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CagriSema

Fixed-dose weekly combination of the amylin analogue cagrilintide with semaglutide, giving about 20% weight loss by hitting two independent satiety pathways at once.

Also known as cagrilintide plus semaglutide, cagri-sema, NN9838-4586

Human RCT — Randomised controlled trials in humans, but not an approved product for this use.

REDEFINE-1 showed 20.4% weight loss at 68 weeks versus 3.0% for placebo, and REDEFINE-2 covered obesity with type 2 diabetes; both were published in NEJM in 2025. REDEFINE-4, the head-to-head against tirzepatide, failed to show non-inferiority. Novo filed with the FDA in December 2025 with a decision expected in late 2026 - so as of mid-2026 it is not yet approved.

How it works

CagriSema is a 1:1 co-formulation of cagrilintide 2.4 mg and semaglutide 2.4 mg. Semaglutide supplies GLP-1 receptor agonism - delayed gastric emptying, reduced food reward, glucose-dependent insulin release. Cagrilintide supplies amylin receptor signalling in the area postrema, which drives meal termination and appears to reduce the compensatory rise in hunger that follows weight loss. Because the receptors are distinct, the effects are additive rather than redundant, and there is a reasonable hypothesis that amylin protects lean mass. The combination did not beat tirzepatide in the head-to-head REDEFINE-4 trial, which tempered expectations considerably.

Targets: GLP-1 receptor, Amylin receptors, Calcitonin receptor

Dosing

ProtocolDoseFrequencyRoute
REDEFINE phase 3 titrationSame day each week.250 mcg – 2.4 mgonce weeklysubcutaneous
  • · Doses refer to each component - the trial escalated cagrilintide and semaglutide together from 0.25/0.25 mg through 0.5, 1.0 and 1.7 mg to a target of 2.4 mg of each, with four weeks at each step.

Titration

Because two nausea-producing agents escalate simultaneously, the titration is the hardest part. REDEFINE-1 allowed dose reductions and a substantial minority of participants never reached the full 2.4/2.4 mg.

Cycling

Chronic therapy, not cycled.

Work out your exact syringe units →

Pharmacology

Half-life
Both components have a roughly one-week half-life, matched deliberately to allow co-formulation.
Onset
Appetite suppression in the first week; weight loss continued through 68 weeks in REDEFINE-1.
Routes
subcutaneous
Molecule
Fixed-dose co-formulation of two acylated peptides (amylin analogue plus GLP-1 analogue)

Handling

Diluent
Not applicable - a pharmaceutical co-formulation, not a compounded mix
Lyophilised
Not applicable.
Reconstituted
Refrigerated at 2-8 C in the commercial pen.
Light sensitive
Yes — keep it out of the light

Mixing

People who combine separately sourced cagrilintide and semaglutide are approximating CagriSema, not reproducing it; mixing two research peptides in one syringe risks aggregation.

Side effects

  • very commonNausea— The dominant tolerability issue; both components contribute.
  • commonVomiting
  • commonConstipation
  • commonLoss of lean mass— Less than expected for the magnitude of weight loss, but still present.
  • uncommonGallbladder disease— Rate scales with the speed of weight loss.

Do not use if

  • Personal or family history of medullary thyroid carcinoma or MEN2.
  • History of pancreatitis.
  • Pregnancy.
  • Severe gastroparesis.

Combining it

  • redundantsemaglutide — Semaglutide is already a component.
  • redundantcagrilintide — Cagrilintide is already a component.
  • cautioninsulin-analogues — Significant hypoglycaemia risk; insulin doses need reducing at initiation.

What to monitor

  • · Weight and body composition.
  • · HbA1c.
  • · Protein intake - the satiety is strong enough to make undereating easy.
  • · Gallbladder symptoms.

Legal status

Investigational; FDA filing submitted December 2025, decision pending. Not legally available for human use anywhere as of mid-2026.

References

  • REDEFINE-1 phase 3 trial in obesity, NEJM 2025 (trial)
  • REDEFINE-2 phase 3 trial in obesity with type 2 diabetes, NEJM 2025 (trial)
  • REDEFINE-4 head-to-head trial vs tirzepatide (trial)

Mechanism in depth

The reason CagriSema is more interesting than a marketing exercise is that the two satiety systems it hits are genuinely independent. GLP-1 receptor agonism produces appetite suppression - a reduction in the drive to eat - through hypothalamic and reward circuitry. Amylin receptor agonism produces satiation - earlier meal termination - through the area postrema and a calcitonin-receptor-plus-RAMP architecture that shares nothing with the incretin receptors. Because the pathways are separate, tolerability does not stack the way efficacy does: you can add a second full-strength satiety mechanism without doubling the nausea, which is exactly what a higher dose of either drug alone would do. The second argument, and the one that matters more to anyone who cares about body composition, is that amylin signalling appears to protect lean mass during a deficit better than incretin signalling alone. REDEFINE 1 delivered 20.4% at 68 weeks against 3.0% for placebo and about 15% for semaglutide alone, which is real. What complicates the story is REDEFINE 4: the head-to-head against tirzepatide failed to demonstrate non-inferiority. That is a genuinely important negative result and it should shape expectations - CagriSema is a substantial improvement on semaglutide and did not beat the best approved dual agonist. Novo filed with the FDA in December 2025 and as of mid-2026 no approval has issued, so nothing available to a consumer is CagriSema.

What usually goes wrong

The first thing is availability - as of mid-2026 CagriSema is not approved anywhere, so anything sold under that name is a grey-market reconstruction, usually two separate research vials that the seller has decided to call CagriSema. Mixing two peptides yourself introduces compounding errors on top of identity uncertainty. The second is escalating both components fast. The tolerability advantage of the combination comes from hitting two pathways at moderate intensity rather than one at maximum, and people who jump straight to 2.4/2.4 lose that advantage entirely. Third, the REDEFINE 4 result matters: this did not beat tirzepatide, and someone switching off tirzepatide onto a self-assembled CagriSema expecting an upgrade is likely to be disappointed. Fourth, the standard rapid-weight-loss problems - gallstones, hair shedding, lean-mass loss - are all larger at 20% than at 15%.

Titration ladder

  1. 250 mcgWeeks 1-4 — Doses are given as the semaglutide component; the cagrilintide component is escalated in parallel at the same milligram value. So this step is 0.25 mg of each.
  2. 500 mcgWeeks 5-8 — 0.5 mg of each component.
  3. 1 mgWeeks 9-12 — 1.0 mg of each component.
  4. 1.7 mgWeeks 13-16 — 1.7 mg of each component.
  5. 2.4 mgWeek 17 onward — 2.4 mg of each component - the REDEFINE 1 maintenance dose that produced 20.4% at 68 weeks.

Bloodwork worth running

MarkerWhenWhy it matters
Body composition by DEXABaseline and every 3-4 months.The central claim of the combination is better lean-mass retention than an incretin alone. This is how you find out whether that is true for you.Act if: More than a third of inter-scan loss being lean tissue means the amylin arm is not delivering what it was added for and the protein and training plan needs fixing.
HbA1c and fasting glucoseBaseline, 3 months, then 3-6 monthly.REDEFINE 2 covered obesity with type 2 diabetes and the glycaemic effect is substantial. Combined with insulin this is a hypoglycaemia setup.Act if: Below 5.5% on background insulin or sulfonylurea means cut that agent.
Calcium and bone turnover markers, with baseline bone densityBaseline and annually.The calcitonin receptor activity of the cagrilintide component plus 20% weight loss plus low food volume is a plausible bone risk that no trial has addressed over a long enough horizon.Act if: No established threshold. The honest position is that this is unmonitored.
Ferritin, B12, vitamin D, albuminBaseline and 6-monthly.Twenty percent weight loss over 68 weeks is a long period of very low food intake.Act if: Albumin under 35 g/L means intake is inadequate.
Creatinine and eGFRBaseline and after any prolonged vomiting.Two emetogenic agents together mean a higher dehydration risk than either alone.Act if: A 30% rise means stop and rehydrate.
LipaseSymptom-driven.Diagnostic only, in someone with abdominal pain.Act if: Three times upper limit of normal with pain means stop and image.

Pharmacokinetics

Protein binding
99%
Time to steady state
35 days
Crosses blood-brain barrier
partial
Accumulates
Yes — doses stack before steady state
Metabolism
Both components are cleared by proteolytic backbone cleavage plus beta-oxidation of their respective fatty di-acid side chains. No CYP450 route.
Elimination
Catabolic, with fragments in urine and faeces.

Receptor targets

  • GLP-1 receptor (GLP1R) — Semaglutide component; low-nanomolar full agonist

    Appetite suppression, delayed gastric emptying, glucose-dependent insulin secretion, glucagon suppression.

  • AMY1R / AMY3R (calcitonin receptor plus RAMP1 or RAMP3) — Cagrilintide component; non-selective amylin receptor agonist

    Meal-terminating satiation through the area postrema, additional gastric-emptying delay, postprandial glucagon suppression, and the apparent lean-mass-sparing effect.

  • Calcitonin receptor (CTR) — Retained activity of the cagrilintide component

    Off-target bone and calcium handling effects that have not been characterised over long exposure.

Trials

  • REDEFINE 1 Phase 3 · n=3417 · 68 weeks · 2025

    Mean weight reduction of 20.4% with CagriSema versus 3.0% with placebo, and versus roughly 15% for semaglutide alone in the same trial.

  • REDEFINE 2 Phase 3 · n=1206 · 68 weeks · 2025

    Weight reduction and glycaemic control in adults with obesity and type 2 diabetes.

  • REDEFINE 5 Phase 3 · 2026

    Co-administered cagrilintide and semaglutide versus semaglutide alone in adults with overweight or obesity in Japan and Taiwan.

  • REIMAGINE 1 Phase 3a · 2026

    CagriSema versus placebo in type 2 diabetes inadequately controlled on diet and exercise.

  • REIMAGINE 2 Phase 3 · 2026

    CagriSema versus semaglutide or cagrilintide alone in type 2 diabetes - the component-deconstruction trial.

  • REIMAGINE 3 Phase 3 · 2026

    CagriSema as an add-on to basal insulin in type 2 diabetes.

  • REDEFINE 4 Phase 3 head-to-head · 72 weeks · 2025

    Reported by the sponsor as failing to demonstrate non-inferiority to tirzepatide for weight loss. This was not confirmed against a peer-reviewed publication in this session.

What to expect, and when

Week 1: appetite suppression from the semaglutide arm plus earlier meal termination from the amylin arm; users often describe the combination as being unable to finish a meal rather than not wanting one. Weeks 4-5: steady state. Weeks 8-40: steepest weight loss. Week 68: 20.4% mean in REDEFINE 1, still with some downward slope. Stopping: regain follows the same pattern as semaglutide alone.

Stacking and comparisons

CagriSema is already a stack, and stacking on top of it is where things go wrong. Adding tirzepatide or retatrutide layers a second incretin onto an existing full-strength GLP-1 arm for no additional effect. Adding a separate cagrilintide vial on top of the fixed combination is a dosing error waiting to happen. What genuinely belongs alongside it is the non-pharmacological work: 1.6-2.2 g/kg protein, hard resistance training three times a week, creatine, and enough electrolytes to tolerate two emetogenic agents at once. If bone health matters to you, a baseline DEXA before starting is sensible given the unresolved calcitonin receptor question.

Against semaglutide alone: clearly better, 20.4% versus about 15% in the same trial, with the additional lean-mass argument. Against tirzepatide: REDEFINE 4 failed to show non-inferiority, which is the single most important comparative fact and is frequently omitted from summaries of this drug. Against retatrutide: retatrutide's reported phase 3 numbers are higher but it is unapproved, carries a glucagon arm and raises heart rate. Against amycretin: amycretin does the same two-mechanism job in one molecule and has shown a steeper early curve in phase 1b/2a, but with far less evidence behind it.

Rough cost

Not approved and not marketed anywhere as of mid-2026, so there is no legitimate price. Grey-market pairs of cagrilintide and semaglutide vials are sold as a substitute at roughly 100-350 per month equivalent. Market observation, not verified pricing.

Genuinely uncertain

  • Cagrilintide-component pharmacokinetics are unpublished; the pharmacokinetic entry here is dominated by verified semaglutide values.
  • REDEFINE 4's failure to show non-inferiority against tirzepatide is a sponsor communication that was not confirmed against a peer-reviewed publication in this session.
  • The lean-mass advantage of adding amylin comes from DEXA sub-analyses, not a dedicated powered comparison.
  • Long-term bone effects of the retained calcitonin receptor activity are uncharacterised.
  • Participant numbers for REDEFINE 1 and REDEFINE 2 are as commonly reported and were not individually re-verified against the papers.
  • Regulatory status is a moving target; no approval had issued as of mid-2026.

Papers