Beyond Diabetes: The Expanding Potential of GLP-1

In recent years, the development of glucagon-like peptide-1 (GLP-1) receptor agonists for weight loss and diabetes has taken the biotech market by storm, thanks to their effectiveness, as demonstrated in multiple studies [1– 4].

GLP-1 is a hormone secreted by the small intestine in response to food intake. As an incretin hormone, it lowers blood glucose by stimulating insulin secretion and inhibiting glucagon production. Additionally, GLP-1 acts on the hypothalamus to prolong satiety by enhancing leptin (the satiety hormone) signals while suppressing ghrelin (the hunger hormone) [3]. Based on these effects, pharmaceutical companies have invested heavily in the development of GLP-1 receptor agonists that mimic and enhance these metabolic functions.

To create synthetic GLP-1 analogs, researchers have employed amino acid substitutions, fatty acid conjugation, and fusion with larger molecules (e.g., albumin) [4]. These modifications increase the molecule’s half-life and resistance to enzymatic degradation (e.g., hydrolysis by dipeptidyl peptidase-4 [DPP-4]), making these drugs more effective and longer-lasting than endogenous GLP-1.

Pharmaceutical Repurposing: A Cost-Effective Strategy

Pharmaceutical repurposing involves identifying new therapeutic applications for existing drugs originally developed for other conditions. A well-known example is Sildenafil (Viagra), which was initially designed to treat hypertension but was later found to be effective for erectile dysfunction. Repurposing reduces development costs and accelerates regulatory approval, as the molecule has already undergone extensive safety testing.

Recent research suggests that GLP-1 receptor agonists may have neuroprotective and anti-inflammatory effects [5–11]. These drugs appear to modulate microglial activity and cytokine signaling, reducing neuroinflammation and oxidative stress while improving mitochondrial integrity and function. This, in turn, could enhance synaptic and motor function, creating a more resilient neurological system.

GLP-1 and Neurodegenerative Disease Prevention

A recent retrospective cohort study [8] examined a population of approximately 5 million obese adults across 17 countries, comparing the incidence of neurodegenerative disorders (e.g., Alzheimer’s disease) between those treated with GLP-1 receptor agonists and those who were not. The results showed a 37% reduction in risk among GLP-1-treated cohorts. Although causality cannot be definitively established, complementary in vivo studies in mouse models have further demonstrated improved neurological function following GLP-1 treatment [9]. In another study [11], in vitro testing of GLP-1 on cultures derived from hyperglycemic rat brain capillary endothelial cells suggested strengthening of the blood-brain barrier (the protein barrier separating the bloodstream from the brain’s extracellular fluid) via inhibition of reactive oxygen species. This ultimately creates a protective environment that could help prevent neurological disorders. These and other emerging studies provide compelling evidence that may inform future therapeutic applications for disorders such as Alzheimer’s and dementia.

The Future of GLP-1: A Multi-Purpose Therapeutic?

While most GLP-1 research has focused on diabetes and weight loss, an expanding body of evidence suggests broader applications. Continued research into GLP-1 repurposing may uncover new therapeutic uses beyond metabolic disorders.

As interest in GLP-1 agonists continues to grow, more findings are likely to emerge from research groups worldwide. With further validation, GLP-1-based therapies may soon extend beyond their traditional applications, offering potential benefits for neurodegenerative diseases, inflammation, and other metabolic conditions.

References:

1.  Moiz A, Filion KB, Toutounchi H, Tsoukas MA, Yu OHY, Peters TM, and Eisenberg MJ (2025) Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes. Ann Intern Med 178, 199–217.

2.  White GE, Shu I, Rometo D, Arnold J, Korytkowski M, and Luo J (2023) Real-world weight loss effectiveness of GLP-1 agonists among patients with type 2 diabetes: a retrospective cohort study. Obesity (Silver Spring) 31, 537–544.

3.  Smith NK, Hackett TA, Galli A, and Flynn CR (2019) GLP-1: Molecular mechanisms and outcomes of a complex signaling system. Neurochem Int 128, 94–105.

4.  Friedman JM (2024) The discovery and development of GLP-1 based drugs that have revolutionized the treatment of obesity. Proceedings of the National Academy of Sciences 121, e2415550121.

5.  Erbil D, Eren CY, Demirel C, Küçüker MU, Solaroğlu I, and Eser HY (2019) GLP-1’s role in neuroprotection: a systematic review. Brain Injury 33, 734–819.

6.  Reich N, and Hölscher C (2022) The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: An in-depth review. Front Neurosci.

7.  Bendotti G, Montefusco L, Lunati ME, et al (2022) The anti-inflammatory and immunological properties of GLP-1 Receptor Agonists. Pharmacological Research 182, 106320.

8.  Siddeeque N, Hussein MH, Abdelmaksoud A, Bishop J, Attia AS, Elshazli RM, Fawzy MS, and Toraih EA (2024) Neuroprotective effects of GLP-1 receptor agonists in neurodegenerative Disorders: A Large-Scale Propensity-Matched cohort study. International Immunopharmacology 143, 113537.

9.  Bomba M, Granzotto A, Castelli V, Onofrj M, Lattanzio R, Cimini A, and Sensi SL (2019) Exenatide Reverts the High-Fat-Diet-Induced Impairment of BDNF Signaling and Inflammatory Response in an Animal Model of Alzheimer’s Disease. Journal of Alzheimer’s Disease 70, 793–810.

10.  Timper K, Del Río-Martín A, Cremer AL, et al (2020) GLP-1 Receptor Signaling in Astrocytes Regulates Fatty Acid Oxidation, Mitochondrial Integrity, and Function. Cell Metab 31, 1189-1205.e13.

11.  Fukuda S, Nakagawa S, Tatsumi R, Morofuji Y, Takeshita T, Hayashi K, Tanaka K, Matsuo T, and Niwa M (2016) Glucagon-Like Peptide-1 Strengthens the Barrier Integrity in Primary Cultures of Rat Brain Endothelial Cells Under Basal and Hyperglycemia Conditions. J Mol Neurosci 59, 211–219.