Cagrilintide + Semaglutide

This entry covers cagrilintide and semaglutide given together once weekly, each at 2.4 mg — the pairing developed under the name CagriSema. Evidence tier: clinical-stage, and unusually well documented for a combination this new: two 68-week phase 3 trials in more than 4,600 people were published in the New England Journal of Medicine in 2025.

The headline result is that in adults with overweight or obesity, the combination reduced body weight by 20.4% over 68 weeks against 3.0% on placebo (Garvey et al., REDEFINE 1, NEJM 2025). Despite that, nothing here is approved: no regulator has authorised the combination, and a DailyMed search returns no US label for cagrilintide or CagriSema.

The rationale is that these are two different receptor systems, not two doses of the same idea.

• Semaglutide activates the GLP-1 receptor, an incretin receptor, which increases glucose-dependent insulin secretion, suppresses glucagon, slows gastric emptying, and reduces appetite via hypothalamic and brainstem circuits.

• Cagrilintide acts on the calcitonin-receptor family. Amylin receptors are assembled by pairing the calcitonin receptor with receptor activity-modifying proteins — AMY1 is CTR plus RAMP1, AMY2 is CTR plus RAMP2, AMY3 is CTR plus RAMP3 (Hay et al., IUPHAR Review 25, Br J Pharmacol 2018). Cagrilintide is a non-selective agonist that hits those amylin receptors and, independently, the calcitonin receptor itself (Fletcher et al., J Pharmacol Exp Ther 2021).

Both routes converge on hindbrain satiety signalling but enter it through separate receptors, which is the mechanistic argument for adding rather than escalating. The phase 2 diabetes trial is where that argument was tested most cleanly: at an identical 2.4 mg semaglutide dose, adding cagrilintide moved weight change from −5.1% to −15.6% over 32 weeks (Frias et al., Lancet 2023).

There is no approved indication anywhere for this combination. Its trials have targeted two populations: adults with overweight or obesity without diabetes (REDEFINE 1), and adults with overweight or obesity plus type 2 diabetes and HbA1c of 7–10% (REDEFINE 2).

Because the product is unapproved, anything sold under the name outside a trial is not the studied drug. Two separate molecules combined at a fixed weekly dose is also not something that compounding or self-mixing reproduces: the trials measured the safety of one specific pairing, escalated on one specific schedule.

Gastrointestinal effects are the defining tolerability problem and they are common rather than rare. In REDEFINE 1, gastrointestinal adverse events — nausea, vomiting, diarrhoea, constipation, or abdominal pain — occurred in 79.6% of participants on the combination versus 39.9% on placebo, described as mainly transient and mild-to-moderate (REDEFINE 1). In the diabetes trial REDEFINE 2, the equivalent figures were 72.5% versus 34.4% (Davies et al., REDEFINE 2, NEJM 2025).

Reading those numbers honestly: four in five participants experienced a gastrointestinal adverse event, at rates roughly double placebo. The phase 2 diabetes trial reported mild-to-moderate gastrointestinal events predominating with no severe hypoglycaemia (Frias et al., 2023). Class-level concerns carried over from GLP-1 therapy — gallbladder events, pancreatitis, effects on lean mass — have not been resolved for this combination by a dedicated outcomes trial.

Both molecules are long-acting by design and both were measured with half-lives of roughly 145–195 hours — about six to eight days — in the phase 1b study, which also showed that cagrilintide did not alter semaglutide's pharmacokinetics (Enebo et al., Lancet 2021). That is what makes a single weekly injection viable.

The published trials describe the two molecules as coadministered once weekly at 2.4 mg each, and that pairing — not a range of ratios — is what the evidence covers. The 2.4 mg/2.4 mg combination was selected out of the phase 1b dose-ranging work, where cagrilintide was tested from 0.16 mg to 4.5 mg against a fixed semaglutide 2.4 mg background (Enebo et al., 2021).

For the components individually, see cagrilintide and semaglutide. The nearest approved alternative in the "two mechanisms in one weekly injection" category is tirzepatide, which achieves dual action within a single molecule (GIP and GLP-1) rather than by pairing two.

• Phase 1b (Lancet 2021, n=95 exposed, 20 weeks). Six ascending cagrilintide cohorts on semaglutide 2.4 mg. Weight reductions of 15.7%, 17.1% and 15.4% at cagrilintide 1.2, 2.4 and 4.5 mg, against 8.0–9.8% for pooled placebo-plus-semaglutide (Enebo et al.).

• Phase 2, type 2 diabetes (Lancet 2023, n=92, 32 weeks). Weight change −15.6% for the combination versus −5.1% for semaglutide alone and −8.1% for cagrilintide alone; HbA1c fell 2.2 percentage points versus 1.8 for semaglutide and 0.9 for cagrilintide (Frias et al.). Small trial — 92 participants across three arms.

• REDEFINE 1 (NEJM 2025, n=3,417, 68 weeks). 2,108 on the combination, 302 on semaglutide alone, 302 on cagrilintide alone, 705 on placebo. Weight change −20.4% versus −3.0%, a difference of 17.3 percentage points, with significantly more participants reaching 5%, 20%, 25% and 30% loss thresholds (Garvey et al.).

• REDEFINE 2 (NEJM 2025, n=1,206, 68 weeks, type 2 diabetes). Weight change −13.7% versus −3.4% on placebo; 73.5% of the treated group reached HbA1c of 6.5% or lower versus 15.9% on placebo (Davies et al.).

The pattern across the two phase 3 trials is worth noting: the weight effect in people with type 2 diabetes (−13.7%) is markedly smaller than in people without it (−20.4%), a difference consistently seen across this whole drug class rather than unique to this combination. What is still missing is a cardiovascular outcomes trial and any head-to-head against tirzepatide.

For deeper dives on this combination, see:

• Cagrilintide + Semaglutide benefits and areas of interest
• Cagrilintide + Semaglutide side effects and safety context
• Cagrilintide + Semaglutide dosing concepts (educational)
• Cagrilintide + Semaglutide research and evidence overview

What is CagriSema? The development name for cagrilintide, an amylin analogue, given with semaglutide, a GLP-1 receptor agonist, at 2.4 mg of each once weekly. It has been studied in the phase 3 REDEFINE programme for obesity and for type 2 diabetes.

How much weight loss did it show? In REDEFINE 1 — 3,417 adults over 68 weeks — an average of 20.4% of body weight versus 3.0% on placebo, a 17.3 percentage-point difference (NEJM 2025). In adults who also had type 2 diabetes it was 13.7% versus 3.4% (REDEFINE 2).

Is CagriSema approved? No — not in the US, not anywhere. Phase 3 results are published and regulatory review is a separate, later step. Nothing sold under the name is the trial drug.

Why combine two drugs instead of raising the semaglutide dose? Because they hit different receptors. The phase 2 diabetes trial held semaglutide at 2.4 mg in both arms and adding cagrilintide moved weight change from −5.1% to −15.6%, which pushing the GLP-1 receptor harder does not reproduce (Lancet 2023).

What is the main downside seen in trials? Gastrointestinal side effects at high frequency — 79.6% of participants in REDEFINE 1 versus 39.9% on placebo, and 72.5% versus 34.4% in REDEFINE 2. Reported as mostly transient and mild-to-moderate, and managed in trials by escalating the dose over months.