Cagrilintide and CagriSema: what the amylin trials found

Cagrilintide works, but its real story is as a partner drug. On its own, at the highest dose, it produced 10.8% weight loss over 26 weeks in a phase 2 trial [2]. Combined with semaglutide as "CagriSema", it produced 20.4% weight loss over 68 weeks in a 3,417-person phase 3 trial [5]. It then failed to prove it was as good as tirzepatide in a head-to-head [8]. Neither cagrilintide nor CagriSema is approved anywhere yet.

What it is

Amylin is a pancreatic hormone that promotes fullness after eating [2]. Human amylin is awkward to turn into a drug because it clumps into amyloid fibrils [1]. An older analogue, pramlintide, fixed the clumping and is sold as an add-on to insulin, but it has to be injected three times a day because it clears so quickly [1].

Novo Nordisk's cagrilintide is a re-engineered, stabilised amylin with a fatty acid chain attached, which lets it circulate for about a week [1,3]. That turns a three-times-daily drug into a once-weekly one. Researchers describe it as a co-agonist of the amylin and calcitonin receptors, which sit in the same receptor family [10].

The idea behind pairing it with semaglutide is that amylin and GLP-1 reduce appetite through partly different brain pathways, so the effects might add up. That is mechanism theory; the trials tested whether the combination beat each drug alone, and it did [4].

The human evidence

All the trials below were funded by Novo Nordisk.

Cagrilintide alone

This was a fair early test: 706 people in ten countries, with an active comparator as well as placebo [2]. The top dose beat liraglutide, the daily GLP-1 injection that was then a standard obesity drug. Gastrointestinal side effects affected 41–63% of cagrilintide groups against 32% on placebo, mostly nausea [2]. Around 10% of participants stopped treatment early, spread evenly across groups, and 4% stopped because of side effects [2]. Twenty-six weeks is short for an obesity trial, so we don't know where weight would have levelled off.

Adding it to semaglutide

A phase 1b study in 95 otherwise healthy adults with overweight added escalating doses of cagrilintide to semaglutide 2.4 mg for 20 weeks [3]. At 1.2 and 2.4 mg of cagrilintide, weight fell by 15.7% and 17.1% against 9.8% for semaglutide with placebo. The main purpose was safety and dosing: cagrilintide did not change how the body handled semaglutide, and both had half-lives of about six to eight days [3]. Almost everyone in the study reported at least one adverse event, including 96% of the semaglutide-plus-placebo group, and 37% of all events were gastrointestinal [3]. That tells you how much of the side-effect burden comes from semaglutide itself. The group was also unusually diverse for an early obesity trial: 54% of participants were Black or African American [3].

A 32-week phase 2 trial in 92 people with type 2 diabetes then compared the combination with each drug alone [4]. CagriSema lowered weight by 15.6%, against 5.1% on semaglutide and 8.1% on cagrilintide. For blood sugar, the combination beat cagrilintide alone but was not statistically better than semaglutide alone (HbA1c −2.2 vs −1.8 points, p = 0.075) [4]. Continuous glucose monitors told a similar story: time spent in the target glucose range rose to 88.9% on CagriSema, 76.2% on semaglutide and 71.7% on cagrilintide [4]. With only about 30 people per group, this small trial is still the clearest direct evidence that the two drugs add together for weight.

The REDEFINE phase 3 trials

The 20.4% figure counts everyone regardless of whether they kept taking the drug [5]. Novo Nordisk's own summary gives 22.7% for people who stayed on treatment [7]. Most of the trial's participants (2,108) got the combination; the single-drug groups had 302 each, enough to compare but smaller [5]. Everyone, including the placebo group, also received lifestyle advice, which is why placebo participants lost 3% [5].

The gap between the two numbers matters when you compare drugs. Headlines for tirzepatide and retatrutide sometimes quote the stay-on-treatment figure and sometimes the everyone-counted figure, so check which one you're looking at before lining them up.

REDEFINE 2 enrolled 1,206 people with type 2 diabetes and obesity. Over 68 weeks, CagriSema reduced weight by 13.7% against 3.4% on placebo, and 73.5% reached an HbA1c of 6.5% or lower against 15.9% [6]. As with every drug in this class, people with diabetes lost less weight.

Against tirzepatide: REDEFINE 4

REDEFINE 4 is not yet peer reviewed. According to Novo Nordisk, it randomised 809 people with obesity to CagriSema or tirzepatide 15 mg for 84 weeks, open-label [8]. CagriSema produced 23.0% weight loss against 25.5% for tirzepatide, and on the treatment-regimen analysis 20.2% against 23.6% [8]. The trial's primary goal was to show CagriSema was not meaningfully worse than tirzepatide. It failed to show that [8].

Two cautions apply in both directions. Open-label trials can inflate or deflate results because people know what they are taking, and dropout patterns can differ between arms. And a 2.5-point gap after 84 weeks is modest in absolute terms, with both drugs producing weight loss above 20% [8]. What REDEFINE 4 settled is narrower. It showed CagriSema is not the strongest option on weight, which matters for how it will be positioned if approved.

What the animal and lab work suggests

The medicinal chemistry paper describes how Novo screened amylin analogues for stability, receptor activity and duration before picking cagrilintide [1]. Newer animal work is looking beyond CagriSema. A September 2026 study in diet-induced obese male rats found that combining cagrilintide with retatrutide cut body weight and food intake more than either drug alone, and more than matched combinations using semaglutide or tirzepatide [10]. Rats are not people, and no human trial of that pairing has been published, but it shows where the field is heading: amylin added on top of whichever incretin drug is strongest.

Safety and side effects

Gut. Gastrointestinal side effects are the main issue and they are frequent. In REDEFINE 1, 79.6% on CagriSema had them against 39.9% on placebo, mostly nausea, vomiting, diarrhoea, constipation or abdominal pain, and mainly mild to moderate and temporary [5]. In REDEFINE 2 the figures were 72.5% against 34.4% [6].

Injection site. Administration-site reactions were among the most common side effects of cagrilintide alone [2].

Low blood sugar. In the 32-week diabetes trial, there was no clinically significant or severe hypoglycaemia in any group [4].

What we don't have yet. Because CagriSema contains semaglutide, it should be expected to carry semaglutide's known warnings about gallbladder disease and pancreatitis, but the full regulatory review of the combination hasn't been published. Long-term data specific to cagrilintide, beyond 84 weeks, don't exist yet.

Legal and regulatory status

What we still don’t know

• How cagrilintide alone performs over a full 68-week trial; the published monotherapy data stop at 26 weeks [2].
• Whether CagriSema reduces heart attacks, strokes or deaths, as semaglutide does.
• The full, peer-reviewed REDEFINE 4 data [8].
• What happens to weight after stopping the combination.
• Whether the FDA will approve it, and on what label.
• Whether the amylin component changes how much lean tissue is lost compared with semaglutide alone, a question none of the published abstracts address.

Educational content only — not medical advice. Many peptides discussed on HPR are not approved for human use. Talk to a qualified clinician before making any decision about your health.

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