Research information only. PrecisePep is an educational library. It is not medical advice and is not intended to assist, encourage or enable self-administration. The compounds documented here are research chemicals — most are not approved for human use. Read the full disclaimer.
PrecisePep/Blends & Stacks/CagriSema
Metabolic Blend
cagrilintide + semaglutide · CagriSema 2.4/2.4
The fixed-dose combination that made every amylin-plus-incretin stack in the grey market look legitimate — and the one whose phase 3 result landed below what the market expected.
CagriSema is the trial programme every amylin-plus-incretin stack in the grey market points at. It pairs semaglutide with cagrilintide in a single fixed-dose weekly injection, on the premise that GLP-1 agonism reduces hunger while amylin agonism accelerates fullness — two anatomically separate satiety routes, so the effects add rather than overlap.
The phase 1b work established tolerability and additive effect.[1] Phase 3 delivered REDEFINE-1 in obesity without diabetes — a mean 22.7% weight reduction at 68 weeks, with 91.9% of participants losing at least 5% of body weight against 31.5% on placebo[2] — and REDEFINE-2 in obesity with type 2 diabetes, where weight fell 13.7% against 3.4% and HbA1c fell 2.0 percentage points against 0.1.[3] A separate programme, REIMAGINE, tested it against semaglutide rather than placebo in type 2 diabetes and reported superiority on both endpoints.[4]
Novo Nordisk filed a new drug application with the FDA on 18 December 2025, with a decision expected in the fourth quarter of 2026. If approved it would be the first once-weekly GLP-1-plus-amylin combination for weight management.
It is also the library's clearest lesson in expectation management. That 22.7% figure was strong in absolute terms and below the roughly 25% the market had priced in, and the sponsor's share price fell sharply on the readout. Nothing about the drug changed — the number was simply lower than the anticipation around it. Worth remembering when reading any claim about what a combination "should" achieve, including the home-assembled ones that cite this programme.
Almost every reta+cagri or sema+cagri stack in circulation justifies itself by citing CagriSema. That citation is legitimate as far as the concept goes — amylin plus incretin is a real, trial-tested architecture. It is not legitimate as evidence about a different incretin, a different ratio, or unregulated material. This page exists to hold that distinction in place.
Two satiety pathways, deliberately separated. GLP-1 receptor agonism acts on hypothalamic and hindbrain appetite circuits and on mesolimbic reward signalling — reducing hunger and food salience. Amylin receptor agonism acts in the area postrema and nucleus tractus solitarius on meal-termination signalling — accelerating fullness. Different neurons, different receptors, additive output.
Why a fixed-dose combination. Both components have half-lives around a week, so a single weekly injection covers both. Co-formulation was practical here in a way it is not for compounds with mismatched kinetics.
Additive gastric emptying delay. Both slow emptying. This contributes to the effect and to the gastrointestinal adverse-event burden, which is higher than semaglutide alone.
Calcitonin receptor agonism. Cagrilintide is deliberately non-selective across amylin and calcitonin receptors, which is thought to add durability to the weight effect and is also the source of the theoretical bone-turnover questions attached to the amylin side.
A blend is not a compound. It is several compounds sharing a vial, and each one carries its own evidence base, dose-response curve and risk profile. Study them individually before studying them together.
| Component | Share of blend | Role in the blend | Monograph link |
|---|---|---|---|
| Semaglutide GLP-1 receptor agonist |
2.4 mg of 4.8 (50%) | Appetite and food-noise suppression, delayed gastric emptying, glucose-dependent insulinotropic effect. The component with cardiovascular and renal outcome data behind it. | Monograph |
| Cagrilintide Long-acting amylin analogue |
2.4 mg of 4.8 (50%) | Amylin and calcitonin receptor agonism — hindbrain meal-termination signalling on circuits the incretins do not reach, plus additional gastric emptying delay. | Monograph |
Unlike every other blend in this library, this one has a defined, published, fixed composition: cagrilintide 2.4 mg with semaglutide 2.4 mg, reached by co-escalation. There is no ratio to guess at and no supplier variation to worry about.
That also means it cannot be titrated independently. Community stacks that pair the two components separately can adjust each side — which is a genuine flexibility advantage over the fixed product, and the reason grey-market users assemble their own rather than waiting for it.
Effects that have been reported. A study-tier entry means a result was published — not that the effect is established, reproducible, or transferable from a rodent to a person.
Highest confidenceReported in peer-reviewed literature, registered clinical trials, or regulatory filings. Note the model: much peptide literature is in vitro or rodent work, not human trial data.
Multiple-dose work demonstrated that cagrilintide co-administered with semaglutide 2.4 mg is tolerable and produces greater weight reduction than semaglutide alone — the finding that launched the programme.
Phase 3 in adults with overweight or obesity and a weight-related condition but without diabetes. Mean weight reduction of 22.7% at 68 weeks, with 91.9% of participants losing at least 5% of body weight against 31.5% on placebo. Strong in absolute terms, and below the roughly 25% the market had priced in — which is what moved the share price rather than anything about the result itself.
Phase 3a in adults with obesity, type 2 diabetes and baseline HbA1c 7–10% (mean 8.0%, mean weight 102.2 kg). Weight fell 13.7% against 3.4% on placebo; HbA1c fell 2.0 percentage points against 0.1. 73.5% reached an HbA1c of 6.5% or below, against 15.9% on placebo. Weight loss is consistently smaller in type 2 diabetes than in obesity alone — a class pattern, not a failure of this combination.
A separate programme tested the fixed 2.4/2.4 mg combination against semaglutide rather than placebo, and reported an HbA1c reduction of 1.91 percentage points with 14.2% weight loss, superior on both endpoints. An active-comparator result is a harder test than placebo, and it is the strongest evidence that the amylin component adds something the incretin alone does not.
This is the entire evidence base for the architecture. Every other amylin-plus-incretin pairing documented on this site is an extrapolation from it.
Unusually for anything in this library, the ratio is defined and public: 2.4 mg of each component.
Unproven — inference onlyExtrapolated from a known mechanism, receptor profile, or adjacent compound class. Biologically plausible but not directly demonstrated for this compound in this context.
The dose-sparing argument — reaching greater effect without pushing the incretin higher. The combination still produces more gastrointestinal adverse events than semaglutide alone, so "better tolerated" is relative rather than absolute.
Proposed as contributing to sustained weight effect. Long-term maintenance data is what would settle it.
A frequently repeated claim about amylin agonism. Body-composition sub-studies are where it gets tested; treat as open.
Semaglutide has SELECT behind it. Whether the combination retains that benefit is a reasonable expectation and a separate question from weight loss.
Uncontrolled reportsAggregated from research-community logs, forums, vendor literature and self-reported experience. Uncontrolled, unverified, subject to placebo, polypharmacy and product-purity confounds. Lowest evidentiary weight.
Because the fixed product is not generally available, community users buy semaglutide and cagrilintide separately and dose them together. That is a different thing from the trialled product, at ratios they choose themselves.
Consistently reported and directly consistent with the additive gastric-emptying mechanism and the trial adverse-event data.
Users describe the incretin as removing food thoughts and the amylin as making meals end early — which maps precisely onto the two mechanisms.
Community users note they can adjust each component separately, which the fixed-dose product cannot do. A genuine point, and it comes at the cost of using material and ratios nobody studied.
Adverse effects, contraindications and unknowns. The grey-market tier is where under-reporting is worst: uncontrolled use produces no systematic safety surveillance at all, so absence of a reported harm is not evidence of safety.
Highest confidenceReported in peer-reviewed literature, registered clinical trials, or regulatory filings. Note the model: much peptide literature is in vitro or rodent work, not human trial data.
Against 39.9% on placebo. Nausea 55.0% (vs 12.6%), constipation 30.7% (vs 11.6%), vomiting 26.1% (vs 4.1%). Two compounds slow gastric emptying here — GLP-1 agonism and amylin agonism do it independently — which is why the trialled product co-escalates both on a defined schedule rather than starting at target dose.
Both components slow gastric emptying, and the combination produces more nausea, vomiting and constipation than the incretin alone. Better tolerated than an equivalent escalation of semaglutide is not the same as well tolerated.
Boxed warning for thyroid C-cell tumours with contraindication in medullary thyroid carcinoma and MEN2; pancreatitis, gallbladder disease, acute kidney injury and retinopathy considerations.
Pramlintide, the approved amylin analogue, carries a boxed warning for severe insulin-induced hypoglycaemia and requires insulin dose reduction on initiation. That precedent applies to anyone combining an amylin analogue with insulin therapy.
Amylin analogues have an immunogenicity history — pramlintide is meaningfully immunogenic — and antibody formation is a standard monitored endpoint in the cagrilintide programme.
Unproven — inference onlyExtrapolated from a known mechanism, receptor profile, or adjacent compound class. Biologically plausible but not directly demonstrated for this compound in this context.
Two independent gastric-emptying delays, relevant to any planned procedure requiring sedation.
Calcitonin inhibits osteoclast activity, and chronic non-selective calcitonin receptor agonism has theoretical bone-remodelling consequences. Unresolved for this combination.
As across the incretin class — improving insulin sensitivity and losing weight restores ovulation in PCOS, and the class is contraindicated in pregnancy with defined washouts.
Both components delay gastric emptying, against a narrow-therapeutic-index, fasting-dependent drug.
Uncontrolled reportsAggregated from research-community logs, forums, vendor literature and self-reported experience. Uncontrolled, unverified, subject to placebo, polypharmacy and product-purity confounds. Lowest evidentiary weight.
The dominant long-run complaint in community stacks assembling the two components.
Adding even a small amount of amylin analogue to an established incretin is frequently reported as producing a larger GI hit than the dose suggests.
Intake falls far enough that protein becomes hard to hit, undercutting the lean-mass rationale usually accompanying these stacks.
Figures below are documented, not recommended. Study ranges come from published protocols in the stated model; grey-market ranges are what the research community reports using and carry no safety validation of any kind.
Highest confidenceReported in peer-reviewed literature, registered clinical trials, or regulatory filings. Note the model: much peptide literature is in vitro or rodent work, not human trial data.
Reached by co-escalation over several months, mirroring the semaglutide titration schedule. A single weekly subcutaneous injection.
Both components are titrated together in the trial protocol, rather than adding the amylin side to an established incretin dose — which is how community stacks usually do it.
| Setting | Cagrilintide | Semaglutide | Frequency |
|---|---|---|---|
| CagriSema (trialled) | 2.4 mg | 2.4 mg | Once weekly, co-escalated |
| Semaglutide alone (comparator) | — | 2.4 mg | Once weekly |
Unproven — inference onlyExtrapolated from a known mechanism, receptor profile, or adjacent compound class. Biologically plausible but not directly demonstrated for this compound in this context.
For a trial it guarantees consistency. For an individual it removes the ability to hold one component steady while adjusting the other — which is the main reason community users assemble their own.
Adding cagrilintide to an already-escalated semaglutide dose is not what the trials did, and community reports of disproportionate GI effects on that approach are consistent with the difference mattering.
Uncontrolled reportsAggregated from research-community logs, forums, vendor literature and self-reported experience. Uncontrolled, unverified, subject to placebo, polypharmacy and product-purity confounds. Lowest evidentiary weight.
Community stacks span a wide range, usually starting the amylin side low and adding it to an established incretin dose.
Very common, and a further step from the evidence — a different incretin with a glucagon arm, and no trial of that pairing.
| Community approach | Amylin side | Incretin side | Note |
|---|---|---|---|
| Sema + cagri | 0.25 – 2.4 mg | Semaglutide 0.25 – 2.4 mg | Closest to the studied product |
| Reta + cagri | 0.25 – 1 mg | Retatrutide 1 – 4 mg | Different incretin; no trial |
| Add-on rather than co-escalated | Added later | Already escalated | Not how trials dosed it |
Combination effects. Almost no peptide combination has been studied as a combination in humans; stack logic is overwhelmingly mechanistic inference and community practice. Each linked compound has its own page.
Highest confidenceReported in peer-reviewed literature, registered clinical trials, or regulatory filings. Note the model: much peptide literature is in vitro or rodent work, not human trial data.
Unproven — inference onlyExtrapolated from a known mechanism, receptor profile, or adjacent compound class. Biologically plausible but not directly demonstrated for this compound in this context.
The most common community deviation. It swaps a molecule with cardiovascular and renal outcome data for an unapproved triple agonist with a glucagon arm, and there is no trial of that pairing.
Both the incretin and amylin classes carry this. Pramlintide has a boxed warning for it.
The usual accompaniment to aggressive fat loss, with the usual unstated counterpart that GH worsens glucose handling.
Uncontrolled reportsAggregated from research-community logs, forums, vendor literature and self-reported experience. Uncontrolled, unverified, subject to placebo, polypharmacy and product-purity confounds. Lowest evidentiary weight.
CagriSema is what community amylin-plus-incretin stacks point to for legitimacy. The concept transfers; the specific evidence does not.
Whole schedules — dosing, titration, cycle length, and off-time — as documented in trials, as proposed from mechanism, and as circulated in the research community. Reproduced for study and comparison only.
Highest confidenceReported in peer-reviewed literature, registered clinical trials, or regulatory filings. Note the model: much peptide literature is in vitro or rodent work, not human trial data.
Registered protocols in obesity and type 2 diabetes with defined co-escalation schedules, monitoring and stopping rules.
Unproven — inference onlyExtrapolated from a known mechanism, receptor profile, or adjacent compound class. Biologically plausible but not directly demonstrated for this compound in this context.
If assembling the components separately, escalating both together is closer to what was actually studied than adding the amylin side to an established incretin dose.
HbA1c and fasting glucose, lipase, liver panel, lipids, body composition, and thyroid function if levothyroxine is involved.
Uncontrolled reportsAggregated from research-community logs, forums, vendor literature and self-reported experience. Uncontrolled, unverified, subject to placebo, polypharmacy and product-purity confounds. Lowest evidentiary weight.
The dominant community approach, at ratios and with material that differ from the trialled product.
Neither the Gold Standard Protocol nor the 15-Compound Matrix names CagriSema; the Gold Standard uses retatrutide with cagrilintide.
CagriSema is the only amylin-plus-incretin combination with real trial data, and the most useful thing this page can do is be precise about what that data belongs to — because it does not belong to two vials mixed at home.
The trialled product is a fixed-dose combination of 2.4 mg semaglutide and 2.4 mg cagrilintide, co-escalated on a defined schedule. Community stacks assemble the two compounds separately at ratios the user chooses, on a schedule nobody studied. Those are different interventions, and only one of them has results.
Pathophysiology
Obesity is physiologically defended, and combination pharmacology is the current strategy for overcoming the compensatory responses that limit single agents.
Mechanistic rationale
REDEFINE-1 reported a mean 22.7% weight reduction at 68 weeks — strong, and below the roughly 25% the market had priced in, which moved the share price and is itself informative. Combining two mechanisms did not produce simple additivity. That is worth sitting with before assuming any home-assembled combination will outperform its components, and it is the most useful single fact about this product.
Community reports
Community reta-plus-cagri and sema-plus-cagri stacks are built on an additivity assumption that the trial of the actual combination did not fully support.
Components carrying the argument: GLP-1 + amylin, co-escalated
Pathophysiology
Insulin resistance with beta-cell failure, in which both incretin and amylin signalling are deficient.
Mechanistic rationale
REDEFINE-2 reported 13.7% weight loss and a 2.0 percentage point HbA1c reduction, with 73.5% reaching an HbA1c of 6.5% or below. The separate REIMAGINE programme then beat semaglutide head-to-head on both endpoints. Replacing both hormones the beta cell produces is a coherent rationale — amylin is co-secreted with insulin and lost alongside it, the same logic that made pramlintide an approved adjunct.
Community reports
Used by people with diagnosed diabetes sourcing components separately, which reintroduces the hypoglycaemia problem below.
Components carrying the argument: Dual hormone replacement
Pathophysiology
Amylin analogues lower post-meal glucose by mechanisms independent of insulin.
Mechanistic rationale
Pramlintide carries a boxed warning for severe insulin-induced hypoglycaemia and requires prandial insulin to be halved at initiation. That is the class precedent, and it applies to the amylin component here. Anyone on insulin assembling this combination from research vials is reproducing the risk without the label, the titration schedule or the dose reduction.
Community reports
The pramlintide precedent is essentially absent from community discussion of amylin analogues.
Components carrying the argument: Amylin — insulin-independent glucose lowering
Pathophysiology
Both GLP-1 agonism and amylin agonism slow gastric emptying, independently.
Mechanistic rationale
The gastrointestinal burden is additive, which is part of why the trialled product co-escalates on a defined schedule rather than starting both at target dose. It also doubles the effect on absorption of orally administered drugs — levothyroxine in particular is narrow-therapeutic-index, fasting-dependent and highly sensitive to gastric conditions, so a thyroid drift after starting this combination is frequently an absorption change rather than a thyroid change.
Community reports
Disproportionate GI effects when adding cagrilintide to an established incretin are consistently reported and are exactly what additive gastric-emptying delay predicts.
Components carrying the argument: Both components
| Question | Position |
|---|---|
| Trialled as | Fixed 2.4 mg + 2.4 mg, co-escalated |
| Community version | Two vials, chosen ratio, no schedule |
| REDEFINE-1 | 22.7% at 68 weeks — below the ~25% expected |
| REDEFINE-2 | 13.7% weight, 2.0 points HbA1c in T2D |
| REIMAGINE | Superior to semaglutide head-to-head |
| Regulatory | NDA filed Dec 2025; decision expected Q4 2026 |
| What that suggests | Combining mechanisms is not simply additive |
| On insulin? | See the pramlintide boxed warning |
| Gastric emptying | Two agents delaying it at once |
| Levothyroxine | Absorption change can look like thyroid change |
For obesity: approved incretins with cardiovascular outcome data, an energy deficit that can be maintained, resistance training to protect lean mass, and bariatric surgery, which still produces the largest and most durable results. For type 2 diabetes: metformin, SGLT2 inhibitors, GLP-1 agonists, and structured education — with any background insulin or sulphonylurea dose reduced whenever another glucose-lowering agent is added.
Physical-chemistry reference for laboratory handling of the lyophilised material. Reproduced so that stability and concentration mathematics can be studied — see the calculator for the arithmetic and the reconstitution guide for sterile technique.
The trialled product is a co-formulated fixed-dose pen requiring no reconstitution. Community stacks use two separate lyophilised vials reconstituted individually — which is not the same product and introduces the usual compatibility question if they are then mixed in one syringe.
Lyophilised components: −20 °C. Reconstituted: 2–8 °C. Cagrilintide is an amylin-family peptide and aggregation-prone; haze or visible fibril means discard.
Trialled product: fixed-dose pen. Community: semaglutide 10–30 mg and cagrilintide 5–10 mg vials.
At weekly microdoses a single vial of either component can sit reconstituted for months — well beyond any characterised in-use window.
Regulatory status changes and differs by country. This is a summary for orientation, not legal advice — check your own jurisdiction.
Under FDA review. Novo Nordisk filed a new drug application on 18 December 2025 for chronic weight management, with a decision expected in the fourth quarter of 2026. If approved it would be the first once-weekly combination of a GLP-1 receptor agonist and an amylin analogue.
Filed is not approved. Until a decision issues there is no approved product, no label, and no legitimate supply of the combination. Semaglutide is separately approved at 2.4 mg as Wegovy; cagrilintide has no standalone approval anywhere and no standalone phase 3 programme.
Anything currently sold as CagriSema in the research-chemical market is two unapproved vials, or one vial of unverified composition, and neither is the product under review.
Regulatory and trial claims re-checked against primary sources on 16 August 2026. Checked: REDEFINE-1 and -2, REIMAGINE, NDA filed Dec 2025. Approvals, trial readouts and compounding decisions move faster than anything else on this page — a date here means someone looked, not that nothing has changed since.
Peptide hormones and metabolic modulators are addressed under the WADA Prohibited List. Verify against the current list.
Links resolve to PubMed records, trial registries, publisher pages or primary documents. Where a body of work rather than a single paper is cited, the link opens a PubMed query so the full result set — including newer papers than this page — can be reviewed. Verify every claim against the primary source before relying on it.
For educational and research reference only. Nothing on this site is medical advice, a recommendation, or an instruction to administer any substance to a human being. Every figure on this page is a record of what has been reported, not a recommendation. Full disclaimer.
