Stack Name
CagriSema
Updated March 22, 2026
CagriSema Protocol - Cagrilintide + Semaglutide
Complete CagriSema research protocol with cagrilintide + semaglutide dosing schedules, titration timeline, reconstitution math, side effects, and Phase 3 clinical references.
Category
Dual-Pathway Weight Management Stack
Separate Dosing
0.25-2.4 mg/week cagrilintide + 0.25-2.4 mg/week semaglutide
Cycle Length
68-week clinical protocol; long-term use expected
Regulatory
Investigational combo with NDA filed Dec 2025
CagriSema Quick Reference
Aliases
Cagrilintide/Semaglutide; Cagri/Sema Stack; Amylin + GLP-1 Stack
Category
Dual-Pathway Weight Management & Metabolic Optimization Stack
Components
Cagrilintide (AM833) - long-acting amylin analog / dual amylin & calcitonin receptor agonist (DACRA), half-life ~184 hours (~7.7 days), Novo Nordisk; Semaglutide - GLP-1 receptor agonist, half-life ~165-168 hours (~7 days), Novo Nordisk.
Standard Blend
5 mg cagrilintide + 5 mg semaglutide (10 mg total, 1:1 ratio)
Separate Dosing
Cagrilintide 0.25-2.4 mg/week + Semaglutide 0.25-2.4 mg/week with synchronized titration
Dosing Frequency
Once weekly (subcutaneous)
Route of Administration
Subcutaneous injection
Cycle Length
68 weeks in clinical trials; long-term continuous use expected
Oral Viable Components
Semaglutide (FDA-approved oral formulation exists; not studied in CagriSema combination orally).
Regulatory Status
Investigational - NDA filed December 2025; FDA review expected 2026. Cagrilintide: not FDA-approved. Semaglutide: FDA-approved separately (Ozempic, Wegovy). CagriSema combination: not yet approved.
Key Stat
22.7% mean body weight loss at 68 weeks in REDEFINE 1 Phase 3 trial (treatment-adherent estimand); 40.4% of participants lost >=25% body weight.
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What Is the CagriSema Stack?
The CagriSema stack is a two-compound weight management protocol combining cagrilintide (a long-acting amylin analog) with semaglutide (a GLP-1 receptor agonist), both administered at 2.4 mg once weekly via subcutaneous injection. Developed by Novo Nordisk as a fixed-dose investigational combination, CagriSema represents a dual-pathway satiety model: amylin receptor activation in the area postrema and hypothalamus (cagrilintide) layered on top of GLP-1 receptor activation in the gut-brain axis (semaglutide). The two pathways target distinct but complementary neuronal circuits involved in appetite regulation, gastric emptying, and metabolic homeostasis.
Unlike single-mechanism approaches, CagriSema extends semaglutide's established GLP-1 biology with cagrilintide's amylin-based satiety signaling. The clinical rationale is straightforward: semaglutide monotherapy produces approximately 14.9% weight loss at 68 weeks, while CagriSema achieved 22.7% in the REDEFINE 1 Phase 3 trial - a 6.6 percentage-point increase attributable to the amylin pathway addition. This positions CagriSema as a next-generation approach for individuals who need greater efficacy than GLP-1 monotherapy provides.
No direct clinical trial has evaluated the CagriSema combination outside of Novo Nordisk's controlled REDEFINE and REIMAGINE programs. When used as separate research-grade vials, protocols are extrapolated from the clinical trial titration schedules and individual compound evidence.
Why Add Cagrilintide to Semaglutide?
Foundation - What Semaglutide Provides
Semaglutide activates GLP-1 receptors in the hypothalamus, gut, and pancreas, reducing appetite through central satiety signaling, delaying gastric emptying, enhancing glucose-dependent insulin secretion, and suppressing glucagon. This GLP-1 biology is well-established (Wegovy, Ozempic) and produces approximately 15% weight loss as monotherapy. CagriSema builds on this platform by adding a mechanistically distinct second pathway. See the Semaglutide Protocol for monotherapy context.
Amylin-Mediated Central Satiety Enhancement
Cagrilintide activates amylin receptors (AMY1R, AMY2R, AMY3R) and calcitonin receptors (CTR) in the area postrema - a circumventricular organ with direct access to systemic circulation that sits outside the blood-brain barrier. This is a distinct neuronal target from semaglutide's hypothalamic GLP-1 receptors. Amylin receptor activation sends satiety signals through the nucleus of the solitary tract to the hypothalamus, reducing meal size and total caloric intake through a pathway that GLP-1 agonists do not directly engage. The result is additive appetite suppression from two independent signaling routes.
Complementary Gastric Emptying Modulation
Both compounds slow gastric emptying, but through different receptor systems. Semaglutide acts through GLP-1 receptors on vagal afferents, while cagrilintide modulates gastric motility through amylin receptors in the dorsal vagal complex. The combination produces sustained postprandial fullness that exceeds either compound alone, extending the interval between hunger signals and reducing snacking behavior - a mechanism that clinical trial investigators describe as complementary action on the gut-brain axis.
Hedonic Appetite Regulation
Clinical trial authors have proposed that CagriSema's superior efficacy results in part from complementary effects on hedonic (reward-driven) appetite regulation. Semaglutide and cagrilintide together act on brain regions involved in both homeostatic appetite control (hypothalamus, hindbrain) and hedonic food motivation (septum, reward circuitry). This dual engagement may explain why CagriSema reduces not only physiological hunger but also food cravings and food noise more effectively than either compound alone.
Metabolic Parameter Enhancement
Beyond weight loss, the combination produces additive improvements in metabolic markers. In REDEFINE 2 (type 2 diabetes population), 73.5% of CagriSema participants achieved HbA1c <=6.5% versus 15.9% on placebo. Cagrilintide's role here is indirect - by amplifying weight loss and reducing postprandial glucose excursions through gastric emptying delay, it creates a metabolic environment where semaglutide's direct glucose-lowering effects are maximized. Lipid parameters, including triglycerides and VLDL-C, also showed reductions consistent with substantial weight loss.
CagriSema Dosing Protocol & Schedule
Evidence Level Notice
CagriSema has been evaluated in multiple Phase 3 clinical trials (REDEFINE 1, 2, 3, 4) as a fixed-dose Novo Nordisk combination. The titration schedule below reflects the protocol used in those trials. When using separate research-grade vials, protocols are derived from this clinical framework. Novo Nordisk filed an NDA in December 2025; CagriSema is not yet FDA-approved.
Format A: Separate Vials Protocol
Synchronized Titration Schedule (Per-Compound)
Phase: Initiation
Weeks: 1-4
Cagrilintide Dose: 0.25 mg
Semaglutide Dose: 0.25 mg
Frequency: Once weekly
Route: Subcutaneous
Notes: Starting dose; GI adaptation begins
Phase: Early Escalation
Weeks: 5-8
Cagrilintide Dose: 0.5 mg
Semaglutide Dose: 0.5 mg
Frequency: Once weekly
Route: Subcutaneous
Notes: First step-up; monitor nausea
Phase: Mid Escalation
Weeks: 9-12
Cagrilintide Dose: 1.0 mg
Semaglutide Dose: 1.0 mg
Frequency: Once weekly
Route: Subcutaneous
Notes: Intermediate dose; GI effects may peak
Phase: Late Escalation
Weeks: 13-16
Cagrilintide Dose: 1.7 mg
Semaglutide Dose: 1.7 mg
Frequency: Once weekly
Route: Subcutaneous
Notes: Final titration step
Phase: Maintenance
Weeks: 17+
Cagrilintide Dose: 2.4 mg
Semaglutide Dose: 2.4 mg
Frequency: Once weekly
Route: Subcutaneous
Notes: Full therapeutic dose; sustained use
Weekly Schedule Example (Maintenance Phase)
Day: Monday (Injection Day)
Cagrilintide: 2.4 mg SC
Semaglutide: 2.4 mg SC
Notes: Both compounds same day; rotate injection sites
Day: Tuesday-Sunday
Cagrilintide: -
Semaglutide: -
Notes: No injections; both compounds have ~7-day half-lives
Format B: Oral Hybrid (Theoretical)
Semaglutide has an FDA-approved oral formulation (Rybelsus and oral Wegovy). A theoretical oral-hybrid protocol could combine oral semaglutide with injectable cagrilintide. This configuration has not been studied in any clinical trial.
Compound: Cagrilintide
Dose: 0.25-2.4 mg (titrated)
Route: Subcutaneous, once weekly
Timing: Consistent day/time
Compound: Semaglutide (oral)
Dose: 14-25 mg
Route: Oral, once daily
Timing: Empty stomach, 30 min before food
Oral semaglutide has approximately 0.4-1% bioavailability. The REDEFINE program used only subcutaneous co-administration. Oral-hybrid dosing remains speculative.
Format C: Pre-Blended Vial
Blend Setup Reference
Parameter: Vial Contents
Typical Value: 5 mg cagrilintide + 5 mg semaglutide (10 mg total)
Parameter: Blend Ratio
Typical Value: 1:1
Parameter: Recommended BAC Water
Typical Value: 3.0 mL
Parameter: Total Concentration
Typical Value: 3.33 mg/mL (1.67 mg/mL per compound)
Parameter: Maintenance Dose Volume
Typical Value: ~1.44 mL (144 units on U-100) for 2.4 mg each
Per-Injection Delivery Breakdown (Titration Doses)
Titration Step: Weeks 1-4
Dose per Compound: 0.25 mg each
Total Draw: 0.15 mL
U-100 Syringe Units: 15 units
Titration Step: Weeks 5-8
Dose per Compound: 0.5 mg each
Total Draw: 0.30 mL
U-100 Syringe Units: 30 units
Titration Step: Weeks 9-12
Dose per Compound: 1.0 mg each
Total Draw: 0.60 mL
U-100 Syringe Units: 60 units
Titration Step: Weeks 13-16
Dose per Compound: 1.7 mg each
Total Draw: 1.02 mL
U-100 Syringe Units: 102 units
Titration Step: Week 17+
Dose per Compound: 2.4 mg each
Total Draw: 1.44 mL
U-100 Syringe Units: 144 units
Pre-Blend Dose Assessment
Component: Cagrilintide
Per-Dose from Blend (Maintenance): 2.4 mg
Typical Standalone Range: 0.25-2.4 mg/week (Phase 3)
Assessment: Matches clinical target dose
Component: Semaglutide
Per-Dose from Blend (Maintenance): 2.4 mg
Typical Standalone Range: 0.25-2.4 mg/week (Wegovy label)
Assessment: Matches clinical target dose
The 1:1 blend enforces synchronized titration. Both compounds escalate at the same rate, which matches the REDEFINE trial protocol. If GI tolerance issues require holding one compound at a lower dose, separate vials are necessary.
Cycle Guidelines
Approach: Clinical Trial Protocol
Duration: 68 weeks (16 wk escalation + 52 wk maintenance)
Off Period: Not studied; weight regain expected
Best For: Full clinical replication
Approach: Extended Continuous
Duration: 12+ months at maintenance
Off Period: None; indefinite use
Best For: Long-term weight management
Approach: Moderate Cycle
Duration: 6-9 months including titration
Off Period: 4-8 weeks reassessment
Best For: Budget-conscious protocols
Protocol Notes
- Injection logistics: Administer both compounds on the same day. When using separate vials, inject at different sites (for example, left abdomen for cagrilintide and right abdomen for semaglutide). Pre-blended vials require a single injection.
- Oral option: Oral semaglutide exists but has not been studied with injectable cagrilintide in combination. If substituting oral semaglutide, note the very low bioavailability (~1%) and the requirement for empty-stomach dosing.
- Titration pacing: The 4-week hold at each dose level is critical. Both compounds have ~7-day half-lives, meaning steady-state concentrations are reached by approximately week 4-5 of each dose tier. Premature escalation significantly increases nausea and vomiting rates.
- GI peak management: GI side effects typically peak during weeks 9-16 when both compounds cross the 1.0 mg threshold. Splitting the timing of injections (for example, cagrilintide Monday and semaglutide Thursday) has been discussed in community protocols but was not studied clinically.
- Missed dose: If a dose is missed, administer as soon as possible within 3 days, then resume the regular weekly schedule. If more than 3 days have passed, skip the missed dose.
- Syringe handling: When drawing from the pre-blended vial, volumes above 1.0 mL exceed standard 1-mL insulin-syringe capacity. Use a 3-mL syringe for maintenance doses or split the draw into two injections.
CagriSema Reconstitution Guide
Format A: Separate Vials
Cagrilintide Reconstitution
Vial Size: 5 mg
BAC Water: 2.5 mL
Concentration: 2 mg/mL
0.25 mg Dose: 0.125 mL (12.5 U)
0.5 mg Dose: 0.25 mL (25 U)
1.0 mg Dose: 0.5 mL (50 U)
1.7 mg Dose: 0.85 mL (85 U)
2.4 mg Dose: 1.2 mL (120 U)
Vial Size: 5 mg
BAC Water: 2.0 mL
Concentration: 2.5 mg/mL
0.25 mg Dose: 0.1 mL (10 U)
0.5 mg Dose: 0.2 mL (20 U)
1.0 mg Dose: 0.4 mL (40 U)
1.7 mg Dose: 0.68 mL (68 U)
2.4 mg Dose: 0.96 mL (96 U)
Vial Size: 10 mg
BAC Water: 5.0 mL
Concentration: 2 mg/mL
0.25 mg Dose: 0.125 mL (12.5 U)
0.5 mg Dose: 0.25 mL (25 U)
1.0 mg Dose: 0.5 mL (50 U)
1.7 mg Dose: 0.85 mL (85 U)
2.4 mg Dose: 1.2 mL (120 U)
Vial Size: 10 mg
BAC Water: 4.0 mL
Concentration: 2.5 mg/mL
0.25 mg Dose: 0.1 mL (10 U)
0.5 mg Dose: 0.2 mL (20 U)
1.0 mg Dose: 0.4 mL (40 U)
1.7 mg Dose: 0.68 mL (68 U)
2.4 mg Dose: 0.96 mL (96 U)
Math verification (5 mg vial, 2.5 mL BAC water): 5,000 mcg / 2.5 mL = 2,000 mcg/mL = 2 mg/mL. A 2.4 mg dose therefore requires 1.2 mL = 120 units on a U-100 syringe.
Semaglutide Reconstitution
Vial Size: 5 mg
BAC Water: 2.5 mL
Concentration: 2 mg/mL
0.25 mg Dose: 0.125 mL (12.5 U)
0.5 mg Dose: 0.25 mL (25 U)
1.0 mg Dose: 0.5 mL (50 U)
1.7 mg Dose: 0.85 mL (85 U)
2.4 mg Dose: 1.2 mL (120 U)
Vial Size: 5 mg
BAC Water: 2.0 mL
Concentration: 2.5 mg/mL
0.25 mg Dose: 0.1 mL (10 U)
0.5 mg Dose: 0.2 mL (20 U)
1.0 mg Dose: 0.4 mL (40 U)
1.7 mg Dose: 0.68 mL (68 U)
2.4 mg Dose: 0.96 mL (96 U)
Vial Size: 10 mg
BAC Water: 5.0 mL
Concentration: 2 mg/mL
0.25 mg Dose: 0.125 mL (12.5 U)
0.5 mg Dose: 0.25 mL (25 U)
1.0 mg Dose: 0.5 mL (50 U)
1.7 mg Dose: 0.85 mL (85 U)
2.4 mg Dose: 1.2 mL (120 U)
Vial Size: 10 mg
BAC Water: 4.0 mL
Concentration: 2.5 mg/mL
0.25 mg Dose: 0.1 mL (10 U)
0.5 mg Dose: 0.2 mL (20 U)
1.0 mg Dose: 0.4 mL (40 U)
1.7 mg Dose: 0.68 mL (68 U)
2.4 mg Dose: 0.96 mL (96 U)
Math verification (5 mg vial, 2.0 mL BAC water): 5,000 mcg / 2.0 mL = 2,500 mcg/mL = 2.5 mg/mL. A 2.4 mg dose therefore requires 0.96 mL = 96 units.
Format B: Pre-Blended Vial
Blend Reconstitution Math
Metric: Vial Contents
Value: 5 mg cagrilintide + 5 mg semaglutide = 10 mg total
Metric: BAC Water Volume
Value: 3.0 mL
Metric: Total Concentration
Value: 10,000 mcg / 3.0 mL = 3,333 mcg/mL (3.33 mg/mL total)
Metric: Per-Compound Concentration
Value: 1,667 mcg/mL (1.67 mg/mL each)
Metric: Maintenance Dose (2.4 mg each)
Value: 2,400 / 1,667 = 1.44 mL (144 units)
Metric: Starting Dose (0.25 mg each)
Value: 250 / 1,667 = 0.15 mL (15 units)
Metric: Approximate Doses per Vial at Maintenance
Value: 10,000 mcg total / 4,800 mcg per dose = ~2.08 doses
Component Delivery at Each Titration Step
Draw Volume: 0.15 mL (15 U)
Cagrilintide Delivered: 0.25 mg
Semaglutide Delivered: 0.25 mg
Draw Volume: 0.30 mL (30 U)
Cagrilintide Delivered: 0.50 mg
Semaglutide Delivered: 0.50 mg
Draw Volume: 0.60 mL (60 U)
Cagrilintide Delivered: 1.00 mg
Semaglutide Delivered: 1.00 mg
Draw Volume: 1.02 mL (102 U)
Cagrilintide Delivered: 1.70 mg
Semaglutide Delivered: 1.70 mg
Draw Volume: 1.44 mL (144 U)
Cagrilintide Delivered: 2.40 mg
Semaglutide Delivered: 2.40 mg
Unit Reminder
Both cagrilintide and semaglutide are dosed in milligrams (mg). At the maintenance dose of 2.4 mg each, you are injecting 4.8 mg of total active compound per week. Clearly label each vial with compound name, concentration, and reconstitution date. Do not confuse mg with mcg: 2.4 mg = 2,400 mcg.
Reconstituted Stability
Peptide: Cagrilintide
Reconstituted Stability: 14-28 days refrigerated (2-8 C)
Notes: Stable at low pH formulation; avoid freeze-thaw cycles
Peptide: Semaglutide
Reconstituted Stability: 28-42 days refrigerated (2-8 C)
Notes: Highly albumin-bound; good reconstituted stability
Peptide: Pre-Blended Vial
Reconstituted Stability: 14-28 days refrigerated
Notes: Cagrilintide is the limiting factor; plan usage around the shorter stability window
Limiting factor: cagrilintide's reconstituted stability (14-28 days) determines the usable window for pre-blended vials. Plan your reconstitution schedule so you use the full vial within this timeframe.
Standard 7-Step Reconstitution Instructions
- Gather supplies: sterile 1 mL insulin syringe (and/or 3 mL syringe for maintenance draws from blend vial), bacteriostatic water, alcohol wipes, peptide vial(s).
- Wipe septum: clean the rubber stopper of each vial with an alcohol wipe and let dry.
- Draw BAC water: using a sterile syringe, draw the appropriate volume of bacteriostatic water for your target concentration (see tables above).
- Inject slowly: insert the needle into the vial and inject BAC water slowly along the inner wall. Do not spray directly onto the lyophilized powder - this can damage the peptide structure.
- Dissolve gently: let the vial sit for 1-2 minutes, then gently roll between your palms until fully dissolved. Do not shake vigorously - both cagrilintide and semaglutide are sensitive to agitation.
- Label: mark each vial with compound name (or "CagriSema Blend"), concentration (mg/mL), reconstitution date, and discard-by date.
- Store: refrigerate reconstituted vials at 2-8 C immediately. Do not freeze reconstituted solution. Use within 28 days (or 14 days for conservative stability, especially blend vials).
Need exact syringe units for a custom vial size or water volume? Use the Peptide Reconstitution Calculator for two-compound CagriSema workflows.
CagriSema Side Effects & Safety
Individual cagrilintide and semaglutide both carry favorable safety profiles in their respective clinical programs. However, the CagriSema combination produces higher rates of gastrointestinal adverse events than either compound alone, as expected from dual-pathway appetite suppression. No multi-peptide stack has been evaluated in long-term (>68 week) clinical trials as a combination.
- Gastrointestinal events (combined): 79.6% in CagriSema group versus 39.9% in placebo (REDEFINE 1). This includes nausea (55% vs 12.6%), constipation (30.7% vs 11.6%), vomiting (26.1% vs 4.1%), and diarrhea. Most events were mild to moderate and transient, diminishing with continued use.
- Additive gastric emptying delay: Both compounds independently slow gastric motility. The combination may produce more pronounced early satiety and post-meal discomfort than either alone, particularly during weeks 9-16 when doses cross 1.0 mg.
- Discontinuation rates: Low overall - 5.9% for CagriSema versus 3.5% for placebo in REDEFINE 1; 8.4% versus 3.0% in REDEFINE 2. GI events were the primary driver of discontinuation.
- Gallbladder events: Cholelithiasis (gallstones) occurred at rates consistent with other significant weight-loss interventions. Rapid weight loss from any cause increases gallstone risk.
- Multi-source quality risk (research-grade): When using separate grey-market vials, each compound introduces independent contamination, purity, and degradation risk. Verify COAs from each supplier independently.
Common community-reported side effects include nausea (especially during weeks 5-16 of titration), reduced appetite (expected and therapeutic), injection site reactions (typically mild; rotating sites helps), fatigue during early titration, and occasional constipation or diarrhea.
Clinical Evidence Context
Critical Note
CagriSema has been evaluated in multiple controlled clinical trials as a Novo Nordisk fixed-dose combination. This is unusual for the PDP stack ecosystem - most stacks have no direct combination-level human evidence. CagriSema's evidence base is among the strongest of any combination protocol on this site.
Compound: CagriSema (combination)
Evidence Snapshot: Phase 3 data published in NEJM in 2025. REDEFINE 1: 22.7% weight loss at 68 weeks (n=2,108). REDEFINE 2: 13.7% weight loss in T2D (n=904). REDEFINE 4: 23% vs 25.5% tirzepatide. NDA filed Dec 2025.
Key Reference: Garvey et al., NEJM 2025; Davies et al., NEJM 2025
Protocol Page: -
Compound: Cagrilintide (alone)
Evidence Snapshot: Phase 2 data: 10.8% weight loss monotherapy at 26 weeks (4.5 mg dose). Phase 3 REDEFINE 1 monotherapy arm: 11.8% at 68 weeks. Half-life ~184 hours.
Key Reference: Lau et al., Lancet 2021; Garvey et al., NEJM 2025
Protocol Page: Cagrilintide Protocol
Compound: Semaglutide (alone)
Evidence Snapshot: FDA-approved (Wegovy, Ozempic). STEP 1: 14.9% weight loss at 68 weeks. SELECT showed 20% CV event reduction. Half-life ~165 hours.
Key Reference: Wilding et al., NEJM 2021
Protocol Page: Semaglutide Protocol
CagriSema is a dual-mechanism satiety stack with robust Phase 3 clinical validation: amylin receptor activation (cagrilintide) layered on GLP-1 receptor activation (semaglutide), producing weight loss that exceeds either compound alone and competes with dual- and triple-agonist approaches.
Storage & Handling
Property: Lyophilized (powder)
Cagrilintide: Room temp or frozen (-20 C preferred); stable 2+ years sealed
Semaglutide: Room temp or frozen (-20 C preferred); stable 2+ years sealed
Property: Reconstituted
Cagrilintide: Refrigerate 2-8 C; use within 14-28 days
Semaglutide: Refrigerate 2-8 C; use within 28-42 days
Property: Color in solution
Cagrilintide: Clear to slightly opalescent
Semaglutide: Clear, colorless
Property: Oral viable
Cagrilintide: No
Semaglutide: Yes (separate oral formulation exists; not validated in CagriSema combo)
Limiting Factor
Cagrilintide's shorter reconstituted stability (14-28 days) governs the usage timeline for pre-blended vials. Plan reconstitution frequency around that window and avoid freeze-thaw cycles for reconstituted solution.
CagriSema vs Cagrilintide + Tirzepatide vs Cagrilintide + Retatrutide
Feature: Components
CagriSema (Cagrilintide + Semaglutide): Amylin analog + GLP-1 agonist
Cagrilintide + Tirzepatide: Amylin analog + GIP/GLP-1 dual agonist
Cagrilintide + Retatrutide: Amylin analog + GLP-1/GIP/glucagon triple agonist
Feature: Pathway Coverage
CagriSema (Cagrilintide + Semaglutide): Amylin + GLP-1 (2 pathways)
Cagrilintide + Tirzepatide: Amylin + GIP + GLP-1 (3 pathways)
Cagrilintide + Retatrutide: Amylin + GIP + GLP-1 + glucagon (4 pathways)
Feature: Clinical Combination Data
CagriSema (Cagrilintide + Semaglutide): Phase 3 REDEFINE program (NEJM 2025); NDA filed
Cagrilintide + Tirzepatide: No combination trial data
Cagrilintide + Retatrutide: No combination trial data
Feature: Weight Loss (per compound alone)
CagriSema (Cagrilintide + Semaglutide): Cagri: 11.8%; Sema: 14.9%; Combo: 22.7%
Cagrilintide + Tirzepatide: Cagri: 11.8%; Tirz: 22.5% (SURMOUNT-1)
Cagrilintide + Retatrutide: Cagri: 11.8%; Reta: 28.7% (TRIUMPH-4)
Feature: FDA Status
CagriSema (Cagrilintide + Semaglutide): NDA filed Dec 2025; review expected 2026
Cagrilintide + Tirzepatide: Both investigational as combination
Cagrilintide + Retatrutide: Both investigational; retatrutide in Phase 3
Feature: Complexity
CagriSema (Cagrilintide + Semaglutide): Low - synchronized titration, matched half-lives
Cagrilintide + Tirzepatide: Moderate - different titration schedules
Cagrilintide + Retatrutide: High - different titration, limited combination data
Feature: Cost (Research-Grade)
CagriSema (Cagrilintide + Semaglutide): $500-900/month (two compounds)
Cagrilintide + Tirzepatide: $600-1,100/month (estimated)
Cagrilintide + Retatrutide: $700-1,200/month (estimated)
Decision Guidance
- Choose CagriSema when you want the most clinically validated combination with Phase 3 NEJM-published data, synchronized titration, and near-term FDA approval potential.
- Choose [Cagrilintide + Tirzepatide](/stacks/cagrilintide-tirzepatide) when you want to layer amylin biology on top of the strongest approved dual-agonist (tirzepatide) - theoretical 3-pathway coverage with no combination clinical data.
- Choose [Cagrilintide + Retatrutide](/stacks/cagrilintide-retatrutide) when pursuing maximum theoretical pathway breadth (4 receptors) - the highest-efficacy single compound plus amylin, but entirely community-derived with no combination safety data.
Frequently Asked Questions - CagriSema
Q1: What is the CagriSema stack?
CagriSema is a two-compound combination of cagrilintide (a long-acting amylin analog, 2.4 mg) and semaglutide (a GLP-1 receptor agonist, 2.4 mg) administered together once weekly via subcutaneous injection. Developed by Novo Nordisk, it targets two complementary appetite-regulation pathways - amylin receptors in the area postrema and hypothalamus, and GLP-1 receptors in the gut-brain axis - to achieve weight loss exceeding either compound alone. In the REDEFINE 1 Phase 3 trial, the combination produced 22.7% mean body weight loss at 68 weeks. Novo Nordisk filed an NDA in December 2025, with FDA review expected in 2026.
Q2: How does CagriSema differ from semaglutide alone?
Semaglutide alone (Wegovy, 2.4 mg) produces approximately 14.9% weight loss at 68 weeks through GLP-1 receptor activation. CagriSema adds cagrilintide's amylin receptor pathway, targeting distinct brain regions involved in satiety (area postrema, nucleus of the solitary tract, arcuate nucleus). In the REDEFINE 1 trial, CagriSema achieved 22.7% weight loss versus 16.1% for semaglutide alone - an additional 6.6 percentage points attributable to cagrilintide's amylin mechanism. The combination also showed greater improvements in waist circumference and blood pressure.
Q3: How do you dose the CagriSema stack?
Both compounds follow a synchronized titration over 16 weeks: Weeks 1-4 at 0.25 mg each, Weeks 5-8 at 0.5 mg each, Weeks 9-12 at 1.0 mg each, Weeks 13-16 at 1.7 mg each, and Week 17+ at the maintenance dose of 2.4 mg each. Both are administered once weekly on the same day via subcutaneous injection. This gradual escalation allows gastrointestinal adaptation and significantly reduces nausea rates. For custom dose-to-volume math, use the PepPal Reconstitution Calculator at https://www.peppal.app/calculator.
Q4: What is in the CagriSema pre-blended vial?
Research-grade pre-blended CagriSema vials typically contain 5 mg cagrilintide + 5 mg semaglutide (10 mg total) as lyophilized powder. When reconstituted with 3 mL bacteriostatic water, this produces a 3.33 mg/mL total concentration (1.67 mg/mL per compound). The starting dose of 0.25 mg each requires 0.15 mL (15 units on a U-100 syringe). The maintenance dose of 2.4 mg each requires 1.44 mL (144 units). At maintenance, each 10 mg vial provides approximately 2 full doses.
Q5: How do you reconstitute the CagriSema stack?
For separate vials: reconstitute each 5 mg vial with 2-2.5 mL bacteriostatic water, producing 2-2.5 mg/mL concentration. For the pre-blended 10 mg vial: add 3 mL BAC water for 3.33 mg/mL total. In both cases, inject water slowly along the vial wall, do not shake, and gently roll to dissolve. Label each vial with reconstitution date and concentration. Store refrigerated at 2-8 C. See the reconstitution tables in Section 6 for dose-to-volume conversions, or use the PepPal Calculator at https://www.peppal.app/calculator for custom configurations.
Q6: What results can be expected from the CagriSema stack?
Phase 3 trial results: REDEFINE 1 (non-diabetic, n=3,417) showed 22.7% mean weight loss at 68 weeks, with 40.4% of participants losing >=25% of body weight and 23% losing >=30%. REDEFINE 2 (type 2 diabetes, n=1,206) showed 13.7% weight loss with 73.5% achieving HbA1c <=6.5%. REDEFINE 4 (head-to-head vs tirzepatide) showed CagriSema at 23% weight loss versus 25.5% for tirzepatide 15 mg (non-inferiority not met). Approximately 54% of obese participants in REDEFINE 1 crossed below the BMI 30 obesity threshold.
Q7: Is the CagriSema stack safe?
CagriSema's safety profile is consistent with the GLP-1 receptor agonist class. Most common side effects are gastrointestinal: nausea (55%), constipation (30.7%), and vomiting (26.1%) in REDEFINE 1. These are predominantly mild to moderate and diminish over time. Discontinuation rates due to adverse events were low (5.9% CagriSema vs 3.5% placebo in REDEFINE 1). Serious adverse events were rare. No unique safety signals attributable to the amylin pathway were identified. However, no long-term (>68 week) combination safety data exists yet, and the ongoing REDEFINE 3 cardiovascular outcomes trial (n=7,000) has not yet reported.
Q8: How long should you run the CagriSema stack?
The REDEFINE trials ran for 68 weeks (16 weeks escalation + 52 weeks maintenance). Studies show approximately two-thirds of lost weight returns within one year of stopping semaglutide-based therapies. This suggests CagriSema is designed for sustained, long-term use rather than fixed cycling. Community protocols may use 6-12 month cycles with reassessment, but these are not clinically validated for the CagriSema combination.
Q9: Should you use separate vials or the pre-blended CagriSema vial?
Both formats are valid. Separate vials allow independent dose titration - useful if one compound causes more GI issues and you need to hold it at a lower dose while continuing to escalate the other. The pre-blended vial offers convenience (single reconstitution, single draw, single injection) but enforces a fixed 1:1 dosing ratio. For users following the standard synchronized protocol from REDEFINE trials, the blend vial is simpler. For users who need flexible per-compound dose adjustment, separate vials are preferred.
Q10: Can any CagriSema components be taken orally?
Semaglutide has an FDA-approved oral formulation (oral Wegovy 25 mg tablet). Cagrilintide requires subcutaneous injection - no oral formulation exists. A theoretical oral-hybrid protocol (oral semaglutide + injectable cagrilintide) has not been studied in any clinical trial. The REDEFINE program exclusively evaluated once-weekly subcutaneous co-administration of both compounds.
Q11: Who should choose CagriSema over tirzepatide or retatrutide stacks?
CagriSema is the strongest choice when clinical validation matters - it has Phase 3 NEJM-published data from over 4,600 participants and an NDA filed for FDA review. For maximum weight loss among single compounds, tirzepatide (22.5%, SURMOUNT-1) and retatrutide (28.7%, TRIUMPH-4) may exceed CagriSema's individual compound efficacy, but neither has been studied in combination with cagrilintide. CagriSema is also the most practical choice for synchronized titration - both compounds have matched ~7-day half-lives and identical dose escalation schedules.
Q12: Does cagrilintide in the stack cause hypoglycemia?
In REDEFINE 1 (non-diabetic population), CagriSema was not associated with increased hypoglycemia risk compared to placebo. Amylin's effects are primarily satiety-driven rather than insulin-secretion driven. In REDEFINE 2 (type 2 diabetes), significant HbA1c improvements occurred without clinically meaningful hypoglycemia in participants not on concurrent insulin or sulfonylureas. Those on concurrent insulin should monitor glucose closely during CagriSema titration.
Q13: What calculator should be used for CagriSema reconstitution math?
The PepPal Reconstitution Calculator at https://www.peppal.app/calculator handles CagriSema workflows for both separate vials and pre-blended formats. Enter your vial size, BAC water volume, and target dose to get exact syringe units. This is particularly important because the CagriSema titration changes every 4 weeks across 5 dose levels - the calculator eliminates manual math errors throughout the entire escalation.
Q14: Is this medical advice?
No. All content on this page is for educational and research reference purposes only. CagriSema is an investigational drug combination not yet FDA-approved (NDA filed December 2025, FDA review expected 2026). Cagrilintide is not approved for any indication. Semaglutide is FDA-approved under separate brand names but the CagriSema combination is not. This page does not constitute medical advice. Consult a qualified healthcare provider before considering any therapeutic agent.
Sources & Research
- Garvey WT, Bluher M, Osorto Contreras CK, et al. "Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity." New England Journal of Medicine, 2025 Link.
- Davies MJ, Bajaj HS, Broholm C, et al. "Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes." New England Journal of Medicine, 2025 Link.
- Lau DCW, Erichsen L, Francisco-Ziller N, et al. "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." The Lancet, 2021 Link.
- Frias JP, Deenadayalan S, Erichsen L, et al. "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." The Lancet, 2023 Link.
- Enebo LB, Berthelsen KK, Kankam M, et al. "Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2.4 mg for weight management: a randomised, controlled, phase 1b trial." The Lancet, 2021 Link.
- Mathieu C, Lau J, Bhatt DL, et al. "Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors." Nature Communications, 2025 Link.
- Dehestani B, Kahathuduwa CN, Garvey WT, et al. "Efficacy and Safety of Cagrilintide Alone and in Combination with Semaglutide (Cagrisema) as Anti-Obesity Medications: A Systematic Review and Meta-Analysis." Indian Journal of Endocrinology and Metabolism, 2024 Link.
- Novo Nordisk "Novo Nordisk files for FDA approval of CagriSema, the first once-weekly combination of GLP-1 and amylin analogues for weight management." Press Release, 2025 Link.
- Wilding JPH, Batterham RL, Calanna S, et al. "Once-Weekly Semaglutide in Adults with Overweight or Obesity." New England Journal of Medicine, 2021 Link.
- ClinicalTrials.gov — (NCT05567796), (NCT05394519), (NCT06131437).
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View protocolDisclaimer & Affiliate Disclosure
All content on this page is for educational and research reference purposes only. CagriSema is an investigational drug combination that is not yet FDA-approved. Cagrilintide is not approved for any indication. Semaglutide is FDA-approved under separate brand names, but the fixed-dose CagriSema combination is not. This page does not constitute medical advice or a recommendation to use any compound.
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