September 25, 2026European Heart Journal
Semaglutide mechanisms of action: the missing pieces
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
HCHelen ColhounProfessor of medicine, University of Edinburgh
“Our analyses could not fully ascribe the effects of semaglutide on cardiovascular disease to known risk factors with any certainty. Whether we combine all risk factors together or look at some subsets of the risk factors, no more than half of the reduction in heart disease could be explained by the changes in these risk factors. These results suggest that semaglutide should be considered as a cardiovascular disease reduction drug and not just as a weight loss drug.”
“By all accounts, the remarkable story of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in cardiovascular medicine has been one of serendipity. Two years ago, in the European Heart Journal, we wrote that the journey of semaglutide was one such story—a drug born to lower glucose that has become the most versatile weapon against cardiometabolic-, kidney-, and obesity-related disease”
Overview
Narrative review reveals unresolved central and peripheral mechanisms of semaglutide in metabolic disease, highlighting key targets for next-generation drug design.
Key Points
- To review the established pharmacology of semaglutide and evaluate critical knowledge gaps in its central and peripheral mechanisms of action.
- Narrative synthesis of preclinical models and clinical trial data investigating semaglutide signaling and physiological outcomes.
- Semaglutide stimulates glucose-dependent insulin secretion, suppresses inappropriate glucagon release, and delays gastric emptying via glucagon-like peptide-1 receptor activation.
- Appetite suppression is mediated primarily by access to hypothalamic and hindbrain circuits, though exact downstream neuronal populations and non-pancreatic peripheral actions remain incompletely defined.
Cite This Study
Verma et al. (2026) studied this question.