Lean mass loss on GLP-1 receptor agonists: a downside of the “miracle drugs”

Clinical trials have generated impressive data on the effects of GLP-1 agonists on body weight and BMI, but how do these drugs perform in terms of body composition?

Peter Attia

Read Time 4 minutes

Back in 2021, I devoted an “Ask Me Anything” podcast discussion to a relatively new class of promising drugs for the treatment of obesity: GLP-1 receptor agonists. Since then, the popularity of these medications – which include semaglutide (trade names Ozempic and Wegovy) and the more recently approved tirzepatide (trade name Mounjaro) – has skyrocketed, fueled by celebrity and influencer testimonials and by the remarkable weight loss observed in clinical trials, which I will cover in more detail in an upcoming AMA as well.

Not all weight loss is healthy

But even for those with obesity, not all weight loss is healthy. While shedding excess fat mass (and in particular, visceral fat mass) has a multitude of beneficial effects on health, shedding lean mass – which includes muscle and bone – is associated with poorer health trajectories and reduced lifespan. Therefore, safe and effective obesity treatments are those which significantly reduce fat mass while minimizing the concurrent loss of lean mass. Though a certain amount of lean loss is inevitable with significant weight reduction (usually about 25% of total weight loss), the goal is to increase the body’s overall proportion of lean mass – in other words, to improve body composition.

How do GLP-1 agonists affect body composition?

Clinical trials have generated impressive data on the effects of GLP-1 agonists on body weight and BMI, but how do these drugs perform in terms of body composition?

The question unfortunately isn’t an easy one to answer based on published data. Though several clinical trials have tested semaglutide and other GLP-1 agonists as treatments for obesity, body composition has not been included among primary endpoints for these studies. Indeed, according to the U.S. Food and Drug Administration’s guidelines for assessing weight management therapies, the only acceptable primary efficacy endpoints for weight loss drug trials are those related directly to changes in body weight. Body composition metrics, by contrast, are considered safety endpoints which require far smaller cohorts for testing. The FDA suggests that only a fraction of all study subjects in phase III trials ought to receive DEXA scans or other body composition measurements. Investigations into body composition changes on GLP-1 agonists are thus limited and likely underpowered. (In my opinion, this is an enormous blindspot on the part of the FDA.)

However, from the information we can scrape together based on sub-cohort data, these “miracle drugs” start to look a bit less miraculous. In 2021’s STEP 1 trial – the first trial demonstrating the efficacy of semaglutide as a treatment for adult obesity – a subset of 140 patients underwent DEXA scans for body composition analysis. Among these patients, lean mass accounted for approximately 39% of total weight loss – substantially higher than ideal. In a substudy of 178 patients from the SUSTAIN 8 trial on semaglutide as a diabetes treatment, the average proportion of lean mass loss was nearly identical at 40%, despite lower doses and less total weight loss than in the STEP 1 trial.

Who should be concerned?

It’s important to note that both of these trials were conducted in adults with overweight or obesity, and higher lean mass loss among such individuals can still be an acceptable cost for dramatic weight reduction as long as overall body composition is improving. Indeed, despite the high lean mass losses, the proportion of lean mass to total body mass still increased in STEP 1 patients by an average of roughly 3% and in SUSTAIN 8 patients by an average of just over 1%.

However, GLP-1 agonists have also grown in popularity as a weight loss drug among those without obesity, a trend I find somewhat disconcerting. While those with obesity stand to reap considerable health benefits from fat loss, the potential benefits of fat loss among healthy-weight individuals are minimal and are unlikely to offset the sizable health risks associated with reduced lean mass. Further, because the only large-scale trials of GLP-1 agonists have been conducted in obese or overweight study populations, we don’t yet know if these drugs affect body composition in normal-weight individuals in an equivalent manner.

Even among patients with obesity, not all can afford to lose significant lean mass. Sarcopenic obesity, which is especially common in older populations, is characterized by the dual hazards of excess fat mass and low levels of skeletal muscle. Further reductions in lean mass among those with too little to begin with could pose a greater threat to health and longevity than the presence of excess fat.

Exercise caution

For those with large amounts of excess fat, reducing fat mass is a critical step in improving overall health. But weight loss is not a great proxy for fat loss, and drugs designed to treat obesity are only beneficial if they can improve body composition in addition to body weight.

GLP-1 agonists have been celebrated for their potency in reducing body mass, but lean mass accounts for an alarming proportion of this weight loss. For patients without excess fat, this considerable risk just doesn’t seem worth the minimal benefits. For patients with sarcopenic obesity, alternative weight loss strategies such as bariatric surgery may be more promising options. And even for patients with obesity and sufficient lean mass – for whom GLP-1 agonists may offer enough benefit from fat loss to justify the lean mass losses – efforts should still be made to minimize the latter as much as possible. Increasing weight-bearing exercise and strength training can help to counteract losses in muscle and bone mass while taking these drugs, and patients should be careful that they’re consuming sufficient protein in spite of the overall reductions in appetite and calorie intake.

As we’ve seen time and again, there are no such things as “miracle drugs,” and GLP-1 agonists are no exception to this rule. While they may have value for certain individuals, these medications come with downsides beyond their hefty price tag, and both physicians and patients ought to exercise extreme caution and discretion in determining whether they are truly the right choice for weight management.

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