Why we wrote this commentary
GLP-1 receptor agonists (GLP-1RAs) have transformed metabolic medicine. Their benefits—robust weight loss, steady glycaemic control, and cardiovascular protection—are unquestioned and widely celebrated. Yet during our clinical practice and research on Exposure-Related Malnutrition (ERM), we encountered a recurring paradox: patients improved metabolically, but many showed subtle declines in muscle reserve and recovery capacity over time.
The scientific literature confirms this pattern. Across trials, 20–25% of total weight lost with GLP-1RAs comes from fat-free mass, including skeletal muscle. However, existing explanations—reduced food intake, appetite suppression, altered mitochondrial efficiency, or qualitative muscle remodeling—could not fully account for the consistency of this observation.
Something was missing.
The question that triggered this paper
The turning point was very simple:
If glucagon is essential for stress adaptation, amino-acid clearance, and hepatic energy mobilization, what happens when we chronically silence it?
Long-acting GLP-1RAs profoundly suppress glucagon—continuously, not rhythmically. Unlike the body’s natural GLP-1 pulse, pharmacological exposure is persistent and supraphysiological, with hours-long half-lives far exceeding endogenous incretin signaling.
In metabolic medicine, glucagon is often treated merely as insulin’s antagonist. But physiologically, glucagon is a foreman at the liver’s portal, coordinating:
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amino acid uptake and ureagenesis
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substrate mobilization during stress
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maintenance of mixed-fuel availability
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support for re-anabolism after catabolism
Our concern was straightforward:
If glucagon’s regulatory role on amino acids is forced offline, will the body compensate by drawing amino acids from the only other major reservoir—skeletal muscle?
What we discovered when we searched the evidence
Experimental data already provided the missing piece.
Human studies of glucagon receptor antagonism show a striking result:
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hepatic amino-acid clearance drops
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hyperaminoacidaemia develops
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skeletal muscle becomes the fallback source of amino acids
This pattern mirrors the very changes we see under GLP-1RA therapy.
Thus we proposed the central idea of our commentary:
Chronic glucagon suppression may shift amino-acid handling toward muscle proteolysis, creating a silent but progressive erosion of muscle reserve.
This mechanism does not contradict the benefits of GLP-1RAs—it complements them by revealing an overlooked trade-off.
Framing the problem through Exposure-Related Malnutrition (ERM)
Our ERM framework describes undernutrition that arises not from calorie scarcity, but from bioenergetic mismatch and substrate misallocation.
GLP-1RA therapy, when prolonged and potent, may lead to a form of iatrogenic ERM:
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Short-term gains: lower glucose, lower weight, lower cardiovascular risk
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Long-term risks: impaired amino-acid balance, reduced re-anabolism, muscle loss, frailty, diminished resilience
This progression can be subtle and clinically silent—biochemically detectable long before symptoms appear.
Why resilience matters
Resilience—the ability to respond to stress, repair, and return to baseline—is deeply dependent on muscle and amino-acid availability.
If glucagon suppression alters this availability, then:
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immune recovery
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wound healing
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recovery from illness
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and metabolic adaptation
may all become compromised over time.
This is especially relevant for:
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older adults
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individuals with sarcopenic obesity
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multimorbid patients
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chronically ill populations
These groups are also the most common recipients of GLP-1RA prescriptions.
What this means for clinical practice
We argue that long-term GLP-1RA use requires a shift from weight-centric monitoring to resilience-centric monitoring.
Specifically:
Monitor routinely
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muscle strength and function
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amino-acid profiles
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short half-life proteins
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emerging resilience markers (e.g., GDF-15)
Mitigate proactively
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adequate protein intake (≥1.2–1.5 g/kg/day)
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resistance or mixed exercise
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consider adjuncts that preserve muscle mass
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identify early biomarker patterns of ERM
These steps do not contradict the use of GLP-1RAs—they optimize it.
What comes next
We believe the next chapter of incretin-based therapies will require:
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better mapping of glucagon dynamics across agents (GLP-1RA vs. dual agonists)
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resilience-focused biomarker panels
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machine-learning derived risk signatures
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trials that treat muscle health as a primary endpoint
GLP-1RAs remain extraordinarily beneficial.
Our goal is not to diminish their value, but to reveal a hidden layer that requires attention if we hope to preserve long-term metabolic and functional health.
As the field shifts from weight loss toward healthy longevity, we hope this commentary helps open a wider conversation—one that bridges endocrinology, nutrition, aging research, and resilience science.
Tippairote, T., Hoonkaew, P., Suksawang, A. et al. Glucagon suppression under GLP-1RA therapy: hidden trade-offs for muscle and resilience. Diabetol Int 17, 2 (2026). https://doi.org/10.1007/s13340-025-00856-4