, with the curve still declining at the endpoint; the oral version delivered 13.1% in just 12 weeks.
• Efficacy came with high rates of gastrointestinal side effects in these dose-escalation studies, plus dysaesthesia and one mild pancreatitis case — tolerability in a properly titrated phase 3 remains unproven.
• Both formulations have advanced directly to phase 3 for obesity, and a phase 2 diabetes trial showed HbA1c reductions up to 1.8%.
• Amycretin is not FDA-approved and cannot be prescribed or compounded; approval, if it comes, is several years away pending phase 3 outcomes.

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References

1. Dahl K, Toubro S, Dey S, et al. Amycretin, a novel, unimolecular GLP-1 and amylin receptor agonist administered subcutaneously: results from a phase 1b/2a randomised controlled study. Lancet. 2025. DOI: 10.1016/S0140-6736(25)01185-7 — PMID: 40550231
2. Gasiorek A, Dahl K, Brian S, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of the first-in-class GLP-1 and amylin receptor agonist, amycretin: a first-in-human, phase 1, double-blind, randomised, placebo-controlled trial. Lancet. 2025. DOI: 10.1016/S0140-6736(25)01176-6 — PMID: 40550229
3. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. DOI: 10.1056/NEJMoa2032183
4. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216. DOI: 10.1056/NEJMoa2206038
5. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. DOI: 10.1056/NEJMoa2301972
6. Enebo LB, Berthelsen KK, Kankam M, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management. Lancet. 2021;397(10286):1736-1748. DOI: 10.1016/S0140-6736(21)01751-7

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Last updated: 2026-06-06 Medical review: Dr. James Chen, MD, PhD, FACE