What is cagrilintide (glucagon-like peptide-1 receptor agonist) used for in the management of type 2 diabetes and obesity?

Cagrilintide: A Long-Acting Amylin Analogue for Weight Management

Cagrilintide is an investigational long-acting amylin analogue that induces significant weight loss (6-11% as monotherapy, 15-17% when combined with semaglutide) and is currently in phase 3 clinical development for obesity and type 2 diabetes management. 1, 2, 3

Mechanism of Action

Cagrilintide mimics the action of natural amylin, a pancreatic hormone that induces satiety and regulates glucose metabolism 1. The drug works through multiple pathways:

• Appetite suppression through central nervous system effects on satiety centers 1
• Delayed gastric emptying, which prolongs the feeling of fullness 4
• Modulation of glucose homeostasis by reducing postprandial glucagon secretion 5

Unlike GLP-1 receptor agonists such as semaglutide or tirzepatide, cagrilintide acts on amylin receptors rather than incretin pathways, representing a novel mechanism for weight management 1, 5.

Clinical Efficacy Data

Monotherapy for Obesity

In a phase 2 trial of 706 adults with overweight or obesity without diabetes, cagrilintide demonstrated dose-dependent weight loss over 26 weeks 1:

• Cagrilintide 4.5 mg weekly: 10.8% weight loss (11.5 kg) versus 3.0% with placebo 1
• Cagrilintide 2.4 mg weekly: 8.9% weight loss 1
• Superior to liraglutide 3.0 mg daily: 10.8% versus 9.0% weight loss (p=0.03) 1

Treatment discontinuation occurred in only 10% of participants, mostly due to adverse events, indicating good overall tolerability 1.

Combination Therapy: CagriSema (Cagrilintide + Semaglutide)

The combination of cagrilintide 2.4 mg with semaglutide 2.4 mg (branded as CagriSema) shows synergistic effects that exceed either monotherapy 2, 3, 6:

For Type 2 Diabetes with Obesity (REDEFINE 2 trial, phase 3a):

• Mean weight loss at 68 weeks: -13.7% with CagriSema versus -3.4% with placebo (difference: -10.4 percentage points, p<0.001) 2
• Glycemic control: 73.5% of patients achieved HbA1c ≤6.5% versus 15.9% with placebo 2
• Clinically meaningful weight loss: More patients achieved ≥5%, ≥10%, ≥15%, and ≥20% weight reduction compared to placebo (all p<0.001) 2

Phase 1b dose-finding study:

• CagriSema 2.4 mg/2.4 mg: 17.1% weight loss at 20 weeks versus 9.8% with semaglutide 2.4 mg alone (difference: -7.4%, 95% CI -11.2 to -3.5) 3
• CagriSema 1.2 mg/2.4 mg: 15.7% weight loss versus 9.8% with semaglutide alone (difference: -6.0%, 95% CI -9.9 to -2.0) 3

Phase 2 trial in type 2 diabetes:

• HbA1c reduction: -2.2 percentage points with CagriSema versus -1.8 with semaglutide alone (not statistically significant, p=0.075) and -0.9 with cagrilintide alone (p<0.0001) 6
• Weight loss: -15.6% with CagriSema versus -5.1% with semaglutide alone (p<0.0001) and -8.1% with cagrilintide alone (p<0.0001) 6
• Continuous glucose monitoring: Time in range (3.9-10.0 mmol/L) improved from 45.9% to 88.9% with CagriSema 6

Pharmacokinetics

Cagrilintide exhibits favorable pharmacokinetic properties for once-weekly dosing 3:

• Half-life: 159-195 hours (approximately 6.6-8.1 days), supporting weekly administration 3
• Time to maximum concentration (tmax): 24-72 hours 3
• Dose-proportional exposure: AUC ranges from 926 to 24,271 nmol×h/L across doses of 0.16-4.5 mg 3
• No drug-drug interaction: Cagrilintide does not affect semaglutide exposure or elimination when co-administered 3

Safety Profile and Adverse Events

Common Adverse Events

Gastrointestinal effects are the most frequent adverse events, similar to GLP-1 receptor agonists 1, 2, 3:

• Nausea: 20-47% with cagrilintide monotherapy versus 18% with placebo 1
• Constipation and diarrhea: Common but typically mild to moderate 1, 2
• With CagriSema: 72.5% experienced gastrointestinal adverse events versus 34.4% with placebo, but most were transient and mild-to-moderate in severity 2

Injection Site Reactions

Administration-site reactions occurred more frequently with cagrilintide than placebo, but were generally mild 1.

Serious Adverse Events

• No fatal adverse events were reported in clinical trials 6
• No level 2 or 3 hypoglycemia occurred in type 2 diabetes trials, even when combined with metformin or SGLT2 inhibitors 6
• Treatment discontinuation: Only 4% of participants discontinued due to adverse events in the phase 2 monotherapy trial 1

Perioperative Considerations

Due to delayed gastric emptying effects, cagrilintide poses aspiration risk during anesthesia 4:

• Recommended cessation period: At least three half-lives (approximately 20-24 days) before elective surgery for patients using cagrilintide for weight management 4
• For patients with type 2 diabetes: Consultation with an endocrinologist is advised, as prolonged cessation may worsen glycemic control 4
• Precautionary approach: Until more evidence becomes available, individualized assessment of aspiration risk is necessary 4

Current Regulatory Status and Development

Cagrilintide is investigational and not yet FDA-approved 1, 5, 2:

• Phase 3 trials ongoing: The REDEFINE 2 trial (NCT05394519) has completed enrollment for type 2 diabetes with obesity 2
• Combination product (CagriSema): Under development as a fixed-dose combination of cagrilintide 2.4 mg and semaglutide 2.4 mg 5, 2
• Expected approval timeline: Pending completion of phase 3 trials and regulatory review 5

Clinical Positioning and Future Role

Advantages Over Current Therapies

Cagrilintide offers a novel mechanism complementary to GLP-1 receptor agonists 1, 5:

• Greater weight loss than liraglutide 3.0 mg: 10.8% versus 9.0% at comparable treatment duration 1
• Synergistic effects with semaglutide: CagriSema produces 15-17% weight loss, exceeding semaglutide 2.4 mg monotherapy (approximately 15% vs 10% in head-to-head comparisons) 3, 6
• Dual benefits in type 2 diabetes: Substantial weight loss combined with excellent glycemic control (73.5% achieving HbA1c ≤6.5%) 2

Comparison to Tirzepatide

While tirzepatide (a dual GIP/GLP-1 receptor agonist) achieves 20.9% weight loss at 72 weeks 7, CagriSema demonstrates comparable efficacy with 17.1% weight loss at 20 weeks in phase 1b trials 3. Direct head-to-head trials are needed to definitively compare these agents 5.

Target Patient Populations

Once approved, cagrilintide or CagriSema would be appropriate for 1, 2, 6:

• Adults with BMI ≥30 kg/m² (obesity) or BMI ≥27 kg/m² with weight-related comorbidities 1
• Patients with type 2 diabetes requiring both glycemic control and substantial weight loss 2, 6
• Individuals who have inadequate response to GLP-1 receptor agonist monotherapy 5, 6
• Patients seeking alternatives to tirzepatide due to availability, cost, or tolerability concerns 5

Practical Prescribing Considerations (When Approved)

Dosing and Administration

Anticipated dosing regimen based on clinical trials 1, 2, 3:

• Starting dose: 0.3 mg subcutaneously once weekly 1
• Dose escalation: Increase by doubling the dose every 4 weeks (0.3 → 0.6 → 1.2 → 2.4 mg) 1, 3
• Maintenance dose: 2.4 mg or 4.5 mg once weekly, depending on tolerability and efficacy 1
• For CagriSema: Co-escalate both cagrilintide and semaglutide to 2.4 mg each over 16 weeks 3

Monitoring Requirements

Patients should be monitored for 2, 6:

• Gastrointestinal tolerability: Assess nausea, vomiting, diarrhea, and constipation at each visit, particularly during dose escalation 2
• Weight and BMI: Track monthly to assess treatment response 2
• Glycemic parameters (in diabetes): HbA1c every 3 months, continuous glucose monitoring if available 6
• Signs of pancreatitis or gallbladder disease: Persistent severe abdominal pain warrants immediate evaluation 7

Contraindications and Precautions

Based on the amylin mechanism and GLP-1 combination data 4, 7, 2:

• Gastroparesis or severe GI motility disorders: Cagrilintide may worsen symptoms due to delayed gastric emptying 4
• Planned surgery: Discontinue at least 3 half-lives (20-24 days) before elective procedures 4
• Pregnancy: Safety not established; likely contraindicated based on class effects 7
• Personal or family history of medullary thyroid cancer or MEN2: Contraindicated when combined with semaglutide (GLP-1 component) 7, 2

Combination with Lifestyle Interventions

Cagrilintide must be used as an adjunct to lifestyle modifications 1, 2:

• Reduced-calorie diet: Essential for maximizing weight loss outcomes 7, 2
• Increased physical activity: Particularly resistance training to preserve lean body mass 7
• Behavioral interventions: Support long-term adherence and weight maintenance 7

Key Clinical Pearls

• Cagrilintide represents a novel amylin-based approach to obesity and diabetes management, distinct from incretin-based therapies 1, 5
• The combination with semaglutide (CagriSema) produces synergistic weight loss exceeding either agent alone, with 15-17% weight reduction 2, 3, 6
• Gastrointestinal adverse events are common but manageable with gradual dose titration and typically resolve over time 1, 2, 3
• Delayed gastric emptying necessitates perioperative precautions, with cessation at least 3 half-lives (20-24 days) before elective surgery 4
• Phase 3 trials are ongoing, with regulatory approval anticipated pending successful completion and review 5, 2