Recent Publication: The Hidden Trade-Offs of GLP-1 Drugs — Short-Term Gains, Long-Term Resilience Loss?

We’re excited to announce the publication of our new commentary in Diabetology International, titled “Glucagon suppression under GLP-1RA therapy: hidden trade-offs for muscle and resilience.”

GLP-1 receptor agonists (GLP-1RAs) such as semaglutide and tirzepatide have transformed diabetes and obesity care. Their ability to lower glucose, reduce appetite, shed body weight, and cut near-term cardiovascular risk is nothing short of remarkable. They deserve credit for that.

But as our commentary argues, these gains come with a less visible cost — a progressive erosion of long-term resilience, driven by the one mechanism few people are talking about:

Chronic suppression of glucagon.

And understanding why this matters requires taking a step back to see the bigger metabolic picture.

The Body’s Emergency Energy System — and Why Glucagon Sits at the Control Tower

In every moment of life, your body prepares for stress. Whether the stress comes from fasting, exercise, illness, or emotional strain, survival depends on mobilizing energy quickly.

Two hormones rise immediately during stress:

• Adrenaline (fast-acting)

• Cortisol (slower but sustained)

Both demand one thing: energy must flow.

And glucagon is the foreman at the liver portal ensuring that flow happens.

Glucagon’s essential roles under stress:

• Signals the liver to break down glycogen (glycogenolysis)

• Activates gluconeogenesis, turning amino acids into glucose

• Clears amino acids from circulation and channels them into ureagenesis

• Maintains stable glucose during fasting, exercise, illness, and shock

• Provides substrates for the brain and immune system during stress

Glucagon doesn’t just counter insulin — it coordinates the entire liver–amino acid–muscle economy that keeps us alive during adversity.

What Happens When GLP-1 Drugs Silence This System?

Long-acting GLP-1RAs strongly suppress glucagon — not just after meals, but persistently. And when that suppression becomes chronic, a series of unintended consequences unfolds.

1. The liver stops taking up amino acids properly

Without glucagon, hepatic amino acid clearance slows. This leads to hyperaminoacidaemia, a pattern identical to what is seen in studies where the glucagon receptor is blocked.

2. Muscle becomes the emergency supplier

Cortisol and adrenaline continue demanding amino acids for stress metabolism. But if the liver won’t take them up for proper processing, where do they come from?

Muscle.

Muscle becomes the “bank account” that gets withdrawn from daily:

• Cortisol stimulates muscle proteolysis

• Amino acids flow out

• The liver fails to use them efficiently

• Excess amino acids remain in blood

• Muscle gradually shrinks

This is not traditional malnutrition — it is bioenergetic mismatch.

3. The result: iatrogenic undernutrition and gradual loss of resilience

Our commentary frames this as a form of Exposure-Related Malnutrition (ERM): short-term metabolic wins masking a slow degradation of the body’s adaptive capacity.

Over months to years, this may contribute to:

• Accelerated muscle loss

• Worsening sarcopenic obesity

• Reduced immune recovery

• Slower stress resolution

• Higher vulnerability to illness, surgery, trauma, or metabolic shocks

Even a few percent of lost lean mass matters—especially in older adults, frail individuals, and those with chronic disease.

Why This Matters Now

GLP-1 drugs are reshaping public health. But the conversation has focused almost entirely on:

• weight loss,

• glucose lowering, and

• cardiovascular benefits.

Meanwhile, a consistent pattern of lean mass decline across trials is dismissed as a side effect — or blamed on lower appetite.

The mechanisms we highlight suggest something deeper:a systemic shift in substrate handling driven by glucagon silencing.

This is not about alarmism.

It’s about balance.

If we’re going to prescribe these drugs for years — perhaps lifelong — we must ask:

What are we trading today’s metabolic improvements for?

A Call for Integrative, Muscle-Preserving Care

Our commentary recommends:

• Routine monitoring of muscle function and amino acid profiles

• Recognizing cross-domain patterns of ERM instead of single biomarkers

• Ensuring adequate protein intake

• Supporting resistance or mixed training programs

• Exploring protective pharmacologic adjuncts (e.g., anti-myostatin therapies)

• Future development of biomarker-guided resilience panels

The goal is simple: Use GLP-1RAs wisely, safely, and sustainably — without sacrificing the very resilience that protects us as we age.

Closing Reflection

GLP-1 drugs are powerful.

But power always comes with trade-offs.

Suppressing a stress-adaptive hormone like glucagon may help us in the short term — lower glucose, less weight, improved cardiometabolic markers.

But long-term, we risk handicapping the very mechanism that keeps us alive during strain.

The future of metabolic medicine is not only about controlling numbers.

It’s about preserving capacity, flexibility, and resilience.

This commentary aims to open that dialogue.

If you'd like to read the full article, the citation and PDF are available here: https://rdcu.be/eRLzb

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