New drug combination shows massive fat loss and muscle gain without steroids - "The End Of Steroids?

#1

Clarification: My excitement isn’t necessarily just about this one study, or these particular compounds. It’s the fact that there are massive incentives for pharmaceutical companies to come up with new solutions in the area of muscle maintenance, muscle gain and strength gain. This will have massive implications on society as a whole helping people who otherwise just don’t have the motivation to improve their body composition.

Original post:
Ok this is actually crazy.

The muscle loss side effects of GLP1 agonists come from poor doctor guidance and patient compliance with altering protein % of macronutrients and performing resistance training to make up for the lower calorie consumption that comes with GLP1 agonist use.

The bright side of this: Due to muscle loss side effects from GLP1 agonists pharma companies have been working on a brand new range of muscle building drugs.

2 new drugs are being tested in combination with semaglutide:
1. Trevogrumab - Myostatin inhibitor
2. Garetosmab - Activin-A inhibitor

4 different groups:
Group 1: Monkeys without semaglutide and on a diet lost 400g body fat and lost 15g muscle.
Group 2: Monkeys with semaglutide lost about 700g body fat but lost about 100g of muscle.
Group 3: Monkeys with semaglutide and trevogrumab lost about 1300g of body fat and lost about 15g of muscle.
Group 4: Monkeys with semaglutide, trevogrumab and garetosmab lost about 1400g of body fat but gained 450g of muscle!

Unknown side effects aside I think this is very impressive.

My main concern with anything that can increase muscle is increasing the size of the heart.

There is evidence that GLP1 agonists prevent heart hypertrophy however:

Evidence that tirzepatide protects against diabetes-related cardiac damages: “Our findings indicate that TZT has beneficial effects on cardiac cells by positively modulating cardiomyocyte death, fibrosis, and hypertrophy in the presence of high glucose concentrations. This suggests that TZT may reduce the risk of diabetes-related cardiac damage, highlighting its potential as a therapeutic option for heart failure management clinical trials. Our study strongly supports the rationale behind the clinical trials currently underway, the results of which will be further investigated to gain insights into the cardiovascular safety and efficacy of TZT.”

Tirzepatide Reduces LV Mass and Paracardiac Adipose Tissue in Obesity-Related Heart Failure: SUMMIT CMR Substudy: “The CMR substudy of the SUMMIT trial demonstrated that tirzepatide therapy in obesity-related HFpEF led to reduced LV mass and paracardiac adipose tissue as compared with placebo, and the change in LV mass paralleled weight loss. These physiologic changes may contribute to the reduction in heart failure events seen in the main SUMMIT trial. (A Study of Tirzepatide [LY3298176] in Participants With Heart Failure With Preserved Ejection Fraction [HFpEF] and Obesity: The SUMMIT Trial”

Tirzepatide attenuates lipopolysaccharide-induced left ventricular remodeling and dysfunction by inhibiting the TLR4/NF-kB/NLRP3 pathway: “In brief, tirzepatide attenuates LPS-induced left ventricular remodeling and dysfunction by inhibiting the TLR4/NF-kB/NLRP3 pathway.”

Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial: “Tirzepatide reduced cardiac injury, reflected by decreases in troponin T, and reduced wall stress, reflected by decreases in NT-proBNP”

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#2

Interim phase 2 results in humans:

https://newsroom.regeneron.com/news-releases/news-release-details/interim-results-ongoing-phase-2-courage-trial-confirm-potential

Note the following:

“triplet combination of semaglutide with both antibodies had a substantially higher rate of discontinuations due to tolerability issues and other adverse events”

28% of the triplet group dropped out of the study due to side effects

Also this: “Two deaths occurred in the triplet group, one due to an undetermined cause in a patient with multiple cardiovascular risk factors and the second due to a cardiac arrest in a person with a history of cardiovascular disease.”

“Triple threat”, indeed! Sounds like the incretin agonist + myostatin inhibitor alone might be the best bet.

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#3

Yes. Still early days. But I think we will get something game changing in this department, simply because these companies want to make GLP1s work for people who are not disciplined enough or educated enough to use them properly.

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#4

Also interesting is that unlike the preclinical monkey study in which the triplet therapy caused the monkeys to GAIN a rather large amount of lean mass, the humans still lost lean mass (although 80% less compared to semaglutide-only group). This is a far, far cry from what Dr. Mike got me all excited for in his video, so clearly we’re farther away from Bodybuilding Utopia than he was hoping. Still, I’m hoping we’ll get there eventually and will be watching this field of research with bated breath!

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#5

But wouldn’t it be an ideal outcome if you could be lean and shredded without ever going to the gym?

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#6

Yes. That’s what might be coming with this. Even if they could achieve such a physique like that pharmacologically there likely are health benefits from exercise they’d be missing, but it would be better than being obese and weak. It could help them make a modest effort at exercise without as much suffering.

This would also be great for the elderly, and people who are disabled or with particular diseases.

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#7

This isn’t really correct. Muscle loss is not a side effect of GLP1’s, but rather a side effect of negative calorie balance. The same muscle loss happens with any diet in which calories in is less than calories out.

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#8

I definitely won’t be an early adopter. The activin A thing worries me the most, since we know that’s so important in cardiac development.

This sounds like weasel words to me

Also this: “Two deaths occurred in the triplet group, one due to an undetermined cause in a patient with multiple cardiovascular risk factors and the second due to a cardiac arrest in a person with a history of cardiovascular disease.”

“Multiple cardiovascular risk factors” - like maybe high blood pressure and cholesterol, which most average people have? That’s such a cop-out sentence, obviously meant to downplay things.

And to be honest, anybody actually exercising and interested in fitness and nutrition doesn’t need the GLP-1RA aspect of this anyway. You just control how much food you put in your mouth and deal with a big of hunger. The bigger deal would be having an anabolic drug that doesn’t shut down your HPTA or have androgenic side effects.

I will withhold my hype. SARMs were supposed to accomplish this same thing by activating muscle androgen receptors specifically, but still end up causing liver toxicity, trashing your circulating lipids, raising blood pressure and suppressing testosterone and fertility.

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#9

I don’t plan on being an early adopter either. I just welcome new tools and medicines.

GLP1s have a large range of health benefits beyond losing weight and I predict will be very valuable for longevity.

It’s easy to say what people should do, but all of the best “eat better, eat less, move more” advice and motivation doesn’t reach all people at all times. Some people need to hit rock bottom before they are receptive. These medicines give people who are not ready to be receptive a complete mindset shift, and comes with a whole host of other benefits for various organ systems (when used appropriately.)

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#10

I 100% agree. I could have worded what I said more accurately.

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#11

Yes, and anybody can become rich just by grinding 16 hours a day every day, it’s just a matter of willpower.

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#12

No criticism towards you. That’s how it’s always written.

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#13

Agree.

That’s not what I said. I was quite careful with my wording. I said “anybody actually exercising and interested in fitness and nutrition doesn’t need the GLP-1RA aspect”, and I stand by that. Bodybuilders are very used to counting calories, tracking macronutrients, and don’t need the “help”. Obviously lay people just eating “ad libitum” are a totally different population.

In this context is massive fat loss and muscle gain, the GLP-1RA is there simply to reduce caloric intake. And it’s that reduction which is causing the muscle loss (in non-training populations). Looking at those who are “into” fitness and nutrition, they are exercising, thus providing stimulation for muscle preservation, and they can control their caloric intake. Thus, the major benefit comes from the muscle gaining drugs, not the fat loss drugs.

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#14

I always wonder about effects in the mouth like saliva reduction… So many molecules and microorganisms depend on oral health… (even nitric oxide formation). Have you seen any investigation focused on the saliva under these drugs combination on the medium run?

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#15

I had never considered that. I used semaglutide for 6-12 months before swapping to tirzepatide 2-3 months ago and I have not noticed any reduction in salivation or oral health problems.

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#16

Caloric deficit causing the loss of lean muscle is the current narrative but there is some emerging evidence and active studies going on showing GLP1’s can tip the myostatin/activin switch towards catabolism.

When you block myostatin/activin while holding the calorie deficit constant (via the identical semaglutide dose), muscle loss largely disappear , so the excess lean-mass loss can’t be pinned on calories alone; it’s drug-linked and ligand-mediated.

Anyway - Something to watch for. And ties back into the results that Mike was so excited about.

https://www.nature.com/articles/s41574-025-01140-w
https://www.nature.com/articles/s41467-025-59485-9

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#17

We’ve seen the benefits of acarbose when combined with rapamycin, but I imagine rapamycin + tirzepatide would perform far better.

Summary of study you provided:

  • Objective & Scope
    Tested whether activating the glucagon-like peptide-1 receptor (GLP-1R) can reverse age-related decline, using comprehensive “multi-omic” profiling (transcriptome, DNA-methylome, plasma metabolome) plus functional read-outs in old mice.
  • Intervention
    A low dose of a GLP-1R agonist was given to aged but not young-adult mice. The dose was chosen specifically because it did not change food intake or body-weight, isolating direct drug effects from weight-loss side-effects.
  • Whole-body functional rejuvenation
    Treated old mice showed better physical performance and cognition (grip-strength, endurance, behavioural memory tasks), indicating that benefits extend beyond glycaemic control.
  • Multi-omic “youthful shift”
  • Transcriptomes: Age-associated gene-expression signatures in multiple organs (brain, liver, kidney, muscle, WBCs) moved toward the young profile.
  • DNA-methylomes: Epigenetic-age patterns in tissues and circulating leukocytes were partially reset.
  • Plasma metabolome: Youth-like metabolite profile, including lowered inflammatory and lipid-dysregulation markers.
  • Organ-specific patterns mediated by the hypothalamus
    Rejuvenation magnitude varied by tissue but, mechanistically, most effects required an intact hypothalamic GLP-1R signal—highlighting a central neuro-endocrine axis.
  • Specific to old age
    Young-adult mice derived no additional benefit, suggesting the drug normalises age-linked damage rather than pushing physiology “beyond youthful”.
  • Benchmark vs. rapamycin
    Molecular signatures produced by GLP-1R agonism overlapped strongly with those seen under mTOR inhibition (rapamycin), a canonical anti-aging strategy—implying convergent downstream pathways.
  • Clinical relevance
    Because GLP-1R agonists are already FDA-approved for diabetes/obesity, the findings support rapid translation into human geroprotection trials and may explain their observed pleiotropic benefits (cardiovascular, renal, neuro-cognitive). [ouci.dntb.gov.ua]
  • Limitations & next steps
    Mouse study, preprint status, lifespan not measured, single agonist & dosing paradigm used—human trials must establish optimal compound, dose, duration, and long-term safety for anti-aging use.
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#19

Sorry, which study are you refering to?

#20

The one that mjmj linked here.

#21

GLP-1’s have quickly become very popular with the bodybuilding community. You can visit some of the forums and verify for yourself. So these folks do want the “help”.

You are incorrect about the muscle loss - at least in mice. Mice broken up into 2 groups, one on a GLP-1, the other was not. The mice on the GLP-1 got to eat what they wanted, whatever they ate was tracked. The other group of mice got to eat the exact same amount as the GLP-1 mice had eaten. So the calories were identical.

The mice on the GLP-1 lost more weight, lost more fat, and retained more lean mass (although they still lost some lean mass) than the other mice. The other mice even started to regain weight - all of it fat - past a certain point in the experiment.

Cleary the GLP-1s are doing something other than simply reducing caloric intake.

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