Cagrilintide

Cagrilintide is a long-acting synthetic analog of amylin, a hormone co-secreted with insulin from pancreatic beta cells that regulates satiety and slows gastric emptying. It is administered as a once-weekly subcutaneous injection at a dose of 2.4 mg. It acts on calcitonin and amylin receptors in the brain and periphery to produce sustained appetite suppression. It is being developed by Novo Nordisk as both monotherapy (in the RENEW Phase 3 program) and in fixed-dose combination with semaglutide as CagriSema (NDA submitted December 18, 2025).

The molecule was developed by Novo Nordisk through structural modifications to native amylin. The clinical positioning is distinct from the GLP-1 class. While semaglutide, liraglutide, and tirzepatide act on the GLP-1 receptor (and tirzepatide also on GIP), cagrilintide acts on the amylin receptor system. The two pathways are complementary in obesity treatment: GLP-1 agonists primarily suppress appetite through hypothalamic GLP-1 receptors. Amylin agonists slow gastric emptying and act on separate satiety circuits. Combining the two mechanisms produces additive weight loss in the CagriSema fixed-dose product.

Cagrilintide activates the amylin receptor system, structurally formed by calcitonin receptor (CTR) plus receptor activity-modifying proteins (RAMP1, RAMP2, or RAMP3) to produce amylin receptors AMY1, AMY2, and AMY3.

Slowed gastric emptying. Amylin slows gastric emptying through both central and peripheral mechanisms. This is the principal effect on meal-related satiety.

Reduced glucagon secretion. Direct effect on pancreatic alpha cells reduces glucagon secretion in response to meals.

Restored leptin sensitivity. Amylin receptor activation appears to restore hypothalamic responsiveness to leptin signaling, allowing the satiety signal to function despite the leptin resistance characteristic of obesity.

Earlier satiation. The combined effect produces sensation of fullness faster during meals, reducing food intake per meal.

Distinct from GLP-1 mechanism. Critical conceptual point. Cagrilintide acts on amylin receptors, not GLP-1 receptors. The mechanisms are complementary, which is why combining with GLP-1 agonists (CagriSema) produces additive weight loss.

The Phase 3 REDEFINE Evidence

REDEFINE 1 was a 68-week double-blind randomized placebo- and active-controlled trial. 3,417 adults with obesity or overweight with comorbidities. Treatment arms: CagriSema, cagrilintide monotherapy, semaglutide monotherapy, placebo. All received lifestyle intervention.

Primary results.

• CagriSema produced 23 percent mean weight loss (treatment-policy estimand).
• 91.9 percent of CagriSema participants achieved 5 percent or greater weight loss.
• 32.0 percent of CagriSema participants achieved 25 percent or greater weight loss.

Cagrilintide monotherapy sub-analysis (presented at EASD 2025): 11.8 percent mean weight loss at 68 weeks for cagrilintide 2.4 mg monotherapy. 31.6 percent of treated participants achieved 15 percent or greater weight loss.

REDEFINE 2 evaluated CagriSema in adults with overweight or obesity with type 2 diabetes.

Regulatory Status

United States (FDA). NDA submitted December 18, 2025 for CagriSema chronic weight management indication. FDA action anticipated in 2026.

Dedicated cagrilintide monotherapy Phase 3. RENEW program began Q4 2025.

WADA status. Cagrilintide is on the WADA Prohibited List under section S2 as an amylin analog. Use in competitive sport is a doping violation.

Cagrilintide Phase 3 dosing in the REDEFINE 1 trial used 2.4 mg subcutaneous injection once weekly, both as monotherapy and as part of the fixed-dose CagriSema combination with semaglutide 2.4 mg. The 2.4 mg dose was selected as the maximum tested in REDEFINE 1.

Dose titration in REDEFINE 1 started at lower weekly doses (0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg) at 4-week intervals before reaching the 2.4 mg maintenance dose. The slow titration is required to manage gastrointestinal tolerability.

The dedicated RENEW Phase 3 program for cagrilintide monotherapy starting Q4 2025 will further characterize dosing. Higher doses than 2.4 mg may be explored in future trials. CagriSema NDA was submitted to FDA December 18, 2025 with FDA action anticipated in 2026.

Tolerability profile broadly similar to GLP-1 agonists.

Gastrointestinal effects. Nausea (most common, 35 to 50 percent), diarrhea, vomiting during dose escalation. Generally mild to moderate. Some evidence suggests slightly fewer GI effects than pure GLP-1 agonists at comparable weight-loss magnitudes.

Injection-site reactions. Common, generally mild.

Heart rate. Mild increase similar to GLP-1 class.

Pancreatitis monitoring. As with the broader incretin class, periodic monitoring is recommended.

Gallbladder events. Cholelithiasis at slightly increased rates over placebo.

Hypoglycemia. Risk increases with concurrent insulin or sulfonylurea therapy.

Discontinuation rates. REDEFINE 1 reported 12 to 15 percent treatment discontinuation due to adverse events at maintenance doses.

Cagrilintide vs Petrelintide. Both long-acting amylin analogs in late-stage development. Comparable monotherapy efficacy (~11 percent). Petrelintide has placebo-like tolerability advantage from ZUPREME-1.

Cagrilintide vs Semaglutide monotherapy. Different mechanism class. Semaglutide produces ~15 percent weight loss; cagrilintide ~12 percent monotherapy. Combining in CagriSema produces additive 23 percent weight loss.

Cagrilintide vs Tirzepatide. Different mechanisms. Tirzepatide produces 22 percent weight loss (SURMOUNT-1). CagriSema (with semaglutide) reaches similar magnitude through different pathway combination.

Cagrilintide vs Retatrutide. Retatrutide produces 28.7 percent at the highest doses. Triple agonist mechanism. Different class.

CagriSema position. The first commercial fixed-dose combination of GLP-1 receptor agonist plus amylin analog. NDA submitted December 18, 2025 with FDA action anticipated in 2026.