After I Tried Retatrutide, I’m Not Sure These Are “Weight Loss Drugs” Anymore

If you’re confused about the growing landscape of weight loss drugs, here is a concise breakdown of their mechanisms, differences, and what you need to know

Everyone’s talking about how these drugs make you eat less. But I’m starting to think that’s the least interesting part.

And a recent experience microdosing the latest evolution has me rethinking what these “weight loss drugs” are actually doing in our bodies…

But let’s back up.

Like them or hate them, GLP-1 receptor agonists are undeniably the revolution in weight loss treatment of this generation. They cause weight loss at a scale hitherto unknown in the modern medical era.

And new generations are emerging like iPhones. First came GLP-1 receptor agonists, then dual agonists targeting two hormonal axes, and now GLP-3s like retatrutide. (I wonder what the GLP-17-Pro will look like.)

What I find particularly interesting are the differences in their effects and underlying biology.

Today’s letter will clarify those differences based on the data and mechanisms. I’ll give you my perspective, make connections I’m certain nobody else has made, and I’ll even share a microdosing experiment I’m running—and what I’ve experienced myself.

First generation: GLP-1 Receptor Agonist

First, let’s discuss each of these medications in turn. GLP-1 receptor agonists include semaglutide (trade names: Ozempic, Wegovy, Rybelsus).

They act on the GLP-1 receptor, which is expressed in the brain—especially in centers that regulate appetite—as well as peripherally, like in the gastrointestinal tract and heart.

Their primary effect is to reduce hunger drive by:

• Enhancing satiety signaling

• Slowing gastric emptying

• Dampening reward-driven food intake via dopamine pathways.

These primary actions follow directly from the distribution of GLP-1 receptors in out bodies.

GLP-1 Receptor Distribution:

• **Brain: Hypothalamus, brainstem (appetite, satiety, nausea signaling)

• GI tract: Slows gastric emptying

• Heart: Cardioprotective signaling (modest direct effects; more below)

• Peripheral nerves: Gut–brain axis signaling

These effects come with trade-offs.

The most common side effects are gastrointestinal—nausea, vomiting, diarrhea, constipation, and a sense of early fullness—largely due to delayed gastric emptying and central appetite suppression.

These effects can be quite profound and unpleasant, especially when lifestyle isn’t properly modified, leading to over 50% of patients prescribed GLP-1s for obesity discontinuing the drug within 12 months.

There is also an increased risk of gallstones, likely related to rapid weight loss and altered bile dynamics. Rare but more serious concerns include pancreatitis and potential worsening of gastroparesis. There is also legitimate concern for lean mass loss if protein intake and resistance training aren’t maintained. (More below.)

Second generation: GLP-1 + GIP Receptor Agonist

Next are the dual agonists, primarily tirzepatide (trade names: Mounjaro, Zepbound).

What makes tirzepatide fundamentally different is that it doesn’t just act on GLP-1—it also targets GIP, a second incretin hormone with distinct effects.

The addition of GIP seems to further improves insulin sensitivity and may directly influence adipose (fat) tissue metabolism.

GIP Receptor Distribution:

• **Adipose tissue: Adipocyte metabolism, nutrient partitioning

• Brain: Modulates energy balance

• Bone: May positively influence bone metabolism

Clinically, this translates into greater weight loss than GLP-1 alone—often approaching or exceeding 20% of body weight in trials.

But the mechanism isn’t just “more appetite suppression.”

There’s evidence that GIP signaling may help shift how nutrients are partitioned, potentially favoring fat energy utilization during the fasted state, and possibly mitigating some of the lean mass loss seen with GLP-1 monotherapy.

In effect, this dual GLP-1 + GIP agonist can improve fat cell metabolic flexibility.

That said, the side effect profile overlaps significantly with GLP-1 agonists—GI symptoms like nausea, vomiting, and diarrhea are still common, especially during dose escalation. However, some patients report better tolerability at equivalent weight loss levels, possibly due to the balancing effects of GIP.

In short, tirzepatide isn’t just a stronger GLP-1—it’s a more complex hormonal signal altogether.

But it gets even more complex…

Third generation: GLP-1 +GIP + Glucagon Receptor Agonist

Now we arrive at the triple agonists—what some are calling “GLP-3”—led by retatrutide.

Retatrutide targets three receptors simultaneously: GLP-1, GIP, and glucagon.

This creates a fundamentally different metabolic state.

And here’s where it gets really interesting—and where most people misunderstand what these drugs are actually doing metabolically. Because once you see how these three signals interact, it completely changes how you think about fat loss, energy expenditure, and even muscle preservation.

In the rest of this letter for StayCurious Metabolism premium members, I’ll break down:

• The unique metabolic state created by retatrutide—including a novel connection I don’t think anyone else has made.

  • I’ll explain who might see the most lean mass preservation on retatritide, and why.

• I’ll tell you about my own early experience microdosing reta, and the result I totally did not expect.

• Then we’ll close with rapid-fire answers to the most important questions around GLP-1s—covering brain health, heart health, joint health, and more.

If you’re someone who takes your health seriously and wants to understand the deeper nuances of metabolism, this is for you! Join a community of genuinely curious people who are thinking about these topics at a deeper level.