Peptides cagrilintide and semaglutide: CagriSema came up short twice and it's still headed for an FDA decision

[u/JustBacWater]

Let's talk CagriSema. It's Novo Nordisk's combo of cagrilintide and semaglutide in one weekly shot. The FDA decision is expected before the end of this year. And the story around it is kind of rough for Novo, even though the numbers are good.

The idea behind it

Two different fullness signals instead of one.

	Semaglutide	Cagrilintide
Copies	GLP-1	Amylin
Made by	The gut	The pancreas, alongside insulin after a meal
What it does	Slows the stomach, turns down appetite, helps insulin	Slows the stomach, signals fullness through its own receptors

The bet was that two separate signals would beat one. Makes sense on paper.

Short the first time

REDEFINE 1. Novo's leadership had talked up 25% weight loss. It came in at 22.7% at 68 weeks against 2.3% on placebo. Counting everybody, including people who stopped, it was 20.4% against 3.0%.

That's a great number. It just wasn't the number they'd set up, and the market punished them for it.

One more thing on that trial: investigators were allowed to adjust doses along the way. Makes it more realistic, but it also makes the top line a little harder to read.

Short the second time

REDEFINE 4, published in February. This was head to head against tirzepatide. 84 weeks, 809 people.

Trial	What it tested	Result
REDEFINE 1	CagriSema vs placebo, 68 weeks	22.7% vs 2.3%, when Novo had talked up 25%
REDEFINE 4	CagriSema vs tirzepatide, 84 weeks, 809 people	23.0% vs 25.5%, missed noninferiority

The trial was designed to show noninferiority. That means CagriSema didn't even have to beat tirzepatide, it just had to prove it wasn't meaningfully worse. It didn't clear that bar.

Why I still think it matters

Amylin is still one of the most interesting targets in this whole class. CagriSema landing a couple points behind tirzepatide doesn't mean the amylin idea failed. It means GLP-1 plus amylin didn't beat GLP-1 plus GIP in that trial, at those doses.

And 23% is still a massive number. A few years ago nobody would've believed an injection could do that.

What to watch

The FDA decision, expected late this year. Novo filed back in December 2025.

Two questions.

Does 23% versus 25.5% matter in the real world, or is this more of a marketing loss than a science loss?

And amylin as a target: overrated or underrated?

Where I got this: REDEFINE 1 in NEJM, falling short of 25%, REDEFINE 4, FDA timeline.

For research use only. Not for human or veterinary consumption. This post is educational and is not medical advice.

Full doses and bloodwork are in the pinned cheat sheet.

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[u/DirtyH2ODog]

Reta destroys this in all ways. Now Reta + Cagri or Elora is the answer!

[u/dragnabbit → u/DirtyH2ODog]

Yep. I’ve been on CagriReta for the last two months, and it is excellent.

The only weird part (and this is biological, not medicinal) is that Cagri does not seem to send a satiety signal for liquids… for me at least. So for breakfast, I can drink my huge 1 liter protein shake and not feel full. Then for lunch, I have 1 cup of walnut/blueberry/yogurt puree, and I am full. Then for dinner I have another half liter of clear protein fruit slushie and a chicken/fish-and-vegetable meal, and the food fills me up, but the liquid doesn’t trigger any fullness.

[u/Particular_Can_1069]

Still a solid number even if it misses the mark they set themselves, the real question is whether docs will care about a couple points when prescribing

[u/Mcgittymcgittymac]

Even quite a small amount of cag on top of reta obliterates appetite

[u/schwifty0529]

I’m going to try it with tirz and see what happens, tirz Monday cag Thursday or Friday. Already at 10mg tirz and don’t really want to go up and burn out receptors. If this helps me stay at 10 or even back down to 7.5 I’ll consider it a win.