By Mia Feldman and Beatrice Acheson

Graphic design by Josip Petrusa

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), known familiarly by brand names like Ozempic and Wegovy, have redefined “virality” in pharmaceuticals. Emerging in a societal landscape shaped by an unmet need for treatments for metabolic disease and a growing obsession with self-optimization, these drugs became a seemingly overnight sensation. 

Despite their sudden cultural ubiquity, GLP-1 RAs are the product of decades of research spearheaded by Dr. Dan Drucker, an endocrinologist and clinician-scientist at the Lunenfeld-Tanenbaum Research Institute and Professor at the University of Toronto. In 1984, Dr. Drucker pursued a research fellowship where he was tasked with characterizing a newly identified protein: GLP-1. Regarding his methodology, he says, “There was no ‘omics back then. It was just very simple biochemistry and physiology.” He employed basic techniques to purify GLP-1 and demonstrate its role as a regulator of insulin, a hormone that maintains normal blood sugar. The findings sparked efforts to harness the protein’s potential as a therapeutic for type 2 diabetes (T2D).¹ 

GLP-1 RAs mimic the GLP-1 peptide to stimulate insulin release in pancreatic cells, promote satiety, and slow digestion. Importantly, they only work in the presence of glucose, reducing the risk of low blood sugar.² Translating the biology of GLP-1 into clinical practice, however, took years. Dr. Drucker attributes the delay to the perception that existing treatment options were sufficient. He recalls, “Why would we want to stimulate insulin secretion through another injection?” Nevertheless, he and his collaborators persisted. Amylin Pharmaceuticals, a small biotech startup, agreed to advance development in 2002 and in 2005, exenatide, the first GLP-1 RA, was approved for clinical use by the Food and Drug Administration (FDA).³ 

Trials led by Dr. Drucker and collaborators demonstrated that exenatide improved blood sugar control and promoted weight loss in individuals with T2D.⁴ Later trials showed that GLP-1 RAs like semaglutide also promote weight loss in individuals without T2D. In 2021, semaglutide was FDA approved for weight loss, marking a major expansion of its clinical use,⁵ and prompted an explosion in prescriptions.⁶ GLP-1 RAs offer the first clinically meaningful solution to weight reduction, reframing obesity as a treatable medical condition rather than a personal failure. 

The widespread use of GLP-1 RAs has provided a wealth of clinical and anecdotal evidence suggesting that the benefits of these drugs extend beyond diabetes and weight management. Importantly, GLP-1 receptors are found in other organs and cell types, not just the pancreas, suggesting that benefits may arise from direct action of GLP-1 RAs that are independent of metabolic improvement.⁷ As these effects emerge, researchers like Dr. Drucker have begun to ask if and how GLP-1 RAs act beyond the pancreas. 

Most recently, Dr. Drucker investigated how GLP-1 RAs exert cardioprotective effects. Vascular smooth muscle cells (VSMCs) regulate blood flow and blood pressure through contraction and relaxation and are known to express GLP-1 receptors.⁸ Dr. Drucker’s lab assessed the involvement of these receptors in the cardioprotective effects of GLP-1 RAs. To test this, they administered semaglutide to mice with and without VSMC GLP-1 receptors and found that the drug lowered blood pressure only in mice expressing intact receptors.⁹ The work provides a potential mechanism for the cardioprotective effects of GLP-1 RAs and inspires future work assessing its relevance in humans. 

Many of the broader benefits of GLP-1 RAs are thought to arise from their ability to modulate inflammation. To understand this effect, Dr. Drucker turned to a less intuitive site: the brain. Unlike cardiovascular cells, immune cells express low levels of GLP-1 receptors, suggesting that GLP-1 RAs may mitigate inflammation indirectly. To explore this, Dr. Drucker’s lab induced inflammation in mice treated with exenatide or placebo. Mice treated with exenatide had lower levels of inflammatory markers, and the effect required intact nervous system GLP-1 receptors.¹⁰ The findings directly implicate the brain-immune axis in the anti-inflammatory actions of GLP-1 RAs. 

The story of GLP-1 RAs is one of immense pharmaceutical success. These drugs have reshaped the treatment of T2D, medicalized weight loss, and demonstrated systemic benefits. Yet, Dr. Drucker emphasizes that progress depends on learning from negative data as much as celebrating the triumphs. This reality was reflected in the EVOKE clinical trials. The ability of GLP-1 RAs to act on the brain and reduce inflammation sparked investigations into their efficacy in treating inflammatory neurodegenerative diseases like Alzheimer’s Disease (AD). Preclinical evidence from other laboratories suggests that GLP-1 RAs attenuate neuroinflammation and neuronal cell death in mouse models of AD.¹¹ Despite initial promise, the EVOKE trials showed that GLP-1 RAs did not significantly reduce the rate of cognitive decline in patients with AD.¹²

Dr. Drucker does not view the outcome as a failure and instead, believes that negative data invites new scientific questions. He explains that the key is to “ask good questions and then use all the available techniques to do rigorous science.” Even when hypotheses are disproven, the knowledge gained moves the field forward.  

The GLP-1 RA story is much more than a viral moment. It is a testament to the slow, methodical nature of scientific discovery, the value of persistence, and the humility necessary to accept negative results and move forward. Dr. Drucker’s work is a reminder that breakthroughs are not instant; they are the product of curiosity, resilience, and a willingness to follow the data where it leads—especially if it’s somewhere unexpected.

References

1. Drucker DJ, Philippe J, Mojsov S, et al Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci U S A. 1987 May;84(10):3434–8. doi:10.1073/pnas.84.10.3434 PubMed PMID: 3033647; PubMed Central PMCID: PMC304885.
2. Drucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab. 2018 Apr 3;27(4):740–56. doi:10.1016/j.cmet.2018.03.001 PubMed PMID: 29617641.
3. Drucker DJ. The GLP-1 journey: from discovery science to therapeutic impact. J Clin Invest. 134(2):e175634. doi:10.1172/JCI175634 PubMed PMID: 38226625; PubMed Central PMCID: PMC10786682.
4. Buse JB, Drucker DJ, Taylor KL, et al. DURATION-1: Exenatide Once Weekly Produces Sustained Glycemic Control and Weight Loss Over 52 Weeks. Diabetes Care. 2010 Mar 9;33(6):1255–61. doi:10.2337/dc09-1914
5. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Mar 17;384(11):989–1002. doi:10.1056/NEJMoa2032183
6. Farahvash A, Lee MC, Jain R, et al. Pattern of semaglutide prescription in a real-world Canadian patient cohort. Prim Care Diabetes. 2025 Oct 1;19(5):512–6. doi:10.1016/j.pcd.2025.06.006
7. GLP1R glucagon like peptide 1 receptor [Homo sapiens (human)] – Gene – NCBI [Internet]. Available from: https://www.ncbi.nlm.nih.gov/gene/2740#gene-expression
8. Pyke C, Heller RS, Kirk RK, et al. GLP-1 Receptor Localization in Monkey and Human Tissue: Novel Distribution Revealed With Extensively Validated Monoclonal Antibody. Endocrinology. 2014 Apr 1;155(4):1280–90. doi:10.1210/en.2013-1934
9. Medak KD, Koehler JA, Baggio LL, et al. Semaglutide Reduces Murine Blood Pressure Through the Vascular Smooth Muscle GLP-1 Receptor. JCI Insight. 2026 Mar 3. doi:10.1172/jci.insight.201148 PubMed PMID: 0.
10. Wong CK, McLean BA, Baggio LL, et al. Central glucagon-like peptide 1 receptor activation inhibits Toll-like receptor agonist-induced inflammation. Cell Metab. 2024 Jan 2;36(1):130-143.e5. doi:10.1016/j.cmet.2023.11.009
11. Sabbagh MN, Cummings JL, Ballard C, et al. Repurposing glucagon-like peptide-1 receptor agonists for the treatment of neurodegenerative disorders. Nat Aging. 2026 Jan;6(1):56–67. doi:10.1038/s43587-025-01029-3
12. Cummings JL, Atri A, Sano M, et al. Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer’s disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trials. The Lancet. 2026 Mar 19;0(0). doi:10.1016/S0140-6736(26)00459-9 PubMed PMID: 41865758.