GLP-1s and Muscle Loss - Part 1 The Basics

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As GLP-1 drugs get heavily marketed for weight loss, we know that when people stop taking the drugs they experience rapid weight regain. We also know that, while the claim is that if people stay on the drugs forever they’ll maintain the weight loss, there isn’t any research proving that and that in the longest study of these drugs for weight loss (4 years) they lost 89.5% of the sample.

There is another aspect that I think is not being discussed nearly enough and that is the subject of how much of the weight that is lost is coming from what is known as lean body mass . This is particularly important as the drug companies and their astroturf organizations relentlessly lobby for these drugs to be covered by Medicare and pushed onto seniors for whom loss of lean body mass can mean decreased balance and mobility and increased fragility, and bone breaks and possibly contribute to the increased mortality attributed to weight loss in this population. It’s not just seniors though, loss of lean body mass (which is defined differently in different studies but is at least predominantly muscle mass) creates problems for people of all ages, especially when the almost inevitable weight regain does not typically include a regain of the full lost muscle mass.

We are going to look at this in three parts. Today we’ll start with Sargeant et al’s 2019 study: A Review of the Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Lean Body Mass in Humans. This will give us an overview of the issues with loss of lean body/muscle mass as well as what was known about this early on (which is to say that this is not a new issue with the weight loss doses.) In Part 2 we’ll look at more recent data on the newest GLP1s for weight loss and in Part 3 we’ll talk about the justifications, excuses, and spin that are being used when discussing the issue of loss of lean body mass.

This study reviewed research that looked at GLP1s and SGLT2 Inhibitors (a separate class of Type 2 Diabetes drugs) to see how much weight was lost and what percentage of that weight loss came from fat mass vs lean body mass.

The authors are fully immersed in the weight-centric paradigm, making statements like

“Weight loss is an important goal in the management of several chronic conditions, including type 2 diabetes mellitus”

as if they are fact, even though research suggests it’s more likely behaviors than weight loss that help manage these chronic conditions.

They disclosed the following conflicts of interest:

Melanie Jane Davies has acted as a consultant, advisory board member and speaker for Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca and Janssen, an advisory board member for Servier and as a speaker for Mitsubishi Tanabe Pharma Corporation and Takeda Pharmaceuticals International Inc. She has received grants in support of investigator and investigator-initiated trials from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, and Janssen.

Kamlesh Khunti has received honoraria from Abbot, AstraZeneca, Berlin-Chemie AG/Menarini Group, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Roche, and Sanofi, and research support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Roche, and Sanofi.

I looked but didn’t find anything that was not disclosed. Let’s dig into the study itself and start with the definitions they used from their Table 1

Fat mass - “mass of all adipose tissue”
Fat free mass - “total body mass minus total fat mass”
Lean body mass - “fat free mass minus total bone mass”
Skeletal musical mass “Skeletal muscle mass is lean body mass minus connective tissue, skin, and other organs
Total body water “summation of intr- and extra cellular water”

The authors explain the serious issues with loss of LBM:

LBM (predominantly comprised of skeletal muscle) has several important functions. It acts as a primary site of glucose disposal (with lower skeletal muscle mass contributing to poorer glycaemic control), and is a strong determinant of resting metabolic rate; and thus loss of skeletal muscle with weight loss may predispose individuals to a greater chance of weight regain.

Lower muscle mass and function, associated with impaired muscular strength and endurance, also result in a higher risk of falls, hospitalisation and physical frailty. The important association between T2DM and frailty is becoming increasingly recognised, with frailty up to five times more likely in individuals with T2DM compared to those without. T2DM represents a state of accelerated metabolic ageing, and some of this frailty risk may be underpinned by an increased loss of LBM and function.

That is accurate, but then things go sideways:

Consequently, whilst weight loss is an important goal in the management of several obe*ity-associated comorbidities, including T2DM, and pharmacological therapies that support such weight loss are appealing, it is important to understand the impact of these therapies on body composition. The aim of this narrative review is to describe the effects of GLP-1RAs and SGLT2is upon body composition, with a particular focus on LBM and skeletal muscle.

This beautifully demonstrates the problem with the weight-centric paradigm.

First of all, “ob*sity-associated comorbidities” are health issues that people of all sizes get that get called “ob*sity-associated” when higher-weight people have them. This idea is scientifically… challenged, which I wrote about in-depth here. They also seem more worried about weight regain than the fact that weight loss can actually make blood sugar issues worse.

Moreover, what we are seeing here is justification for doing harm to prop up the weight-centric paradigm. They could have said “losing LBM is dangerous in multiple ways and weight neutral options can (or, if they wanted to hedge, may) help manage chronic conditions in people of all sizes without risking the loss of LBM. In fact, they could help manage these conditions while increasing LBM, so more research should be done to understand those options.” Instead, studies like this are written as if weight loss is not only a proven option (it’s not) but, in fact, the ONLY option to manage chronic diseases, but we’ll come back to this in Part 2.

So what did they find in their review?

“In over half of the studies identified, the proportion of LBM reduction ranged between 20% and 50% of total weight lost, which is consistent with diet-induced weight loss and bariatric surgery.”

Here again, this seems to be a good reason to at least consider abandoning the weight-centric paradigm. They are admitting that all methods of weight loss cause a loss of LBM, which they’ve admitted can cause numerous problems. What they didn’t do was even consider how many of the issues that are caused by loss of LBM have been/will be blamed on higher-weight bodies (aka “ob*sity-associated) and used to justify EVEN MORE weight loss attempts resulting in even more loss of LBM.

Of 53 groups, they found that 5 actually “saw a loss of LBM, FFM, or skeletal muscle mass (depending on reporting) that was greater than FM lost”

This is an older study, done prior to the approval of these new drugs for weight loss, so most of the research looked at two precursors to the most modern GLP1s - liraglutide or exenatide. Only 1 study looked at semaglutide and it found that 22% of the weight lost was LBM. That said, this was a 12 week study that titrated up from .25mg to the 1mg (Type 2 Diabetes) dose (a typical titration schedule would be 4 weeks at .25mg, 4 weeks at 0.5mg and then titrated up to the full 1mg dose.)

The weight loss dose for semaglutide is almost two and a half times the dose tested here at 2.4mg and, at least short-term, typically causes more weight loss so it’s important to see if that also means more LBM loss.

In part 2 we’ll look at more recent studies around semaglutide (Wegovy) and tirzepatide (Zepbound) for weight loss, as well as analyzing the arguments the weight loss industry is using to try to excuse/justify/rationalize LBM loss in GLP-1 drugs.

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*Note on language: I use “fat” as a neutral descriptor as used by the fat activist community, I use “ob*se” and “overw*ight” to acknowledge that these are terms that were created to medicalize and pathologize fat bodies, with roots in racism and specifically anti-Blackness. Please read Sabrina Strings’ Fearing the Black Body – the Racial Origins of Fat Phobia and Da’Shaun Harrison’s Belly of the Beast: The Politics of Anti-Fatness as Anti-Blackness for more on this.