Cagrilintide: the long-acting amylin analogue behind CagriSema

Insulin's quieter partner

Every time the beta cells of the pancreas release insulin after a meal, they release a second hormone with it. That hormone, amylin, has spent most of its scientific life in insulin's shadow. Yet it does something insulin does not: it tells the brain that the meal is under way ^[3].

Most of the attention in obesity research has gone to GLP-1, a gut hormone. Amylin offers a second, separate route to the same feeling of fullness. Cagrilintide is a long-acting amylin analogue that has already been tested in phase 3 trials, and it is the "Cagri" in CagriSema, Novo Nordisk's combination with semaglutide ^[8]. Whether amylin becomes a pillar of obesity treatment or a supporting act depends largely on what this molecule shows.

A hormone found inside amyloid

Amylin was discovered in an unusual place. In 1987, two groups independently pulled the same 37-amino-acid peptide out of amyloid, the insoluble protein deposits that build up in the pancreatic islets of people with type 2 diabetes ^[1,2]. Garth Cooper and colleagues found it in pancreases from people with diabetes and called it diabetes-associated peptide ^[1]. Per Westermark and colleagues purified it from a human insulin-producing tumour and from diabetic cats, and showed that normal beta cells also contain it ^[2].

That origin story hints at the problem drug developers faced. Human amylin has a strong tendency to clump into amyloid fibrils, which makes it a difficult starting point for a medicine ^[5]. The first amylin drug, pramlintide, was engineered to be less prone to clumping and was approved by the FDA on 16 March 2005 as an add-on to insulin in type 1 and type 2 diabetes ^[3,4,5]. Its short half-life, however, meant three injections a day ^[5].

Novo Nordisk's chemists set out to build a stable amylin analogue that would last a week. In 2021 they described cagrilintide, compound 23 in their structure-activity series, a lipidated analogue selected for clinical development in obesity ^[5]. Its fatty side chain, the same kind of modification used in semaglutide, is what makes it long-acting ^[5].

Two smoke detectors for one meal

Think of the brain's fullness system as a building with several smoke detectors wired to different circuits. GLP-1 is one detector. Amylin is another, wired through different receptors and different brain regions. When both go off, the brain gets a stronger, better-confirmed message that food has arrived.

Amylin works mainly in the circumventricular organs of the brain, small regions such as the area postrema where the blood-brain barrier is leaky enough for hormones to be sensed directly ^[3]. Its receptors are unusual: they are built from the calcitonin receptor paired with one of three accessory proteins called RAMPs, which creates several receptor subtypes ^[3]. Through these, amylin promotes fullness, slows stomach emptying and restrains glucagon release after meals ^[3].

Cagrilintide activates the amylin receptors and also the calcitonin receptor on its own, which is why it is sometimes described as a dual amylin and calcitonin receptor agonist ^[14]. Because this machinery is separate from the GLP-1 system, researchers have tested whether the two add up. In obese rats, combining cagrilintide with the triple agonist retatrutide produced more weight loss than either drug alone ^[14].

What the research shows

Phase 1b: the first pairing with semaglutide

In a phase 1b trial in 96 otherwise healthy adults with overweight or obesity, cagrilintide at several doses or placebo was given together with semaglutide 2.4 mg for 20 weeks, without lifestyle advice ^[6]. With cagrilintide 2.4 mg added, average weight loss was 17.1%, against 9.8% with semaglutide plus placebo ^[6]. The study also established the half-life of 159 to 195 hours ^[6].

Phase 2: cagrilintide on its own

A dose-finding phase 2 trial randomised 906 adults without diabetes for 26 weeks: 706 to one of five weekly cagrilintide doses, 99 to daily liraglutide 3.0 mg (an approved GLP-1 drug) and 101 to placebo ^[7]. Weight fell 6.0% to 10.8% across the cagrilintide doses, against 3.0% on placebo; the top dose, 4.5 mg, outperformed liraglutide (10.8% versus 9.0%) ^[7]. Gastrointestinal side effects affected 41% to 63% on cagrilintide versus 32% on placebo, mainly nausea, and injection-site reactions were among the most frequent adverse events ^[7].

Phase 3: REDEFINE 1

REDEFINE 1, published in the New England Journal of Medicine in 2025, randomised 3,417 adults without diabetes to CagriSema (2,108), semaglutide alone (302), cagrilintide alone (302) or placebo (705) for 68 weeks ^[8]. Counting everyone randomised, CagriSema produced an average weight loss of 20.4%, against 3.0% on placebo ^[8]. Gastrointestinal events affected 79.6% of the CagriSema group versus 39.9% on placebo, mostly mild to moderate and transient ^[8].

The single-drug arms tell the cagrilintide story more directly:

Source: Novo Nordisk company announcement ^[10].

At the end of REDEFINE 1, 82.5% of people on cagrilintide alone were on the full dose, compared with 57.3% on CagriSema ^[10].

That detail matters. The trial allowed participants to adjust their dose, and far more people stayed at the top dose of cagrilintide alone than of the combination ^[10]. It hints that cagrilintide on its own may be easier to tolerate, although it also produces less weight loss.

Phase 3 in type 2 diabetes: REDEFINE 2

In REDEFINE 2, 1,206 adults with type 2 diabetes and overweight or obesity received CagriSema or placebo for 68 weeks ^[9]. Weight fell 13.7% versus 3.4%, and 73.5% of the CagriSema group reached an HbA1c of 6.5% or lower, against 15.9% on placebo ^[9].

Head to head: REDEFINE 4

In February 2026, Novo Nordisk reported that CagriSema had missed its primary goal in REDEFINE 4, an open-label 84-week trial in 809 adults comparing it with tirzepatide 15 mg ^[12]. Weight loss was 23.0% versus 25.5% if everyone had stayed on treatment, and 20.2% versus 23.6% counting everyone randomised, so non-inferiority was not shown ^[12].

What we don't know yet

Cagrilintide as a standalone treatment. The only phase 3 data for cagrilintide alone come from a 302-person comparator arm in REDEFINE 1 ^[8,10]. A dedicated phase 3 programme, RENEW, began in November 2025; its first trial is not expected to complete its primary phase until 2027 ^[13].

Long-term outcomes. Weight-loss trials are not designed to show effects on heart attacks, strokes or survival, and no such outcome data have been published for cagrilintide.

The calcitonin side. Cagrilintide also activates the calcitonin receptor ^[14]. What years of that stimulation mean in humans has not been studied.

The best partner and dose. REDEFINE 4 showed that pairing cagrilintide with semaglutide at the doses tested did not match tirzepatide ^[12]. Animal work suggests other partners could add more ^[14], but that has not been tested in people.

Quality of weight lost. How much of the weight lost is fat rather than lean tissue, and whether amylin-based treatment differs from GLP-1 drugs in this respect, remains an open question. For context on how to weigh evidence of this kind, see our guide to levels of evidence.

Regulatory status

• Cagrilintide alone: Not approved anywhere. It is in phase 3 development (the RENEW programme) ^[13].
• CagriSema: Novo Nordisk submitted a New Drug Application to the FDA on 18 December 2025, based on REDEFINE 1 and REDEFINE 2 ^[11]. In February 2026 the company said it expected a decision by late 2026 ^[12]. As of October 2026, we found no announced FDA decision. At filing, Novo stated that CagriSema was not approved in the US or the EU ^[11].
• Pramlintide: Approved in 2005, it is so far the only amylin analogue approved by the FDA ^[4].
• Sport: Cagrilintide is not named on the WADA Prohibited List, but the list's S0 class covers pharmacological substances in clinical development with no regulatory approval, which applies to it ^[15].

In the lab: handling and storage

Research-grade cagrilintide, like our 10 mg vial, is supplied as a lyophilised (freeze-dried) powder. Common lab practice is long-term storage at −20 °C, with 2–8 °C acceptable for short periods, protected from light and moisture. Native amylin is notoriously prone to aggregation, and although cagrilintide was engineered for stability ^[5], reconstituted solutions are usually kept refrigerated, used within a limited period and not frozen and thawed repeatedly. Our guide to storing research peptides covers these steps in more detail.

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