Dual glucagon/GLP-1 agonists address the full cardiometabolic disease spectrum from obesity to heart failure | Research

The takeaway

Dual glucagon/GLP-1 receptor agonists like survodutide and mazdutide target weight loss, glycemic control, liver fat, and cardiovascular protection simultaneously through synergistic glucagon-mediated energy expenditure and GLP-1 appetite suppression.

Burn more + eat less
Dual glucagon/GLP-1 agonists combine GLP-1 appetite suppression with glucagon-driven energy expenditure and liver fat clearance—a synergy not achievable with GLP-1 alone

What the researchers found

Dual Gcg/GLP-1 agonists: GLP-1 reduces appetite + glucagon increases energy expenditure. Benefits across obesity, T2DM, MASLD/MASH, CVD. Survodutide: significant weight loss + liver fat reduction. Mazdutide: weight + glycemic benefits. Glucagon component adds thermogenesis and hepatic fat clearance.

Why it matters

Pure GLP-1 drugs suppress appetite but do not increase energy expenditure. Adding glucagon agonism creates a "burn more, eat less" dual mechanism that could achieve superior metabolic outcomes.

How the study worked

Narrative review of clinical evidence for dual glucagon/GLP-1 receptor agonists across cardiometabolic conditions.

What this study cannot tell us

Review of emerging clinical data. Most agents in mid-stage development. Long-term safety of glucagon agonism unknown. Glucagon could theoretically worsen glycemia.

How to read the evidence

Review of emerging clinical trial data. Agents in various development stages.

When this study was published

Published in 2025.

The bigger picture

This represents the next evolution in incretin-based therapy: moving from single (GLP-1) to dual (GLP-1/glucagon) to triple (GLP-1/GIP/glucagon) receptor engagement for comprehensive metabolic control.

Questions still open

Will glucagon co-agonism cause hyperglycemia in some patients?
How do dual Gcg/GLP-1 agents compare to tirzepatide?
Is the liver fat reduction from glucagon clinically meaningful?

Common questions

What are dual glucagon/GLP-1 drugs?

These new drugs activate two receptors simultaneously: GLP-1 (which reduces appetite and improves blood sugar) and glucagon (which increases the body's energy burning and clears liver fat). Together, they produce a "burn more, eat less" effect that may achieve better results than GLP-1 drugs alone.

Are these better than semaglutide?

They may be for certain outcomes, especially liver fat reduction. The glucagon component specifically helps clear fat from the liver—a major advantage for patients with fatty liver disease. However, they are still in clinical trials, so head-to-head comparisons with approved drugs are needed.

Read the original research

Efficacy of Dual Glucagon and Glucagon-like Peptide-1 Receptor Agonists Across the Cardiometabolic Continuum: A Review of Current Clinical Evidence.

Reviews in cardiovascular medicine, 26(7), 39691

View on PubMed ↗Publisher’s paper ↗

Citation

Stachteas, Panagiotis; Nasoufidou, Athina; Karakasis, Paschalis; Koiliari, Markella; Karagiannidis, Efstratios; Koufakis, Theocharis; Fragakis, Nikolaos; Patoulias, Dimitrios. (2025). Efficacy of Dual Glucagon and Glucagon-like Peptide-1 Receptor Agonists Across the Cardiometabolic Continuum: A Review of Current Clinical Evidence.. Reviews in cardiovascular medicine, 26(7), 39691. https://doi.org/10.31083/RCM39691