Ozempic, Wegovy, Mounjaro, Oh My: Exploring the Science and History of GLP-1 Receptor Agonist Use for Type 2 Diabetes Mellitus and Weight Loss

Written by: Allison Gundrum

Edited by: Zahra Khan and Rachel Smith

Illustrated by: Kate Jang

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Introduction

Within the past two years, the names of GLP-1 receptor agonist (GLP-1RA) medications such as Ozempic and Wegovy have been launched from relative obscurity to their current dominance across health-related news, social media feeds, and dinnertime conversations. In the wake of skyrocketing public interest in GLP-1RAs, conflicting messages and overt misinformation about these drugs have become increasingly common across mainstream and social media platforms [1]. Simultaneously, rising interest in and prescription of these drugs has driven an expansion of scientific research on the use of GLP-1RAs to treat conditions beyond type 2 diabetes mellitus (T2DM, a chronic disease characterized by insulin resistance, resulting in high blood glucose levels), for which they were initially approved. This dual proliferation of misinformation and scientific research has made it increasingly difficult to navigate the information ecosystem surrounding GLP-1 agonists. This article aims to provide a basic overview of the science behind GLP-1 receptor agonists and their historical use in order to provide an accurate foundation for understanding and evaluating how these medications are used today.

What are GLP-1 Agonists?

Glucagon-like-peptide 1 receptor agonists, or GLP-1RAs, are medications that mimic the GLP-1 hormone that the body naturally produces [2]. GLP-1 is mostly produced and secreted by cells in the intestine in response to meals, then transported through the bloodstream to bind GLP-1 receptors in tissues throughout the body [3]. GLP-1 receptor activation triggers increased insulin secretion (which lowers blood glucose), increases feelings of satiety, and slows the movement of food from the stomach to the gut [3]. Because of the efficacy of these mechanisms in regulating blood glucose in patients with T2DM, GLP-1 agonists have been prescribed to treat T2DM in the United States since 2005 [4, 5]. While there are over half a dozen unique drugs in this class, all GLP-1RAs function through the same mechanism described above, varying based on their distinct formulations rather than through unique pathways. For example, semaglutide (a drug approved under the brand names Ozempic and Wegovy at different doses to treat T2DM and obesity, respectively) has been formulated to be administered weekly, while liraglutide (approved under the brand names Victoza and Saxenda to treat T2DM) must be administered daily [6]. 

Use of GLP-1 Agonists for T2DM

Over the past two decades, GLP-1RAs have become critical tools for successful management of T2DM, primarily as a treatment option for patients who do not tolerate metformin, the most commonly used drug to treat T2DM [7]. GLP-1RAs are also now recommended as first-line treatments for T2DM in patients with comorbidities such as chronic kidney disease or congestive heart failure due to evidence that these medications are effective in improving cardiovascular events, all-cause mortality (death by any cause during the study period), and kidney outcomes for patients with these comorbidities [5, 8, 9]. 

Though the prescription of GLP-1RAs for weight loss has increased sharply over the past several years, the use of these medications has lagged over the past two decades in patients with T2DM who are at high risk of adverse events due to underlying cardiovascular or kidney disease [8, 10]. One 2023 report estimates that while roughly 46% of US patients with T2DM meet the recommended criteria for GLP-1RA use, only 3.7% used the drug between 2017 and 2020 [11]. Low uptake of these medications despite potentially life-saving benefits is likely attributable to a wide range of systemic and personal factors, including potential unfamiliarity of some physicians with the benefits of these drugs for patients with certain comorbidities, patient hesitancy surrounding injection medications, and high cost. Though the amount patients will pay for their medication varies significantly depending on the specific brand and dose of GLP-1RA used and their insurance coverage, the average cost per year (based on manufacturer price) of treatment with GLP1-RAs is typically between 10 and 20 times higher than treatment with metformin [12]. 

In addition to broader factors influencing GLP-1RA use to treat T2DM, several cohort studies have uncovered alarming disparities in GLP-1RA use based on socioeconomic status and racial/ethnic background [13]. One such study evaluating GLP-1 agonist use in US patients with T2DM found significantly lower rates of GLP-1 agonist treatment in Black, Hispanic, and Asian patients compared with White patients [14]. Additionally, several studies have found that patients in lower-income households and those with fewer years of education are also significantly less likely to receive treatment with GLP-1RAs for their T2DM [13]. These studies cite suboptimal health insurance, provider biases, cultural and/or linguistic barriers, and financial barriers as potential drivers of these disparities in GLP-1RA use [13]. Given the efficacy of GLP-1 agonists in treating T2DM and reducing risks of adverse kidney and cardiovascular events, further investigation of these disparities in GLP-1RA use and implementation of strategies to promote more equitable access to these medications is critical.

Use of GLP-1 Agonists for Obesity + Weight Loss

Obesity is a chronic disease with a high (and climbing) prevalence globally and multiple associated comorbidities such as T2DM, hypertension, cardiovascular disease, and depression [15]. The success rates of previous clinical interventions for long-term obesity treatment are relatively low. In this context, GLP-1RAs, which had been previously shown to induce significant weight loss in patients with T2DM, emerged as potential therapeutic agents for treating obesity [15]. The GLP-1RA liraglutide was approved by the FDA for weight loss in non-diabetic obesity under the name Saxenda in 2014 after clinical trials showed 76% of patients who took the drug for 20 weeks successfully lost more than 5% of their total body weight, as compared to 30% success in the placebo group [16]. Liraglutide has also been found to lower blood pressure and reduce the prevalence of prediabetes (high blood sugar that is not yet elevated enough to be considered T2DM), two common obesity-related complications [17]. A second GLP-1RA, semaglutide, was approved by the FDA for weight loss in non-diabetic obesity in 2021 under the name Wegovy and has been found to have similar effectiveness in treating obesity and related complications [10,17]. 

The use of these drugs to treat non-diabetic obesity has increased dramatically in recent years. Saxenda (approved in 2014) observed a 543% increase in prescription volume per 1,000 Medicaid enrollees between 2019 and 2022 [10]. Increased demand for GLP-1RAs for treating non-diabetic obesity has also driven increased off-label prescription (prescription of a drug by a physician to treat something it is not FDA approved for) of GLP-1RAs formulated to treat T2DM [18]. An analysis of Ozempic (a semaglutide drug approved exclusively for the treatment of T2DM) users found that the proportion of patients taking the drug who had a diagnosis of diabetes or prediabetes fell from 92% to 77% between 2018 and 2021 [10]. This surge in demand, driven in part by several notable celebrities crediting the drug with their weight loss and buzz on social media, resulted in shortages of several GLP-1RAs approved to treat T2DM as well as those approved for obesity across multiple countries, and as of early 2024, several drug companies say they are still struggling to meet demand [19, 20].

Conclusions

Beyond the flashy headlines and celebrity weight loss testimonials that have fed public discourse surrounding GLP-1RAs over the past several years, incidence of T2DM and obesity continue to rise globally [15]. Currently, treatment with GLP-1RAs remains one of the most effective options for improving common comorbidities of and reducing all-cause mortality in T2DM, and early studies suggest similar cardioprotective effects may be observed in patients being treated with GLP-1RAs for non-diabetic obesity [21]. In this context, understanding and promptly addressing systemic factors behind disparities in use of these medications to treat patients with T2DM based on socioeconomic status and racial/ethnic background is crucial, especially in light of the higher burden of T2DM and cardiovascular disease in these populations [13]. Additionally, the availability of clear, accurate, and accessible information about these medications to the public as new research emerges is critical in promoting better understanding of these drugs and empowering patients who are considering taking a GLP-1RA to make informed decisions about their health.

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References

[1] Basch, Corey H., et al. (2023). Descriptive analysis of TikTok videos posted under the hashtag #Ozempic. Journal of Medicine, Surgery, and Public Health, 1, 100013. https://doi.org/10.1016/j.glmedi.2023.100013.

[2] Vilsbøll, T., et al. (2003). Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus. The Journal of Clinical Endocrinology & Metabolism, 88, 2706–2713. https://doi.org/10.1210/jc.2002-021873. 

[3] Smith, N. K., et al. (2019). GLP-1: Molecular mechanisms and outcomes of a complex signaling system. Neurochemistry International, 128, 94–105. https://doi.org/10.1016/j.neuint.2019.04.010.

 [4] Sheahan, K. H., et al. (2019). An overview of GLP-1 agonists and recent cardiovascular outcomes trials. Postgraduate Medical Journal, 96, 156–161. https://doi.org/10.1136/postgradmedj-2019-137186.

[5] American Diabetes Association. (2018) 9. pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2019. Diabetes Care, 42, no. Supplement_1. https://doi.org/10.2337/dc19-s009.

[6] Collins, L., Costello, RA. (2023). Glucagon-Like Peptide-1 Receptor Agonists. Stat Pearls. https://www.ncbi.nlm.nih.gov/books/NBK551568/

[7] Pernicova, I., & Korbonits, M. (2014). Metformin--mode of action and clinical implications for diabetes and cancer. Nature reviews. Endocrinology, 10(3), 143–156. https://doi.org/10.1038/nrendo.2013.256

[8] Honigberg, M. C., Chang, L. S., McGuire, D. K., Plutzky, J., Aroda, V. R., & Vaduganathan, M. (2020). Use of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Type 2 Diabetes and Cardiovascular Disease: A Review. JAMA cardiology, 5(10), 1182–1190. https://doi.org/10.1001/jamacardio.2020.1966

[9] Sattar, N., Lee, M. M. Y., Kristensen, S. L., Branch, K. R. H., Del Prato, S., Khurmi, N. S., Lam, C. S. P., Lopes, R. D., McMurray, J. J. V., Pratley, R. E., Rosenstock, J., & Gerstein, H. C. (2021). Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. The lancet. Diabetes & endocrinology, 9(10), 653–662. https://doi.org/10.1016/S2213-8587(21)00203-5

[10] Niakan, K. (2024). GLP-1 Agonists in Medicaid: Utilization, Growth, And Management. Milliman White Paper. www.milliman.com/-/media/milliman/pdfs/2024-articles/1-18-24_glp1-agonists-in-medicaid-utilization-growth-and-management.ashx.

[11] Tang, S., Shao, H., Ali, M. K., & Zhang, P. (2023). Recommended and Prevalent Use of Glucagon-like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors in a National Population-Based Sample. Annals of internal medicine, 176(4), 582–583. https://doi.org/10.7326/M22-3051

[12] Canadian Agency for Drugs and Technologies in Health. (2019). Pharmacoeconomic Review Report: Semaglutide (Ozempic). Novo Nordisk Canada Inc. https://www.ncbi.nlm.nih.gov/books/NBK543967/

[13] Karagiannis, T., et al. (2023). Socioeconomic aspects of incretin-based therapy. Diabetologia, 66,  1859–1868. https://doi.org/10.1007/s00125-023-05962-z.

[14] Eberly, L. A., Yang, L., Essien, U. R., et al. (2021). Racial, Ethnic, and Socioeconomic Inequities in Glucagon-Like Peptide-1 Receptor Agonist Use Among Patients With Diabetes in the US. JAMA Health Forum, 2(12). https://doi.org/10.1001/jamahealthforum.2021.4182

[15] Popoviciu, M. S., Păduraru, L., Yahya, G., Metwally, K., & Cavalu, S. (2023). Emerging Role of GLP-1 Agonists in Obesity: A Comprehensive Review of Randomised Controlled Trials. International journal of molecular sciences, 24(13), 10449. https://doi.org/10.3390/ijms241310449

[16] Astrup, A., Rössner, S., Van Gaal, L., Rissanen, A., et al. (2009). Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet (London, England), 374(9701), 1606–1616. https://doi.org/10.1016/S0140-6736(09)61375-1

[17] Gao, X., Hua, X., Wang, X., Xu, W., Zhang, Y., Shi, C., & Gu, M. (2022). Efficacy and safety of semaglutide on weight loss in obese or overweight patients without diabetes: A systematic review and meta-analysis of randomized controlled trials. Frontiers in pharmacology, 13, 935823. https://doi.org/10.3389/fphar.2022.935823

[18] Wojtara, M., Mazumder, A., Syeda, Y., & Mozgała, N. (2023). Glucagon-Like Peptide-1 Receptor Agonists for Chronic Weight Management. Advances in medicine, 2023, 9946924. https://doi.org/10.1155/2023/9946924

[19] Blum, D. (2022). What Is Ozempic and Why Is It Getting so Much Attention? The New York Times. www.nytimes.com/2022/11/22/well/ozempic-diabetes-weight-loss.html. 

[20] Gilbert, D. (2024). Makers of Ozempic, Mounjaro Race to Meet Demand for Weight-Loss Drugs. The Washington Post. www.washingtonpost.com/business/2024/02/08/novo-nordisk-eli-lilly-manufacturing/. 

[21] Singh, S., Garg, A., Tantry, U. S., Bliden, K., Gurbel, P. A., & Gulati, M. (2024). Safety and efficacy of glucagon-like peptide-1 receptor agonists on cardiovascular events in overweight or obese non-diabetic patients. Current problems in cardiology, 49(3), 102403. https://doi.org/10.1016/j.cpcardiol.2024.10240