What Reta Actually Does To Your Muscle (First DXA Data)

Retatrutide is losing more total weight than any drug tested so far, and that fact changes how you have to think about every percentage you hear attached to it.

Here is the system first, so the numbers make sense when we get there.

When you take a GLP-1 receptor agonist, the drug activates receptors in your gut and brain that slow gastric emptying, reduce appetite, and lower the amount of food your body thinks it needs. You eat less, your body runs a calorie deficit, and you lose weight. The problem is that the body does not lose weight cleanly. It pulls from both fat stores and lean tissue, meaning muscle, organ tissue, and the protein structures that make up your functional mass. The ratio of how much comes from fat versus lean tissue tells you the quality of the weight loss, not just the quantity.

Retatrutide adds two more receptor targets on top of GLP-1. It also activates the GIP receptor, which improves insulin sensitivity and may amplify the fat-burning signal, and the glucagon receptor, which is the part that generated the most excitement before any scan data existed.

The glucagon receptor theory went like this. Glucagon is a hormone your body releases during fasting and exercise, and it signals the liver to release stored energy and shifts fuel burning toward fat oxidation. The logic was that a drug with a glucagon component would essentially tell your body to preferentially burn fat for fuel, which would protect lean tissue during the deficit. That theory was reasonable, and it was based on real biology.

The Lancet just published the first DXA data to test whether that theory holds in actual human tissue.

DXA, which stands for dual-energy X-ray absorptiometry, is the standard for measuring how much of your body is fat versus lean mass. It is more accurate than body weight alone because weight does not tell you what you are actually losing. The substudy scanned 103 people with type 2 diabetes at baseline and again at 36 weeks, and the results give us the clearest picture we have had of what retatrutide is actually doing to body composition.

At the 12 milligram dose, total fat mass dropped by 23.2 percent and visceral fat, which is the fat that sits around your internal organs and drives metabolic disease, dropped by 31.4 percent. Those are large reductions, and the visceral number in particular is clinically meaningful because visceral fat is more metabolically active and more dangerous than subcutaneous fat.

The split was roughly 75 to 80 percent of total weight lost coming from fat, and 20 to 25 percent coming from lean mass.

Now here is where most of the conversation stops, and where it should actually start.

That ratio compares favorably to the other drugs on the market. Tirzepatide, which targets GLP-1 and GIP, sits at approximately 75 percent fat to 25 percent lean, a nearly identical split. Semaglutide, which only targets GLP-1, performs worse at roughly 60 percent fat and 40 percent lean. So by the ratio, retatrutide looks like the best or at least tied for the best drug in this class.

But ratios are not the whole picture. Absolute numbers are.

In the phase 2 trial published in the New England Journal of Medicine in 2023, people on the 12 milligram dose lost an average of 24.2 percent of their body weight at 48 weeks. For someone starting at 100 kilograms, that is roughly 24 kilograms gone. Apply the 20 to 25 percent lean mass figure to that number and you are looking at somewhere between 4.8 and 6 kilograms of lean tissue lost. That is over 13 pounds of muscle and functional tissue gone in under a year.

The percentage looks acceptable. The absolute number is significant in a way the percentage hides.

This is the structural problem with being the most effective weight loss drug ever tested. When you move more total weight, even a respectable ratio produces a large absolute loss. A drug that loses 10 kilograms with a 25 percent lean loss costs you 2.5 kilograms of lean tissue. A drug that loses 24 kilograms with the same ratio costs you 6 kilograms. The efficiency looks the same. The outcome is not.

And this matters because lean mass is not just cosmetic. Muscle tissue is directly connected to insulin sensitivity, to glucose disposal, to metabolic rate, and to long term physical function. Losing 6 kilograms of lean tissue while treating type 2 diabetes is trading one metabolic liability for another.

Now back to the glucagon receptor theory, because the scan data gives a direct answer.

The glucagon receptor is known to upregulate something called hepatic amino acid catabolism, which is the liver breaking down amino acids for energy. Research from Sherwood and colleagues in 2022 showed that glucagon receptor activation increases this process, coupled to a rise in energy expenditure. So glucagon does increase calorie burn, but part of the mechanism it uses involves pulling amino acids, the building blocks of muscle, into the energy system. This means the glucagon signal may actually work against lean mass preservation at the same time it is working for fat oxidation. The two effects are not separate. They are happening in the same tissue, through related pathways.

The scan data reflects exactly that. Despite the glucagon component, the lean mass loss ratio on retatrutide is no better than tirzepatide, which does not have a glucagon receptor at all. The theory that glucagon would spare muscle did not survive contact with actual DXA measurements in actual humans.

What this means practically is straightforward. The drug will not protect your lean mass because no drug in this class currently does that job on its own. Resistance training at a frequency of three to five sessions per week provides the mechanical signal your muscle needs to be retained during a calorie deficit, and protein intake at a meaningful level gives your body the amino acids it needs to maintain tissue rather than catabolize it. One gram of protein per pound of goal body weight is the working target most practitioners use in this context.

The drug handles the appetite suppression, the fat oxidation, and the metabolic improvements. The muscle retention signal has to come from somewhere else, and that signal is not built into the receptor pharmacology.

Retatrutide is not failing. It is doing what it is designed to do, and it is doing it better than any other drug in the class. But the weight loss it produces is large enough that the parts it cannot do for you matter more with this drug than they would with a less effective one.

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References

1. Retatrutide Body Composition Substudy, 2025, The Lancet Diabetes & Endocrinology, Vol 13(8), 674-684. Phase 2, 42 centers, 103 DXA-completed participants with T2D. Fat mass reduction: 23.2% at 12mg. Lean mass: 20-25% of total weight lost. Visceral fat: -31.4% at 12mg.
2. SURMOUNT-1 Body Composition Substudy (Tirzepatide), 2025, Lancet Diabetes Endocrinol. PMC11965027. ~75% fat / 25% lean mass ratio.
3. STEP 1 Body Composition Substudy (Semaglutide), PMC8089287. ~60% fat / 40% lean mass ratio.
4. Jastreboff et al., 2023, NEJM. Retatrutide phase 2 trial (N=338): 24.2% weight loss at 48 weeks (12mg). DOI: 10.1056/NEJMoa2301972.
5. Sherwood et al., 2022, Cell Reports Medicine. GCGR activation upregulates hepatic amino acid catabolism, coupled to energy expenditure increase. PMC9729826.

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