CagriSema's first phase 3 readout disappoints investors

Novo Nordisk's first phase 3 results for CagriSema, a once-weekly shot that combines semaglutide with the amylin analog cagrilintide, showed about 22.7% average weight loss at 68 weeks in adults with obesity or overweight without diabetes. That is one of the largest figures reported for an obesity injection to date, but it came in under the roughly 25% Novo Nordisk had internally aimed for, and investors reacted to the gap rather than the absolute number ^[1].

What the trial showed

REDEFINE 1 enrolled 3,417 adults with obesity (BMI of 30 or higher) or overweight (BMI of 27 or higher) plus at least one weight-related health problem, and no diabetes. Participants got CagriSema, semaglutide 2.4 mg alone, cagrilintide 2.4 mg alone, or placebo, all on top of diet and exercise counseling, for 68 weeks ^[2].

The trial reported two different weight-loss numbers, and the difference explains a lot of the confusion. Counting everyone regardless of whether they stayed on the drug or added other weight-loss treatments, CagriSema produced 20.4% weight loss versus 3.0% for placebo, from an average starting weight of about 236 pounds. In the idealized analysis that assumes everyone stayed on treatment, the figure was 22.7% versus 2.3% ^[2]. Novo Nordisk's later press materials rounded that to "an average of 23%" ^[2].

For comparison inside the same trial, semaglutide alone produced 14.9% weight loss and cagrilintide alone produced 11.5%. About 40.4% of CagriSema participants lost 25% or more of their starting weight ^[1]. Nearly all — 91.9% — lost at least 5%, compared with 31.5% on placebo, and about 54% of those who started with obesity dropped below a BMI of 30, versus 11.1% on placebo ^[2].

One explanation Novo Nordisk offered for falling short of its target: only about half of trial participants reached the highest dose during the study window. The company later started a study testing a slower, more tolerable dose escalation schedule ^[1].

Side effects and the diabetes trial

Safety looked like the GLP-1 class overall. In REDEFINE 1, 79.6% of CagriSema users reported gastrointestinal side effects versus 39.9% on placebo, including nausea (55% vs 12.6%), constipation (30.7% vs 11.6%) and vomiting (26.1% vs 4.1%). Discontinuations due to side effects were 5.9% for CagriSema and 3.5% for placebo ^[2].

A companion trial, REDEFINE 2, tested CagriSema in 1,206 adults with type 2 diabetes and obesity or overweight. Average weight loss was 13.7% versus 3.4% for placebo, or 15.7% in the stayed-on-treatment analysis ^[1][2]. Discontinuation for side effects in that trial was 8.4% for CagriSema versus 3% for placebo ^[2].

Why it matters for patients

CagriSema is not a pure GLP-1. It pairs semaglutide, the molecule in Wegovy, Ozempic and Rybelsus, with cagrilintide, which mimics amylin — a pancreatic hormone that slows stomach emptying and increases fullness through a different pathway ^[1]. That is why the combination beat semaglutide alone in the same trial.

The practical takeaway is that headline weight-loss percentages depend heavily on which analysis is quoted. A 20.4% figure and a 22.7% figure come from the same trial and the same people; one reflects real-world dropout and switching, the other an idealized scenario ^[2]. Expect both numbers to appear in marketing and news coverage.

Side effect rates were also high in absolute terms, with more than half of participants reporting nausea ^[2], which is relevant for anyone weighing tolerability against extra pounds lost.

Indirect comparisons have limits. Source material notes tirzepatide (Zepbound, Mounjaro) delivered up to 21% weight loss over 72 weeks in the SURMOUNT program, but that was a separate trial with a different length, so a head-to-head study is underway to settle it ^[1].

What happens next

The full REDEFINE 1 and 2 datasets were presented at the American Diabetes Association meeting in June 2025 and published in the New England Journal of Medicine ^[1]. Novo Nordisk submitted a New Drug Application to the FDA on December 18, 2025, for CagriSema 2.4 mg/2.4 mg in obesity and overweight with a weight-related condition. The FDA is expected to review the application in 2026 ^[2].

Two more trials are running: REDEFINE 3, a cardiovascular outcomes study, and REDEFINE 11, a longer trial in people with a BMI of 30 or higher ^[2]. Pricing has not been announced, and CagriSema is not approved in the US or the EU ^[1][2].