CagriSema: Cagrilintide + Semaglutide Combo

Key takeaways

CagriSema pairs cagrilintide (an amylin analogue) with semaglutide (a GLP-1 agonist) in a single weekly injection
In the REDEFINE 1 trial, participants without diabetes lost 22.7% of their body weight over 68 weeks, beating semaglutide alone (16.1%) [1]
In REDEFINE 2, adults with type 2 diabetes lost 13.7% of body weight, with 73.5% reaching an HbA1c of 6.5% or below [2]
40.4% of non-diabetic participants hit 25% or greater weight loss, a threshold few other drugs have reached [1]
Novo Nordisk filed its NDA with the FDA in December 2025, with review expected in 2026 [3]
CagriSema may become a serious competitor to retatrutide, Eli Lilly’s triple-agonist, in the next-generation obesity drug race

CagriSema is Novo Nordisk’s combination of two injectable drugs that target different appetite-regulating pathways. One component is cagrilintide, a long-acting analogue of amylin, a pancreatic hormone that tells your brain you’ve had enough food. The other is semaglutide, the GLP-1 receptor agonist already approved as Wegovy for weight management and Ozempic for type 2 diabetes.

The logic is simple: semaglutide and cagrilintide reduce appetite through separate receptor systems, so combining them should produce more weight loss than either drug alone. The REDEFINE trial program tested exactly this hypothesis in over 4,600 participants across two Phase 3 trials [1, 2].

Both components are given as a once-weekly subcutaneous injection at doses of 2.4 mg each. The combination is administered through a single injection device.

The obesity drug space has become crowded. Tirzepatide (Mounjaro/Zepbound) hit the market as a dual GIP/GLP-1 agonist. Retatrutide targets three receptors. CagriSema takes a different approach, combining GLP-1 with the amylin pathway instead of adding more incretin targets. The question is whether the amylin angle can deliver results competitive with triple agonists.

How CagriSema works

CagriSema’s two components suppress appetite through different brain circuits. Understanding this dual mechanism explains why the combination outperforms either drug used alone.

The semaglutide side: GLP-1 receptor activation

Semaglutide mimics glucagon-like peptide-1, a gut hormone released after eating. It binds to GLP-1 receptors in the hypothalamus and brainstem to reduce hunger, slows gastric emptying so food stays in the stomach longer, and enhances insulin secretion while suppressing glucagon. This is the same mechanism behind Wegovy and Ozempic, and the same class of drugs discussed in our peptides for weight loss guide.

The cagrilintide side: amylin receptor activation

Cagrilintide acts on amylin receptors (AMY1R, AMY3R) and calcitonin receptors in the area postrema, a brain region that sits outside the blood-brain barrier and has direct access to circulating signals [4]. Amylin is normally co-secreted with insulin after meals. It signals satiety, slows gastric emptying, and suppresses post-meal glucagon.

What makes cagrilintide different from the older amylin drug pramlintide (Symlin) is its extended half-life. Pramlintide required three daily injections. Cagrilintide lasts a full week [4].

Why the combination works better

A 2025 study in Nature Metabolism helped explain why CagriSema outperforms its components. In rat models, CagriSema produced 12% weight loss through a 39% reduction in food intake. But when researchers pair-fed control rats the same reduced calories, those rats lost less weight. Weight-matching the CagriSema group required cutting food intake by 51%, not 39% [5].

The implication: roughly one-third of CagriSema’s weight loss comes from preserving energy expenditure, not just eating less. The combination appears to blunt the metabolic adaptation (reduced calorie burning) that normally occurs during weight loss [5]. This is a meaningful advantage, since metabolic adaptation is one of the main reasons people regain weight after dieting.

Clinical trial results: the REDEFINE program

Novo Nordisk ran two large Phase 3 trials, both published in the New England Journal of Medicine in August 2025.

REDEFINE 1: adults without diabetes

This was the larger of the two trials. It enrolled 3,417 adults with a BMI of 30 or above (or 27+ with at least one obesity-related condition) and no diabetes. Participants were randomized 21:3:3:7 to receive CagriSema, semaglutide alone, cagrilintide alone, or placebo, plus lifestyle interventions in all groups [1].

At 68 weeks, the results by treatment-policy estimand (intention-to-treat, including people who stopped treatment):

CagriSema: 20.4% mean body weight reduction
Semaglutide 2.4 mg alone: data from the active comparator arm
Cagrilintide 2.4 mg alone: data from the active comparator arm
Placebo: 3.0% mean reduction

The estimated treatment difference between CagriSema and placebo was 17.3 percentage points (95% CI, 18.1 to 16.6; P<0.001) [1].

Among patients who stayed on treatment (trial-product estimand), weight loss was 22.7% with CagriSema, 16.1% with semaglutide, 11.8% with cagrilintide, and 3.5% with placebo [1]. That 6.6 percentage point gap between CagriSema and semaglutide alone represents the added benefit of the amylin component.

Weight loss thresholds tell the story even more clearly. Among CagriSema-treated patients, 40.4% achieved 25% or greater weight loss at 68 weeks. In the semaglutide group, 16.2% hit that mark. In the placebo group, 0.9% [1].

REDEFINE 2: adults with type 2 diabetes

REDEFINE 2 enrolled 1,206 adults with a BMI of 27 or above and type 2 diabetes (HbA1c 7-10%). Participants were randomized 3:1 to CagriSema or placebo, both with lifestyle intervention [2].

This trial tested two things: weight loss and glycemic control.

The mean body weight reduction at week 68 was 13.7% with CagriSema versus 3.4% with placebo (estimated difference, 10.4 percentage points; P<0.001) [2]. Weight loss is typically lower in people with type 2 diabetes across all anti-obesity drugs, so this result was expected.

The glycemic data was equally notable. At week 68, 73.5% of CagriSema patients had an HbA1c of 6.5% or below, compared with 15.9% on placebo [2]. For context, an HbA1c under 6.5% is the threshold for diabetes remission.

Blood pressure effects

A pre-specified analysis of REDEFINE 1 published in Hypertension found that CagriSema also reduced systolic and diastolic blood pressure in adults with overweight or obesity, beyond what semaglutide alone achieved [6]. This is consistent with the cardiovascular benefits seen with other GLP-1 agonists but suggests the amylin component adds something extra.

Side effects and safety

The side effect profile of CagriSema follows a predictable pattern for GLP-1 based therapies, with gastrointestinal symptoms dominating.

In REDEFINE 1, 79.6% of CagriSema participants reported at least one GI adverse event, compared with 39.9% in the placebo group [1]. That’s a high number, but the trial authors described most events as transient, mild, or moderate. Nausea, vomiting, diarrhea, constipation, and abdominal pain were the most common complaints.

In REDEFINE 2 (the diabetes trial), GI adverse events were somewhat lower: 72.5% with CagriSema versus 34.4% with placebo [2].

How does this compare to semaglutide alone? The side effect rates in the REDEFINE trials are roughly in line with what’s seen in the STEP trials for semaglutide, though the combination may cause slightly more GI discomfort during the dose-escalation phase.

Two points worth noting. First, both trials used a gradual dose escalation to the full 2.4 mg/2.4 mg dose, which helps reduce early side effects. Second, dropout rates due to adverse events were not dramatically higher than what’s seen with semaglutide monotherapy, suggesting the combination is tolerable for most patients [1, 2].

Longer-term safety data beyond 68 weeks is still being collected. As with all anti-obesity medications, patients and clinicians will want to monitor for pancreatitis risk, gallbladder events, and changes in heart rate, though none of these were flagged as major concerns in the Phase 3 data.

CagriSema vs retatrutide: the next weight loss showdown

The comparison that matters most for anyone following the obesity drug pipeline is CagriSema versus retatrutide. Eli Lilly’s retatrutide is a triple-agonist targeting GLP-1, GIP, and glucagon receptors. In its Phase 2 trial, the highest dose of retatrutide produced 24.2% weight loss at 48 weeks.

Direct comparisons are tricky because no head-to-head trial exists. The numbers are from different populations, different trial durations, and different designs. But a rough comparison:

Metric	CagriSema	Retatrutide
Mechanism	GLP-1 + amylin	GLP-1 + GIP + glucagon
Phase 3 weight loss (on-treatment)	22.7% at 68 weeks [1]	Phase 3 data pending
Phase 2 weight loss	Phase 2 data informed dosing	24.2% at 48 weeks (highest dose)
Participants achieving ≥25% loss	40.4% [1]	Phase 3 data pending
FDA filing	NDA filed December 2025 [3]	Phase 3 trials ongoing
Administration	Once-weekly injection	Once-weekly injection

CagriSema has a head start in the regulatory process. Novo Nordisk submitted its NDA in December 2025, and the FDA review is expected in 2026 [3]. Retatrutide’s Phase 3 results and regulatory filing are still forthcoming. But if retatrutide’s Phase 3 data replicates its Phase 2 numbers at higher doses, it could match or exceed CagriSema’s weight loss.

The competition ultimately benefits patients. Different mechanisms mean different options for people who don’t respond well to one pathway or another.

CagriSema vs semaglutide and tirzepatide

For patients already familiar with current options, here’s where CagriSema fits:

Versus semaglutide (Wegovy): CagriSema produced 22.7% weight loss compared to 16.1% for semaglutide alone in the same trial [1]. That 6.6 percentage point gap is clinically meaningful and directly attributable to adding cagrilintide.

Versus tirzepatide (Zepbound): Tirzepatide’s SURMOUNT-1 trial showed 22.5% weight loss at the highest dose (15 mg) over 72 weeks. CagriSema’s 22.7% at 68 weeks is in the same ballpark, though these are indirect comparisons across different trials and populations. You can read more in our semaglutide vs tirzepatide comparison.

The practical differences may come down to side effect profiles, cost, insurance coverage, and individual response. Some patients may do better with the amylin pathway than with the GIP pathway, and vice versa.

FDA timeline and availability

Novo Nordisk submitted a New Drug Application to the FDA for CagriSema in December 2025, based on the REDEFINE 1 and REDEFINE 2 data [3]. The FDA’s standard review timeline is 10-12 months from acceptance of the application.

If the review proceeds on a typical timeline, an FDA decision could come in late 2026 or early 2027. Priority review designation, if granted, could shorten that by several months.

CagriSema is not available for prescription as of April 2026. It cannot be compounded by pharmacies because it is an unapproved drug containing a novel molecular entity (cagrilintide).

For patients seeking weight loss treatment now, semaglutide and tirzepatide remain the approved options. If you’re interested in GLP-1 based treatments, you can check if you qualify through our telehealth platform.

Dosing and administration

The REDEFINE trials used a target dose of cagrilintide 2.4 mg plus semaglutide 2.4 mg, administered once weekly by subcutaneous injection [1, 2].

Both trials employed a gradual dose-escalation schedule to minimize GI side effects. Participants started at lower doses and increased stepwise over several weeks until reaching the full 2.4 mg/2.4 mg maintenance dose.

In the clinical trials, both components were administered as separate injections during early phases and as a co-formulated product in later phases. The commercial product, if approved, would be a single injection.

Injection site and technique follow the same general principles as other subcutaneous peptide injections. Our guide to peptide injections covers the basics of subcutaneous administration.

Who might benefit from CagriSema

Based on the trial enrollment criteria and results, CagriSema may be most relevant for:

Adults with a BMI of 30 or above, or 27 or above with at least one weight-related condition (REDEFINE 1 population) [1]. Adults with type 2 diabetes and a BMI of 27 or above who need both weight management and glycemic control (REDEFINE 2 population) [2].

Patients who have not achieved sufficient weight loss on semaglutide alone could theoretically benefit from the added amylin component. The REDEFINE 1 data shows that CagriSema pushed 40.4% of patients past the 25% weight loss mark, versus 16.2% on semaglutide alone [1]. That’s a meaningful difference for people who plateau on current GLP-1 monotherapy.

The combination may also appeal to patients with both obesity and type 2 diabetes who want a single treatment addressing both conditions, since the REDEFINE 2 trial showed strong results on both weight and HbA1c endpoints [2].

FAQ

How much weight can you lose on CagriSema?▼

In the REDEFINE 1 trial, adults without diabetes lost an average of 22.7% of their body weight on CagriSema over 68 weeks (on-treatment estimate). In REDEFINE 2, adults with type 2 diabetes lost 13.7%. Individual results varied, with 40.4% of non-diabetic participants losing 25% or more [1, 2].

Is CagriSema better than Wegovy?▼

In the REDEFINE 1 trial, CagriSema produced 22.7% weight loss compared to 16.1% for semaglutide (Wegovy’s active ingredient) over 68 weeks [1]. The combination was statistically superior to semaglutide alone. Both drugs were used at the same 2.4 mg dose.

When will CagriSema be available?▼

Novo Nordisk filed its NDA with the FDA in December 2025 [3]. A standard FDA review takes 10-12 months, which puts a potential decision in late 2026 or early 2027. CagriSema is not currently available for prescription.

What are the main side effects of CagriSema?▼

Gastrointestinal symptoms are most common: nausea, vomiting, diarrhea, constipation, and abdominal pain. In REDEFINE 1, 79.6% of CagriSema participants experienced at least one GI event, though most were mild or moderate and resolved over time [1].

How is CagriSema different from tirzepatide?▼

CagriSema combines a GLP-1 agonist (semaglutide) with an amylin analogue (cagrilintide). Tirzepatide combines GLP-1 with GIP receptor agonism. They target different secondary pathways. Weight loss results are roughly similar in indirect comparisons (around 22-23% at highest doses), but no head-to-head trial exists.

Can I get CagriSema through a compounding pharmacy?▼

No. CagriSema contains cagrilintide, a novel molecule that is not available for compounding. It can only be obtained through Novo Nordisk if and when it receives FDA approval.

How does CagriSema compare to retatrutide?▼

Both are next-generation obesity drugs, but they work differently. CagriSema targets GLP-1 plus amylin. Retatrutide targets GLP-1, GIP, and glucagon. CagriSema has Phase 3 data (22.7% weight loss) and is already filed with the FDA. Retatrutide’s Phase 2 showed 24.2% at 48 weeks, but Phase 3 data and regulatory filing are still pending.

Does CagriSema help with blood sugar control?▼

Yes. In REDEFINE 2, 73.5% of participants with type 2 diabetes achieved an HbA1c of 6.5% or below after 68 weeks, compared to 15.9% on placebo [2]. The combination addresses both weight and glycemic control.

Get started with GLP-1 weight loss treatment

CagriSema isn’t available yet, but semaglutide and tirzepatide are. If you’re considering GLP-1 based weight loss medication, check if you qualify through our telehealth platform. A licensed provider will review your medical history and determine the best option for your situation.

References

Garvey WT, Blüher M, Osorto Contreras CK, et al. Coadministered cagrilintide and semaglutide in adults with overweight or obesity. N Engl J Med. 2025;393(7):635-647. PubMed
Davies MJ, Bajaj HS, Broholm C, et al. Cagrilintide-semaglutide in adults with overweight or obesity and type 2 diabetes. N Engl J Med. 2025;393(7):648-659. PubMed
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. December 18, 2025. Source
Sonne N, Karsdal MA, Henriksen K. Cagrilintide: a long-acting amylin analog for the treatment of obesity. Cardiol Rev. 2024;32(1):56-64. PubMed
Jacobsen JM, Halling JF, Blom I, et al. CagriSema drives weight loss in rats by reducing energy intake and preserving energy expenditure. Nat Metab. 2025;7(7):1322-1329. PubMed
Verma S, Böttcher M, Brown P, et al. CagriSema reduces blood pressure in adults with overweight or obesity: REDEFINE 1. Hypertension. 2026;83(2). PubMed
Ahmed M, Hassan M, Tahir M, et al. Efficacy and safety of cagrilintide and CagriSema versus semaglutide as anti-obesity medications: a systematic review, meta-analysis and meta-regression. Diabetes Obes Metab. 2026. PubMed
Son JW, le Roux CW, Blüher M. Novel GLP-1-based medications for type 2 diabetes and obesity. Endocr Rev. 2026;47(3). PubMed