What Is CagriSema? Novo Nordisk's Amylin + GLP-1 Weight Loss Combination

CagriSema is a fixed-dose combination of two drugs — cagrilintide 2.4 mg (an amylin receptor agonist) and semaglutide 2.4 mg (a GLP-1 receptor agonist) — delivered together as a single once-weekly subcutaneous injection. Developed by Novo Nordisk, it is designed to target two distinct appetite-regulation pathways simultaneously: the amylin pathway and the GLP-1 pathway.

In the REDEFINE 1 Phase 3 trial, CagriSema produced 20.4% weight loss at 68 weeks — significantly more than either cagrilintide alone (11.5%) or semaglutide alone (14.9%). The combination is additive: the amylin pathway provides roughly 5-6 additional percentage points of weight loss on top of what semaglutide achieves by itself.

Novo Nordisk filed a New Drug Application (NDA) for CagriSema with the FDA in December 2025, with a regulatory decision expected in 2026. If approved, CagriSema would be the first amylin + GLP-1 combination therapy on the market.

How CagriSema Works

CagriSema's core principle is dual-pathway appetite suppression. Rather than pushing one receptor harder, it engages two biologically distinct systems that reduce food intake through different mechanisms.

The GLP-1 Pathway (Semaglutide)

Semaglutide is the same GLP-1 receptor agonist found in Wegovy and Ozempic. It mimics the incretin hormone GLP-1, which is released from the gut after meals. GLP-1 receptor activation reduces appetite through hypothalamic signaling, slows gastric emptying, and improves insulin secretion. Semaglutide 2.4 mg alone produces approximately 15-17% weight loss in clinical trials.

The Amylin Pathway (Cagrilintide)

Cagrilintide is a long-acting amylin receptor agonist. Amylin is a hormone co-secreted with insulin from pancreatic beta cells after meals. It acts on amylin receptors (AMY1R, AMY2R, AMY3R) in the brain — particularly the area postrema and hypothalamus — to reduce appetite, slow gastric emptying, and suppress post-meal glucagon secretion. For a deep dive into cagrilintide specifically, see What Is Cagrilintide?.

Why Two Pathways Matter

GLP-1 and amylin receptors are entirely separate biological targets. They reduce food intake through different neural circuits in the brain. Activating both at the same time produces additive appetite suppression — which is exactly what the clinical data shows. In REDEFINE 1, the combination (20.4%) outperformed both semaglutide alone (14.9%) and cagrilintide alone (11.5%).

This dual-pathway strategy contrasts with retatrutide's approach. Retatrutide is a single molecule that activates three incretin-related receptors (GLP-1, GIP, and glucagon). CagriSema instead pairs an incretin agonist with a non-incretin amylin agonist — a fundamentally different pharmacological strategy.

Clinical Trial Data

CagriSema's Phase 3 program is called REDEFINE. Three key trials have reported results.

REDEFINE 1 (Obesity Without Diabetes)

The landmark REDEFINE 1 trial was a 68-week, randomized, double-blind, placebo-controlled trial in 3,417 adults with obesity or overweight (without diabetes). It tested CagriSema against its individual components and placebo.

The trial also measured the proportion of participants reaching clinically meaningful weight loss thresholds:

Over half of CagriSema participants lost at least 20% of their body weight — nearly double the rate achieved by semaglutide alone.

REDEFINE 2 (Type 2 Diabetes)

REDEFINE 2 studied CagriSema in adults with type 2 diabetes and overweight or obesity over 68 weeks. CagriSema produced -13.7% weight loss vs -3.4% for placebo. In addition, 73.5% of CagriSema participants achieved HbA1c of 6.5% or below, compared to 15.9% on placebo. Weight loss is consistently lower in diabetic populations across all drugs in this class, but the glycemic improvements are a significant additional benefit.

REDEFINE 4 (Head-to-Head vs Tirzepatide)

REDEFINE 4 was an 84-week, open-label, head-to-head trial comparing CagriSema directly against tirzepatide 15 mg (the highest approved dose of Zepbound/Mounjaro).

CagriSema did not meet its primary endpoint of non-inferiority to tirzepatide. This was a significant setback for Novo Nordisk, as it means CagriSema cannot claim equivalent efficacy to Eli Lilly's approved drug. For a detailed breakdown of this trial, see CagriSema vs Tirzepatide.

Dosing

CagriSema is administered as a single once-weekly subcutaneous injection. Both components are titrated gradually to minimize gastrointestinal side effects. The titration schedule used in the REDEFINE trials:

Both components reach their full maintenance dose of 2.4 mg by week 13. The gradual escalation mirrors the approach used with semaglutide alone (Wegovy) and is designed to allow the GI tract to adapt, reducing the severity of nausea and other digestive side effects.

Side Effects

The most common side effects of CagriSema are gastrointestinal, consistent with both the GLP-1 and amylin drug classes. Data from REDEFINE 1:

Key points on tolerability:

• GI side effects were higher with CagriSema (79.6%) than with either component alone, which is expected when combining two drugs that both affect gastric motility.
• Most side effects were mild to moderate and concentrated during the dose titration period. They generally improved once participants reached the maintenance dose.
• Serious adverse events were low and comparable across treatment groups. No new safety signals emerged beyond what is known for semaglutide and cagrilintide individually.
• Discontinuation due to adverse events was approximately 6% for CagriSema — lower than many other weight loss drug trials.

How CagriSema Compares to Other Weight Loss Drugs

CagriSema sits in the middle of the efficacy spectrum — more effective than semaglutide alone, similar to (but slightly less than) tirzepatide, and below retatrutide. Its distinctive feature is not raw efficacy but its unique mechanism: it is the only product combining amylin and GLP-1 pathways.

CagriSema vs Retatrutide

CagriSema and retatrutide represent two different strategies for next-generation obesity treatment. CagriSema pairs two drugs targeting amylin + GLP-1 pathways. Retatrutide is a single molecule activating GLP-1 + GIP + glucagon receptors — including the energy-expenditure-boosting glucagon component that CagriSema lacks.

Based on Phase 3 data (from different trials), retatrutide produces greater maximum weight loss (28.7% vs 20.4%). Retatrutide also has the advantage of being a single peptide rather than a two-drug combination, which may simplify manufacturing and potentially pricing.

CagriSema is further along in the regulatory process (NDA filed December 2025) compared to retatrutide (still completing Phase 3 trials). For a full comparison of efficacy, mechanisms, side effects, and timelines, see Retatrutide vs CagriSema.

FDA Timeline

CagriSema is on a clear path toward potential FDA approval:

• Phase 3 program (REDEFINE): Multiple trials completed, including REDEFINE 1, 2, and 4
• NDA filed: December 18, 2025
• FDA review: Currently under review
• Expected decision: 2026
• REDEFINE 4 setback: CagriSema failed to demonstrate non-inferiority to tirzepatide, which could influence the FDA's labeling decisions but is not expected to prevent approval, since CagriSema demonstrated clear superiority over placebo

If approved, CagriSema would be the first amylin + GLP-1 combination therapy available by prescription.

Frequently Asked Questions

Sources

1. Garvey WT, et al. "Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity." New England Journal of Medicine. 2025;393:635-647. NEJM
2. Novo Nordisk. "CagriSema demonstrated 23% weight loss in REDEFINE 4 trial." February 2026. Press Release
3. Novo Nordisk. "CagriSema demonstrates superior weight loss in adults with obesity or overweight and type 2 diabetes in the REDEFINE 2 trial." March 2025. GlobeNewsWire
4. Novo Nordisk. "Novo Nordisk files for FDA approval of CagriSema." December 2025. Press Release

This article is for informational purposes only and does not constitute medical advice. CagriSema is an investigational drug currently under FDA review. Always consult a healthcare provider before starting any medication. This site is not affiliated with Novo Nordisk or any pharmaceutical manufacturer.