CagriSema vs Tirzepatide (Zepbound): REDEFINE 4 Head-to-Head Results
Novo Nordisk's CagriSema went head-to-head against Eli Lilly's tirzepatide in the REDEFINE 4 Phase 3 trial — and lost. Results announced on February 23, 2026, showed CagriSema achieved 23.0% weight loss versus tirzepatide's 25.5% at 84 weeks, failing to meet its primary endpoint of non-inferiority.
This page breaks down the trial results, what they mean for both drugs, and where Eli Lilly's retatrutide fits in the next-generation obesity drug landscape.
Side-by-Side Comparison
| CagriSema | Tirzepatide (Zepbound) | |
|---|---|---|
| Developer | Novo Nordisk | Eli Lilly |
| Mechanism | Amylin analog (cagrilintide 2.4 mg) + GLP-1 agonist (semaglutide 2.4 mg) | Dual GLP-1 + GIP agonist |
| Receptors | Amylin + Calcitonin + GLP-1 | GLP-1 + GIP |
| Administration | Once-weekly injection (two peptides combined) | Once-weekly injection (single peptide) |
| Max dose | Cagrilintide 2.4 mg / semaglutide 2.4 mg | 15 mg |
| FDA status | NDA submitted December 2025, decision expected late 2026 | Approved (Zepbound 2023, Mounjaro 2022) |
REDEFINE 4 Trial Results
The Trial Design
REDEFINE 4 (NCT06131437) was an 84-week, open-label, head-to-head Phase 3 trial. It enrolled 809 adults with obesity (BMI of 30 or higher) and at least one weight-related comorbidity, with a mean baseline body weight of 114.2 kg (252 lbs).
Participants were randomized to receive either CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg) or tirzepatide 15 mg, both administered once weekly by subcutaneous injection.
The primary endpoint was the relative percent change in body weight from baseline to week 84.
Weight Loss Results
| Measure | CagriSema | Tirzepatide 15 mg |
|---|---|---|
| Efficacy estimand (if all participants adhered) | -23.0% | -25.5% |
| Treatment-regimen estimand (regardless of adherence) | -20.2% | -23.6% |
| Primary endpoint met? | No — failed to demonstrate non-inferiority | Won |
CagriSema fell short by approximately 2.5 percentage points under the efficacy estimand and 3.4 percentage points under the treatment-regimen estimand. The gap was too large for the trial to declare CagriSema statistically equivalent to tirzepatide.
What "Non-Inferiority" Means
The trial was designed to show that CagriSema was "not worse" than tirzepatide — a lower bar than showing superiority. Even by this more lenient standard, CagriSema could not match tirzepatide. This was a significant miss for Novo Nordisk, whose stock fell approximately 15% on the announcement.
Key Caveats
Open-label design — Both investigators and participants knew which drug they were receiving. This can introduce bias, particularly in subjective outcomes like eating behavior and adherence. Participants on tirzepatide, an already-approved blockbuster drug, may have had different expectations than those on an investigational combination.
Dose comparison — Tirzepatide was tested at its maximum approved dose of 15 mg. CagriSema was tested at the current formulation of cagrilintide 2.4 mg + semaglutide 2.4 mg. Novo Nordisk is planning a higher-dose CagriSema study (REDEFINE 11, with a 2.4/7.2 mg formulation) with results expected in H1 2027.
Different adherence rates — The gap between the efficacy estimand (if all adhered) and treatment-regimen estimand (actual) was larger for tirzepatide (1.9 percentage points) than CagriSema (2.8 percentage points), suggesting slightly lower adherence in the CagriSema arm.
Safety Comparison
| CagriSema (REDEFINE 4) | Tirzepatide (SURMOUNT-1) | |
|---|---|---|
| Most common AEs | Nausea, vomiting, diarrhea, constipation | Nausea, diarrhea, vomiting, constipation |
| GI severity | Mostly mild-moderate, diminished over time | Mostly mild-moderate, during dose escalation |
| Discontinuation rate | Not yet disclosed for REDEFINE 4 | 4.3-7.1% (SURMOUNT-1) |
| Unique signals | None beyond GI class effects | None beyond GI class effects |
Both drugs showed comparable safety profiles consistent with the broader GLP-1 drug class. Full safety data from REDEFINE 4 will be available when the complete study is published.
The Broader REDEFINE Program
REDEFINE 4 is one of several Phase 3 trials studying CagriSema:
| Trial | Duration | Focus | Participants | Status |
|---|---|---|---|---|
| REDEFINE 1 | 68 weeks | CagriSema vs placebo and individual components | 3,417 (no T2D) | Completed — CagriSema -22.7% |
| REDEFINE 2 | 68 weeks | CagriSema vs placebo in type 2 diabetes | 1,206 | Completed — CagriSema -15.7% |
| REDEFINE 3 | Event-driven | Cardiovascular outcomes | 7,000 | Ongoing |
| REDEFINE 4 | 84 weeks | CagriSema vs tirzepatide | 809 | Completed — failed non-inferiority |
| REDEFINE 8 | 104 weeks | Body composition and maintenance | 400 | Ongoing |
| REDEFINE 11 | 80 weeks | Higher-dose CagriSema (2.4/7.2 mg) | 600 | Expected H1 2027 |
Novo Nordisk's FDA submission for CagriSema (filed December 2025) was based on REDEFINE 1 and REDEFINE 2, not REDEFINE 4. The FDA decision is expected in late 2026.
Where Retatrutide Fits
Both CagriSema and tirzepatide are likely to be on the market before retatrutide. But retatrutide's Phase 3 data tells a striking story in context:
| Drug | Mechanism | Max Weight Loss | Trial |
|---|---|---|---|
| CagriSema | Amylin + GLP-1 | -23.0% (84 wks) | REDEFINE 4 |
| Tirzepatide 15 mg | GLP-1 + GIP | -25.5% (84 wks) | REDEFINE 4 |
| Retatrutide 12 mg | GLP-1 + GIP + Glucagon | -28.7% (68 wks) | TRIUMPH-4 |
Retatrutide achieved greater weight loss in less time than either CagriSema or tirzepatide, using a single molecule. The glucagon receptor agonism — which neither CagriSema nor tirzepatide has — increases energy expenditure on top of appetite suppression.
Important caveats: these are cross-trial comparisons with different populations. TRIUMPH-4 enrolled patients with obesity and knee osteoarthritis (445 participants). REDEFINE 4 enrolled a broader obesity population (809 participants). Only a head-to-head trial could definitively rank these drugs.
For a detailed retatrutide vs CagriSema comparison, see Retatrutide vs CagriSema. For retatrutide vs tirzepatide, see Retatrutide vs Tirzepatide.
Frequently Asked Questions
Did CagriSema beat tirzepatide?
No. In REDEFINE 4, CagriSema achieved 23.0% weight loss versus tirzepatide's 25.5% at 84 weeks. CagriSema failed to demonstrate non-inferiority (statistical equivalence) to tirzepatide. Novo Nordisk is developing a higher-dose version (REDEFINE 11) with results expected in 2027.
Will CagriSema still be approved despite losing to tirzepatide?
Likely yes. Novo Nordisk's FDA submission was based on REDEFINE 1 and 2 (where CagriSema beat placebo and its individual components), not REDEFINE 4. The FDA decision is expected in late 2026. CagriSema's 22-23% weight loss still exceeds semaglutide alone (16.1%) and is clinically meaningful.
Is tirzepatide better than CagriSema?
Based on REDEFINE 4, tirzepatide produced greater weight loss (25.5% vs 23.0%) in a head-to-head trial. However, the trial was open-label (both patients and doctors knew which drug was given), and CagriSema was tested at its current dose. A higher-dose CagriSema formulation (REDEFINE 11) is being studied.
Is retatrutide better than both CagriSema and tirzepatide?
Retatrutide produced 28.7% weight loss at 68 weeks in TRIUMPH-4, which exceeds both CagriSema (23.0%) and tirzepatide (25.5%) from REDEFINE 4. However, these are cross-trial comparisons — different patient populations, different trial designs. No head-to-head trial has compared all three drugs directly.
When will CagriSema be available?
Novo Nordisk filed an NDA for CagriSema in December 2025. An FDA decision is expected in late 2026. If approved, CagriSema would be the first amylin + GLP-1 combination product on the market.
What is the difference between CagriSema and tirzepatide?
CagriSema combines two drugs: cagrilintide (an amylin analog) and semaglutide (a GLP-1 agonist). It targets appetite through two brain pathways — amylin signaling and GLP-1 signaling. Tirzepatide is a single molecule that activates both GLP-1 and GIP receptors, targeting insulin sensitivity and appetite. They use fundamentally different biological mechanisms.
Sources
- Novo Nordisk. (2026). CagriSema demonstrated 23% weight loss in open-label head-to-head REDEFINE 4 trial. Press release
- ClinicalTrials.gov. REDEFINE 4. NCT06131437
- Aronne, L.J., et al. (2025). Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity (REDEFINE 1). New England Journal of Medicine. DOI: 10.1056/NEJMoa2502081
- Eli Lilly. (2025). TRIUMPH-4 results. Press release
- Gardner, J. (2026). Novo's next-gen obesity shot fails to match Lilly drug in head-to-head study. BioPharma Dive. Article
Medical Disclaimer
The content on glp3.wiki is for informational purposes only and does not constitute medical advice, diagnosis, or treatment. CagriSema is an investigational drug that has not been approved by the FDA. Tirzepatide is FDA-approved as Zepbound (obesity) and Mounjaro (type 2 diabetes).
Do not use this information to make decisions about your health without consulting a qualified healthcare provider. If you are considering weight loss medication, talk to your doctor about currently approved options.
This site is not affiliated with Novo Nordisk, Eli Lilly, or any pharmaceutical manufacturer.
Sources
- REDEFINE 4 results
Novo Nordisk
- REDEFINE 4 trial
ClinicalTrials.gov
- REDEFINE 1 trial
NEJM
Related reading
Retatrutide vs CagriSema (Cagrilintide + Semaglutide): Triple Agonist vs Amylin + GLP-1 Combo
Cagrilintide vs retatrutide: triple agonist vs amylin + GLP-1 combo — 28.7% vs 22.7% weight loss, different receptors, and stacking considerations.
Retatrutide vs Tirzepatide (Zepbound): Triple Agonist vs Dual Agonist
Retatrutide produces 28.7% weight loss (triple agonist) vs tirzepatide's 22.5% (dual agonist). A head-to-head trial is underway.
Cagrilintide and Tirzepatide: Stacking Amylin With a Dual Agonist
Cagrilintide + tirzepatide stacking: no human trial data, CagriSema lost to tirzepatide in REDEFINE 4, and retatrutide offers 28.7% weight loss from one molecule.