Zepbound Outperforms CagriSema in Head-to-Head Phase III Obesity Trial

Zepbound Outperforms CagriSema in Head-to-Head Phase III Obesity Trial

By, Admin 24 February 2026

A pivotal Phase III trial has delivered a setback for Novo Nordisk, after its obesity candidate CagriSema was outperformed by Eli Lilly’s Zepbound (tirzepatide) in a direct comparison study.

The REDEFINE 4 trial (NCT06131437) failed to meet its primary endpoint of demonstrating non-inferiority in weight loss for CagriSema versus Zepbound at 84 weeks.

Trial Results: Zepbound Leads on Weight Loss

The 84-week, open-label, randomised Phase III study enrolled 809 adults with obesity and at least one comorbidity. The mean baseline body weight was 114.2 kg.

Primary Analysis

  • CagriSema 2.4mg: 23.0% mean weight loss
  • Zepbound 15mg: 25.5% mean weight loss

Treatment Regimen Estimand (Real-World Effectiveness)

  • CagriSema: 20.2% weight loss
  • Zepbound: 23.6% weight loss

Because CagriSema did not demonstrate non-inferiority, the trial’s primary endpoint was not met.

Safety Profile

CagriSema appeared safe and well tolerated in the study. The most common adverse events were gastrointestinal in nature, largely mild to moderate in severity and consistent with the GLP-1 receptor agonist (GLP-1RA) class.

Novo Nordisk’s Positioning

Despite missing the primary endpoint, Novo Nordisk executives highlighted the magnitude of weight loss achieved with CagriSema.

The investigational therapy combines semaglutide with cagrilintide, aiming to become the first GLP-1/amylin combination therapy for obesity. The company argues that cagrilintide provides additive weight loss beyond GLP-1 biology alone.

Novo Nordisk submitted CagriSema to the U.S. Food and Drug Administration in December 2025, based on data from REDEFINE 1 and REDEFINE 2. A regulatory decision is expected by late 2026.

CagriSema has also shown superiority over Ozempic in the REIMAGINE study. Additionally, the Phase III REDEFINE 11 trial is ongoing, with data expected in the first half of 2027. A higher dose arm is set to begin in the second half of 2026.

Market Reaction

Investors reacted negatively to the REDEFINE 4 results. Novo Nordisk’s Copenhagen-listed shares dropped 16.48%, falling from DKr301.00 on 20 February to DKr251.40 on 23 February.

The trial outcome adds competitive pressure in an obesity market increasingly dominated by Eli Lilly.

The Intensifying GLP-1 Race

While Novo Nordisk recently secured FDA approval for an oral version of semaglutide — becoming the first to market an oral GLP-1RA for obesity — Eli Lilly continues to lead in injectable sales with:

  • Zepbound (obesity)
  • Mounjaro (type 2 diabetes)

Lilly is also awaiting an FDA decision on its oral candidate, orforglipron.

Meanwhile, competition continues to intensify. Pfizer has entered the space through the acquisition of Metsera, and Roche recently reported positive Phase II data for its dual GLP-1/GIP receptor agonist in January 2026.

What It Means for the Obesity Market

The REDEFINE 4 outcome underscores how competitive and data-driven the obesity therapeutic landscape has become. Even clinically meaningful weight loss of 23% may not be sufficient when rival therapies push the benchmark higher.

With regulatory decisions pending and next-generation combinations in development, the battle between Novo Nordisk and Eli Lilly for obesity market leadership is far from over.

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