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. CagriSema did not meet the prespecified non-inferiority endpoint. Results announced on February 23, 2026, showed CagriSema achieved 23.0% weight loss versus tirzepatide's 25.5% at 84 weeks, using the efficacy estimand, which estimates results if participants adhered to treatment.

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

REDEFINE 4 Trial Results

The Trial Design

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

CagriSema fell short by approximately 2.5 percentage points under the efficacy estimand and 3.4 percentage points under the treatment-regimen estimand. The prespecified non-inferiority criterion was not met. Non-inferiority is not the same as statistical equivalence.

What "Non-Inferiority" Means

A non-inferiority trial tests whether a treatment is worse than a comparator by no more than a prespecified margin. Failure to meet that criterion means non-inferiority was not demonstrated. It does not, by itself, establish superiority for every outcome or determine whether CagriSema can be approved.

Key Caveats

Safety Comparison

Novo's headline release says gastrointestinal events were the most common events with CagriSema and were mostly mild to moderate. It does not provide a full head-to-head adverse-event table or discontinuation comparison.

Comparing one arm's topline description with tirzepatide percentages from SURMOUNT-1 would not establish equivalent safety in REDEFINE 4. Detailed trial results are needed to compare tolerability, serious events and treatment discontinuation.

The Broader REDEFINE Program

REDEFINE 4 is one of several Phase 3 trials studying CagriSema:

Novo Nordisk's FDA submission for CagriSema (filed December 2025) was based on REDEFINE 1 and REDEFINE 2, not REDEFINE 4. Novo's August 2026 update anticipates a Q4 2026 FDA decision; this is a company expectation, not a guarantee of approval.

Where Retatrutide Fits

Retatrutide is not a treatment arm in REDEFINE 4. Its separate TRIUMPH-4 trial reported 28.7% mean weight loss at 12 mg at week 68 under the efficacy estimand, in adults with obesity or overweight and knee osteoarthritis. That cannot establish superiority to either REDEFINE 4 treatment.

Retatrutide adds glucagon receptor agonism to GLP-1 and GIP activity. Increased energy expenditure was demonstrated in preclinical work; the size of that contribution to human weight loss cannot be inferred from these trial percentages.

Lilly plans a retatrutide BLA submission in Q1 2027. That filing plan does not establish a launch date or the order in which future products will become available.

Frequently Asked Questions

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
• Novo Nordisk. Q2 2026 investor presentation.
• Coskun, T., et al. Retatrutide discovery and early pharmacology. Cell Metabolism (2022).
• Lilly. Retatrutide BLA filing plan. July 2026.
• FDA. Non-inferiority clinical trial guidance.