CagriSema REDEFINE Phase 3: 22.7% Weight Loss and FDA Submission 2026

Important Notice: This article is intended exclusively for scientific information and research purposes. All substances mentioned are not intended for human consumption. Always consult qualified professionals before using peptides.

Introduction: Novo Nordisk's Answer in the GLP-1 Race

On 18 December 2025, Novo Nordisk submitted a New Drug Application (NDA) to the US FDA for CagriSema, a once-weekly fixed-dose combination of cagrilintide 2.4 mg (a long-acting amylin analogue) and semaglutide 2.4 mg (a GLP-1 receptor agonist). If approved, it would be the first combination of a GLP-1 agonist and an amylin analogue for weight management.

The underlying Phase 3 trial REDEFINE 1 delivered a mean weight loss of 22.7% in participants with full treatment adherence (20.4% with typical adherence) over 68 weeks. 40.4% of participants achieved at least 25% weight loss, a threshold previously reserved almost exclusively for bariatric surgery. In the sister trial REDEFINE 2 in patients with type 2 diabetes, CagriSema produced 13.7% weight loss versus 3.4% on placebo.

CagriSema positions itself between tirzepatide (roughly 20 to 22% weight loss) and retatrutide (up to 28.7%), with a mechanistically unique profile. With an FDA decision expected during 2026, CagriSema could fundamentally reshape the GLP-1 market segment.

What Is CagriSema? The Amylin and GLP-1 Combination

CagriSema is not a new class of compound but an intelligent fixed-dose combination of two established peptide hormones in a single once-weekly injection product:

1. Cagrilintide 2.4 mg (Amylin Analogue)

Cagrilintide is a long-acting analogue of the pancreatic hormone amylin, which is co-secreted with insulin from beta cells. It acts via calcitonin and amylin receptors in the central nervous system and:

slows gastric emptying, prolonging satiety
suppresses postprandial glucagon release
reduces food intake through effects in the area postrema
reduces body weight by approximately 10% even as monotherapy

2. Semaglutide 2.4 mg (GLP-1 Agonist)

Semaglutide is the GLP-1 receptor agonist already approved as Wegovy with well-characterised effects on the hypothalamus and reward centres:

appetite suppression via hypothalamic POMC neurons
glucose-dependent insulin secretion and HbA1c reduction
cardiovascular protection (SELECT trial)
approximately 15 to 17% weight loss as monotherapy

Synergy Rather than Addition

Crucially, the two hormones act on complementary axes: GLP-1 dominates central appetite regulation, while amylin dominates gastric emptying and postprandial physiology. In REDEFINE 1, both monotherapies (cagrilintide alone, semaglutide alone) produced significantly weaker effects than the combination, confirming genuine synergy.

REDEFINE 1 in Detail: Obesity Without Diabetes

REDEFINE 1 was a 68-week, randomised, placebo- and active-controlled Phase 3 study in 3,417 adults with overweight or obesity plus at least one weight-related comorbidity (excluding type 2 diabetes).

Weight Loss Results

CagriSema (full adherence): –22.7% body weight
CagriSema (intention-to-treat / typical adherence): –20.4%
Semaglutide 2.4 mg alone: significantly weaker than the combination
Cagrilintide 2.4 mg alone: significantly weaker than the combination
Placebo: –3.0%

Responder Analysis

40.4% of participants achieved ≥25% weight loss
A substantial share achieved ≥20% weight loss
Placebo control showed virtually no comparable responders

Metabolic and Cardiovascular Secondary Endpoints

Improved lipid profile and systolic blood pressure
Reduction in waist circumference and visceral fat
Improved glucose homeostasis even in non-diabetic participants

The results were published in the New England Journal of Medicine (DOI 10.1056/NEJMoa2502081).

REDEFINE 2: CagriSema in Type 2 Diabetes

REDEFINE 2 studied adults with type 2 diabetes and overweight or obesity over 68 weeks. Key results:

CagriSema: –13.7% body weight
Placebo: –3.4% body weight
HbA1c: significant reduction on CagriSema
Glycaemic control: consistent throughout the trial

The smaller absolute weight loss in T2D compared with REDEFINE 1 follows a well-known pattern across GLP-1-based therapies: patients with type 2 diabetes consistently respond less strongly in terms of weight reduction than non-diabetic patients, while also benefiting from improved glycaemic control. The data are indexed in PubMed (ID 40544432).

The Comparison: CagriSema in the 2026 GLP-1 Landscape

The Phase 3 data now allow a well-grounded positioning of CagriSema relative to other leading incretin and incretin-adjacent therapies:

Parameter	Semaglutide 2.4 mg	Tirzepatide 15 mg	CagriSema	Retatrutide 12 mg
Mechanism	GLP-1	GLP-1 + GIP	GLP-1 + Amylin	GLP-1 + GIP + Glucagon
Dosing	Once weekly s.c.	Once weekly s.c.	Once weekly s.c.	Once weekly s.c.
Weight loss	~14.9%	~22.5%	22.7%	28.7%
Trial length	68 weeks	72 weeks	68 weeks	68 weeks
≥25% loss	~13%	~40%	40.4%	58.6%
HbA1c reduction (T2D)	~2.0%	~2.4%	significant	~2.0%
Notable	first-in-class, CV protection	dual agonist, established	first amylin/GLP-1 combo	strongest effect, triple agonist
Approval status	approved (Wegovy)	approved (Zepbound)	FDA NDA 12/2025	Phase 3, approval 2027/28

At 22.7% CagriSema is practically level with tirzepatide, but the two differ fundamentally in mechanism. Neither GIP nor glucagon are activated; instead, amylin opens an entirely different satiety axis. This matters because patients with inadequate response to pure GLP-1 therapy may benefit from this complementary mode of action.

Why Amylin Plus GLP-1 Work Synergistically

The pharmacological rationale behind CagriSema is notable:

Satiety on Two Levels

GLP-1 agonists act centrally in the hypothalamus and the nucleus tractus solitarii and reduce appetite primarily before and during food intake. Amylin analogues additionally slow gastric emptying and extend postprandial satiety by hours. The combination therefore achieves a significantly longer overall satiety envelope.

Glucose Homeostasis

Both compounds suppress glucagon-mediated hepatic glucose output, but through different routes: GLP-1 glucose-dependently via alpha cells, amylin via central mechanisms. The result is more stable postprandial glucose control than with either compound alone.

Less Weight Regain

Animal data and Phase 2 findings suggest that the combination dampens the typical adaptive increase in appetite after weight loss more effectively than GLP-1 monotherapy, which benefits long-term weight maintenance.

Safety and Tolerability

The safety profile of CagriSema is broadly consistent with the GLP-1 agonist class:

Most Common Side Effects

Nausea, vomiting, diarrhoea: gastrointestinal effects dominate, as with semaglutide and tirzepatide
Constipation: in part driven by amylin-mediated slowing of gastric emptying
Decreased appetite: the desired primary effect, but can lead to insufficient calorie intake

Adherence

As with all GLP-1-based therapies, slow dose titration plays a decisive role. The gap visible in REDEFINE 1 between intention-to-treat (–20.4%) and full adherence (–22.7%) underlines that patients with gastrointestinal side effects more frequently reduce the dose or discontinue. Studies with improved titration protocols may narrow this gap further.

Open Questions

Long-term cardiovascular outcome data are still pending
Effects on muscle mass and bone density are the subject of ongoing studies
Weight regain rates after discontinuation are likely similar to other GLP-1 therapies

FDA NDA and 2026 Timeline

Novo Nordisk submitted the NDA to the FDA on 18 December 2025. The typical path forward:

FDA Process

December 2025: NDA submission
Early 2026: FDA filing acceptance decision
Mid to late 2026: priority or standard review completed
Q3/Q4 2026: potential FDA approval

EMA and Launch

For European approval a comparable procedure at the EMA is expected, with the usual 6 to 12 month delay relative to the FDA. An EU market authorisation is realistic at earliest by mid-2027.

Commercial Positioning

CagriSema is expected to be positioned as an alternative to Wegovy (semaglutide) and Zepbound (tirzepatide), with a focus on patients who do not respond adequately to classic GLP-1 monotherapy or who benefit from the stronger gastric satiety mediated by amylin.

Significance for the EU Research Context

CagriSema is currently not commercially available in either the EU or the US; outside of clinical trials the product does not exist on the market. For preclinical and in vitro research, semaglutide and cagrilintide are individually available. Combinatorial protocols can be examined in suitable research settings to characterise the synergy of the two receptor axes.

The comparison with other developmental peptides is also instructive: while retatrutide achieves the numerically highest weight loss, CagriSema provides a mechanistically unique profile that may be valuable in GLP-1 non-responders or when investigating gastric physiology.

Conclusion: The Amylin Renaissance

The REDEFINE results mark not only another milestone in metabolic medicine but also the return of the long-underappreciated hormone amylin to the centre of obesity research. At 22.7% weight loss CagriSema is the first GLP-1 plus amylin combination therapy to reach values in the range of dual agonists such as tirzepatide, and it does so through a complementary mechanism.

Key findings:

22.7% mean weight loss with full adherence (REDEFINE 1)
40.4% of patients with ≥25% weight loss
13.7% weight loss in T2D (REDEFINE 2)
FDA NDA submitted on 18 December 2025

Open questions:

Cardiovascular outcome data still pending
No head-to-head trials against tirzepatide or retatrutide
Long-term effects on muscle mass and weight maintenance after discontinuation

For researchers, CagriSema reinforces the thesis that multi-hormonal approaches produce superior results in metabolic medicine, regardless of whether the combination is a triple agonist (retatrutide), a dual agonist (tirzepatide) or a fixed-dose combination (CagriSema). The amylin-GLP-1 axis opens new perspectives that extend beyond pure weight reduction and could address the question of long-term metabolic resilience.

Sources

Garvey WT, et al. "Cagrilintide-Semaglutide in Adults with Overweight or Obesity (REDEFINE 1)." New England Journal of Medicine. DOI: 10.1056/NEJMoa2502081.
Novo Nordisk. "Novo Nordisk files for FDA approval of CagriSema, the first once-weekly combination of GLP-1 and amylin analogues for weight management." PR Newswire, 18 December 2025.
American Diabetes Association. "CagriSema Demonstrates Significant Weight Loss in Adults with Obesity." ADA press release, 2025.
PubMed. "REDEFINE 2 Trial: Cagrilintide-Semaglutide in Adults with Obesity and Type 2 Diabetes." PMID 40544432.