I Answered Retatrutide's Biggest Unanswered Questions

Retatrutide could become the biggest drug in history. But there are some strange rumors. So, I tried it. Here's why and what happened.

There’s a new weight loss drug that people think could become the biggest drug in history.

It’s called retatrutide.

We’ve discussed it before.

Briefly, in the published trials people are losing a quarter of their body weight, like a snake shedding its skin, or like they just flew through a 20 second body recomposition movie montage.

The power of this compound is insane, outperforming all other weight loss drugs, by a wide margin.

It seems to be constantly in the news.

In fact, I'm releasing this letter a little earlier than planned because, just yesterday, a series of major headlines dropped reporting that pharmaceutical stocks surged after this next-generation weight-loss drug posted record-breaking results, with participants losing 28.3% of their body weight over 80 weeks.

(To be clear: I have no financial or other conflict of interest with Eli Lilly or any pharmaceutical company.)

So, I tried it.

Wait… Pause!

I know exactly what you’re thinking. Nick, you’re skinny as heck.

Why would you try a weight loss drug?

Are you crazy?

Well, probably a little. But that’s beside the point, and perhaps even why some of you like me.

Here’s why I felt compelled to try it:

In addition to being a highly credentialed professional guinea pig, I was hearing rumors about this specific drug that didn’t quite add up.

There were two main paradoxes bothering my brain:

• First, some people taking it and actually getting hungrier

• Second, people were claiming they were shedding body fat without losing muscle.

And frankly, that piqued my curiosity enough to feel a compulsion to dabble, not for my health but at the risk of my health—just to see what the hype was about.

I logged my personal experience: the good, bad, and ugly.

And I collected 127 biomarkers to see what was changing under the hood over the course of 4 weeks.

What happened to me was not what I expected.

But I can tell you this upfront: it’s not like any other weight loss drug on the market.

Why Reta Is Different?

Retatrutide—sometimes called “Reta,” or informally “GLP-3”—is the next evolution in a class of weight loss drugs known as GLP-1 receptor agonists.

The first generation—think the original iPhone—was drugs like Ozempic and Wegovy. These target the GLP-1 receptor, which, in simple terms, makes you less hungry.

There are other effects we’ll get into, but at a high level: GLP-1 = less hunger.

Then came the second generation, think the next iPhone upgrade. This was tirzepatide—or perhaps you’ve heard of Mounjaro and Zepbound. These hit two pathways: GLP-1, plus another hormone called GIP, which plays a role in how your body handles and partitions fuel.

So now you have: less hunger (GLP-1), plus improvements in how your body uses energy (GIP).

And then comes retatrutide, yet the next iPhone upgrade!

This adds a third mechanism: activation of the glucagon receptor. Which, at a high level, increases energy expenditure.

So now it’s not just that you’re eating less, you are also burning more.

And that’s part of why people report things like an elevated heart rate. In my case, my resting heart rate went from around 40 beats per minute to about 65. A pretty dramatic shift. I’ll talk about the biological relevance of this later.

So zooming out: retatrutide is hitting three different hormonal pathways—reducing appetite (GLP-1), altering how your body uses fuel (GIP), and increasing energy expenditure (glucagon).

And as a quick side bar, I use the iPhone analogy because I find it a bit funny how these compounds are being marketed. Reta is often called “GLP-3,” even though there is no such thing. But it’s clearly a play on the original GLP-1s.

This honestly makes me think, “what will GLP-17 Pro look like?” But that’s a story for later.

The Two Big Reta Paradoxes

Retatrutide Making Some People Hungier?

Now, you’d think—because this is a weight loss drug—it would make you less hungry.

And for many people, it does. It crushes appetite. But that’s not the whole story.

I kept hearing something strange. From friends, from scientists, and people I trust.

But they were reporting the opposite. They were getting hungrier. Which doesn’t make sense. They were still losing weight. But their initial response was increased appetite.

And that alone was enough to make me curious. Because as counterintuitive as it sounds… There actually is a mechanistic explanation for it. We’ll get to that.

But that wasn’t the only thing.

“Retatrutide Might be Muscle Sparing”

There was a second rumor floating around: that retatrutide could drive fat loss, without loss of muscle mass.

This was such a powerful article of common knowledge that even famous scientists (e.g. Andrew Huberman) were suggesting “retatrutide might be muscle sparing,” on TV.

This, if true, would be very different from earlier drugs in this class, where roughly 25 to 40% of the weight lost tends to come from lean mass.

But here’s the thing: The actual human data on retatrutide doesn’t really support that.

In the main body composition studies, especially at higher doses, around 38% of the weight lost is still lean mass.

So now you have two paradoxes:

1. People getting hungrier… while still losing weight.

2. And people seemingly preserving muscle… despite clinical data suggesting otherwise.

So, what’s actually happening here?

I thought these claims sounded exaggerated too… until I tried retatrutide myself and tracked 127 biomarkers.

I'm not overselling it to say that some of the results surprised me and revealed truths about retatrutide that nobody else has talked about.

So that's what we're going to get into…

In the rest of this letter, StayCurious Metabolism premium members, we will dive into:

• My Experiment

  • Personal experience

  • Biomarkers

• Resolving the Retatrutide Paradoxes

  • Why some people get hungrier while others lose their appetite

  • Why some preserve muscle while others lose it

• We will address the trillion-dollar question: Should you?

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