CagriSema: Why Novo Nordisk Added Amylin to GLP-1 — and Got 22.7% Weight Loss

CagriSema combines semaglutide with cagrilintide, a long-acting amylin analog, in a single weekly injection. The REDEFINE 1 trial showed 22.7% weight loss at 68 weeks — 60% of patients lost at least 20% of their body weight. Novo Nordisk filed for FDA approval in December 2025.

Semaglutide works on the GLP-1 receptor. Tirzepatide works on GLP-1 and GIP receptors. Novo Nordisk's next move was to combine semaglutide with an entirely different hormone system — amylin — to create CagriSema. The rationale: GLP-1 and amylin both reduce appetite, but through different receptors and brain pathways. Activating both simultaneously should produce greater satiety than either alone.

The Phase 3 data, published in the New England Journal of Medicine and presented at ADA 2025, confirms this hypothesis. CagriSema produced 22.7% mean weight loss in the REDEFINE 1 trial — significantly more than semaglutide alone (16.1%) and cagrilintide alone (11.8%). Novo Nordisk submitted an NDA to the FDA in December 2025.

What Amylin Does

Amylin is a peptide hormone co-secreted with insulin by pancreatic beta cells after meals. It slows gastric emptying, suppresses glucagon secretion, and reduces food intake through signaling in the area postrema and nucleus of the solitary tract in the brainstem. These are distinct from the hypothalamic pathways that GLP-1 primarily targets.

Cagrilintide is a long-acting amylin analog engineered for once-weekly dosing (natural amylin has a very short half-life). By combining it with semaglutide, CagriSema activates complementary appetite-suppression pathways through different receptors — creating genuine pharmacological synergy rather than simply increasing the dose of a single mechanism.

REDEFINE 1: The Obesity Trial

REDEFINE 1 (NCT05567796) was a Phase 3a, 68-week, double-blind trial that enrolled 3,417 adults with obesity or overweight with at least one complication, without type 2 diabetes. Participants were randomized to CagriSema (n=2,108), semaglutide 2.4 mg alone (n=302), cagrilintide 2.4 mg alone (n=302), or placebo (n=705).

CagriSema was statistically superior to both semaglutide monotherapy and cagrilintide monotherapy. An additional finding: 88% of participants with prediabetes at baseline achieved normoglycemia by week 68. Broad cardiometabolic improvements in blood pressure, waist circumference, and lipids were also observed.

REDEFINE 2: Type 2 Diabetes

A parallel trial, REDEFINE 2 (NCT05394519), tested CagriSema in 1,206 adults with obesity/overweight and type 2 diabetes. CagriSema produced 15.7% weight loss and superior HbA1c reduction compared to placebo. The REIMAGINE program further evaluates CagriSema specifically for glycemic control in type 2 diabetes.

Safety

The most common adverse events were gastrointestinal — consistent with both incretin and amylin-based therapies. Discontinuation rates due to adverse events were low, in the single digits. No new safety signals emerged beyond the known GLP-1 and amylin class effects.

One notable detail: only 57.3% of CagriSema patients reached the maximum dose at trial end, compared to 70.2% on semaglutide alone and 82.5% on cagrilintide alone. Despite this, the combination still produced greater weight loss — suggesting the synergy exists even at submaximal doses.