GLP-1RAs and the Hidden Costs of Weight Loss: Beyond the Scale

Over the past few years, GLP-1 receptor agonists (GLP-1RAs) have taken center stage in the treatment of obesity and type 2 diabetes. Branded as breakthrough drugs, they can induce 15–25% body weight loss over a year or two — results once thought possible only through bariatric surgery.

But as prescriptions skyrocket, the scientific community is starting to ask a deeper question: what happens to the body beyond the shrinking waistline?

New Concerns: Sarcopenic Obesity

A recent mini-review in the Journal of Nutrition, Health & Aging (Prokopidis et al., 2025) raised a critical warning. While GLP-1RAs help reduce fat mass, they also contribute to muscle loss. When patients stop treatment — which many do due to side effects or cost — rapid fat regain often outpaces lean mass recovery.

This dynamic sets the stage for sarcopenic obesity, a condition where excess fat coexists with low muscle mass and function. Sarcopenic obesity is already a growing challenge in older adults, linked to frailty, fractures, diabetes, and early mortality. The review suggests GLP-1 therapy, if started and stopped repeatedly, could unintentionally accelerate this problem.

The Overlooked Hormone: Glucagon

While the review focuses on muscle mass, there’s another piece of the puzzle that deserves attention: glucagon suppression.

GLP-1RAs work in part by reducing glucagon, the hormone that normally signals the liver to release glucose and burn fat during fasting, exercise, or illness. But unlike natural, context-specific glucagon pulses, long-acting GLP-1RAs dampen glucagon chronically.

That’s good for lowering blood sugar. But what about the long-term trade-offs?

• Brain: Glucagon supports alternative fuels (like ketones) that help the brain adapt during stress. Prolonged suppression could blunt resilience.

• Immune system: Immune cells depend on rapid shifts in fuel use. If glucagon is chronically muted, the body’s defense system may lose flexibility.

• Muscle & heart: Both rely on fatty acid oxidation for endurance and recovery. Reduced glucagon tone could impair this capacity.

• Aging: Health depends on the natural rhythm between anabolic (insulin-dominant) and catabolic (glucagon-driven) states. Flattening this rhythm may push the body toward metabolic inflexibility, a hallmark of accelerated aging.

Why This Matters

GLP-1RAs are powerful — and for many patients, life-changing. But as with any therapy that tinkers with fundamental hormones, the long-term picture may be more complicated than the clinical trial snapshots.

Losing muscle during weight loss is not surprising. What’s more concerning is the possibility that prolonged glucagon suppression could undermine the body’s ability to adapt, repair, and withstand stress.

Moving Forward

If GLP-1 therapy is to be a cornerstone of long-term obesity management, we need to:

• Pair treatment with resistance training and adequate protein to protect muscle.

• Monitor not just weight, but body composition and functional capacity.

• Study the long-term impact of chronic glucagon suppression on brain, immune, and cardiovascular resilience.

As history has shown with other “miracle drugs,” the first wave of enthusiasm often overlooks hidden trade-offs. GLP-1RAs are no exception. The challenge now is not to abandon them — but to ask smarter questions about what resilience costs we might be paying behind the scenes.

Prokopidis, K., Daly, R. M., & Suetta, C. (2025). Weighing the risk of GLP-1 treatment in older adults: Should we be concerned about sarcopenic obesity? The Journal of Nutrition, Health & Aging, 29, 100652. https://doi.org/10.1016/j.jnha.2025.100652

#GLP-1 receptor agonists, #Sarcopenic obesity, #Weight cycling, #Glucagon suppression, #Metabolic flexibility