Semaglutides
Am I eligible?
Research

CagriSema loses to tirzepatide in REDEFINE 4; Novo Nordisk shares fall

Novo Nordisk's CagriSema fell short of Eli Lilly's tirzepatide in an 84-week head-to-head trial, missing its main goal and raising questions about where the shot fits if the FDA approves it in late 2026.

By the Semaglutides news desk·

Novo Nordisk said on Feb. 23, 2026, that its experimental obesity injection CagriSema did not match Eli Lilly's tirzepatide in a head-to-head Phase 3 trial called REDEFINE 4. The trial missed its primary endpoint of showing that CagriSema was non-inferior — statistically no worse — than tirzepatide 15 mg on weight loss at 84 weeks [1][2].

CagriSema is a fixed-dose combination of cagrilintide 2.4 mg, a long-acting amylin analogue, and semaglutide 2.4 mg, the same active ingredient in Wegovy. Both are given once weekly by injection under the skin [1]. Tirzepatide 15 mg is the highest dose of the molecule sold as Zepbound for weight management and Mounjaro for type 2 diabetes [2].

What the numbers showed

REDEFINE 4 randomized 809 adults with obesity and at least one weight-related health condition. Mean starting body weight was 114.2 kg, or about 252 pounds. The trial was open-label, meaning participants and investigators knew which drug was being given [1].

Novo reported results two ways. Under the efficacy estimand — an estimate of what happens if everyone stays on treatment — CagriSema produced 23.0% weight loss at 84 weeks versus 25.5% with tirzepatide 15 mg. Under the treatment-regimen estimand, which counts results regardless of whether people stuck with treatment, CagriSema produced 20.2% versus 23.6% for tirzepatide [1]. BioPharma Dive described the same treatment-regimen figures as roughly 20% versus 24% [2].

Either way, the gap was about 2.5 to 3.4 percentage points in tirzepatide's favor — too wide for the trial to declare the two drugs equivalent [1][2].

On safety, Novo said CagriSema "appeared to have a safe and well-tolerated profile," with the most common side effects being gastrointestinal. The company said the vast majority were mild to moderate and eased over time, consistent with the GLP-1 receptor agonist class [1]. Novo's release did not report discontinuation rates or side-effect rates for either drug, so how the two compared on tolerability is not yet known from this announcement.

Novo's R&D chief, Martin Holst Lange, said the company is "pleased with the weight loss of 23% for CagriSema in this open-label trial" and that CagriSema could become the first GLP-1/amylin combination on the market [1]. On a call with reporters, he argued that "from a strict label perspective, CagriSema will actually have a strong and very competitive weight loss label" [2].

Analysts were less convinced. William Blair's Andy Hsieh called the result a "worst case scenario" and said Zepbound and similar drugs "will continue to command market leadership in the United States" [2]. Jefferies analyst Michael Leuchten said "it is difficult to command a premium positioning for the drug" [2]. Novo shares fell more than 15% in U.S. trading on Monday and are down more than 50% over the past year [2].

Why it matters for patients

CagriSema is not available in the United States. Novo submitted it to the FDA in December 2025 based on the earlier REDEFINE 1 and REDEFINE 2 trials, and a decision is anticipated by late 2026 [1][2].

If approved, REDEFINE 4 gives the first direct comparison against the current highest-efficacy injection. In this single open-label trial, average weight loss with CagriSema was lower than with tirzepatide 15 mg [1]. Averages, though, describe groups, not individuals — some people in the CagriSema arm lost more than the average and some in the tirzepatide arm lost less. The trial did not test whether one drug works better for particular types of patients.

The result also matters for choice and cost. CagriSema uses a different biological pathway — amylin on top of GLP-1 — than tirzepatide's GIP/GLP-1 approach [1]. A third approved-market option could affect insurance coverage and pricing, but the sources do not say what CagriSema would cost or how insurers would treat it. Analysts questioned whether it can command premium pricing given the data [2].

Separately, BioPharma Dive noted Novo forecast earlier in February that its obesity drug sales would shrink in 2026 amid pricing pressure and competition for Wegovy [2].

What happens next

  • Second half of 2026: Novo plans to start a Phase 3 trial of higher-dose CagriSema, 2.4 mg/7.2 mg, in adults with obesity [1].
  • Late 2026: An FDA decision on CagriSema for weight management is anticipated [1].
  • First half of 2027: REDEFINE 11, an 80-week trial in 600 adults designed to assess CagriSema's "full weight-loss potential," is expected to report [1].

Full REDEFINE 4 data, including detailed safety findings, have not yet been presented at a medical meeting or published.

Sources

  1. https://www.globenewswire.com/de/news-release/2026/02/23/3242381/0/en/Novo-Nordisk-A-S-CagriSema-demonstrated-23-weight-loss-in-an-open-label-head-to-head-REDEFINE-4-trial-in-people-with-obesity-the-primary-endpoint-was-not-achieved.html
  2. https://www.biopharmadive.com/news/novo-nordisk-cagrisema-zepbound-head-to-head-results/812810/

Semaglutides.org is for information only and is not medical advice. Always talk to a licensed healthcare provider about your own care. Some links to telehealth services are affiliate links, labeled where they appear.