Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have revolutionised the management of type 2 diabetes mellitus (T2DM) and obesity. However, emerging evidence demonstrates a broad spectrum of clinical benefits extending beyond glycaemic and weight control. This article attempts to summarises current and emerging therapeutic indications for GLP-1 RAs outside obesity. While not an exhaustive list, it provides insight into the possible future development and clinical uses of GLP-1 RAs.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are incretin-based therapies that mimic endogenous GLP-1 to stimulate insulin secretion, inhibit glucagon release, delay gastric emptying, and promote satiety. Initially developed for T2DM management, these agents have demonstrated profound weight-loss effects and have been widely adopted for obesity treatment.
Beyond metabolic control, GLP-1 receptors are expressed in diverse tissues, including the heart, vasculature, kidneys, liver, and brain, implicating broader physiologic functions.1–3 The pleiotropic actions of GLP-1 RAs ranging from anti-inflammatory and anti-oxidative effects to modulation of cell signalling and fibrosis have prompted clinical trials across multiple organ systems.4
GLP-1 RAs act through both central and peripheral pathways. In addition to their incretin effects, they influence endothelial function, lipid metabolism, and inflammatory signaling.5 Preclinical studies demonstrate that GLP-1 activation reduces oxidative stress, improves mitochondrial bioenergetics, and inhibits apoptosis in cardiomyocytes and neurons.6
These mechanisms underpin observed clinical benefits, suggesting that GLP-1 RAs exert direct organ-protective effects independent of glucose or weight modulation.
The Broad Case for GLP-1 RAs
GLP-1 receptor agonists (GLP-1 RAs) offer significant therapeutic benefits well beyond weight management and type 2 diabetes treatment, leveraging their systemic effects on multiple organs. The most established uses are in cardiovascular and renal health. Certain GLP-1 RAs are approved to reduce the risk of major adverse cardiovascular events like heart attack and stroke in high-risk patients. They also play a crucial role in slowing the progression of chronic kidney disease, reducing the risk of kidney failure. Tirzepatide has gained approval for obstructive sleep apnoea by targeting excess upper airway tissue.
Emerging research indicates potential off-label applications across various other conditions: they show promise in neurodegenerative disorders such as Alzheimer’s and Parkinson’s due to their neuroprotective properties; they are being investigated for treating metabolic dysfunction-associated steatotic liver disease (MASLD) by reducing liver inflammation and fibrosis; and they may aid in managing substance use disorders by modulating the brain’s reward pathways to reduce cravings for alcohol and nicotine. Furthermore, they are explored for conditions like polycystic ovary syndrome and knee osteoarthritis, benefiting from both weight loss and direct anti-inflammatory actions. This broad range of effects highlights the extensive therapeutic potential of GLP-1 RAs across various medical disciplines. Below, we will go into further detail on some of the potential use cases for GLP-1 RAs.
