The Maximum Effective Dose of Retatrutide

Happy Friday!

Two weeks ago, I wrote an email about the newest study released on Retatrutide that included DEXA scan results.

Today, I released a YouTube video where I break the study down in even more depth.

In the process of preparing the video, I noticed something very interesting about the dosing and outcomes of retatrutide.

When it comes to dosing, more didn’t always turn out to be better.

We live in a “more is better” culture.

If 2 mg works, then surely 12 mg is the holy grail, right?

But in the world of biology, metabolism, and receptor signaling…It’s rarely that simple.

That’s why I’m such a big fan of microdosing and using the minimum effective dose (the exact amount your body needs to create your desired effect without extra baggage like side effects, adaptation, or wasted product).

And in the newest Lancet study on retatrutide, 8 mg actually outperformed 12 mg for total fat mass reduction.

Not by much, but enough to make us rethink the idea that higher dosing is always better.

Let’s unpack why this matters.

Minimum Effective Dose Thinking

In the performance and longevity world, the smartest people I know share one principle.

Do the least to get the most.

Why?

Because in biological systems, higher doses alter the effects.

They hit different receptor sensitivities, stress pathways differently, and sometimes engage compensatory mechanisms that blunt results.

In this study, retatrutide at 8 mg/week gave the best ratio of fat loss to muscle preservation.

At 12 mg/week, fat loss actually dipped slightly.

The extra 4 mg didn’t give an edge, and might have triggered subtle adaptations that reduced net benefit.

The body is a dynamic, adaptive machine.

Push too hard, and you’ll often get diminishing returns.

And that’s the beauty of the minimum effective dose.

You get the results you want, you spend less, you avoid over-suppressing appetite or slowing metabolism, and you keep the tool working for the long term.

The 8 mg Sweet Spot

The study compared multiple doses (0.5 mg, 4 mg, 8 mg, and 12 mg) against placebo and dulaglutide.

They measured total body weight and body composition using DEXA scans.

That means they saw exactly how much fat and muscle was lost.

Here’s the jaw-dropper:

• 8 mg/week → 26.1% total fat mass reduction

• 12 mg/week → 23.2% total fat mass reduction

That’s right.

The lower dose beat the higher dose for fat mass loss, while lean mass loss was exactly the same for both groups (about 6.4–6.5 kg).

From a physique and longevity standpoint, this means we got the same muscle preservation, with more fat lost.

Even more interesting, visceral fat (the “toxic” fat around your organs) dropped by 29.4% at 8 mg and 31.4% at 12 mg.

That’s only a 2% edge for the higher dose, which is negligible compared to the extra cost and potential adaptation.

Visceral Fat Reduction

We talk a lot about scale weight, but visceral fat is the killer.

It drives inflammation, wrecks insulin sensitivity, and ages your arteries from the inside out.

In this study, even the smallest dose (0.5 mg) shaved off 3.6% visceral fat, while 4 mg knocked off nearly 20%.

But the 8 mg dose?

Almost 30% gone in 36 weeks, WITHOUT changing diet or exercise.

Now imagine stacking that with strength training, a clean diet, and peptides that protect muscle.

That’s why I get more excited about visceral fat loss than just total pounds lost.

You can lose 20 pounds and still be metabolically sick.

But when visceral fat melts, everything from your liver enzymes to your cardiovascular risk profile starts moving in the right direction.

Lean Mass Preservation

One of the biggest criticisms of GLP-1 therapies (and now triple agonists like retatrutide) is muscle loss.

Critics love to say, “Sure, you’re losing weight, but you’re losing muscle too!”

The truth?

Some muscle loss is inevitable in a caloric deficit.

But what matters is proportion.

In this study, retatrutide’s fat-to-muscle loss ratio was right in line with other therapies… while producing more total fat loss.

Both the 8 mg and 12 mg groups lost about 6.5 kg of lean mass, but here’s the difference:

• 8 mg produced more fat loss for the same muscle loss.

• That means your “return on investment” for each pound of muscle lost was higher.

And remember, this was in type 2 diabetics, not exercising or eating differently.

In a dialed-in fitness context, you can protect far more lean mass, making the fat-to-muscle loss ratio even better.

Why More Isn’t Always Better With Retatrutide

So why did 12 mg underperform 8 mg for fat loss?

We can’t say for certain, but here are my theories:

1. Receptor saturation — At a certain dose, GLP-1, GIP, and glucagon receptors may already be maximally stimulated. Extra drug = no extra benefit.

2. Adaptive signaling — Higher doses may trigger counter-regulatory hormones that blunt fat loss.

3. Side effects & adherence — More nausea, fatigue, or appetite suppression at higher doses can paradoxically lead to lower nutrient intake, muscle breakdown, or inconsistent use.

4. Individual variability — 8 mg might simply hit the “sweet spot” for the average metabolic profile in this study group.

Whatever the reason, the takeaway is clear: chasing the highest dose can be counterproductive.

Microdosing Philosophy

If you’ve followed me for a while, you know I’m a broken record on this.

Start low, go slow, find your minimum effective dose.

In the real world, I’ve seen people achieve phenomenal results on as little as 2–4 mg/week, especially when stacking with other metabolic agents, mitochondrial peptides, or resistance training.

The benefits of microdosing retatrutide:

• Lower cost per month

• Fewer side effects

• Less receptor desensitization

• Easier to cycle on/off without rebound

And as this study shows, even sub-maximal dosing can deliver better-than-expected results, sometimes outperforming the “max dose” altogether.

Putting It Into Practice

If you’re considering retatrutide, here’s my ideal approach based on this and other data:

1. Start low — 2mg/week broken up into EOD injections, titrate up over 4–6 weeks.

2. Assess response — Look at both weight and body composition if possible.

3. Find your sweet spot — Many land in the 4-8 mg range for maximum fat loss with minimal downside.

4. Stack wisely — Pair with resistance training, protein adequacy, and peptides that preserve or grow muscle.

5. Cycle strategically — Give your receptors a break to maintain long-term sensitivity.

Final Thoughts

The Lancet data stands as proof that more is not always better.

For many, 8 mg/week may be the maximum effective dose of retatrutide.

It’s cheaper, safer, and may deliver better results than maxing out.

Best,

Hunter Williams