Amylin and GLP-1 Combinations: CagriSema, Amycretin and What the Trials Show

Recent obesity drug research has centred on the incretin hormones GLP-1 and GIP. Several companies are now adding a second, separate satiety signal: amylin.

What does amylin do?

Amylin is a 37-amino-acid peptide hormone made by the beta cells of the pancreas and released together with insulin after meals (Hay et al., 2015). It slows stomach emptying, suppresses glucagon release after meals and promotes fullness through the brain (Fischer and Borner, 2026). It acts mainly on brain areas outside the blood-brain barrier, such as the area postrema (Hay et al., 2015).

Amylin's receptors are built from the calcitonin receptor paired with one of three receptor activity-modifying proteins (RAMPs), giving the amylin 1, 2 and 3 receptors. The calcitonin receptor on its own responds strongly to the bone hormone calcitonin and only weakly to amylin (Hay et al., 2015). Newer drugs differ in how strongly they activate each of these.

Human amylin readily clumps into fibrils, which makes it a poor drug. Pramlintide, based on the non-clumping rat sequence (Bailey et al., 2026), was approved by the FDA in 2005 for type 1 diabetes and insulin-treated type 2 diabetes (Walker et al., 2025). It found only limited use as an add-on to insulin, and efforts to develop it for obesity stalled over how often it had to be given, safety and formulation (Bailey et al., 2026; Walker et al., 2025). Long-acting analogues such as cagrilintide, covered in our cagrilintide research overview, were designed to get past those limits.

Why pair amylin with GLP-1?

GLP-1 receptor agonists act on GLP-1 receptors in the pancreas, gut and brain: they increase insulin release when glucose is high, slow the stomach and reduce appetite (see understanding GLP-1 peptides). Amylin analogues reach a similar end point, eating less, through a different receptor family. Hay et al. (2015) noted that clinical studies suggested amylin agonists could be especially useful in combination with other agents.

Rat work suggests the two routes are partly separate: the longer-term effects of cagrilintide ran through a group of brainstem neurons that make prolactin-releasing hormone, and reducing that hormone blocked the effects of cagrilintide but not of the GLP-1 drug semaglutide (Ludwig et al., 2026). For blood glucose, amylin's effects on glucagon and stomach emptying sit alongside GLP-1's effect on insulin.

The first human signal came from a 20-week phase 1b safety study in 96 adults, all given semaglutide plus either cagrilintide or placebo. Weight loss was an exploratory measure: 17.1% with cagrilintide at the strength later used in CagriSema, against 9.8% with semaglutide plus placebo (Enebo et al., 2021).

What did the CagriSema trials show?

CagriSema is Novo Nordisk's combination of cagrilintide and semaglutide (more on semaglutide in our semaglutide research overview). The main published trials:

• Phase 2 in type 2 diabetes: 92 adults for 32 weeks. HbA1c fell by 2.2 percentage points with CagriSema, 1.8 with semaglutide and 0.9 with cagrilintide; the difference from semaglutide was not statistically significant. Weight fell by 15.6%, 5.1% and 8.1% respectively (Frias et al., 2023).
• REDEFINE 1: 3,417 adults with obesity or overweight and no diabetes, 68 weeks. Mean weight change was minus 20.4% with CagriSema against minus 3.0% with placebo (Garvey et al., 2025), and minus 14.9% and minus 11.5% in the semaglutide-only and cagrilintide-only groups. Gastrointestinal events, mainly mild to moderate and temporary, affected 79.6% against 39.9% on placebo.
• REDEFINE 2: 1,206 adults with type 2 diabetes, 68 weeks. Weight change was minus 13.7% against minus 3.4%, and 73.5% of the CagriSema group reached an HbA1c of 6.5% or lower against 15.9% on placebo (Davies et al., 2025).
• REIMAGINE 2: 2,713 adults with type 2 diabetes, 68 weeks. CagriSema lowered HbA1c by 1.91 percentage points against 1.75 with semaglutide alone, a small but statistically significant difference (Buse et al., 2026).

Against tirzepatide the picture is less favourable. Novo Nordisk reported in February 2026 that REDEFINE 4, an open-label 84-week trial in 809 people, did not show CagriSema to be non-inferior to tirzepatide for weight loss: 20.2% against 23.6% when counting everyone randomised (Novo Nordisk, 23 February 2026). Those are company figures and the trial is not yet published.

Regulatory status as of October 2026

Novo Nordisk submitted CagriSema for weight management to the US FDA in December 2025, based on REDEFINE 1 and REDEFINE 2, and said a decision was anticipated by late 2026 (Novo Nordisk, 23 February 2026). Its August 2026 half-year report still listed the US decision as a 2026 milestone (Novo Nordisk, 4 August 2026). We found no announced FDA decision as of mid-October 2026, and no company announcement of a filing in the EU or UK. CagriSema is not an approved medicine.

What is amycretin (zenagamtide)?

Amycretin, now named zenagamtide, takes a different approach: one molecule instead of two. Its phase 2 paper describes it as acting on GLP-1, amylin and calcitonin receptors (Mora et al., 2026).

• Phase 1b/2a, obesity: 125 participants at a single US centre. In the part testing the highest level, mean weight change at 36 weeks was minus 24.3% against minus 1.1% with placebo. Many participants withdrew, and the study was designed mainly to test safety (Dahl et al., 2025).
• Phase 2, type 2 diabetes: 262 adults for 36 weeks. HbA1c fell by 0.9 to 1.7 percentage points across the groups, and most side effects were gastrointestinal and mild to moderate (Mora et al., 2026). Novo Nordisk reported weight loss of up to 14.6% against 2.1% with placebo (Novo Nordisk, 6 June 2026).
• Phase 3: the AMAZE obesity programme started with AMAZE 1 in February 2026 (NCT07339423), and a diabetes programme, AMBITION, began recruiting in August 2026. No phase 3 results have been reported.

What other combinations are being studied?

Eloralintide with tirzepatide (Eli Lilly)

Lilly's eloralintide is an amylin analogue designed to favour the amylin 1 receptor (see our eloralintide research overview). Its partner, tirzepatide, activates both GIP and GLP-1 receptors. In a 48-week phase 2 trial of 367 adults with obesity or overweight and type 2 diabetes (NCT06603571), Lilly reported mean weight loss of up to 23.3% with the combination, against 14.8% with tirzepatide alone and 3.0% with placebo, figures that assume participants stayed on treatment. Gastrointestinal events were more common with the combination, and more people stopped treatment because of side effects than with tirzepatide alone (Eli Lilly, 30 September 2026). They are not yet peer reviewed. The two drugs were given separately; Lilly plans phase 3 trials of a single co-formulated product by the end of 2026.

Petrelintide with enicepatide (Zealand Pharma and Roche)

In March 2025 Roche and Zealand Pharma agreed to develop Zealand's amylin analogue petrelintide on its own and as a fixed-dose combination with CT-388, Roche's GLP-1 and GIP dual agonist (Roche, 12 March 2025), now named enicepatide. A phase 2 trial of the pair is registered (NCT07589686), and Zealand said on 7 October 2026 that it is planned to start in the second half of 2026 (Zealand Pharma, 7 October 2026). Petrelintide alone is further ahead: in the phase 2 ZUPREME 1 trial, weight fell by up to 9.8% at 28 weeks against 1.7% with placebo (Garvey et al., 2026), and its phase 3 programme has started.

Other pairings and add-on trials

AstraZeneca's phase 2b ASCEND trial paired its amylin agonist lenbelintide (AZD6234) with AZD9550, a GLP-1 and glucagon dual agonist (NCT06862791); the registry lists it as completed, and we found no published results. Two phase 3 trials are testing an amylin analogue added to existing incretin treatment: Lilly's ENLIGHTEN-6 (NCT07392190) and AstraZeneca's SELENE 3 (NCT07776509).

Amylin and incretin combinations at a glance

What is not known?

• Retatrutide with cagrilintide. Searches of PubMed and ClinicalTrials.gov on 15 October 2026 found no human trial of this pair, published or registered. The only published test is a 2026 study in diet-induced obese male rats, in which the two given together reduced body weight and food intake more than either alone and more than matched combinations using semaglutide or tirzepatide (Petersen et al., 2026). That is rodent evidence only, in one sex, and says nothing about safety or effects in people. Retatrutide itself is still investigational (see retatrutide vs tirzepatide).
• Long-term safety. Published CagriSema data stop at 68 weeks. REDEFINE 3, a cardiovascular outcomes trial of about 7,100 people (NCT05669755), lists primary completion for September 2027. Gastrointestinal side effects were common in every combination trial above, and reviewers have asked whether calcitonin receptor activity pushes reduced eating towards nausea and aversion (Fischer and Borner, 2026).
• Which combination works best. No published trial has compared amylin combinations with each other. Comparing figures across trials is unreliable because populations, durations and statistical methods differ.
• Research blends are not studied drugs. CagriSema is a specific fixed-dose combination with a developed formulation, tested in controlled trials. Even Lilly, having tested eloralintide and tirzepatide given separately, plans new phase 3 trials for a co-formulated version. A blend mixed outside that process has no published stability, compatibility or clinical data, and none of the trial results above can be transferred to it.

The bottom line

Pairing amylin with GLP-1 now has phase 3 evidence: in REDEFINE 1 the combination beat both of its parts, and CagriSema awaits an FDA decision. Amycretin is in phase 3, and eloralintide with tirzepatide has topline phase 2 data. Pairings such as retatrutide with cagrilintide have been tested only in rats.

References

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