Metabolic · 9 min read · Published September 8, 2026

Cagrilintide: The Amylin Half of CagriSema, and Why People Search 'Cagrilintide with Retatrutide'

What amylin does, what cagrilintide showed on its own in its 2021 Lancet trial, what REDEFINE 1, 2 and 4 showed for CagriSema, where the December 2025 FDA filing stands, how eloralintide, petrelintide and AZD6234 compare, and why the 'cagrilintide plus retatrutide' stack has no trial behind it.

What is cagrilintide?

Cagrilintide is a long-acting synthetic analogue of amylin, a hormone the pancreas releases with insulin. It is investigational: no regulator has approved it. Its only late-stage use is inside CagriSema, a fixed combination with semaglutide 2.4 mg that Novo Nordisk filed with the FDA on December 18, 2025 after the 68-week REDEFINE 1 and REDEFINE 2 trials.

Most of the weight-loss drugs people know are incretin mimetics, built on GLP-1 and GIP. Cagrilintide is the first of a different family to reach a regulator: it copies amylin, the hormone that pancreatic beta cells co-secrete with insulin after a meal. Amylin acts on receptors made of the calcitonin receptor paired with one of three RAMP proteins, concentrated in the hindbrain's area postrema and nucleus of the solitary tract and in the hypothalamus. Through those sites it ends meals earlier, slows gastric emptying and suppresses glucagon (Diabetes Therapy review, 2025). Pramlintide, the short-acting amylin analogue approved for insulin-treated diabetes, proved the mechanism but needed injections with every meal. Cagrilintide's fatty-acid chain lets it last a week. Profiles: cagrilintide, CagriSema.

What did cagrilintide do on its own?

In its 26-week Phase 2 dose-finding trial (Lancet, 2021; 706 participants with overweight or obesity across 57 sites), weekly cagrilintide 0.3 to 4.5 mg produced 6.0 to 10.8 percent weight loss versus 3.0 percent on placebo. The 4.5 mg arm beat liraglutide 3.0 mg (10.8 versus 9.0 percent). Four percent stopped for adverse events.

Gastrointestinal events occurred in 41 to 63 percent of cagrilintide participants versus 32 percent on placebo (Lancet, 2021). Evidence tier: human RCT, Phase 2. That result, a GLP-1-sized effect from a non-GLP-1 mechanism, is the whole reason for CagriSema: two different pathways that might add up. Novo Nordisk never took cagrilintide alone into Phase 3 for obesity, so the monotherapy data stop at 26 weeks.

What did the REDEFINE trials show for CagriSema?

REDEFINE 1 (n=3,417, no diabetes, 68 weeks): 20.4 percent weight loss versus 3.0 percent for placebo on the treatment-policy estimand, 22.7 percent if participants stayed on treatment. REDEFINE 2 (n=1,206, type 2 diabetes, 68 weeks): 13.7 versus 3.4 percent. REDEFINE 4 (n=809, 84 weeks, open-label): 23.0 percent versus 25.5 percent on tirzepatide 15 mg, missing non-inferiority.

The REDEFINE 1 number disappointed the market because Novo had guided toward 25 percent, but it remains the second-highest Phase 3 figure after retatrutide's 28.3 percent at 80 weeks in TRIUMPH-1 (NEJM, REDEFINE 1; NEJM, REDEFINE 2). REDEFINE 4 is the more important result for understanding amylin: adding cagrilintide to semaglutide did not match tirzepatide alone over 84 weeks (Novo Nordisk, February 2026). Novo's response is a higher-dose CagriSema (cagrilintide 2.4 mg with semaglutide 7.2 mg) entering Phase 3 in the second half of 2026.

Is CagriSema approved yet?

No. Novo Nordisk submitted the New Drug Application on December 18, 2025 for chronic weight management in adults with obesity or overweight with a comorbidity, and said it expected review during 2026. As of September 2026 no FDA decision has been announced. Cagrilintide by itself has not been filed anywhere.

The filing rests on REDEFINE 1 and 2 (Novo Nordisk, December 2025). A standard review would place a decision around late 2026. Until then, every vial labeled cagrilintide sold online is an unapproved product with no verified identity, purity or dose; see how to read a certificate of analysis for why that matters and the FDA's 2026 peptide status for the legal picture.

How do the other amylins compare?

Eloralintide (Lilly) leads: 9.5 to 20.1 percent at 48 weeks in a 263-person Phase 2 (Lancet, November 2025), now in Phase 3 alone and with tirzepatide. Petrelintide (Roche) reached 10.7 percent at 42 weeks in ZUPREME-1 (n=493, March 2026) with placebo-level discontinuations. AZD6234 (AstraZeneca) has Phase 3 trials registered from August 2026 but no published Phase 2 numbers.

The amylin pitch is tolerability as much as efficacy. In ZUPREME-1 vomiting was less common on petrelintide than on placebo (Roche, March 2026), and eloralintide's two lowest doses had adverse event rates similar to placebo, though nausea reached 64 percent at the highest doses (Lancet, 2025). AstraZeneca's Phase 3 listing (ClinicalTrials.gov NCT07784725) is the only public evidence of its Phase 2 outcome.

Why do people search 'cagrilintide with retatrutide'?

Because it sounds like CagriSema with a stronger partner: retatrutide reported 28.3 percent weight loss at 80 weeks in TRIUMPH-1 (n=2,339, May 2026). But no trial has combined the two. Cagrilintide belongs to Novo Nordisk and retatrutide to Eli Lilly, both are unapproved, and REDEFINE 4 showed amylin plus GLP-1 did not beat a strong incretin alone.

The logic behind the search is additive: if cagrilintide added about 5 points to semaglutide in REDEFINE 1, why not add it to the strongest triple agonist? Three problems. First, nobody has tested it. There are no safety data on combining an amylin with a glucagon-receptor agonist in humans, and glucagon agonism raises energy expenditure in ways that could interact with amylin's effects on glucose and gastric emptying. Second, the companies will not run that trial; Lilly is pairing its own amylin, eloralintide, with tirzepatide in Phase 3 instead. Third, the additive assumption already failed once: CagriSema, the best-tested amylin combination, lost to tirzepatide in REDEFINE 4. Whatever is sold online under both names is unverified material combined in a way no ethics committee has reviewed. For the incretin side of the comparison see retatrutide versus tirzepatide.

The bottom line

Cagrilintide proved that amylin can move weight on its own and became the first amylin to reach an FDA filing, inside CagriSema. The evidence is Phase 3 and large, the effect is real and second only to retatrutide among reported pivotal trials, and the head-to-head against tirzepatide showed the ceiling. The amylin class is now a race of four, with eloralintide's 48-week result the one to watch. Cagrilintide combined with retatrutide exists only as a search term.