GLP-1s and Muscle Loss: What the Headlines Get Wrong

As the GLP-1 drugs become ever more available, they’ve been dogged by a nagging concern – loss of muscle. It’s a common red flag waved on social media and it undoubtedly contributes to the high drop-off rate we’ve seen in GLP-1 prescriptions. Which is a shame. The drugs – semaglutide (Ozempic and Wegovy) and tirzepatide (Mounjaro and Zepbound) – are a once-in-a-generation pharmaceutical phenomenon. When people with weight and metabolic issues forgo their benefits because of concerns rooted in misunderstanding and scare-mongering, the record needs to be corrected.  

Let’s start with some basic biophysics. When people gain weight, they add muscle, in addition to the new adipose tissue they put on. A now heavier body requires more strength to move it, so it adapts to this greater load by synthesizing more muscle tissue to get the job done. And when people lose weight, that load decreases. Unless they compensate by doing more physical activity, especially resistance work (we’ll get into that in a minute), the extra muscle is no longer needed. The iron law of anabolic metabolism says “use it or lose it.” If that tissue is no longer being stimulated by the nervous system it will eventually disappear, broken down into the amino acids it was originally made from. A rough estimate from decades of weight-loss research that preceded the arrival of the GLP-1s is that for every pound of weight loss, about ¾ will be fat and ¼ not fat, otherwise known as “lean mass.” 

The alarm first loudly sounded in 2021 with the publication of a “substudy” of the landmark STEP 1 trial in the New England Journal that led to the FDA approval of Wegovy for weight loss. But this substudy analyzing body composition in a smaller group of patients found that roughly 40% of that weight loss was lean mass. OK, that sounds alarming. But subsequent studies have found smaller losses – in the 25% range, in line with non-GLP-driven weight loss – as that STEP 1 substudy comes to look more and more like an outlier. 

In part, it and some other early studies seem to have suffered from a measurement problem. They used DEXA scans to measure body composition – a low-radiation form of X-ray -- which doesn’t have enough resolution to distinguish among different types of lean mass, for instance, extracellular water, organ tissue, glycogen, and the contractile muscle tissue that does the actual heavy lifting. So, researchers often overestimated the amount of muscle tissue in their overweight subjects, and accordingly, after weight-loss, overestimated the loss of muscle. More sophisticated studies are now using highly sensitive, and very expensive, MRI technology. (At Raffaele Medical we use the InBody scanner, a sophisticated form of bioelectrical impedance analysis or BIA, valuable for tracking patients’ body composition progress, if not for making the precise discriminations that research requires.) 

But there’s a more fundamental issue here as well. Muscle mass, even accurately measured muscle mass, is not the most important metric to consider. That would be muscle function – how muscle actually performs. You can sum that up in one word – strength. 

The pre-GLP-1 calorie-restriction research consistently showed that while subjects often do lose substantial lean mass, they still manage to hold on to most of their muscular strength, in addition to the improvements in metabolic health that we’d expect with weight loss. In a 2018 meta-analysis, older obese adults who were on a CR diet and an exercise program actually held on to their lean mass and their strength and mobility increased.

In other words, any loss of muscle quantity can be offset by an increase in muscle quality, or, another way of putting it, improved muscle health. This can play out at a tissue level, when people lose intra-muscular fat -- fat that accumulates inside muscle tissue and impairs muscular function – as well as at a macro level, when people take more readily to exercise, unburdened by the extra weight they’ve been carrying. 

Most of the initial GLP-1 studies were done on sedentary subjects. But one forward-looking 2021 study, again in the New England Journal, looked at a group of subjects taking an early GLP-1 drug, liraglutide, who were put on a 150-minute a week exercise schedule -- everything from cycling intervals to resistance training. The verdict: the GLP-1 plus exercise group did lose some lean mass, but significantly less than the GLP-1-only group, and maintained most of their muscle strength and lost more weight. The weight-loss field is just now catching up with the implications of this five-year-old study. Newer GLP-1 studies in progress, from the University of Kansas Medical School and a Kuwaiti/University of Glasgow collaboration to name two, are measuring muscle loss in a placebo group versus subjects who are following a resistance exercise protocol and consuming a relatively high protein diet. Which makes sense. A diet with adequate protein and an exercise regimen that includes strength work are two modalities that have been found to limit lean mass loss and enhance strength. The protein provides the raw material, the amino acids, and the resistance work provides the stimulus the body needs to turn dietary protein into skeletal muscle. 

If the message is plain that people can do more with less – get stronger with less lean mass – the lesson from my clinical experience is that it’s also possible to do more with more. I have patients who have recorded strength gains and increased lean mass while losing weight on the meds. They follow our resistance work protocols and eat plenty of protein. (When you’re eating say 500 fewer calories a day, you may well have to make a conscious effort to ensure you’re still getting enough protein in the mix.) How they are able to gain mass as well as strength boils down to one factor that has not been addressed in any GLP-1 study to date, supplemental testosterone. 

In men, after about the age of 30, free testosterone levels decline about 1-3% a year. Muscle mass declines about 3-8% per decade, the older we get, the faster the decline. Yes, there’s a connection -- testosterone is a powerful anabolic hormone that’s intimately involved in the synthesis of new muscle. Over the past few decades, researchers have introduced the concept of “anabolic resistance” to explain how and why the aging body has a harder time building muscle. Sensitivity to the amino acids we ingest declines, sensitivity to the anabolic boost exercise provides declines, and our anabolic hormone levels drop, testosterone being arguably the best studied and most consequential. 

The basic prescription for effectively pushing back against anabolic resistance, and maintaining both muscle mass and strength, should be obvious by now – sufficient protein, resistance training and, for the many individuals who have relatively modest free testosterone levels, supplemental testosterone. Most of my male patients, and a significant minority of my female patients, are on supplemental testosterone, and they’ve been able to hold the line against muscle loss without resorting to very high protein diets, for instance, a doubling of the current protein RDA to 1.6 grams of protein per kilogram of body weight a day, which some medical protein-boosters advocate.

For published proof, we can go back to a 2016 Australian study of 100 obese men with below-average testosterone levels who were put on a very low-calorie diet for 10 weeks and then monitored for the better part of a year. The group on the supplemental testosterone lost more fat and preserved more lean mass than the placebo group. The authors concluded that their weight loss “was almost exclusively due to loss of body fat.” 

The Australian study came up with another salient finding. Despite the improvements in body composition, the men in the testosterone group did not fare any better on functional strength tests than the men in the placebo group. That’s because the testosterone group didn’t do any resistance training. Just as protein intake and resistance training work in concert to maintain or build muscle and muscular strength, so do testosterone and resistance training. The exercise sends the signal to the brain to adapt to the greater demand; the supplemental testosterone enhances the body’s capacity to synthesize muscle to meet that demand. So, when we look at those population figures showing declining muscle mass and strength with age, that’s capturing not only declining hormone levels but less physical activity in general, and less resistance training specifically, which could slow that decline. In my clinical experience, the energy boost that my male patients experience on supplemental testosterone usually translates to more energy invested in an exercise regimen, a “virtuous cycle” to be sure.  

I like to think of a vigorous exercise program, strength training especially, as a kind of insurance policy against disability in old age. Not only are muscle mass and strength defended against but so is bone density, important protections all against sarcopenia and frailty in the senior years. 

The story doesn’t end there. I’ve made the case that we have effective ways to push back against the loss of muscle that comes with the weight loss made possible for the first time for so many people on the GLP-1 meds. But our pharma tools may be on the verge of getting even better. Within the next two years, the FDA is likely to approve the Eli Lilly drug retatrutide, currently in Phase 3 trials, and the implications for body composition are part of what’s fueling the anticipation surrounding the compound. 

The first GLP-1 drug to explode on the marketplace was semaglutide which stimulates the body’s receptors for the gut/brain GLP-1 hormone, suppressing appetite through several different mechanisms. The second powerhouse drug, tirzepatide, works through GLP-1 and a companion gut hormone, GIP, further suppressing appetite and possibly by sharpening metabolism in ways that are still being puzzled out. Retatrutide, a “triple receptor agonist,” adds a third receptor to the mix, glucagon. In the trials to date, retatrutide has delivered greater weight loss than its predecessors, with a fat loss approaching twice as much, meaning more lean mass is spared. Crucially, the additive weight-loss effect that glucagon yields is thought to derive not from appetite suppression but from tweaking our metabolism to mobilize stored energy more efficiently, enhancing the oxidation of stored fatty acids. It’s a breathtaking proposition: lose weight by burning more calories at rest! But we don’t yet know how big a contribution this metabolic fine-tuning is making to the weight loss and I for one can’t help but wonder about the long-term safety of a drug that boosts metabolic rate. We’ll have to see how this story plays out. 

Interestingly, there’s a small-molecule drug being developed by a UK start-up, MitoRx, still in the press-release stage, that purports to do the same thing, not by working through well-established hormonal channels a la retatrutide but by altering the way mitochondria burn fuel, a considerably more radical and risk-laden endeavor.

Certainly, we’ve entered a brave new world of weight-loss drugs. Renee Rogers, an exercise physiologist co-leading the University of Kansas research on exercise and the GLP-1s, estimates that there are currently 162 drugs in the pharma pipeline. However the winners and losers shake out, one thing is already clear. When we invest in a diet with adequate protein, a resistance training program and hormone optimization, we get to keep our muscle. 

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Sardeli, A.V.; Komatsu, T.R.; Mori, M.A.; Gáspari, A.F.; Chacon-Mikahil, M.P.T. Resistance Training Prevents Muscle Loss Induced by Caloric Restriction in Obese Elderly Individuals: A Systematic Review and Meta-Analysis. Nutrients 2018, 10, 423. https://doi.org/10.3390/nu10040423

Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined

Authors: Julie R. Lundgren, M.D., Ph.D., Charlotte Janus, Ph.D. https://orcid.org/0000-0001-5111-7047, Simon B.K. Jensen, M.Sc., Christian R. Juhl, M.D., Lisa M. Olsen, M.Sc., Rasmus M. Christensen, B.Sc.Med. https://orcid.org/0000-0003-0590-6285, Maria S. Svane, M.D., Ph.D., +7 , and Signe S. Torekov, Ph.D.  

Published May 5, 2021

N Engl J Med 2021;384:1719-1730

DOI: 10.1056/NEJMoa2028198

VOL. 384 NO. 18

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