REDEFINE 1 and 2 published: CagriSema passes 20% weight loss

Novo Nordisk's CagriSema — a once-weekly combination of semaglutide 2.4 mg and the amylin analogue cagrilintide 2.4 mg — produced an estimated average weight loss of 20.4% over 68 weeks in adults with overweight or obesity and no diabetes, compared with 3.0% on placebo, according to the published REDEFINE 1 trial ^[1]. In the companion REDEFINE 2 trial in adults with type 2 diabetes, average weight loss was 13.7% versus 3.4% on placebo ^[2].

What the two trials tested

REDEFINE 1 was a phase 3a, 68-week, multicenter, double-blind trial that was both placebo-controlled and active-controlled ^[1]. It enrolled adults without diabetes who had a body mass index of 30 or higher, or 27 or higher with at least one weight-related complication ^[1]. A total of 3,417 people were randomly assigned in a 21:3:3:7 ratio: 2,108 to cagrilintide–semaglutide, 302 to semaglutide alone at 2.4 mg, 302 to cagrilintide alone at 2.4 mg, and 705 to placebo ^[1]. Everyone also received lifestyle intervention ^[1].

The difference between the combination and placebo was 17.3 percentage points (95% confidence interval, −18.1 to −16.6; P<0.001) ^[1]. Results were calculated using the treatment-policy estimand, which counts everyone as randomized whether or not they stayed on the drug — generally a more conservative figure than "if you take it as directed" analyses ^[1]. More people on the combination than on placebo hit weight-loss thresholds of 5% or more, 20% or more, 25% or more, and 30% or more (P<0.001 for each) ^[1]. The published abstract does not report the specific results for the semaglutide-alone or cagrilintide-alone arms, so how much the combination beat semaglutide by is not stated in that summary ^[1].

REDEFINE 2 ran in 12 countries and enrolled adults with type 2 diabetes, a BMI of 27 or higher, and an A1c of 7% to 10% ^[2]. Of 1,206 patients randomized 3-to-1, 904 received cagrilintide–semaglutide and 302 received placebo, both with lifestyle intervention, for 68 weeks ^[2]. The weight difference was 10.4 percentage points (95% CI, −11.2 to −9.5; P<0.001) ^[2]. On blood sugar, 73.5% of the combination group reached an A1c of 6.5% or lower, versus 15.9% on placebo ^[2]. More patients on the drug also hit weight thresholds of 5%, 10%, 15% and 20% or more ^[2].

Side effects

Stomach and gut side effects were common and more frequent than with placebo. In REDEFINE 1, gastrointestinal adverse events — nausea, vomiting, diarrhea, constipation or abdominal pain — were reported by 79.6% of the combination group and 39.9% of the placebo group, and were described as mainly transient and mild to moderate ^[1]. In REDEFINE 2, the figures were 72.5% versus 34.4%, again mostly transient and mild or moderate ^[2]. Neither abstract gives discontinuation rates due to side effects.

Both trials were funded by Novo Nordisk ^[1][2]. REDEFINE 1 is registered as NCT05567796 and REDEFINE 2 as NCT05394519 ^[1][2].

Why it matters for patients

The 20.4% figure is notable because it comes from the conservative analysis method and because it is higher than what semaglutide alone has typically delivered in obesity trials — though the head-to-head comparison inside REDEFINE 1 is not spelled out in the published abstract ^[1]. For people weighing options, CagriSema represents a different approach: pairing a GLP-1 drug with an amylin analogue rather than adding a GIP component, as tirzepatide (Mounjaro, Zepbound) does.

The gap between the two trials is also worth noting. As with other incretin drugs, weight loss was smaller in people with type 2 diabetes — 13.7% versus 20.4% — while the blood sugar effect was substantial ^[1][2].

CagriSema is an investigational combination, not a product you can fill at a pharmacy today. These publications report trial results only; they do not address US regulatory review, timing of any FDA decision, pricing or insurance coverage, and none of that is known from these sources.

What happens next

Both papers were published by the New England Journal of Medicine in 2025 ^[1][2]. On November 20, 2025, the journal published a set of correspondence letters about REDEFINE 1, along with replies from the trial investigators ^[1]. Longer-term data, including any cardiovascular outcomes and how weight loss holds up past 68 weeks, are not covered in these two reports.