The CagriSema protocol is one once-weekly injection that climbs through a 16-week dose escalation and then holds at cagrilintide 2.4 mg plus semaglutide 2.4 mg. That is the schedule. In phase 3 REDEFINE 1, the escalation window ran 16 weeks and the maintenance period ran 52 weeks, which is how the trial reached 68 weeks.[4] This guide covers which milligram values are trial-documented and which are reconstructed, why both molecules escalate together, and what the 20.4 and 22.7 percent figures each mean.
🔑 Key Takeaways
- CagriSema is one product, not two drugs given side by side. Novo Nordisk calls it "a fixed-dose combination of a long-acting amylin analogue, cagrilintide 2.4 mg and semaglutide 2.4 mg".[8]
- REDEFINE 1's registry entry states a 16-week escalation plus a 52-week maintenance period in identical wording for the combination arm and both single-molecule arms, so the halves escalated in parallel.[4]
- The steps 0.25, 0.5, 1.0, 1.7 and 2.4 mg come from the FDA Wegovy label, where four four-week steps fill exactly 16 weeks. Novo published the endpoint and the window, not the cagrilintide rungs, so that column is a reconstruction.[6]
- At 68 weeks the trial reported -20.4 percent versus -3.0 percent for placebo on the treatment-policy estimand, and 22.7 percent versus 2.3 percent on the trial-product estimand.[1][9]
- Gastrointestinal adverse events hit 79.6 percent of the combination group versus 39.9 percent on placebo, the strongest argument against compressing the ladder.[1]
What the CagriSema Protocol Actually Is: One Pen, Two Molecules, 2.4 mg Each
Novo Nordisk describes CagriSema as "a fixed-dose combination of a long-acting amylin analogue, cagrilintide 2.4 mg and semaglutide 2.4 mg".[8] That phrasing matters: a fixed-dose combination means both molecules sit in one solution at a fixed ratio, are drawn by the same device, and move up the ladder together because there is no mechanical way to separate them. Every dose decision applies to both halves at once.
Semaglutide is the GLP-1 receptor agonist half; cagrilintide is the amylin analogue half, engineered to last about a week per injection so it can share a once-weekly cadence. For the single-molecule picture, including the vial-and-syringe details this article deliberately skips, see our cagrilintide peptide guide.
The REDEFINE Co-Titration Ladder: 0.25 to 2.4 mg, Four Weeks a Step
The published skeleton is short: 16 weeks of escalation, then 52 weeks at 2.4 mg of each molecule.[4] The step values that fill the window come from the FDA-approved Wegovy label, whose Section 2 table reads 0.25 mg for weeks 1 to 4, 0.5 mg for weeks 5 to 8, 1 mg for weeks 9 to 12, 1.7 mg for weeks 13 to 16, and 2.4 mg once weekly from week 17.[6] Four weeks per step across four steps fills exactly 16 weeks, matching the trial's stated window step for step.
Why the Semaglutide Cagrilintide Stack Escalates Both Sides in Parallel
The registry describes the 16-week escalation and 52-week maintenance structure in identical wording for the combination arm and both comparator arms, so the two molecules were brought up together rather than one being loaded first.[4] The reason is that both halves cause the same class of side effect. The Wegovy label states that escalation exists "to reduce the risk of gastrointestinal adverse reactions".[6] Cagrilintide has its own version: in phase 2, gastrointestinal events occurred in 41 to 63 percent of the cagrilintide groups versus 32 percent on placebo, mostly nausea at 20 to 47 percent versus 18 percent, plus administration-site reactions.[3] Parallel escalation is the only way to bring two overlapping nausea profiles to full strength without stacking two separate adjustment periods.
What Is Actually Published About the Ladder, and What Is Reconstructed
Three things are documented: the 2.4 mg plus 2.4 mg maintenance dose, the 16-week escalation window, and the 52-week maintenance period.[4][8] One is not: the milligram value of the cagrilintide half at each of the four steps, which appears in no source available outside the paywalled full text. The cagrilintide column above is therefore an inference from two facts, that a fixed-dose combination has to move both molecules together and that the Wegovy schedule fills the stated window exactly. Sound reasoning, not a quoted protocol. Our cagrilintide dosage chart keeps single-molecule trial ranges separate from combination figures for the same reason.
REDEFINE 1 at 68 Weeks: What the 20.4% and 22.7% Figures Each Mean
REDEFINE 1 randomised 3,417 adults with overweight or obesity and without diabetes, at a BMI of 30 or above, or 27 or above with a complication. Randomisation ran 21:3:3:7: 2,108 to cagrilintide-semaglutide, 302 to semaglutide 2.4 mg alone, 302 to cagrilintide 2.4 mg alone, 705 to placebo.[1] At 68 weeks, mean body-weight change was -20.4 percent versus -3.0 percent with placebo, a difference of -17.3 percentage points (95 percent CI -18.1 to -16.6; P less than 0.001).[1]
The 22.7 percent figure is the same trial measured differently. Novo's release reports 22.7 percent versus 2.3 percent on the trial-product estimand, which answers "what happens if all patients adhere". The 20.4 percent pair is the treatment-policy estimand, "regardless of adherence", and that is what the NEJM co-primary endpoints used.[1][9] The treatment-policy figure is the conservative one.
The two 302-patient single-molecule arms are what allow the claim that the combination beat either half alone, but next to the 2,108-patient combination arm they were not powered head-to-head tests, so read them as supportive. Secondary coverage also reports that a substantial share of participants were not at the full 2.4 mg plus 2.4 mg dose by week 68, since the trial allowed flexible dose adjustment; the NEJM full text is paywalled, so treat that as reported rather than verified.
Why 2.4 mg of Cagrilintide Is Not Cagrilintide's Best Dose
Cagrilintide sits at 2.4 mg because that is semaglutide's maintenance dose, not because 2.4 mg is where the amylin analogue performs best. Its phase 2 dose-finding trial tested 0.3, 0.6, 1.2, 2.4 and 4.5 mg weekly over 26 weeks in 706 adults, and the largest reduction came at the top: 4.5 mg produced 10.8 percent weight loss against a 6.0 to 10.8 percent spread across the full range, and beat liraglutide 3.0 mg head to head at 10.8 percent versus 9.0 percent, a difference of 1.8 percent with p equal to 0.03.[3]
Matching both molecules at 2.4 mg is what makes one titration schedule in one pen possible: a co-formulation decision, not a pharmacological ceiling. That matters when comparing CagriSema with combinations never constrained by shared-device design, such as the retatrutide and cagrilintide stack, which has no fixed-dose product or phase 3 data behind it, or with single-molecule designs covered in our amycretin versus CagriSema comparison.
CagriSema Dosing Beyond Obesity: REDEFINE 2 and the Tirzepatide Head-to-Head
REDEFINE 2 ran the same regimen for 68 weeks in 1,206 adults with overweight or obesity and type 2 diabetes, randomised 3:1 against placebo. Body weight fell 13.7 percent versus 3.4 percent, a difference of -10.4 percentage points (95 percent CI -11.2 to -9.5; P less than 0.001), and 73.5 percent versus 15.9 percent reached HbA1c of 6.5 percent or below. Gastrointestinal events occurred in 72.5 percent versus 34.4 percent.[2] The same ladder and maintenance dose produce materially less weight loss in type 2 diabetes than in the non-diabetic population.
REDEFINE 4 took the regimen to 84 weeks in 809 adults against tirzepatide 15 mg, open-label, and missed its primary endpoint of non-inferiority: 23.0 percent versus 25.5 percent on the efficacy estimand, 20.2 percent versus 23.6 percent on the treatment-regimen estimand.[8] Relevant to dosing, the registry records CagriSema on a 16-week escalation and tirzepatide on a 20-week escalation there.[5] For launch timing, pricing and the competitive picture, see our CagriSema 2026 overview.
REDEFINE 1 and 2 use treatment-policy estimands; REDEFINE 4 uses the treatment-regimen estimand. Efficacy-estimand values run higher.
Side Effects Along the Ladder and When to Hold a Step
In REDEFINE 1, gastrointestinal adverse events affected 79.6 percent of the cagrilintide-semaglutide group versus 39.9 percent on placebo, covering nausea, vomiting, diarrhoea, constipation and abdominal pain, and described as "mainly transient and mild-to-moderate in severity".[1] Discontinuation was 6 percent versus 3.7 percent.[9] Four in five participants having symptoms is why the escalation window exists at all.
The Wegovy label sets out the response when a step is not tolerated, and it is not to push through: "consider delaying dosage escalation for 4 weeks".[6] Repeating a rung is part of the schedule. Our breakdown of cagrilintide side effects covers the amylin side of that profile.
What Two Research Vials Cannot Replicate About a Fixed-Dose Combination Pen
Reproducing a fixed-dose combination from two separate research vials is a different procedure, and the FDA has published what goes wrong with it. In its alert on compounded injectable semaglutide, the agency reports that "the majority of the reports described patients mistakenly drawing up more than the prescribed dose from a multiple-dose vial during self-administration. In these instances, patients administered five to 20 times more than the intended dose." Providers "incorrectly calculating the intended dose when converting from milligrams to units or milliliters" caused five to ten times overdoses. The named causes are unfamiliarity with vials, "confusion between different units of measurement (e.g., milliliters, milligrams and 'units')", and varying concentrations between compounders. Reported harms include vomiting, fainting, dehydration, acute pancreatitis and gallstones, some requiring hospitalisation.[10]
Titration speed is called out separately. The FDA states it has received adverse event reports tied to doses "beyond what is in the FDA-approved drug label. This could mean using more product in a single dose, taking doses more frequently or increasing the amount more quickly (titration schedule)."[7] A shortened ladder is one of the behaviours the agency links to harm, and the 79.6 percent gastrointestinal rate at the trial pace shows how little headroom exists.
The agency has also warned companies selling products "falsely labeled 'for research purposes' or 'not for human consumption'" that were "sold directly to consumers for human use with dosing instructions". As of 31 May 2026 it held 990 adverse event reports for compounded semaglutide, likely underreported.[7]
Regulatory Status: Cagrilintide Is Investigational and CagriSema Is Not Approved
The FDA's wording is unusually direct: "Retatrutide and cagrilintide cannot be used in compounding under federal law. Additionally, these are not components of FDA-approved drugs and have not been found safe and effective for any condition."[7] That covers the amylin half of every CagriSema-style protocol.
Novo Nordisk submitted an NDA to the FDA on 18 December 2025 on the strength of REDEFINE 1 and 2, with a decision expected during 2026, and states that CagriSema is not approved in the US or EU.[11] There is no approval anywhere at the time of writing. Anyone evaluating research-grade material anyway should read our cagrilintide buying guide.
Frequently Asked Questions About CagriSema Protocol and Dosing
Bottom Line
The CagriSema protocol is simple: one weekly injection, four four-week steps, then 2.4 mg of each molecule held for the rest of the course. What deserves care is provenance. The 16-week window, the 52-week maintenance period and the 2.4 mg endpoint are documented; the cagrilintide rungs are inferred from the semaglutide label because Novo has not published them. The 20.4 and 22.7 percent figures are one trial under two estimands. The 2.4 mg cagrilintide dose reflects what fits in a shared pen, not what the amylin pathway can do alone. And cagrilintide remains investigational, with CagriSema unapproved anywhere.
References
- Garvey WT, et al. REDEFINE 1. NEJM 2025 (PMID 40544433).
- Cagrilintide-Semaglutide in Type 2 Diabetes (REDEFINE 2). NEJM 2025 (PMID 40544432).
- Lau DCW, et al. Once-weekly cagrilintide dose-finding phase 2 trial. Lancet 2021;398:2160-2172 (PMID 34798060).
- ClinicalTrials.gov NCT05567796 (REDEFINE 1).
- ClinicalTrials.gov NCT06131437 (REDEFINE 4).
- WEGOVY Prescribing Information, Section 2, via DailyMed.
- FDA. Concerns with Unapproved GLP-1 Drugs for Weight Loss.
- Novo Nordisk. REDEFINE 4 head-to-head results, February 2026.
- Novo Nordisk. CagriSema 22.7% weight reduction in REDEFINE 1.
- FDA. Dosing errors with compounded injectable semaglutide.
- Novo Nordisk files CagriSema NDA, 18 December 2025.