CagriSema

CagriSema names the clinical combination of cagrilintide, a long-acting amylin analogue, and semaglutide, a GLP-1 receptor agonist. It brings two appetite-related mechanisms into the same treatment programme. Published phase 3 trials show substantial weight reduction in adults with and without type 2 diabetes, while direct comparisons establish how its results depend on the population, comparator and component amounts tested. A February 2026 comparison with tirzepatide failed its prespecified noninferiority endpoint; a later sponsor report described a favourable comparison at different amounts in diabetes. These are separate experiments with different implications. CagriSema remained investigational on October 13, 2026. Garvey et al. (2025), Davies et al. (2025), Novo Nordisk (2026).

Overview

Molecular profile

Identity: Clinical combination of cagrilintide and semaglutide Source
Cagrilintide component: Long-acting amylin analogue Source
Semaglutide component: GLP-1 receptor agonist Source
Studied material: Coadministration in phase 2 and REDEFINE 1; fixed-dose combination described in REIMAGINE 2 Source
Clinical status: Investigational; US application submitted December 2025 Source

The combination contains two molecular identities. Semaglutide activates GLP-1 receptors; cagrilintide activates amylin-family and calcitonin receptors. Each component has its own sequence, modifications and pharmacokinetics. The name CagriSema therefore has no single amino-acid sequence or molecular formula.

The published phase 2 report explicitly describes coadministration, and the REDEFINE 1 paper is titled Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. The published REIMAGINE 2 report describes a fixed-dose combination, as do Novo Nordisk's development announcements. These descriptions identify the materials studied; an independently prepared mixture would require evidence about its formulation, stability and exposure before the trial findings could be applied to it. Frias et al. (2023), Garvey et al. (2025), Buse et al. (2026).

Uses and research areas

The REDEFINE programme studies weight management, and REIMAGINE studies type 2 diabetes. These programmes address connected but distinct outcomes. Weight reduction can affect metabolic disease, mobility and blood pressure, while HbA1c directly measures the longer-term glucose response. Cardiovascular outcome research asks whether the combination changes clinical events such as myocardial infarction or stroke, a question that requires its own follow-up.

Mechanism of action

GLP-1 is released from the gut in response to food. Its receptor signals influence appetite and enhance insulin secretion when glucose is elevated. Amylin is released from pancreatic beta cells alongside insulin and contributes to fullness and meal-related glucose regulation. The combination extends both sets of signals through long-acting analogues.

Amylin receptors have an unusual architecture: the calcitonin receptor pairs with a receptor activity-modifying protein, or RAMP, to form one of three receptor complexes. Structural studies show how that partner changes peptide binding. Cagrilintide engages these complexes and the calcitonin receptor itself, whereas semaglutide acts at a different receptor. This provides a biological rationale for complementary effects, which the trials test by comparing the combination with its separate components. Cao et al. (2022).

Pharmacokinetics

Semaglutide and cagrilintide were each engineered for prolonged exposure. Their molecular modifications support persistence, but they remain separate analytes when investigators measure plasma concentrations. A combined treatment does not acquire a shared elimination half-life simply because both components are administered within the same clinical programme.

A single combined exposure curve would obscure those separate kinetics. The component profiles explain their measured pharmacokinetic evidence; the combination studies reviewed here establish clinical outcomes without providing a verified common concentration–time dataset for one graph.

Research findings

The phase 2 comparison with each component

Frias and colleagues enrolled 92 adults with type 2 diabetes, BMI at least 27 and treatment with metformin with or without an SGLT2 inhibitor. At 32 weeks, the trial-product estimand produced weight changes of −15.6% with the coadministered combination, −5.1% with semaglutide and −8.1% with cagrilintide. The combination reduced HbA1c more than cagrilintide; its comparison with semaglutide did not reach statistical significance (P=0.075). The primary glucose comparison and the weight result therefore convey different information about what the combination added. Frias et al. (2023).

Weight outcomes in REDEFINE 1 and 2

REDEFINE 1 randomised 3,417 adults without diabetes to combination, semaglutide, cagrilintide or placebo, with lifestyle intervention in every group. At 68 weeks, treatment-policy mean weight change was −20.4% with the combination versus −3.0% with placebo. The adjusted difference was −17.3 percentage points (95% confidence interval −18.1 to −16.6). The treatment-policy estimand follows the intention-to-treat principle, incorporating the consequences of stopping or changing treatment. Garvey et al. (2025).

REDEFINE 2 enrolled 1,206 adults with type 2 diabetes and BMI at least 27. It assigned 904 to the combination and 302 to placebo, without separate component arms. At 68 weeks, treatment-policy mean weight change was −13.7% versus −3.4%, with an adjusted difference of −10.4 percentage points (95% confidence interval −11.2 to −9.5). The different diabetes status, eligibility and comparator structure make this a distinct clinical result. Davies et al. (2025).

Blood pressure within the REDEFINE 1 cohort

Verma and colleagues analysed blood pressure in the existing REDEFINE 1 population. Under the trial-product estimand, systolic pressure changed by −10.9 mmHg with CagriSema and −2.8 mmHg with placebo; diastolic changes were −5.4 and −1.7 mmHg. In the resistant-hypertension subset, the odds ratio for reaching the blood-pressure target was 1.7, with a wide confidence interval of 0.7–4.4. That subset result was inconclusive. The analysis adds information about a risk factor within the original cohort; it does not establish fewer cardiovascular events. Verma et al. (2026).

Published phase 3 diabetes studies

REIMAGINE 1 enrolled 189 adults whose diabetes was inadequately controlled with diet and exercise. At 40 weeks, efficacy-estimand HbA1c changes were −1.8 and −1.5 percentage points for combinations containing 2.4 mg or 1.0 mg of each component, versus −0.1 with placebo. Weight changes were −13.8%, −11.8% and −1.4%, respectively. Aroda et al. (2026).

REIMAGINE 2 randomised 2,713 adults using metformin with or without an SGLT2 inhibitor. Its primary efficacy-estimand comparison at 68 weeks found HbA1c changes of −1.91 percentage points with the 2.4-mg-per-component combination and −1.75 with semaglutide 2.4 mg. The difference was −0.16 percentage points (95% confidence interval −0.27 to −0.05; P=0.0035). This larger study demonstrated a modest additional glucose effect beyond the earlier phase 2 comparison. Buse et al. (2026).

REIMAGINE 3 studied the combination as an addition to basal insulin in 274 adults. At 40 weeks, efficacy-estimand HbA1c changes were −2.33 and −2.10 percentage points in the two active groups versus −0.66 with placebo. The background insulin treatment gives this study a distinct glucose and safety context. Rosenstock et al. (2026).

Novo Nordisk's February 23, 2026 announcement reported the open-label REDEFINE 4 trial in 809 adults with obesity and comorbidities over 84 weeks. CagriSema containing 2.4 mg of each component did not meet the primary noninferiority endpoint against tirzepatide 15 mg. Treatment-regimen weight reductions were 20.2% and 23.6%; adherence-assuming efficacy estimates were 23.0% and 25.5%. Noninferiority tests a prespecified acceptable difference from a comparator, and the primary requirement was not demonstrated. Novo Nordisk (February 2026).

The September 21 sponsor report described different assignments: REIMAGINE 5 compared CagriSema containing 1.0 mg of each component with tirzepatide 5 mg in adults with type 2 diabetes. At 60 weeks, efficacy-estimand weight reductions were 12.4% and 9.1%, while HbA1c reductions of 1.71 and 1.67 percentage points met the reported noninferiority comparison. The same announcement reported efficacy-estimand weight reductions of 21.0% versus 2.0% placebo at 68 weeks for the 1.0-mg-per-component group in REDEFINE 9. Detailed peer-reviewed reports are needed to examine these newer results fully; they do not alter the earlier REDEFINE 4 endpoint. Novo Nordisk (September 2026).

Safety and tolerability

Gastrointestinal events were common in the pivotal trials. They affected 79.6% of combination recipients versus 39.9% with placebo in REDEFINE 1, and 72.5% versus 34.4% in REDEFINE 2. The papers describe most events as transient and mild or moderate. Nausea, vomiting, diarrhoea and constipation can still affect treatment continuation and daily life even when classified below severe. Garvey et al. (2025), Davies et al. (2025).

Novo Nordisk submitted a US application in December 2025 and continued to call CagriSema investigational in September 2026. An application is a regulatory review milestone; the status evidence reviewed for October 13 does not establish marketing approval. Combination safety also requires the actual combination data, because adding adverse-event percentages from separate component trials would ignore differences in participants, exposure and symptom overlap. Novo Nordisk (2025), Novo Nordisk (September 2026).

The insulin-treated REIMAGINE 3 population reported no severe hypoglycaemia. That finding belongs to the supervised trial with its background treatment and protocol; it supplies useful safety context alongside the gastrointestinal events reported across the programme. Rosenstock et al. (2026).

What the research means

CagriSema demonstrates that combining amylin-family and GLP-1 signalling can produce substantial weight reduction, with direct component comparisons supporting the additional weight effect in the tested settings. Its glucose and comparator results are more specific: the early semaglutide HbA1c comparison was inconclusive, the larger REIMAGINE 2 trial found a modest additional glucose effect, and the higher-assignment obesity trial failed its tirzepatide noninferiority endpoint.

The newer sponsor findings illustrate why the question must include the population, component amounts and estimand. A favourable lower-assignment comparison in diabetes and a failed higher-assignment comparison in obesity can coexist. Published trial methods and event tables will determine how confidently the newer results can be interpreted alongside the established evidence.

FAQs

Does CagriSema have one molecular formula?

It contains two separately identified peptides. Each has its own sequence, modifications and circulating exposure; a unified peptide formula would misdescribe the combination.

Why did the tirzepatide comparisons differ?

The trials tested different doses in different patients. REDEFINE 4 compared CagriSema containing 2.4 mg of each component with tirzepatide 15 mg in adults with obesity over 84 weeks; it did not establish that CagriSema met the planned margin for being no less effective. The later sponsor report for REIMAGINE 5 compared 1.0 mg of each CagriSema component with tirzepatide 5 mg in people with type 2 diabetes over 60 weeks. A favorable result in that second setting does not resolve the first trial’s result.

Has it improved glucose beyond semaglutide alone?

The small phase 2 HbA1c comparison was inconclusive. The larger REIMAGINE 2 trial found a modest 0.16-percentage-point additional reduction under the efficacy estimand versus its specified semaglutide arm.

What does a fixed-dose combination establish about another mixture?

It identifies the development product. Stability, formulation and exposure of a separately prepared mixture would need direct evidence before clinical trial results could be applied to it.

The cagrilintide and semaglutide profiles explain the components' chemistry and pharmacology. Tirzepatide provides the direct active-comparator context, while the pharmacokinetics explainer describes why two analytes retain separate concentration profiles.

References

Frias JP, Deenadayalan S, Erichsen L, et al. (2023). Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet (London, England) 402(10403):720–730. DOI: 10.1016/S0140-6736(23)01163-7.
The component-controlled diabetes trial distinguishes weight findings from the inconclusive HbA1c comparison with semaglutide.
Garvey WT, Blüher M, Osorto Contreras CK, et al. (2025). Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. The New England journal of medicine 393(7):635–647. DOI: 10.1056/NEJMoa2502081.
REDEFINE 1 tests the combination and individual components within one randomised obesity cohort.
Davies MJ, Bajaj HS, Broholm C, et al. (2025). Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes. The New England journal of medicine 393(7):648–659. DOI: 10.1056/NEJMoa2502082.
REDEFINE 2 reports combination outcomes in type 2 diabetes without separate component-only arms.
Verma S, Böttcher M, Brown P, et al. (2026). CagriSema Reduces Blood Pressure in Adults With Overweight or Obesity: REDEFINE 1. Hypertension (Dallas, Tex. : 1979) 83(2):e26055. DOI: 10.1161/HYPERTENSIONAHA.125.26055. · Full text (PMC)
This blood-pressure analysis uses the existing REDEFINE 1 cohort and preserves the inconclusive resistant-hypertension result.
Novo Nordisk (23 February 2026). CagriSema demonstrated 23% weight loss in an open-label head-to-head REDEFINE 4 trial in people with obesity, the primary endpoint was not achieved. Company announcement.
The sponsor reports failure of the prespecified noninferiority endpoint against tirzepatide, with distinct estimand results.
Cao J, Belousoff MJ, Liang YL, et al. (2022). A structural basis for amylin receptor phenotype. Science 375(6587):eabm9609. DOI: 10.1126/science.abm9609.
The structural study explains the calcitonin receptor–RAMP partnership.
Aroda VR, Buzzetti R, Dalskov SM, et al. (2026). Efficacy and safety of once-weekly cagrilintide-semaglutide (CagriSema) in adults with type 2 diabetes inadequately controlled on diet and exercise (REIMAGINE 1): a randomised, double-blind, placebo-controlled, phase 3a study. Lancet Diabetes & Endocrinology 14(8):649–661. DOI: 10.1016/S2213-8587(26)00126-9.
REIMAGINE 1 examines the combination in diabetes controlled inadequately by diet and exercise.
Buse JB, Bajaj HS, Dalskov SM, et al. (2026). Cagrilintide-semaglutide (CagriSema) versus semaglutide or cagrilintide in people with type 2 diabetes (REIMAGINE 2): a double-blind, randomised, controlled, phase 3 study. Lancet Diabetes & Endocrinology 14(8):662–677. DOI: 10.1016/S2213-8587(26)00125-7. · PubMed record
REIMAGINE 2 finds a modest additional HbA1c effect and reports separate component safety.
Rosenstock J, Billings LK, Gajria R, et al. (2026). Cagrilintide-semaglutide (CagriSema) as an add-on to basal insulin in adults with type 2 diabetes (REIMAGINE 3): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Lancet 408(10549):38–51. DOI: 10.1016/S0140-6736(26)01022-6.
REIMAGINE 3 studies background basal insulin and glucose outcomes.
Novo Nordisk (21 September 2026). Novo's CagriSema delivers superior weight loss versus tirzepatide in REIMAGINE 5 trial. Company announcement.
The sponsor describes REIMAGINE 5 and REDEFINE 9 efficacy-estimand findings and investigational status.
Novo Nordisk (18 December 2025). Novo Nordisk files for FDA approval of CagriSema, the first once-weekly combination of GLP-1 and amylin analogues for weight management. Company announcement.
The filing milestone identifies the pivotal supporting trials.

Glossary

Coadministration: Use of separately identified treatments within the same treatment setting.
Fixed-dose combination: A combination product with specified component amounts.
Noninferiority: A test of whether a treatment performs no worse than its comparator by more than a difference specified before the study.
HbA1c: Glycated haemoglobin, reflecting average blood glucose over preceding months.
Treatment-policy estimand: A treatment-effect question that includes what happens after participants stop or change treatment, according to the trial’s rules.
Efficacy estimand: A trial-defined intended-treatment effect under assumptions about continuing treatment.
RAMP: An accessory protein that helps form an amylin receptor complex.
Basal insulin: Insulin treatment intended to provide background glucose control.