CagriSema: Combination Therapy Research
Novo Nordisk made [semaglutide](/peptides/semaglutide-complete-pharmacology-guide/) the biggest drug in the world. Now they're betting that adding a second hormone — amylin — can push weight loss even further.
Novo Nordisk made semaglutide the biggest drug in the world. Now they're betting that adding a second hormone — amylin — can push weight loss even further. CagriSema combines semaglutide with cagrilintide, a long-acting amylin analog, in a single weekly injection. The idea is straightforward: two hormones that suppress appetite through different brain pathways should work better than one. Phase 3 data published in the New England Journal of Medicine in June 2025 showed 22.7% mean weight loss at 68 weeks — outperforming either component alone. Novo Nordisk filed a New Drug Application with the FDA in December 2025, and a decision could come by late 2026.
Table of Contents
- Quick Facts
- What Is CagriSema?
- Development History
- How CagriSema Works: Mechanisms of Action
- Clinical Research
- Administration and Dosing
- Safety Profile and Side Effects
- Legal and Regulatory Status
- Frequently Asked Questions
- The Bottom Line
Quick Facts
| Property | Detail |
|---|---|
| Full Name | Cagrilintide 2.4 mg / Semaglutide 2.4 mg |
| Brand Name | CagriSema (proposed) |
| Developer | Novo Nordisk |
| Drug Class | Long-acting amylin analog + GLP-1 receptor agonist (fixed-ratio combination) |
| Route | Subcutaneous injection, once weekly |
| Target Dose | Cagrilintide 2.4 mg + Semaglutide 2.4 mg |
| Primary Indications | Obesity/overweight (weight management); Type 2 diabetes (under investigation) |
| Key Trial | REDEFINE 1 — 22.7% mean weight loss at 68 weeks |
| Regulatory Status | NDA submitted to FDA (December 2025); under review |
| ClinicalTrials.gov | NCT05394519 |
What Is CagriSema?
CagriSema is a fixed-dose combination of two distinct peptide hormones in a single prefilled pen:
Cagrilintide is a long-acting synthetic analog of amylin, a 37-amino-acid peptide hormone co-secreted with insulin from pancreatic beta cells after meals. Amylin signals satiety through the hindbrain — specifically the area postrema and nucleus of the solitary tract — and slows gastric emptying. Native amylin has a half-life measured in minutes and a tendency to form amyloid fibrils, making it impractical as a drug. Cagrilintide solves both problems through fatty acid acylation (the same lipidation strategy Novo Nordisk used for semaglutide), extending the half-life to roughly 184 hours and enabling once-weekly dosing.
Semaglutide is a GLP-1 receptor agonist already approved under the brand names Ozempic (for type 2 diabetes) and Wegovy (for weight management). It works primarily by activating GLP-1 receptors in the hypothalamus and other brain regions, suppressing appetite, slowing gastric emptying, and improving insulin secretion.
The logic behind combining them: amylin and GLP-1 regulate appetite through overlapping but distinct neural circuits. GLP-1 acts mainly through the hypothalamus. Amylin acts mainly through the hindbrain. Hitting both pathways simultaneously produces additive weight loss that neither hormone achieves alone.
CagriSema is not a new molecule — it is two established peptides co-formulated in a single pen.
Development History
1986–1987: Two research groups identified amylin as the major component of amyloid deposits in pancreatic islets, reframing diabetes as a bihormonal deficiency — lacking both insulin and amylin.
2005: The FDA approved pramlintide (Symlin), the first synthetic amylin analog. It required three daily injections and never gained commercial traction.
2018–2019: Novo Nordisk ran a phase 1b trial of cagrilintide (AM833), their next-generation long-acting amylin analog, alongside semaglutide 2.4 mg in 96 adults. The combination was safe, with no pharmacokinetic interference between the two peptides.
2019–2021: A phase 2 dose-finding trial of cagrilintide alone in 706 adults showed dose-dependent weight loss of 6.0% to 10.8% over 26 weeks. The highest dose (4.5 mg) beat liraglutide 3.0 mg (10.8% vs. 9.0%).
August 2022: A 32-week phase 2 trial of CagriSema in 92 people with type 2 diabetes showed 15.6% weight loss versus 5.1% for semaglutide alone. Published in The Lancet in June 2023, these results justified the large phase 3 program.
Late 2022: Novo Nordisk launched the REDEFINE phase 3 program.
December 2024: REDEFINE 1 results — 22.7% weight loss at 68 weeks, beating both components but falling short of the 25% analysts expected.
March 2025: REDEFINE 2 — 15.7% weight loss in adults with type 2 diabetes.
June 2025: Both trials published in the NEJM.
December 2025: NDA submitted to the FDA for chronic weight management.
February 2026: REIMAGINE 2 confirmed CagriSema beat semaglutide on HbA1c (1.91 vs. 1.76 points) and weight loss (14.2% vs. 10.2%) in 2,728 people with type 2 diabetes.
How CagriSema Works: Mechanisms of Action
CagriSema's two components target separate but complementary hormonal systems involved in appetite regulation, glucose control, and energy balance. Here is how each one works and why the combination produces more weight loss than either alone.
The Amylin Pathway (Cagrilintide)
Amylin is the "forgotten" pancreatic hormone. Every time beta cells release insulin after a meal, they also release amylin — at a ratio of roughly 100:1. While insulin tells cells to absorb glucose, amylin tells the brain that food has arrived.
Cagrilintide activates two receptor families: amylin receptors (AMYRs) and calcitonin receptors (CTRs). These receptors sit in brain regions that control appetite:
- Area postrema and nucleus of the solitary tract (hindbrain): These regions process satiety signals from the gut. Amylin receptor activation here reduces meal size and promotes earlier meal termination.
- Hypothalamus: Amylin receptors in the hypothalamus modulate homeostatic hunger — the drive to eat based on energy balance.
- Ventral tegmental area: Receptors here influence hedonic eating — the desire to eat for pleasure rather than hunger.
Beyond the brain, cagrilintide slows gastric emptying (keeping food in the stomach longer, which extends the feeling of fullness) and suppresses postprandial glucagon secretion (reducing the liver's glucose output after meals).
The GLP-1 Pathway (Semaglutide)
Semaglutide activates GLP-1 receptors concentrated in the hypothalamus, hindbrain, gut, and pancreas. It suppresses appetite, stimulates glucose-dependent insulin release, reduces glucagon secretion, and slows gastric emptying — though through different receptor pathways than amylin. For comparisons with other GLP-1 drugs, see our profiles on tirzepatide, liraglutide, exenatide, and dulaglutide.
Why Two Pathways Are Better Than One
The REDEFINE 1 investigators described the mechanism this way: the combined effects "probably result from the complementary effect of the two molecules on appetite regulation through direct actions in brain regions known to be involved in hedonic and homeostatic appetite regulation, such as the hypothalamus, hindbrain, and septum."
In simpler terms: semaglutide reduces how hungry you feel. Cagrilintide reduces how much you eat per meal and how much pleasure you get from eating. The two effects stack.
This dual approach sets CagriSema apart from both single-agent GLP-1 drugs (like Wegovy or Ozempic) and dual-incretin agents (like tirzepatide, which combines GIP and GLP-1 in one molecule). CagriSema's amylin pathway is entirely separate from the incretin system.
Clinical Research
Phase 2: Proof of Concept
A 32-week trial published in The Lancet enrolled 92 adults with type 2 diabetes across 17 U.S. sites. CagriSema produced 15.6% weight loss and a 2.18-percentage-point HbA1c drop, versus 5.1% weight loss with semaglutide alone and 8.1% with cagrilintide alone. The combination tripled semaglutide's weight loss.
Phase 3: The REDEFINE Program
REDEFINE 1 — Obesity Without Diabetes
Published in N Engl J Med 2025;393:635-647. Lead investigators: W. Timothy Garvey, Matthias Bluher, and the REDEFINE 1 Study Group.
Design: 68-week, multicenter, double-blind trial in 3,417 adults with BMI 30+ (or 27+ with comorbidities) without type 2 diabetes.
Primary results (trial product estimand — participants who adhered to treatment):
| Treatment | Mean Weight Loss | Achieved 20%+ Loss | Achieved 25%+ Loss | Achieved 30%+ Loss |
|---|---|---|---|---|
| CagriSema | 22.7% | 60% | 40.4% | 23% |
| Semaglutide 2.4 mg | 16.1% | — | — | — |
| Cagrilintide 2.4 mg | 11.8% | — | — | — |
| Placebo | 2.3% | — | — | — |
When counting all randomized participants regardless of adherence, CagriSema still achieved 20.4% mean weight loss versus 14.9% for semaglutide and 3.0% for placebo. Half of CagriSema participants reached BMI below 30 (vs. 10.2% on placebo), and 88% of those with prediabetes returned to normoglycemia. Blood pressure, waist circumference, and lipid levels all improved significantly.
REDEFINE 2 — Obesity With Type 2 Diabetes
Published in N Engl J Med 2025;393:648-659. Lead investigators: Melanie J. Davies, Julio Rosenstock, and the REDEFINE 2 Study Group.
Design: 68-week, double-blind, placebo-controlled trial in ~1,200 adults with BMI 27+, HbA1c 7–10%, and type 2 diabetes across 12 countries.
Results:
| Measure | CagriSema | Placebo |
|---|---|---|
| Mean weight loss (adherent) | 15.7% | 3.1% |
| Mean weight loss (all randomized) | 13.7% | 3.4% |
| Achieved 5%+ loss | 83.6% | 30.8% |
| Achieved 10%+ loss | 65.6% | 10.3% |
| Achieved 15%+ loss | 43.8% | 2.4% |
| Achieved 20%+ loss | 22.9% | 0.5% |
| HbA1c ≤6.5% | 73.5% | 15.9% |
Weight loss in people with type 2 diabetes is typically harder to achieve with GLP-1 drugs alone, making CagriSema's 15.7% loss in this population one of its strongest differentiators.
REIMAGINE 2 — Type 2 Diabetes (February 2026)
This 68-week trial tested two CagriSema doses against semaglutide, cagrilintide, and placebo in 2,728 people with type 2 diabetes.
The high dose achieved 1.91 percentage points of HbA1c reduction (vs. 1.76 for semaglutide 2.4 mg), 14.2% weight loss (vs. 10.2% for semaglutide), and no weight loss plateau at week 68.
Ongoing Trials
- REDEFINE 3: Cardiovascular outcomes trial — will test whether CagriSema reduces heart attacks, strokes, and cardiovascular death
- REDEFINE 4: Head-to-head trial against tirzepatide (Zepbound) in 800 adults with obesity
- REDEFINE 11: Longer-duration phase 3 trial with modified protocol
Administration and Dosing
CagriSema is delivered as a once-weekly subcutaneous injection from a single prefilled pen. Both components are co-formulated, so patients give one injection rather than two.
Titration Schedule
Like other injectable obesity medications, CagriSema uses a gradual dose escalation over 16 weeks to reduce gastrointestinal side effects:
| Weeks | Weekly Dose (each component) |
|---|---|
| 1–4 | 0.25 mg |
| 5–8 | 0.50 mg |
| 9–12 | 1.0 mg |
| 13–16 | 1.7 mg |
| 17 onward | 2.4 mg (maintenance) |
Both cagrilintide and semaglutide are escalated in lockstep through each dose level. The 16-week titration period is similar in length to the titration schedules used for semaglutide and tirzepatide monotherapy.
Injection Details
Patients inject in the abdomen, thigh, or upper arm on the same day each week, rotating sites to prevent lipohypertrophy. If a dose is missed, it should be administered within 3 days, then resume the regular schedule. The pen is stored refrigerated and brought to room temperature before use.
Pharmacokinetics
The two components have nearly matched half-lives — cagrilintide at approximately 184 hours and semaglutide at approximately 158 hours — meaning both peptides maintain steady-state levels on the same dosing schedule.
Safety Profile and Side Effects
Safety data comes primarily from the REDEFINE trials (4,600+ participants combined).
Gastrointestinal Side Effects
GI events are the most common side effect — consistent with both GLP-1 and amylin pharmacology. In REDEFINE 1:
- CagriSema group: 79.6% experienced at least one GI event
- Placebo group: 39.9%
The most frequently reported GI events:
- Nausea
- Vomiting
- Diarrhea
- Constipation
- Abdominal pain
Most were mild to moderate and transient, concentrated during dose escalation (weeks 9–16) and subsiding at maintenance dose.
Discontinuation Rates
Approximately 6% of CagriSema participants stopped treatment due to adverse events, compared to 3.7% on placebo. These rates are comparable to those seen with other GLP-1 drugs like Wegovy and Mounjaro/Zepbound.
Injection Site Reactions
Injection site reactions have been noted with cagrilintide at higher rates than with semaglutide alone. These are typically mild (redness, swelling, or discomfort at the injection site) and are being evaluated further in ongoing trials.
Hypoglycemia
Reassuringly, CagriSema was not associated with increased hypoglycemia risk in people without diabetes. In the type 2 diabetes trials, the risk profile was similar to that of semaglutide alone — though clinicians may need to adjust other diabetes medications (such as insulin or sulfonylureas) to avoid lows.
Serious Adverse Events
About 1 in 10 CagriSema participants experienced a serious adverse event (vs. ~1 in 16 on placebo). No new safety signals beyond those known for GLP-1 agonists and amylin analogs have emerged.
Precautions
Based on the semaglutide component and broader GLP-1 class, standard precautions apply: GLP-1 agonists carry a boxed warning about thyroid C-cell tumors in rodents (contraindicated in people with personal or family history of medullary thyroid carcinoma or MEN2 syndrome). Patients should discuss history of pancreatitis, gallbladder disease, or kidney impairment with their clinician. Rapid weight loss itself increases gallstone risk. Safety in pregnancy or breastfeeding is not established.
Legal and Regulatory Status
Current Status
CagriSema is not yet FDA-approved. As of February 2026:
- December 18, 2025: Novo Nordisk submitted an NDA to the FDA for CagriSema in chronic weight management (obesity/overweight with comorbidities).
- Expected PDUFA date: Under standard FDA review timelines, a decision would come approximately 10–12 months after submission — potentially late 2026.
- Type 2 diabetes indication: Following results from REIMAGINE 1 and REDEFINE 3, Novo Nordisk plans to discuss the regulatory pathway for CagriSema in type 2 diabetes with authorities. A separate submission is expected in 2026–2027.
Competitive Field
CagriSema enters a crowded field: tirzepatide (Zepbound/Mounjaro) is already approved with ~20–22.5% weight loss; retatrutide showed up to 24% in phase 2; survodutide and pemvidutide target GLP-1/glucagon; and orforglipron offers an oral option.
CagriSema's distinguishing feature is its mechanism. While competitors combine incretin hormones, CagriSema pairs a GLP-1 agonist with an amylin analog — a fundamentally different hormonal axis. The REDEFINE 4 head-to-head trial against tirzepatide, now underway with 800 patients, will provide the first direct comparison.
Analyst expectations had pegged CagriSema at 25%+ weight loss. When REDEFINE 1 delivered 22.7%, Novo Nordisk's market cap dropped sharply. But 22.7% is the highest from any completed phase 3 obesity drug trial, and 60% of participants reached 20% loss. The "disappointment" was relative to hype, not clinical significance.
Frequently Asked Questions
How is CagriSema different from Wegovy?
Wegovy is semaglutide alone. CagriSema adds cagrilintide 2.4 mg, a long-acting amylin analog, to the same 2.4 mg semaglutide dose. In REDEFINE 1, this added roughly 6.6 percentage points of weight loss (22.7% vs. 16.1%). Both are made by Novo Nordisk.
Is CagriSema better than tirzepatide (Zepbound)?
Cross-trial comparisons are unreliable. CagriSema showed 22.7% in REDEFINE 1; tirzepatide showed 20–22.5% in SURMOUNT. The REDEFINE 4 head-to-head trial should provide a definitive answer.
When will CagriSema be available?
Novo Nordisk submitted an NDA to the FDA in December 2025. Under standard review timelines, a decision is expected in late 2026. If approved, commercial availability would depend on manufacturing ramp-up and supply chain readiness. The type 2 diabetes indication would follow separately.
Can CagriSema be compounded?
Cagrilintide is not yet approved, and CagriSema is a proprietary fixed-ratio combination. There is no legal pathway for compounding pharmacies to produce it. The FDA has been cracking down on compounded GLP-1 drugs, and the same enforcement would apply to amylin analogs.
What about weight regain after stopping?
Like other anti-obesity medications, weight regain after discontinuation is expected — a consistent finding across the GLP-1 class. Long-term treatment is likely necessary to maintain results.
Does CagriSema work for people with type 2 diabetes?
Yes. REDEFINE 2 showed 15.7% weight loss and 73.5% of participants reaching HbA1c of 6.5% or below. REIMAGINE 2 (February 2026) confirmed superiority over semaglutide alone. Since people with type 2 diabetes typically lose less weight on GLP-1 drugs, these results are particularly notable.
What are the most common side effects?
Nausea, vomiting, diarrhea, constipation, and abdominal pain — reported in about 80% of CagriSema participants in REDEFINE 1. Most were mild to moderate, concentrated during dose escalation, and about 6% of participants stopped treatment due to side effects.
The Bottom Line
CagriSema represents a bet that the next generation of obesity treatment will come from combining hormonal pathways, not just optimizing a single one. The data support that bet: adding amylin to GLP-1 consistently produced more weight loss than either alone across phase 2 and phase 3 trials, in both diabetic and non-diabetic populations.
The 22.7% mean weight loss in REDEFINE 1 is the largest effect reported from any completed phase 3 obesity drug trial. Sixty percent of participants lost at least a fifth of their body weight. In people with type 2 diabetes — historically a harder population to treat — CagriSema still delivered 15.7% weight loss and brought nearly three-quarters of participants below an HbA1c of 6.5%.
Open questions remain. How will CagriSema perform head-to-head against tirzepatide? Will REDEFINE 3's cardiovascular outcomes data match semaglutide's track record? Can Novo Nordisk manufacture enough supply, given ongoing semaglutide shortages? And will insurers cover a combination drug when its individual components already strain budgets?
What is clear: amylin — once dismissed as a minor pancreatic player — has re-entered the metabolic drug conversation. CagriSema may become the first drug to combine these two hormonal systems in a single injection.
For researchers tracking this space, the related peptide profiles on this site cover the broader GLP-1 field: semaglutide, tirzepatide, liraglutide, exenatide, dulaglutide, retatrutide, survodutide, orforglipron, and pemvidutide. For non-GLP-1 approaches to body composition, see our profiles on AOD-9604 and tesamorelin.
This article is for educational purposes only. It is not medical advice and does not constitute an endorsement of any product, compound, or treatment protocol. Always consult a qualified healthcare provider before making any decisions about your health.
References:
- Garvey WT, et al. "Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity." N Engl J Med 2025;393:635-647. NEJM
- Davies MJ, et al. "Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes." N Engl J Med 2025;393:648-659. NEJM
- Frias JP, 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." The Lancet 2023. The Lancet
- Lau DCW, et al. "Once-weekly cagrilintide for weight management in people with overweight and obesity." The Lancet 2021. PubMed
- Novo Nordisk. "Files for FDA approval of CagriSema." Dec 2025. Press Release
- Novo Nordisk. "REIMAGINE 2 trial results." Feb 2026. GlobeNewsWire
- Lund A, et al. "Development of Cagrilintide, a Long-Acting Amylin Analogue." J Med Chem 2021. ACS
- Dehestani B, et al. "Efficacy and Safety of Cagrilintide Alone and in Combination with Semaglutide as Anti-Obesity Medications." PMC
- CagriSema FDA approval history. Drugs.com