Retatrutide and crazy fast weight loss made all the headlines this week. And as a 25 year practitioner, I’m scared we’ve lost the plot. I fully understand the desire to optimize weight health and to be at your “finish line” as fast as possible. But the body doesn’t like to be super stressed or suboptimally nourished and the data (not headlines) is showing us a lot of its concerns.
So that’s why I want you to meet Amylin. In writing my book two years ago and even around the release this January, I debated sharing about this weight-health hormone. I decided against it because it felt like just explaining what GLP-1, GIP, PYY, and CCK do and how versions of them were now available as hormone replacement therapies was plenty for practitioners, patients and the media.
But this week I got asked about some new data by the media. It’s for an Amylin agonist. And it told me it’s time.
INFObesity warning: if you are overwhelmed by the last two paragraphs and the alphabet soup of weight-health hormones already, save this one for a future date.
We make Amylin in our body. It’s a peptide hormone. And now it’s a weight-health hormone replacement therapy being studied — and noticed — because it’s got a different way of working, and one that may make a lot of sense for many patient types.
Those are the basics, proceed if you want to geek out with me or are worried about too fast, too much including digestive intolerances.
The Current Situation, A New Consideration
As we increase the amount of hormones medications can agonist to 3 with retatrutide, a new-to-most hormone is getting deserved attention and its own agonist medication.
Sustained fat loss especially with a GLP1 could happen by using a tool that produces slower fat loss but with much, much less digestively upset. Thats the Amylin story.
Before you file this under one more thing to feel behind on, let me introduce you to and explain Amylin. Its story is distinct because it isn’t “new drug, more weight loss.” This one pulls a completely different lever. That matters.
First, reminder of the reframe: these are not weight-loss hormones, or drugs.
I felt I needed to say it once and now we can move on, because regular readers here know I don’t do weight loss.
Out shared goal is weight health, it requires optimal functioning of your weight-health hormones for fat loss, bone and muscle building, blood sugar, blood pressure and inflammation optimizations. GLP-1, GIP, PYY, CCK and now Amylin are these hormones.
They importantly help govern when you’re hungry, when you’re full, how fast food leaves your stomach, how your blood sugar behaves after a meal. They are weight-health hormones. Drugs that act on them aren’t weight-loss drugs that happen to affect health — they’re hormone replacement tools that can be part of a plan to optimize weight health.
Keep that lens on. It’s the whole game.
The two you know best: GLP-1 and GIP (the incretins)
GLP-1 and GIP are “incretins” meaning they are gut hormones. The word just means “gut-derived signals that tell your pancreas a meal is coming.”
GLP-1 comes from L-cells in your intestine. When you eat, it tells the pancreas to release insulin (but only when glucose is actually high — that’s the glucose-dependent safety feature), eases off glucagon, slows gastric emptying, and travels to the brain to say you’re full now.
GIP comes from K-cells, slightly higher up. It also boosts glucose-dependent insulin, and its role in appetite is messier and more context-dependent. For those of you who followed the bone series: GIP directly impacts bone-building with receptors on osteoblasts. The two incretins are not interchangeable. Hold that thought, I will come back to it in a minute.
The single-mechanism drug you know, semaglutide, pulls the GLP-1 lever. Dual-agonists like tirzepatide pull GLP-1 and GIP. Retatrutide, the new triple-agonist goes one further, pulling 3 levers: GLP-1, GIP and glucagon. For most, the story goes - better blood sugar with all, the more levers, faster and more weight loss, with additional benefits including liver fat and inflammation.
So far, familiar. Now the new one.
The NEW one: Amylin
Amylin is not an incretin. It doesn’t come from your gut. It comes from the same pancreatic beta cells that make insulin and it’s co-released with insulin, in a roughly fixed ratio, every time you eat.
Picture insulin and amylin as a two-person crew that clocks in together. Insulin handles the glucose. Amylin handles the messaging as it crosses into the brain and lands in the brainstem (the area postrema, if you want to impress someone). Its headline job is satiety: telling you the meal is over. It also suppresses inappropriate glucagon (release of sugar into the bloodstream) and, yes, contributes too to delay gastric emptying; that last one is a supporting player for amylin, not its lead.
That’s a distinction worth focusing on. Slowing the stomach is GLP-1’s signature, front-and-center move. GLP-1 is wired close to the gut plumbing and slows emptying largely as a local gut-brain reflex. Amylin reaches the same effect from the opposite direction: from the brainstem out. Same endpoint, but a different control point. So when you hear “they both slow gastric emptying,” that’s technically true but it’s GLP-1 as the lead actor and amylin’s a bit part.
Amylin’s real signature is something GLP-1 doesn’t do the same way at all.
The distinction is the entire reason Amylin could be the breakout star of the weight-health hormone story in 2026.
Where amylin actually works matters for weight health, including your bones.
🚨 The Big Ah-Ha Moment 🚨 Amylin’s receptor is a composite — a calcitonin receptor that pairs with a helper protein (a RAMP) to form the amylin receptors AMY1, 2, and 3. Confirmed locations include the area postrema, the brainstem and …the brain’s dopamine reward hubs!
That last bit is the signature lever, the thing GLP-1 doesn’t pull the same way. Amylin receptors sit on the dopamine neurons of the reward system, and activating them turns down the dopamine “hit” that palatable fat and sugar deliver. Read that carefully, because the precise version is more interesting than the loose one: amylin doesn’t just make you feel full sooner, it reduces the reward of the rewarding foods. It acts on wanting, not only on fullness. The cookie stops calling your name.
So there are really two things happening at once. You fill up sooner (ordinary satiation), and the hedonic foods lose some of their grip (reduced food reward).
This should terrify the ultra-processed food product industry who’s banked billions on designs that override it.
Dampening the drive for fat and sugar specifically is Amylin’s novel lever.
The satiation signal itself, meanwhile, runs heavily through noradrenaline in the brainstem; roughly half the amylin-activated neurons there are “noradrenergic” knock them out and the appetite effect disappears.
So Amylin’s unique roles and story are brain and neurotransmitter ones, not gut ones.
Research caveat and considerations: most of the dopamine-reward data is preclinical (rodent VTA studies), so treat it as well-supported mechanism, not proven-in-humans outcome.
A point worth making out loud, because it’s the same lesson we learned with GLP-1: we almost certainly haven’t found all the places Amylin receptors live. Remember, we didn’t know GLP-1 receptors were sitting in your blood-vessel lining and on your tongue until relatively recently. With amylin, the literature openly admits the map is partial — the receptor’s components have barely been studied for co-expression in the periphery since they were first described in 1998. So when someone tells you they know exactly what an amylin drug does and doesn’t touch, hold the receipt. We’re early.
Moving on. What we are learning in real-time about Amylin is occurring and exclusive to the impact of its agonist. Like other agonists it works by giving the body exponentially more for a longer time - a supraphysiologic dose. Let’s look at the considerations for the Amylin agonists based on the new data we have now.
Consideration #1: less nausea and vomiting (but read the fine print)
This is the impressive, headline worthy data. A weight-health agonist with significantly less nausea and vomiting.
My instinct was: amylin is pancreas-made and GLP-1 is gut-made, so maybe amylin is gentler on the gut. Elegant. Also probably wrong — because once you inject either one, you’ve delivered it to receptors directly and are not dealing with origin organ impact.
Looking at the Amylin agonist alone and with Semaglutide (GLP-1) we get a more full picture of considerations.
• Cagrilintide (targeting Amylin and calcitonin in the brain) alone produced about 11.8% weight loss — comparable to semaglutide, but with notably less nausea and roughly 62% less vomiting. That part of the gentleness story holds.
• Notably, cagrilintide has more injection-site reactions.
• And the combination — CagriSema — is not more gentle, it’s the same: about 80% had GI events (nausea 55%, constipation 31%, vomiting 26%), the combo’s GI profile looked similar to semaglutide alone, not worse.
Remember with all GLP-1 agonists: the real driver of tolerability isn’t origin — it’s dose escalation, pre-existing digestive health and total nutrition. In the trials, the GI events clustered during titration. Ramp slower, likely tolerate better. That’s the actionable truth, and it’s the same truth for every drug in this class.
Consideration #2: what benefits and harms bones
Last month I made and rested my case for if your bone health is suboptimal it’s a weight health issue and a weight-health hormone function signal. Amylin helps us understand that more clearly.
Amylin is a member of the calcitonin family of hormones. Same structural family as calcitonin — the hormone we’ve used for decades to treat bone loss. And amylin is bone-active in the good direction:
• It inhibits osteoclasts — the cells that break bone down.
• It promotes osteoblasts — the cells that build bone up. Dripped over bone in animal models, it drove two- to four-fold increases in bone-building activity.
• And it does this through two separate receptors — one on the osteoclast, one on the osteoblast. Brakes demolition, funds construction. That’s important at every life stage, but especially as aging can promote bone loss.
The connundrum of the The GLP-1 medication era: bone loss while getting higher, sustained amounts of hormones that promote bone-building and prevent bone breakdown. rapid weight loss strips bone, and pure GLP-1 monotherapy doesn’t bring a building signal to the table. We know bone loss on these medications is the result of rapid weight loss, suboptimal nutrition, and digestive challenges. But it should look different for someone on a GLP-1 only medication versus ones with GIP … and now Amylin. Because these hormones help osteoblasts do their jobs.
So a joint Amylin-Semaglutide should have similar bone health wins to a GIP-GLP1 (Tirzepatide) one.
Consideration #3: delaying gastric emptying
Nothing that modifies body function is all “win”
Every one of these hormones slows gastric emptying and suppresses appetite. That’s the point. But here’s the arithmetic: the better the drug works, the less you eat — and the less you eat, the harder it is to hit your actual nutritional needs.
I’ve said this since before it was fashionable: nutritional deficits don’t start when you fill the prescription. They’re usually already there. The medication just turns down the appetite that was masking them.
Now stack a second satiety mechanism on top. Amylin slows your stomach and GLP-1 slows your stomach. You feel full faster, longer, harder. Maybe a win on the scale. A real problem if “full” means you ate 600 calories of nothing and walked away from your protein, your minerals, your hydration — and yes, the very calcium-and-cofactor picture that decides whether amylin’s bone-building potential ever gets the raw materials to do its job.
Two levers on satiety means two levers pushing intake down. The drug got more sophisticated. Your nutrition strategy has to get more sophisticated to match it — or the weight comes off while the health quietly leaves the building.
That’s not a reason to avoid these tools. It’s the reason to use them with a plan. Repair and optimize, then layer the intervention on top. Better, not perfect.
Know someone this could help? Please 👇🏽
The Summary
GLP-1: gut hormone, the one you know — single lever on satiety and blood sugar, and it’s on your tongue.
GIP: the other gut hormone — messier role in weight, the incretin that talks to your bones.
Amylin: not a gut hormone — insulin’s beta-cell partner, hits satiety through its own door, quiets the reward of fat and sugar (acts on wanting, not just fullness), and — quietly — builds bone.
CagriSema: amylin + GLP-1, two independent doors, synergy not addition, FDA pending.
And underneath all of it: these are weight-health hormones. These medications are a weight-health hormone replacement tool. Whether it builds health — including the skeleton you’re going to need for the next forty years — depends entirely on what you do with your nutrition and behavior between doses.
And that’s a wrap on Amylin
Ashley Koff RD
Your “backwards DR”
If you’re a practitioner optimizing patients on these medications, check out my certification and the community where we collaborate to optimize care.
If you’re on one yourself — or not a wanting weight health outcomes — consider a total nutrition plan that keeps up with the pharmacology, fat loss, bone, muscle health and all — that’s exactly what I do.
Grab a free 15-minute chat to discuss what it includes, how it helps you achieve lasting weight health, and is different than what else you’ve tried.
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