GLP-1 Drugs Don't Fix Everything

[keangkong]

There have been a variety of scholarly articles extolling the virtues of GLP-1 drugs for treating a variety of ailments other than just diabetes and weight loss. Here is a rare negative article on GLP-1 drugs. It concludes that while people lose weight on GLP-1 drugs, their aerobic fitness appears not to improve.

Liu, et al. (2025). Incretin Receptor Agonism, Fat-free Mass, and Cardiorespiratory Fitness - A Narrative Review. J. Clin. Endocrinology & Metabolism 110(10), 2709-2717.

 

[nevets]

Skimmed the full paper and honestly not that surprised, they looked at dual GLP/GIP and triple GLP/GIP/glucagon and still showed lots of reductions in Fat Free Mass (FFM) loss. People who gain weight and get on these peptides can live their same sedentary lifestyle and it is not surprising that we see lots of lean body mass being lost if this lifestyle is maintained. Hopefully this motivates people to increase protein intake and start some resistance training. I attached a screenshot of the paper regarding some unknowns that they have acknowledged in the study.

 

[AndyPanda]

I think the solution to this is pretty simple. People need to lift weights. The problem is that these drugs work so well on sedentary people that they often don’t make lifestyle changes. If the only reason you had muscle mass was because you were carrying around extra weight, of course you are going to lose muscle as you lose weight. If you starve weight off, you will also gain it all back as soon as you start eating again. Probably even more. If exercise is part of your regimen, you will keep it off longer. Even body weight exercises like pushups and body squats are great for building and maintaining muscle.

 

[nevets]

Here’s a direct quote from the full paper regarding FFM.

“In the STEP trials evaluating semaglutide, FFM loss accounted for ∼40% of total weight loss (5, 42). Similarly, the SUSTAIN 8 trial revealed that, after 52 weeks of semaglutide treatment, total fat mass was reduced by 3.4 kg, while total lean mass decreased by 2.3 kg (44). In the SURMOUNT-1 trial, the dual GLP-1/ GIPRA tirzepatide reduced fat mass by 17 kg (33.9%) but also led to a 6-kg (10.9%) reduction in lean body mass(5, 45). Similarly, the GLP-1/GIP/glucagon receptor triagonist retatrutide demonstrated that approximately 33% of weightloss resulted from FFM reduction in phase II studies (5).”

 

[Nathanologist]

Here’s one showing that diet and exercise can help mitigate the glp-1 weight loss.

Resistance Training + Protein May Lower GLP-1 RA Muscle Loss

Supervised lifestyle intervention from a medical professional may help maximize fat loss and minimize muscle tissue loss in people taking the potent weight loss drugs.

www.medscape.com

Taking a GLP-1 agonist helps you lose weight, which is good for many health markers. But CRF isn’t just about being lighter. It’s about how well your heart, lungs, blood vessels, and muscles can perform.

To improve CRF (not just maintain it) you typically need an aerobic training stimulus (e.g., sustained moderate‐to‐high intensity cardio), plus muscle endurance/ strength work, and good nutrition (protein, micronutrients, recovery). Drug‐induced weight loss alone doesn’t provide that stimulus.

Body builders know this, many are using these drugs to enhance will power during cutting cycles. They stick to the muscle sparing workouts and diet while doing this. I bet you dollars to donuts if they were seeing a higher than normal % of lean mass loss from it they’d ditch the GLP-1 post haste.

 

[AvayaMango]

Here’s a direct quote from the full paper regarding FFM.

“In the STEP trials evaluating semaglutide, FFM loss accounted for ∼40% of total weight loss (5, 42). Similarly, the SUSTAIN 8 trial revealed that, after 52 weeks of semaglutide treatment, total fat mass was reduced by 3.4 kg, while total lean mass decreased by 2.3 kg (44). In the SURMOUNT-1 trial, the dual GLP-1/ GIPRA tirzepatide reduced fat mass by 17 kg (33.9%) but also led to a 6-kg (10.9%) reduction in lean body mass(5, 45). Similarly, the GLP-1/GIP/glucagon receptor triagonist retatrutide demonstrated that approximately 33% of weightloss resulted from FFM reduction in phase II studies (5).”

Yikes, a 33% loss of FFM on Reta is pretty significant.

It’ll be interesting to see more on this as most people seem to be drawn to reta for its muscle preservation qualities.

Results like these are so important as a reminder that no matter the glp you’re on, none of them prevent lean mass loss so strength training is essential.

 

[lessthanhalf]

GLP-1 drugs significantly improve functional capacity, even with no exercise or improvement in cardiovascular fitness. Simply weighing less substantially improves your ability to do normal daily activities, and is especially obvious in things like walking, walking up hills or stairs, and just getting up from a couch or bed. If you are not severely overweight and younger and fitter, then this may be less obvious, but for me the difference in weight from 145kg to 71kg made an enormous difference to my ability to do anything physical.
Now, GLP-1 drugs were not actually responsible for most of that weight loss, but are definitely making a huge difference to my ability to keep the weight off.
While I was losing weight, and still fairly heavy I noticed a huge difference in walking up a steep hill from just 10kg weight loss, from having to stop halfway to breathe to being able to make it to the top, and it was obvious at the time my leg muscles were shrinking. Not to mention every joint in my feet hurt like hell walking at 115 kg, pain was gone by about 85kg.
Generally the loss in muscle mass with weight loss from GLP's is proportional and does not result in lowered physical capacity, but generally improves it , mainly as not as much muscle is required to move the lowered total mass.
I am not suggesting that reasonable or high protein intake, aerobic and resistance training are a bad idea, they will improve health and capability as weight loss occurs, but improvements occur without their benefits, just from weight loss. And the long term benefits of GLP drugs on cardiovascular, kidney disease, diabetes, arthritis, cancer and many other outcomes will still occur without exercise. A fairly large percentage of the population do not succeed in maintaining regular exercise, and I would guess this is more likely in those who might benefit from GLP's. And initiating and maintaining regular exercise is less difficult at lower body weights.