Cagrilintide

Summary

Cagrilintide is an investigational amylin analogue administered by subcutaneous injection. It is being studied alone and in combination with the GLP‑1 receptor agonist semaglutide (CagriSema) for the treatment of obesity and type 2 diabetes, with the aim of producing greater weight loss and improved glycaemic control than existing therapies.

Mechanism of Action

Cagrilintide mimics the hormone amylin and activates amylin receptors, which are calcitonin‑receptor complexes expressed in the brain and gastrointestinal tract. Activation slows gastric emptying, reduces post‑prandial glucagon secretion and promotes satiety, leading to lower food intake and better glucose regulation. When combined with semaglutide, the dual agonism of amylin and GLP‑1 pathways produces additive effects on appetite suppression and glycaemic control.

What the Research Shows

Phase 2 data (Lancet 2023) showed that once‑weekly cagrilintide‑semaglutide (2.4 mg each) lowered HbA1c by 2.2 % and reduced body weight by 15.6 % over 32 weeks, outperforming cagrilintide alone and achieving greater weight loss than semaglutide alone. The REDEFINE 2 phase 3 trial (NEJM 2025) in 1,206 adults with type 2 diabetes reported a mean 13.7 % weight reduction with the combo versus 3.4 % with placebo, and 73.5 % of participants reached HbA1c ≤6.5 % compared with 15.9 % on placebo. REDEFINE 1, a similar trial in non‑diabetic overweight adults, demonstrated a 20.4 % weight loss versus 3.0 % with placebo. A network meta‑analysis (BMJ 2024) identified CagriSema as delivering the greatest mean weight loss among GLP‑1‑based regimens. Gastro‑intestinal adverse events were common but mostly mild to moderate.

Reported Benefits

Clinical trials consistently show that cagrilintide, especially when combined with semaglutide, produces substantial weight loss (13–20 % of baseline body weight) and meaningful reductions in HbA1c (up to ~2.2 %). The combination also improves continuous glucose monitoring metrics such as time‑in‑range. Network meta‑analysis ranks the combo as the most effective GLP‑1‑based regimen for weight reduction, suggesting a therapeutic advantage over monotherapy with either agent.

Limitations of the Evidence

Evidence is limited to phase 2 and phase 3a trials; long‑term safety and durability beyond 68 weeks are not yet established. The drug remains investigational and has not received regulatory approval. Most data involve weekly subcutaneous dosing in adult populations with BMI ≥27 kg/m², so applicability to lower‑BMI or pediatric groups is unknown. Cardiovascular outcomes and rare adverse events have not been fully evaluated, and gastrointestinal side effects are frequent.

Safety Considerations

Across trials, 70–80 % of participants receiving cagrilintide‑semaglutide reported gastrointestinal adverse events such as nausea, vomiting, diarrhea or constipation; these were generally transient and of mild‑to‑moderate severity. No severe hypoglycaemia or fatal events were reported in the phase 2 study. Monitoring for dehydration, electrolyte imbalance, and tolerability of GI symptoms is recommended, especially during dose escalation. Caution is advised in patients with a history of pancreatitis or severe gastroparesis, although specific data are lacking.

How It Is Administered

Cagrilintide is formulated for once‑weekly subcutaneous injection. In combination trials the dose was 2.4 mg of cagrilintide together with 2.4 mg of semaglutide, administered via prefilled pens. Monotherapy studies also used weekly subcutaneous dosing. No oral or alternative routes have been reported in the literature.

Routes of Administration

Goals & Uses

• Weight loss / anti-obesityMetabolicModerate
• Cardiovascular risk reductionCardiovascularLow
• Weight lossMetabolicModerateChronic weight management and appetite reduction
• Appetite suppressionMetabolicModerate
• Gastric emptying modulationGastrointestinalModerate
• Glycemic controlDiabetesModerate
• Glycemic control in type 2 diabetesMetabolicModerate

Contraindications

• Personal or family history of medullary thyroid carcinomaOncologicHigh
• Multiple endocrine neoplasia syndrome type 2 (MEN2)OncologicHigh
• Hypersensitivity to cagrilintide or excipientsImmunologicHigh
• PregnancyPopulationHighPotential fetal risk or insufficient safety data
• Medullary thyroid carcinomaOncologyModerate
• Hypersensitivity to amylin analoguesAllergyHigh

Adverse Effects

• HypoglycemiaMetabolicUncommonAbnormally low blood glucose
• Injection site reactionsLocalUncommon
• HeadacheNeurologicUncommonPain in the head or upper neck
• NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
• VomitingGastrointestinalCommonForceful expulsion of stomach contents
• Decreased appetiteMetabolicCommonReduced desire to eat
• DiarrheaGastrointestinalCommonLoose or frequent stools
• Injection‑site reactionLocalCommon

Drug Interactions

• InsulinModerateMay increase risk of low blood sugar
• Oral medications with narrow therapeutic indexModerate
• SulfonylureasModerateMay increase risk of low blood sugar
• SemaglutideLow

Population Constraints

• PregnancyReproductive SafetyRelative
• Severe renal impairmentOrgan ImpairmentRelative
• Pediatric patientsAgeRelative
• Pediatric (<18 y)AgeAbsolute
• Pregnant or breastfeeding womenReproductiveRelative
• Severe hepatic impairmentOrgan ImpairmentRelative

Regulatory Status

• European UnionInvestigationalUnder EMA review; no marketing authorization.
• United StatesInvestigationalPhase 2/3 trials ongoing; not FDA‑approved.
• United KingdomInvestigationalNo approval; clinical trial participation ongoing.

Not approved in any jurisdiction; currently in Phase 2/3 clinical development.

Evidence & Sources

• Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial
  Journal ArticleModerateFrias JP, et al.2023-01-01T00:00:00.000000Z
• Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes
  Journal ArticleModerateDavies MJ, et al.2025-01-01T00:00:00.000000Z
• Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity
  Journal ArticleModerateGarvey WT, et al.2025-01-01T00:00:00.000000Z
• Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis
  Journal ArticleHighYao H, et al.2024-01-01T00:00:00.000000Z
• 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
  Journal ArticleModerateLau DCW, et al.2021-01-01T00:00:00.000000Z
• Novel GLP-1-based Medications for Type 2 Diabetes and Obesity
  Journal ArticleModerateSon JW, et al.2026-01-01T00:00:00.000000Z

Frequently Asked Questions