Zenagamtide (amycretin)

Zenagamtide, formerly called amycretin, is an investigational peptide that combines GLP-1 and amylin-family receptor activity in one molecule. Novo Nordisk is developing both oral and subcutaneous formulations for weight management and type 2 diabetes. Early obesity trials produced substantial weight reductions, and the phase 2 diabetes program has now shown improved glycemic control with both routes. Understanding this candidate requires keeping its molecular design, the two formulations and the different trial populations connected to their results.

Overview

Kuhre and colleagues (2025) describe a 68-residue peptide with GLP-1-receptor-active and amylin-receptor-active regions joined by a short linker. A C18 fatty-diacid side chain promotes reversible albumin binding, while an unusual amino acid near the GLP-1 region's N-terminus helps resist degradation by DPP-4. The peptide is amidated at its C-terminus.

Molecular profile

Current name: Zenagamtide Source
Earlier names: Amycretin; NNC0487-0111 Source
Molecular form: Acylated, C-terminally amidated unimolecular peptide Source
Residue count: 68 Source
Formula of characterized peptide: C343H550N94O116 Source
Reported average molecular mass: 7,847 Da Source
Receptor activity: GLP-1, amylin and calcitonin receptor agonism Source
Clinical formulations: Oral and subcutaneous, evaluated in separate groups Source
Clinical status: Investigational; phase 3 development programs Source

Forms and derivatives

Amycretin / zenagamtide

Zenagamtide is the current name for the candidate originally called amycretin; both names identify the same peptide in the clinical literature.

Oral and subcutaneous formulations

Both deliver zenagamtide, with different absorption requirements and separately tested treatment groups. Route-specific trial results remain attached to their formulations.

The 2026 clinical papers use the name zenagamtide and explicitly describe agonism at GLP-1, amylin and calcitonin receptors. Older papers and registries use amycretin or NNC0487-0111. These names connect the same development candidate across its research history. Oral and injected preparations are separate formulations of that candidate and have been evaluated in separate trial groups.

Uses and research areas

The program addresses two related clinical goals: reducing weight in obesity and improving glycemic control in type 2 diabetes. Weight was an important outcome in the early obesity trials, while the phase 2 diabetes papers made change in HbA1c their primary endpoint. HbA1c reflects average glycemic exposure over preceding months, which makes it useful for evaluating sustained treatment rather than the glucose response to a single meal.

Novo Nordisk's second-quarter 2026 development presentation describes the AMAZE obesity and AMBITION diabetes phase 3 programs. It also outlines studies of obesity-related conditions and cardiovascular outcomes. A planned or ongoing trial identifies what the program aims to establish; its results will determine whether benefit extends to those specific clinical outcomes.

Mechanism of action

Complementary receptor systems in one peptide

The GLP-1 and amylin systems influence appetite and metabolism through overlapping but distinct receptor networks. GLP-1 receptor activity contributes to glucose-dependent insulin secretion and the regulation of eating. Amylin-family signaling contributes another appetite pathway, making combined receptor activity a rational target for drug development. Connecting the active regions in one peptide also fixes their relationship within each molecule: both travel as part of the same administered candidate.

The amylin receptor family has an unusual architecture. A calcitonin receptor associated with a receptor activity-modifying protein, or RAMP, forms an amylin receptor. Christopoulos and colleagues (1999) showed how RAMP association changes receptor pharmacology. This helps explain why the terms amylin and calcitonin appear together in zenagamtide's characterization. The observed receptor profile is compound-specific; the architecture alone does not require every amylin agonist to activate the unpaired calcitonin receptor to the same extent.

What preclinical measurements add

In a 21-day study, Kuhre and colleagues (2025) compared subcutaneous amycretin in male rats with diet-induced obesity against rats given the injection preparation without amycretin (the vehicle) and calorie-restricted rats whose weight loss was matched to the treated group. The two weight-loss groups ended with similar body composition, but the calorie-restricted controls had lower total energy expenditure than amycretin-treated rats. Expenditure in the amycretin group did not differ significantly from vehicle. The authors interpreted this pattern as attenuation of metabolic adaptation, the decline in energy use that can accompany weight loss. Matching weight loss makes that adaptation visible alongside the reduction in food intake.

The comparison examined energy balance during rat weight loss. Determining the contribution of each receptor system requires component comparisons or experiments directed at those targets. The clinical trials evaluate the whole peptide and quantify the response while both active regions are present.

Pharmacokinetics

The two formulations solve different exposure problems. Subcutaneous administration allows absorption into circulation from tissue, while an oral peptide must also cross the digestive barrier and withstand conditions encountered before absorption. Gasiorek and colleagues (2025) studied SNAC-based oral formulations, using an absorption-enhancing formulation strategy. Consequently, the amount in a tablet and the amount in an injected preparation do not by themselves establish equivalent circulating exposure.

The clearest current human exposure comparison comes from Oldenburg and colleagues (2026), who studied 42 adults after a single subcutaneous administration. Four groups with differing degrees of renal impairment were compared with a normal-function group. Geometric mean total exposure ranged from 520 to 715 h·nmol/L across impairment groups, compared with 543 h·nmol/L with normal function; the investigators judged the differences clinically unimportant under those study conditions.

Total exposure, expressed as the area under the concentration-time curve, integrates how much compound is present over time. It can remain broadly similar even when peak concentration or the timing of the peak changes. This renal study addresses the handling of the injected candidate across renal-function groups; it does not measure oral absorption or the long-term response to repeated treatment in those groups.

Research findings

The first oral and subcutaneous studies

Gasiorek and colleagues (2025) enrolled 144 people across a multipart first-in-human study. The oral treatment periods assessed safety, exposure and weight response, with gastrointestinal events forming the main adverse-event pattern. The findings established that an oral formulation could produce a clinical response and supported subsequent dose-finding research.

In the subcutaneous phase 1b/2a study, Dahl and colleagues (2025) randomized 125 adults with overweight or obesity. The group escalated to the highest studied amount had an estimated mean weight change of −24.3% at week 36, compared with −1.1% for its placebo group. The authors also reported substantial withdrawal, much of it for reasons unrelated to treatment-emergent adverse events. Small cohorts and attrition make the estimated treatment response particularly important to read alongside the trial's participant flow.

Phase 2 diabetes findings with both routes

Mora and colleagues' subcutaneous study (2026) randomized 262 adults whose type 2 diabetes was inadequately controlled on metformin, with or without an SGLT2 inhibitor. At 36 weeks, estimated HbA1c change ranged from −0.9 to −1.7 percentage points across zenagamtide groups. For the highest studied dose, the estimated difference from placebo was −1.56 percentage points, with a 95% confidence interval from −2.05 to −1.07. The analysis estimated the effect while participants were receiving treatment without additional rescue medication, which matters when comparing it with analyses that include treatment stopping or rescue therapy.

The companion oral paper by Mora and colleagues (2026) included 186 participants, with 156 allocated to active treatment and 30 to placebo. At 36 weeks, estimated mean HbA1c reductions were 0.9, 1.3 and 1.4 percentage points across its three active groups. The highest group's estimated difference from placebo was −1.09 points. Both papers therefore show glycemic activity in the studied diabetes population, while their different routes and treatment groups prevent a simple comparison based on administered amounts.

Novo Nordisk's June 2026 report also reported weight reduction of up to 14.6% in the subcutaneous diabetes program. This belongs to the diabetes population and 36-week study; the larger early obesity estimate came from a different trial. The population difference is essential when comparing those headline figures.

Safety and tolerability

Zenagamtide remains investigational and is not FDA-approved as of October 13, 2026. Gastrointestinal symptoms recur across its oral and injected studies. In the oral phase 2 diabetes trial, gastrointestinal events occurred in 26%, 41% and 47% of active-treatment groups, compared with 23% with placebo. Seven active-treatment participants had serious adverse events, compared with none on placebo, and no deaths occurred. The report's safety assessment concerns the complete trial and event characteristics rather than an assumption that every event was caused by the peptide.

The subcutaneous phase 2 paper reported 21 participants with serious adverse events among 261 exposed participants, including three in the placebo group, with no deaths. Most adverse events were gastrointestinal and mild to moderate. Taken together, the trials characterize a tolerability pattern that later studies must examine over longer follow-up and in larger populations.

The renal study provides useful exposure information after one administration, but broader clinical safety in chronic kidney disease depends on continuing-treatment evidence. Pregnancy, pediatric use and unsupervised combinations are also outside the established evidence summarized here. Trial findings apply to the controlled formulations used in the program.

What the research means

Zenagamtide now has more than an early weight-loss signal: randomized phase 2 diabetes studies demonstrate glycemic activity with both oral and injected formulations. Its unimolecular design gives the program a coherent way to combine GLP-1 and amylin-family effects, while the route options address different formulation and exposure requirements.

The remaining development questions are clinically consequential. Larger trials need to determine sustained weight and glycemic responses, treatment continuation, effects on obesity-related complications and long-term safety. A direct clinical comparison with an active treatment would also help place the candidate relative to established alternatives. The current studies support continued investigation without establishing a numerical ranking among compounds tested in different trials.

FAQs

Why do newer papers call amycretin zenagamtide?

The 2026 phase 2 papers use zenagamtide and explicitly identify amycretin as the former name. Mora and colleagues (2026) connect the current name to the earlier development literature, so both are retained for searching and reading.

Does it act at the calcitonin receptor as well?

The 2026 clinical papers explicitly include calcitonin-receptor agonism in the candidate's characterization. Mora and colleagues (2026) describe the receptor scope directly. Amylin receptors themselves contain a calcitonin-receptor component associated with a RAMP, although each candidate's activity profile requires its own assays.

Why are oral and injected results reported separately?

The formulations have different absorption requirements and were studied in distinct treatment groups. A tablet's administered amount therefore cannot be compared directly with an injected amount as a measure of exposure. Gasiorek and colleagues (2025) describe the absorption-enhancing oral formulation strategy.

Is zenagamtide the same as CagriSema?

Zenagamtide joins receptor-active regions within one peptide. CagriSema combines cagrilintide and semaglutide as distinct medicines. The related profiles explain those candidates; sharing a broad pharmacological goal does not make their formulations, trial populations or results interchangeable.

Why is the early obesity weight estimate larger than the diabetes estimate?

The figures came from separate populations, study groups and analyses. Dahl and colleagues (2025) studied early subcutaneous treatment in overweight or obesity, while the later diabetes program tested glycemic control in people receiving background diabetes treatment. Their headline percentages do not constitute a direct comparison.

Is either formulation approved?

Both remain investigational as of October 13, 2026. Novo Nordisk's 2026 presentation documents continued development through the AMAZE and AMBITION programs.

Cagrilintide and semaglutide explain the two pharmacological areas that motivated combined amylin and GLP-1 strategies. Zenagamtide joins active regions in one peptide, while the cagrilintide–semaglutide program evaluates two distinct medicines. Eloralintide and petrelintide provide related amylin-directed candidates with their own receptor profiles, chemical modifications and clinical programs.

References

Kuhre RE, Ballarín-González B, Brand CL, Glendorf T, Madsen KG, Hjøllund KR, et al. The effect of amycretin, a unimolecular glucagon-like peptide-1 and amylin receptor agonist, on body weight and metabolic dysfunction in mice and rats. EBioMedicine. 2025;118:105862. doi:10.1016/j.ebiom.2025.105862.
Defines the structure and receptor profile; the weight-matched rat experiment examines energy use during comparable weight loss.
Gasiorek A, Heydorn A, Gabery S, Hjerpsted JB, Kirkeby K, Kruse T, Petersen SB, Toubro S, Vegge A, Key C. 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. The Lancet. 2025;406(10499):135–148. doi:10.1016/S0140-6736(25)01176-6.
The first oral study establishes clinical activity and documents the use of absorption-enhancing formulations.
Dahl K, Toubro S, Dey S, Duque do Vale R, Flint A, Gasiorek A, et al. Amycretin, a novel, unimolecular GLP-1 and amylin receptor agonist administered subcutaneously: results from a phase 1b/2a randomised controlled study. The Lancet. 2025;406(10499):149–162. doi:10.1016/S0140-6736(25)01185-7.
Supplies early obesity weight estimates and makes substantial participant withdrawal part of their interpretation.
Mora P, Aroda VR, Asong M, Blüher M, Heftdal LD, Fenger Carlander AL, Vilsen LN, Rosenstock J. Efficacy and safety of once-weekly subcutaneous zenagamtide, a novel unimolecular GLP-1 and amylin receptor agonist, in type 2 diabetes: a multicentre, randomised, parallel, double-blind, placebo-controlled, dose-finding, phase 2 trial. The Lancet. 2026;408(10555):621–635. doi:10.1016/S0140-6736(26)01248-1.
The injected phase 2 paper quantifies HbA1c change in diabetes and explicitly identifies calcitonin-receptor agonism.
Mora P, Aroda VR, Asong M, Blüher M, Fenger Carlander AL, Kaltoft M, Vilsen LN, Rosenstock J. Efficacy and safety of once-daily oral zenagamtide, a novel unimolecular GLP-1 and amylin receptor agonist, in adults with type 2 diabetes: a multicentre, randomised, parallel, double-blind, placebo-controlled, dose-finding, phase 2 trial. The Lancet. 2026;408(10555):607–620. doi:10.1016/S0140-6736(26)01247-X.
The companion oral trial reports glycemic responses and gastrointestinal events in route-specific treatment groups.
Oldenburg LIK, Haugaard SP, Karlsson T, Kegel-Hübner V, Parwez M, Wiingaard C, Flint A. Renal Impairment Does Not Affect Pharmacokinetics, Safety or Tolerability of Zenagamtide. Diabetes, Obesity and Metabolism. 2026;28(10):8946–8954. doi:10.1111/dom.71096.
The single-administration study compares total exposure across renal-function groups and supplies a measured human PK context.
Novo Nordisk. Zenagamtide Phase 2 T2D Data at ADA 2026. Sponsor press release. June 5, 2026.
Reports the subcutaneous diabetes program's bodyweight endpoint in its own trial population.
Novo Nordisk. Investor presentation: Second quarter of 2026. August 2026.
Documents the renamed candidate and the AMAZE and AMBITION development programs.
Christopoulos G, Perry KJ, Morfis M, Tilakaratne N, Gao Y, Fraser NJ, Main MJ, Foord SM, Sexton PM. Multiple amylin receptors arise from receptor activity-modifying protein interaction with the calcitonin receptor gene product. Molecular Pharmacology. 1999;56(1):235–242. doi:10.1124/mol.56.1.235.
Coexpression experiments explain how calcitonin receptors acquire amylin-receptor pharmacology through RAMP association.

Glossary

Unimolecular: Contained within one molecular entity rather than separate coadministered components.
DPP-4: An enzyme that can cleave susceptible peptides, including native GLP-1.
SNAC: An absorption enhancer used in the studied oral formulation strategy.
Area under the curve: An integrated measure of concentration over time, used to quantify total systemic exposure.
SGLT2 inhibitor: A diabetes medicine class that reduces renal glucose reabsorption.
HbA1c: Hemoglobin with glucose attached; its proportion in blood helps estimate average blood glucose over the preceding months.
RAMP: A receptor activity-modifying protein that changes receptor-complex pharmacology.