Lyle McDonald has made clear his position on the recent surge of GLP-1 use in fitness circles, particularly targeting retatrutide and the claims surrounding its metabolic effects. In his comprehensive analysis, McDonald questions not whether retatrutide works for weight loss, but how it achieves those results and whether lean athletes should be using it at all.
The controversy centers on retatrutide, a triple-agonist GLP-1 treatment that targets three receptors: GLP-1, GIP, and glucagon. While earlier ones like semaglutide and tirzepatide focused solely on appetite suppression, retatrutide’s glucagon component supposedly increases energy expenditure. This claim has made it popular among physique competitors and bodybuilders seeking an edge during contest preparation.
McDonald, who published a book on GLP-1s in January 2025, anticipated this trend. He noted that competitors were gravitating toward retatrutide specifically because of the purported metabolic boost. However, he remained skeptical even then writing that he could think of cheaper, more effective ways to raise energy expenditure than relying on retatrutide’s unproven effects.
The core issue McDonald identifies is the mechanism by which retatrutide might increase energy expenditure. Research on glucagon infusions shows modest increases, ranging from 70 to 250 calories per day at most. But the critical question is where those calories come from.
According to a 2023 paper published in the journal Peptides, glucagon appears to increase energy expenditure primarily by breaking down amino acids for fuel through a process called gluconeogenesis. The paper examined multiple studies and concluded that glucagon-stimulated energy expenditure operates through what researchers call an “amino acid-centric paradigm.” In simpler terms, it may be burning protein for energy.
This presents a significant problem for lean athletes and physique competitors. While GLP-1 and GIP components suppress appetite without direct metabolic effects, the glucagon receptor activation appears to work differently. Studies show that elevated glucagon levels increase protein turnover and nitrogen excretion, both indicators that the body is breaking down protein tissue.
McDonald points out that while glucagon receptors are not found directly in muscle tissue, the effect on amino acids is indirect but potentially concerning. The body maintains amino acid pools in the bloodstream and muscle tissue that exist in dynamic balance. When glucagon causes the liver to break down amino acids, it pulls from the bloodstream pool, which in turn can pull from muscle stores.
The practical implication is sobering. If retatrutide increases energy expenditure by 200 to 250 calories per day through amino acid oxidation, that translates to approximately 50 to 60 grams of protein being burned daily. For athletes already in a caloric deficit during contest preparation, this represents a substantial additional drain on protein resources.
Several competitors using retatrutide have reported coming in looking stringier with more apparent muscle loss, according to discussions in McDonald’s community. This anecdotal evidence aligns with the theoretical mechanism suggesting amino acid breakdown.
McDonald said, “And let’s face it, they are now being used intensively in contest prep for physique competitors for bodybuilders. And while they’re not necessarily doing anything to improve anybody’s appearance, because that’s not what they’re going to do, what they’re
going to do is allow a lot more mediocre physiques to get to stage to actually get in shape.”
He then went on to sarcastically talk about fitness expert Mike Israetel, saying, “Except for Mike Israetel, who despite using two GLP1s, still doesn’t know how to get into shape. I digress. Even then, what I was starting to see was that competitors and also people in the general fitness industry were entranced by the new shiny, which at that time the new [ ] was reatride.”
The paper McDonald references also notes that in animal studies, providing a 40% protein diet helped maintain amino acid levels during glucagon exposure. However, this creates a paradox: if eating more protein prevents the drop in blood amino acids, it might also negate the energy expenditure increase that made retatrutide attractive in the first place.
McDonald contrasts this with alternatives like clenbuterol, which recent research shows increases energy expenditure by 20% at just 80 micrograms. For someone with a 2,000 calorie basal metabolic rate, that represents a 400 calorie per day increase, double what retatrutide might provide. Critically, clenbuterol has decades of documented use and actually shows anabolic effects in muscle tissue rather than catabolic ones.
Adding low-dose T3 thyroid hormone to the mix could potentially increase energy expenditure by 30% or 600 calories daily, according to McDonald’s analysis. These compounds have extensive human research backing their effects and mechanisms, unlike retatrutide’s theoretical energy expenditure boost.
Throughout his analysis, McDonald emphasizes a crucial distinction: direct human data on retatrutide’s effects on energy expenditure does not currently exist. The claims are based on animal studies and glucagon infusion research, neither of which definitively proves retatrutide works the same way in humans taking it long-term.
He also notes that as of his book’s publication, no studies had directly measured whether retatrutide raises energy expenditure in humans, despite this being a major selling point. The weight loss effects are clear, achieving 12 to 24% average weight loss and up to 30% maximum, but attributing this specifically to increased metabolic rate remains unproven.
For individuals with overweight or obesity, the amino acid breakdown issue may be less concerning. These populations naturally carry additional lean body mass alongside fat mass, and some loss of non-muscle lean tissue is expected and safe during significant weight loss. McDonald emphasizes that lean body mass and skeletal muscle mass are not synonyms, a distinction often confused in discussions about these.
However, for already-lean physique competitors trying to reach stage-ready condition, the calculus changes entirely. These athletes cannot afford to sacrifice muscle mass, and any compound that potentially burns amino acids for energy represents a liability rather than an asset.
McDonald’s recommendation from his book now appears prescient. He suggested that combining semaglutide or tirzepatide with proven thermogenic compounds would be more effective both metabolically and financially than jumping to retatrutide. Now, with the emerging understanding of how glucagon receptor activation may work, that recommendation carries even more weight.
