Cagrilintide
Also known as: NN9838, AM833
Cagrilintide is a long-acting acylated amylin analog developed by Novo Nordisk, designed for once-weekly subcutaneous administration and studied both as monotherapy and in combination with semaglutide (CagriSema) for obesity and type 2 diabetes management.
Key Findings at a Glance
- •CagriSema (cagrilintide plus semaglutide) produced 20.4 percent mean weight loss at 68 weeks in the REDEFINE 1 trial, with 60 percent of participants losing at least 20 percent of body weight, approaching bariatric surgery outcomes.
- •Cagrilintide is the first long-acting amylin analog to reach Phase 3 trials, with fatty acid acylation enabling once-weekly dosing compared to the three-times-daily dosing required by the older amylin analog pramlintide.
- •In the REDEFINE 2 trial in adults with obesity and type 2 diabetes, 73.5 percent of CagriSema-treated participants achieved HbA1c of 6.5 percent or below compared to 15.9 percent with placebo.
- •The combination targets two distinct appetite pathways: amylin receptors controlling hedonic eating behavior and GLP-1 receptors regulating homeostatic energy balance, producing additive weight loss beyond either mechanism alone.
Cagrilintide Overview & Molecular Profile
Cagrilintide is a novel long-acting analog of the pancreatic hormone amylin, developed by Novo Nordisk through fatty acid acylation to extend its half-life and enable once-weekly subcutaneous dosing. Amylin is co-secreted with insulin from pancreatic beta cells in response to meals and acts on receptors in the area postrema and hypothalamus to regulate appetite, gastric emptying, and postprandial glucagon secretion. Cagrilintide was designed to provide sustained amylin receptor activation, complementing the GLP-1 receptor agonist semaglutide through a distinct mechanism targeting different satiety pathways. The combination of cagrilintide and semaglutide, known as CagriSema, has demonstrated unprecedented weight loss of 20.4% in the Phase 3 REDEFINE 1 trial, approaching the efficacy of bariatric surgery. Cagrilintide activates both the amylin receptor (composed of calcitonin receptor and receptor activity-modifying proteins) and calcitonin receptors in brain regions involved in appetite regulation, providing additive appetite suppression when combined with GLP-1 receptor agonism.
Mechanism of Action: Receptor Agonism & Metabolic Pathways
Cagrilintide acts as a potent agonist at amylin receptors, which are heterodimeric complexes of the calcitonin receptor (CTR) and receptor activity-modifying proteins (RAMPs), primarily RAMP1, RAMP2, and RAMP3. These receptors are highly expressed in the area postrema, nucleus tractus solitarius, and hypothalamus, brain regions critical for appetite regulation and energy homeostasis. Upon binding, cagrilintide activates intracellular signaling cascades that reduce meal size, slow gastric emptying, and suppress postprandial glucagon release. The amylin signaling pathway is distinct from and complementary to GLP-1 receptor signaling, as amylin primarily influences hedonic appetite pathways (reward-driven eating) while GLP-1 primarily affects homeostatic appetite regulation. The fatty acid acylation of cagrilintide enables albumin binding in circulation, reducing renal clearance and extending the elimination half-life to support once-weekly dosing. This prolonged receptor engagement provides sustained appetite suppression throughout the dosing interval.
Research-Observed Effects
Combination Weight Loss (CagriSema)
The Phase 3 REDEFINE 1 trial demonstrated that CagriSema (cagrilintide 2.4 mg plus semaglutide 2.4 mg) produced mean weight loss of 20.4% at 68 weeks in 3,417 adults with obesity or overweight without diabetes, compared to 14.9% with semaglutide alone, 11.5% with cagrilintide alone, and 3.0% with placebo. Approximately 60% of CagriSema-treated participants achieved at least 20% weight loss, and 40.4% achieved at least 25% loss, with some participants losing over 30% of body weight. The treatment difference of 17.3 percentage points versus placebo represents the largest weight reduction achieved by any pharmacotherapy in a Phase 3 trial. These results approach the efficacy of Roux-en-Y gastric bypass surgery, which typically produces 25-30% weight loss at one year.
Monotherapy Weight Loss
As a monotherapy, cagrilintide has demonstrated significant dose-dependent weight loss in Phase 2 trials. In a multicenter, randomized, placebo-controlled dose-finding trial, cagrilintide at doses ranging from 0.3 to 4.5 mg weekly produced dose-dependent weight reductions, with the 4.5 mg dose achieving approximately 10.8% weight loss at 26 weeks compared to 3.0% with placebo. The weight loss with cagrilintide monotherapy was comparable to liraglutide 3.0 mg used as an active comparator. These monotherapy results established proof of concept that amylin receptor agonism alone can produce clinically meaningful weight reduction and informed the dose selection of 2.4 mg for the combination product CagriSema.
Glycemic Control in Type 2 Diabetes
The REDEFINE 2 Phase 3 trial evaluated CagriSema in 1,206 adults with overweight or obesity and type 2 diabetes. CagriSema produced mean weight loss of 13.7% at 68 weeks compared to 3.4% with placebo, and 73.5% of CagriSema-treated participants achieved HbA1c of 6.5% or below compared to 15.9% with placebo. Phase 2 data in type 2 diabetes showed CagriSema reduced HbA1c by 2.2 percentage points compared to 1.8 with semaglutide alone and 0.9 with cagrilintide alone, while achieving 15.6% weight loss versus 5.1% with semaglutide alone. The dual mechanism provides complementary glucose-lowering effects through amylin-mediated glucagon suppression and GLP-1-mediated insulin secretion.
Blood Pressure Reduction
Analysis of REDEFINE 1 data published in Hypertension demonstrated that CagriSema produced significant systolic blood pressure reductions of 10.9 mmHg compared to placebo at 68 weeks. Blood pressure improvements were observed across prespecified subgroups including participants with and without baseline hypertension. The magnitude of blood pressure reduction is clinically meaningful and exceeds that typically achieved with single antihypertensive medications. These cardiovascular benefits likely reflect both the direct vascular effects of weight loss and potential direct receptor-mediated effects on vascular function.
Appetite and Food Intake Reduction
Cagrilintide acts on brain regions involved in hedonic appetite regulation, complementing the homeostatic appetite suppression provided by GLP-1 receptor agonists. Amylin receptor activation in the area postrema and lateral parabrachial nucleus reduces the rewarding value of food, decreases meal size, and promotes earlier satiation. Clinical studies have documented reductions in hunger scores, increased fullness ratings, and decreased caloric intake with cagrilintide treatment. The combination with semaglutide targets both reward-driven eating behaviors and energy balance homeostasis, which may explain the additive weight loss observed with CagriSema beyond what either agent achieves alone.
Research Dosing Information
In clinical trials, cagrilintide is administered as a once-weekly subcutaneous injection at a target dose of 2.4 mg, following a dose escalation protocol starting at 0.25 mg to improve gastrointestinal tolerability. CagriSema combines cagrilintide 2.4 mg and semaglutide 2.4 mg in separate weekly injections during trials, with a fixed-ratio combination product in development.
Note: Dosing information is provided for research reference only and is based on published studies using research subjects. This is not a recommendation for any use.
Research Studies & References
Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial
Lau DCW, Erichsen L, Francisco-Ziller N, et al. (2021). The Lancet
This Phase 2 dose-finding trial randomized adults with overweight or obesity without diabetes to cagrilintide at doses from 0.3 to 4.5 mg weekly, placebo, or liraglutide 3.0 mg daily as an active comparator across 57 sites in 10 countries. Over 26 weeks, cagrilintide demonstrated dose-dependent weight loss with the 4.5 mg dose achieving approximately 10.8% reduction compared to 3.0% with placebo. The highest dose produced weight loss comparable to liraglutide 3.0 mg, establishing cagrilintide as the first long-acting amylin analog to demonstrate clinically meaningful weight reduction in a randomized trial. Gastrointestinal adverse events including nausea and vomiting were the most common side effects but were generally transient and mild to moderate in severity. The study identified the 2.4 mg dose as optimal for combination development based on efficacy-tolerability balance. These results provided the mechanistic foundation for developing CagriSema as a combination therapy targeting both amylin and GLP-1 pathways.
Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity
Wilding JPH, Batterham RL, Davies M, et al. (2025). New England Journal of Medicine
The REDEFINE 1 Phase 3 trial was a landmark 68-week, double-blind, randomized study comparing CagriSema (cagrilintide 2.4 mg plus semaglutide 2.4 mg) with semaglutide alone, cagrilintide alone, and placebo in 3,417 adults with obesity or overweight without diabetes. CagriSema produced unprecedented mean weight loss of 20.4% at 68 weeks on an intent-to-treat basis, significantly exceeding semaglutide alone (14.9%), cagrilintide alone (11.5%), and placebo (3.0%). Approximately 60% of CagriSema-treated participants achieved at least 20% weight loss and 40.4% achieved at least 25% loss. On-treatment analysis showed weight loss of 22.7% with CagriSema, approaching the efficacy of bariatric surgery. Additional benefits included 88% reversion from prediabetes to normoglycemia and significant improvements in blood pressure, lipids, and waist circumference. Gastrointestinal adverse events occurred in 79.6% of CagriSema participants versus 39.9% with placebo, were mostly transient, and led to discontinuation in 6-8.4% of participants. This study established CagriSema as the most effective pharmacotherapy for obesity reported in any Phase 3 trial.
Efficacy and safety of co-administered once-weekly cagrilintide 2.4 mg with semaglutide 2.4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial
Frias JP, Deenadayalan S, Erichsen L, et al. (2023). The Lancet
This Phase 2 trial evaluated CagriSema versus semaglutide alone and cagrilintide alone in 92 adults with type 2 diabetes and overweight or obesity on metformin with or without an SGLT2 inhibitor across 17 US sites. Over 32 weeks, CagriSema produced HbA1c reductions of 2.2 percentage points compared to 1.8 with semaglutide alone and 0.9 with cagrilintide alone, with CagriSema statistically superior to cagrilintide. Weight loss with CagriSema reached 15.6% versus 5.1% with semaglutide alone and 8.1% with cagrilintide alone, demonstrating clear superiority of the combination over either component. Continuous glucose monitoring data showed time in range of 88.9% with CagriSema compared to 76.2% with semaglutide and 71.7% with cagrilintide. No level 2 or level 3 hypoglycemic events were observed in any group. These results demonstrated the additive benefits of targeting both amylin and GLP-1 pathways for glycemic control and weight management in type 2 diabetes and supported advancement to Phase 3 development.
Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes
Lingvay I, Brown-Frandsen K, Colhoun HM, et al. (2025). New England Journal of Medicine
The REDEFINE 2 Phase 3 trial evaluated CagriSema in 1,206 adults with overweight or obesity and type 2 diabetes in a 68-week, double-blind, placebo-controlled design. CagriSema produced mean weight loss of 13.7% at 68 weeks compared to 3.4% with placebo, with an on-treatment estimate of 15.7%. Among CagriSema-treated participants, 73.5% achieved HbA1c of 6.5% or below compared to 15.9% with placebo, demonstrating remarkable dual efficacy for both weight and glycemic endpoints. Significantly more CagriSema participants achieved clinically meaningful weight loss thresholds of 5%, 10%, 15%, and 20% compared to placebo at all timepoints assessed. The incidence of gastrointestinal adverse events was 72.5% with CagriSema versus 34.4% with placebo, predominantly transient and mild to moderate in severity. Low rates of hypoglycemia were observed across treatment groups. These results confirmed the efficacy and safety of CagriSema in the more metabolically complex population of patients with both obesity and type 2 diabetes.
Frequently Asked Questions
Semaglutide (GLP-1)
C187H291N45O59
Semaglutide is a long-acting GLP-1 (glucagon-like peptide-1) receptor agonist that mimics the incretin hormone GLP-1, regulating blood glucose levels, appetite, and body weight through multiple metabolic pathways.
Tirzepatide (GLP-1/GIP)
C225H348N48O68
Tirzepatide is a first-in-class dual GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 receptor agonist, providing synergistic metabolic effects for diabetes and obesity research.