Why GLP-1 Drugs May Need Glucagon to Boost Metabolism for Better Weight Loss | Research

The takeaway

GLP-1 drugs suppress appetite but don't increase energy expenditure — adding glucagon receptor activation could close this metabolic gap for more effective obesity treatment.

Energy expenditure gap
GLP-1 drugs suppress appetite but don't prevent the metabolic slowdown that limits long-term weight loss

What the researchers found

Glucagon receptor agonism increases lipid oxidation, substrate mobilization, and energy expenditure, complementing GLP-1R appetite suppression and potentially overcoming adaptive metabolic decline during weight loss.

Why it matters

The metabolic slowdown during weight loss is a major reason people plateau or regain weight. Adding glucagon receptor activation could be the key to sustaining weight loss long-term.

How the study worked

Narrative review integrating historical, preclinical, and clinical evidence on glucagon as a regulator of energy expenditure and its therapeutic potential alongside GLP-1 agonism.

What this study cannot tell us

Review article — no new experimental data. Glucagon's hyperglycemic effects pose safety challenges that need to be balanced against metabolic benefits.

How to read the evidence

Narrative review integrating preclinical and clinical evidence — provides strong mechanistic rationale but no new trial data.

When this study was published

Published in 2026; directly relevant to next-generation obesity drugs in development.

The bigger picture

This explains the rationale behind next-generation triple agonists (GLP-1/GIP/glucagon) like retatrutide and survodutide that are showing unprecedented weight loss in clinical trials.

Questions still open

Can the EE-boosting effects of glucagon be separated from its blood sugar-raising effects?
Will triple agonists including glucagon produce more durable weight loss than GLP-1 alone?

Common questions

Why does metabolism slow during weight loss?

When you lose weight, your body adapts by burning fewer calories — this is called adaptive thermogenesis. It's a survival mechanism that makes continued weight loss harder and promotes weight regain.

What are triple agonist drugs?

Triple agonists target three hormone receptors (GLP-1, GIP, and glucagon) simultaneously. By combining appetite suppression with increased energy burning, they may produce more weight loss than current drugs like semaglutide or tirzepatide.

Read the original research

GLP-1 is not enough: can glucagon fill the energy expenditure gap?

Neuroendocrinology, 1-26

View on PubMed ↗Publisher’s paper ↗

Citation

Beji, Sarra; Caron, Alexandre. (2026). GLP-1 is not enough: can glucagon fill the energy expenditure gap?. Neuroendocrinology, 1-26. https://doi.org/10.1159/000550812