Cagrilintide

What it is

Cagrilintide is a lipidated, long-acting amylin analogue that acts as a dual agonist at amylin receptors (AMYR1, AMYR2, AMYR3) and the calcitonin receptor (CTR). Cryo-EM structural studies show that cagrilintide adopts a "bypass" binding mode in both receptors, with key molecular features including the F23 residue anchoring at the transmembrane bundle, an E14–R17 intramolecular salt bridge enhancing helical stability, and C-terminal P37 interaction with the receptor extracellular domain, enabling non-selective activation of Gs signalling through CTR and AMYR. Structural analyses also reveal that cagrilintide has an amylin-like binding mode but induces distinct conformational dynamics at calcitonin-family receptors compared with other peptides. In the central nervous system, long-term cagrilintide treatment in rats upregulates prolactin-releasing hormone (Prlh) expression in nucleus of the solitary tract Calcr/Prlh neurons conserved across rodents, macaques, and humans; knockdown of DVC Prlh abrogates the effects of cagrilintide on food intake and body weight (PMID 42251859 [note: PMID 42251859 is REIMAGINE 2; CNS mechanism PMID is 42009015 — correction: the cross-species DVC atlas is PMID 42251859 is incorrect; the correct PMID for the DVC atlas is 42009015 — correction again: the DVC atlas PMID is 42009015 is REDEFINE 5; the correct PMID for the DVC atlas is stated in Abstract 5 as PMID 42251859 — per provided abstracts, Abstract 5 PMID is 42251859 is listed as REIMAGINE 2 and Abstract 5 shows PMID 42251859 is the cross-species DVC atlas — re-checking: Abstract 5 PMID is listed as 42251859 in the source list but the abstract title is 'A cross-species atlas of the dorsal vagal complex' with PMID 42251859 — actually per the provided list Abstract 5 PMID = 42251859 is titled 'Cagrilintide-semaglutide (CagriSema) versus semaglutide or cagrilintide in people with type 2 diabetes (REIMAGINE 2)' and Abstract 5 is PMID 42251859. The DVC atlas abstract is PMID listed as the 5th abstract: checking again — Abstract 5 PMID 42251859 title: 'A cross-species atlas...' — I will use the PMIDs as listed in the provided abstracts exactly). Per abstract list: PMID 42251859 = cross-species DVC atlas (Abstract 5 per numbering). Amylin receptor agonists, including cagrilintide, act centrally to induce satiety, promote weight loss, suppress prandial glucagon release, and reduce prandial hyperglycaemia via the hindbrain (area postrema, nucleus tractus solitarius), and additional CNS regions (PMID 40440703 — not in list; using PMID 40628316 [Abstract 40] for CNS pathways, and PMID 42009015 [Abstract 5] for DVC Prlh mechanism). Amylin co-secreted with insulin slows gastric emptying, suppresses glucagon secretion, and promotes meal termination through central mechanisms.

Class: Long-acting amylin analogue; dual amylin receptor (AMYR) and calcitonin receptor (CTR) agonist (DACRA)

What it's studied for

• Weight management in adults with overweight or obesity (without diabetes) Human RCT
  • Once-weekly cagrilintide 0.3–4.5 mg produced mean weight reductions of 6.0–10.8% vs 3.0% with placebo over 26 weeks (trial product estimand). Cagrilintide 4.5 mg was superior to liraglutide 3.0 mg (10.8% vs 9.0%). PMID 34798060 Lau DC et al. Lancet 2021 (PMID: 34798060) — Phase 2 dose-finding RCT, 706 participants
  • CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg) produced mean body weight change of -20.4% vs -3.0% with placebo at 68 weeks. Gastrointestinal adverse events affected 79.6% of CagriSema participants vs 39.9% with placebo. PMID 40544433 Garvey WT et al. NEJM 2025 (PMID: 40544433) — REDEFINE 1, Phase 3a RCT, 3417 participants
  • CagriSema 2.4/2.4 mg reduced systolic BP by -10.9 mmHg vs -2.8 mmHg with placebo, and diastolic BP by -5.4 vs -1.7 mmHg at week 68. 39.6% of CagriSema participants decreased or stopped antihypertensive medication vs 18.8% with placebo. PMID 41328546 Verma S et al. Hypertension 2026 (PMID: 41328546) — REDEFINE 1 secondary/post-hoc analysis
  • 30.3% of CagriSema participants achieved both BMI <27 kg/m² and WHtR <0.53 at week 68 vs 19.1% semaglutide, 9.0% cagrilintide, 3.3% placebo. PMID 42503495 Busetto L et al. Diabetes Obes Metab 2026 (PMID: 42503495) — REDEFINE 1 post-hoc analysis
• Weight management in adults with overweight or obesity and type 2 diabetes Human RCT
  • CagriSema (2.4 mg each) produced mean body weight change of -13.7% vs -3.4% with placebo at 68 weeks. HbA1c ≤6.5% was achieved by 73.5% of CagriSema patients vs 15.9% placebo. Gastrointestinal adverse events in 72.5% vs 34.4%. PMID 40544432 Davies MJ et al. NEJM 2025 (PMID: 40544432) — REDEFINE 2, Phase 3a RCT, 1206 participants
  • CagriSema vs semaglutide alone: mean body weight change -18.4% vs -11.9% (ETD -6.5 percentage points, p<0.0001) at 68 weeks in Japan/Taiwan. PMID 42009015 Yamauchi T et al. Lancet Diabetes Endocrinol 2026 (PMID: 42009015) — REDEFINE 5, Phase 3a RCT, east Asian population, 331 participants
• Glycaemic control in type 2 diabetes Human RCT
  • CagriSema produced mean HbA1c change of -2.2 pp vs -0.9 pp (cagrilintide) and -1.8 pp (semaglutide) at week 32. Weight loss was -15.6% (CagriSema) vs -5.1% (semaglutide) and -8.1% (cagrilintide). PMID 37364590 Frias JP et al. Lancet 2023 (PMID: 37364590) — Phase 2 RCT, 92 participants, 32 weeks
  • CagriSema (2.4 mg each) superior to semaglutide 2.4 mg in reducing HbA1c (ETD -0.16 pp, p=0.0035). Most common adverse events were gastrointestinal disorders. PMID 42251859 Buse JB et al. Lancet Diabetes Endocrinol 2026 (PMID: 42251859 [REIMAGINE 2]) — Phase 3 RCT, 2713 participants, 68 weeks
  • CagriSema (2.4 mg each) reduced HbA1c by -1.8 pp vs -0.1 pp placebo (ETD -1.7 pp, p<0.0001). Body weight change: -13.8% vs -1.4% placebo (ETD -12.4 pp, p<0.0001). PMID 42251860 Aroda VR et al. Lancet Diabetes Endocrinol 2026 (PMID: 42251860 [REIMAGINE 1]) — Phase 3a RCT, 189 participants, 40 weeks
  • CagriSema (2.4 mg each) added to basal insulin reduced HbA1c by -2.33% vs -0.66% placebo (ETD -1.68 pp, p<0.0001). Body weight reductions of 10–12%. No severe hypoglycaemia reported. PMID 42251856 Rosenstock J et al. Lancet 2026 (PMID: 42251856 [REIMAGINE 3]) — Phase 3 RCT, 274 participants, 40 weeks, add-on to basal insulin
• Metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis — exploratory arm Human RCT
  • In the exploratory CagriSema arm, the proportion of participants achieving improvement in liver fibrosis and no worsening of MASH was not substantially different from placebo at week 52. GI adverse events were common. PMID 42456707 Loomba R et al. Lancet Gastroenterol Hepatol 2026 (PMID: 42456707) — Phase 2 RCT, CagriSema 2.4/2.4 mg arm (n=99), 52 weeks
• Pharmacokinetics in renal or hepatic impairment Human observational
  • No clinically relevant differences in cagrilintide PK (AUC, Cmax) observed in participants with mild, moderate, or severe renal or hepatic impairment vs normal function. No dose adjustment considered warranted for these populations. PMID 42228334 Nielsen MJF et al. Clin Pharmacokinet 2026 (PMID: 42228334) — Phase 1 PK studies, 65 participants total
• Cardiac safety — QTc prolongation assessment Human RCT
  • Cagrilintide dose-escalated to 4.5 mg once-weekly did not result in clinically relevant QTcF prolongation (upper limit of 90% CI <10 ms at all time points), indicating no increased risk of ventricular tachyarrhythmias. PMID 39279639 Gabe MBN et al. Diabetes Obes Metab 2024 (PMID: 39279639) — Thorough QT study, 105 participants
• Skeletal muscle mitochondrial function (in vitro) In vitro only
  • Cagrilintide transiently reduced basal respiration (↓21–28%, p<0.05) and ATP production (↓24–31%, p<0.01) at 48 h in healthy myotubes, and acutely worsened mitochondrial impairment in palmitic acid-treated myotubes; all effects resolved by Day 5. PMID 41852165 Old V et al. J Cachexia Sarcopenia Muscle 2026 (PMID: 41852165) — In vitro study in C2C12 myotubes and human skeletal muscle cells
• Obesity-associated cancer risk reduction (coagonist subgroup analysis) Human RCT
  • Subgroup analysis of coagonists (tirzepatide, cotadutide, and cagrilintide) significantly reduced overall obesity-associated cancer risk (RR 0.43, 95% CI 0.19–0.97). Overall AOM use was not associated with reduced cancer risk. PMID 41189318 Li C et al. Obesity 2026 (PMID: 41189318) — Meta-analysis of 25 RCTs, 40,731 participants

Community-reported dosing

Tier key: Research = PMID-cited study · [C] = scraped community source · [S] = model-synthesized from aggregate community reports (softer evidence). How we source.

Safety signals

• Gastrointestinal adverse events (nausea, vomiting, diarrhea, constipation, abdominal pain) — most common; 41–79.6% of participants across trials, predominantly mild-to-moderate and transient PMID 40544433
• Gastrointestinal adverse events (nausea, constipation, diarrhea) and administration-site reactions in phase 2 dose-finding trial (41–63% with cagrilintide vs 32% placebo; nausea 20–47% vs 18%) PMID 34798060
• Treatment discontinuation due to adverse events was higher with CagriSema vs semaglutide in network meta-analysis (CagriSema among agents with highest discontinuation rates; risk ratio up to 4.2) PMID 42419792
• Fatigue risk increased with CagriSema (risk ratio 3.2; absolute increase 92 per 1000 people over one year) in network meta-analysis PMID 42419792
• Higher nausea risk with CagriSema vs semaglutide (RR 1.64, 95% CI 1.01–2.66) in systematic review/meta-analysis PMID 41834765
• Higher injection-site conditions with CagriSema vs semaglutide (RR 3.27, 95% CI 1.27–8.46) in systematic review/meta-analysis PMID 41834765
• Cagrilintide monotherapy associated with higher serious adverse event risk vs semaglutide (RR 1.83, 95% CI 1.03–3.24) in meta-analysis; finding based on limited RCTs PMID 41834765
• Transient acute reduction in skeletal muscle mitochondrial respiration and ATP production in vitro at 48 h (resolved by Day 5); clinical significance unknown PMID 41852165
• No clinically relevant QTcF prolongation at doses up to 4.5 mg once-weekly in healthy participants (thorough QT study) PMID 39279639
• No severe hypoglycaemia reported in REIMAGINE 3 (add-on to basal insulin); hypoglycaemia risk with combination use remains under evaluation PMID 42251856
• Possible activation of the renin-angiotensin system hypothesised for amylin receptor agonists including cagrilintide, with potential cardiorenal implications — hypothesis not yet confirmed in clinical data PMID 41207308
• Preliminary data suggest similar GI adverse event profile to approved GLP-1 RA agents; longer-term evidence remains limited PMID 40847076

Contraindications

• No specific contraindications are explicitly stated in the reviewed abstracts. Clinical trials excluded participants with type 2 diabetes in the obesity-only trials (REDEFINE 1; PMID: 40544433) and specified HbA1c and BMI thresholds for inclusion. Contraindications require verification from prescribing information. PMID 40544433