The Rise of glp-1 agonists: understanding their impact on health

Written By Alina Schmidt

Glucagon-like peptide-1 receptor agonists, commonly known as GLP-1 agonists, have surged into the mainstream, with celebrities often attributing their physiques to these medications. But what exactly are these drugs, where did they originate, and how do they work?

What is a GLP-1 Agonist? 

GLP-1 drugs are termed "agonists" because they mimic the actions of the natural GLP-1 hormone. The key difference lies in their duration of action: the natural GLP-1 hormone has a very short half-life, lasting only a few minutes, whereas GLP-1 drugs have an extended action, lasting for hours or even days, depending on the specific medication (Cleveland Clinic, n.d.). This prolonged action provides sustained blood sugar control by enhancing insulin secretion and inhibiting glucagon. Consequently, it increases fullness and suppresses hunger for longer, significantly contributing to weight loss (Harvard Health, n.d.).

The Organic GLP-1 hormone Function 

The naturally occurring GLP-1 hormone produced in the gut is a hormone that plays a crucial role in regulating blood sugar, appetite, and digestion. It primarily functions by stimulating the pancreas to release insulin. Insulin (a hormone) acts as a key, opening cell doors to allow carbohydrates to enter and be used for various metabolic functions, including energy production (ATP) (Mojsov et al., 1986).

When you eat, blood sugar naturally rises with carbohydrate intake. The GLP-1 hormone activates, triggering an increase in insulin release from the pancreas (more keys open more doors). This process shuttles sugar molecules from the blood into cells and tissues, lowering blood sugar to a normal range. Simultaneously, the GLP-1 hormone inhibits the release of glucagon from the pancreas, another hormone responsible for raising blood sugar in times of fasting, exercise, or starvation (Kreymann et al., 1987; Cleveland Clinic, 2025.). 

The Original Natural Appetite Suppressant

Beyond blood sugar regulation, the GLP-1 hormone also acts on the brain's appetite center, signaling a feeling of fullness during or after meals. This signal travels through the vagus nerve to the brainstem. The GLP-1 hormone activates GLP-1 receptors on vagal afferents (sensory communicator), leading to a reduction in stomach muscle contractions and an increased contraction of the pylorus (the valve/trap door between the stomach and small intestine). This causes food to remain in the stomach for longer periods, contributing to prolonged satiety. It further influences the hypothalamus, the part of the brain that controls hunger, to promote feelings of fullness, aiding in nutrient absorption and blood glucose regulation (Cleveland Clinic, n.d.).

The Scientific Journey of Discovery

The path to GLP-1 agonists is a fascinating scientific journey:

  • 1970s-1980s: The Incretin Clue 

    • Doctors notice the incretin effect: meals, especially those with carbohydrates and fats, trigger more insulin release post-meal.

    • Scientists map the proglucagon gene and predict new peptides, GLP-1 and GLP-2.

    • A short fragment, GLP-1 (7-36) amide, proves powerfully insulin-stimulating in humans (Mojsov, 2024; Kreymann et al., 1987). 

  • Early 1990s: Targets and Tougher Molecules

    • The GLP-receptor is cloned! We now know the lock the key fits into (Thorens, 1992).

    • Native GLP-1 is destroyed within minutes by DPP-4 (a native enzyme in the body that plays a role in regulating blood sugar levels) → infusions work, injections do not last. 

    • A naturally DPP-4 resistant cousin, exendin-4 (from Gila monster, see right, venom), points to longer-acting drugs (Holst, 2007). 

  • 2005-2014: First Medicines Hit Clinics 

    • Exenatide  launches (first GLP-1 receptor agonist, (RA’s) mimics natural hormone), then liraglutide and weekly options like dulaglutide. 

    • Real-world impact: meaningful A1c drops with low hypoglycemia  risk and weight loss. 

  • 2015-2021: Beyond Glucose - Hard Outcomes and Obesity 

    • Large trials show fewer major cardiovascular events with several GLP-1 RA’s.

    • Higher-dose formulations gain chronic weight-management approvals; semaglutide sets a new bar for average weight loss. ~15% mean weight loss vs placebo  (Pi-Sunyer et al., 2015).  

  • 2017- Present: Potency, Convenience, Broader Benefits

    • Once-weekly semaglutide and the first oral GLP-1 RA expand access.

    • Labels add cardiovascular risk-reduction (and, for some products, kidney-related benefits) in specific populations (Garvey et al., 2022).  

Important Nutritional Considerations with GLP-1 Agonists 

When using GLP-1 agonists, certain nutritional considerations are important:

  • Protein: Adequate protein intake can help maintain muscle mass and promote satiety.

  • Hydration: Staying well-hydrated is crucial for overall health and can help manage potential side effects.

  • Small, Frequent Meals: This approach can help regulate blood sugar and reduce digestive discomfort.

  • Multivitamin with Minerals: Ensuring adequate micronutrient intake is important, especially with changes in eating patterns.

Long-Term Effects and Discontinuation

Within a year on GLP-1 medicines, most people see a decrease in A1c, weight, and blood pressure (and fewer strokes/kidney events) compared with placebo (Alexander et al., 2021). Continued use for 2 years depict a maintained weight loss (about ~15% with semaglutide 2.4 mg in STEP 5); stopping usage usually leads to weight regain (Garvey et al., 2022; Rubino et al., 2021’ Wilding et al., 2022). Duration of 2-5+ years shows fewer major heart events, including in people without diabetes, and kidney protection in type 2 diabetes with CKD (Marso et al., 2016a; Gerstein et al., 2019; Marso et al., 2016b; Lincoff et al., 2023; Perjovic et al., 2024). 

Discontinuing glucagon-like peptide-1 receptor agonists and body habitus: A systematic review and meta-analysis published  in April 2025  looked at what happens to body weight after people stop a GLP-1 medicine (Berg et al., 2025). The researchers reviewed results from 8 randomized trials with over 2,000 adults all with BMIs >27. The study found a pattern when people stop GLP-1 drugs weight is gained back, often the total amount that had been lost. It depicts that these drugs help while taking them, but stopping usually means some weight comes back, so long-term plans of action matter.To sustain weight loss and blood sugar management, it's essential to build long-term, maintainable, and achievable lifestyle habits. Consulting a dietitian can be invaluable in developing these strategies (Berg et al., 2025; Alexander et al., 2021).

References

  • Cleveland Clinic. (n.d.). GLP-1 agonists. Retrieved from https://my.clevelandclinic.org/health/treatments/13901-glp-1-agonists

  • Harvard Health. (n.d.). GLP-1 diabetes and weight loss drug side effects: Ozempic face and more. Retrieved from https://www.health.harvard.edu/staying-healthy/glp-1-diabetes-and-weight-loss-drug-side-effects-ozempic-face-and-more

  • Cleveland Clinic. (2025, January 21). Glucagon: What it is, function & related conditions. https://my.clevelandclinic.org/health/articles/22283-glucagon my.clevelandclinic.org

  • Kreymann, B., Ghatei, M. A., Williams, G., & Bloom, S. R. (1987). Glucagon-like peptide-1 7-36: A physiological incretin in man. The Lancet, 329(8542), 1300-1304.

  • Mojsov, S. (2024). The development of glucagon-like peptide-1 as a therapeutic agent. PNAS. Retrieved from https://www.pnas.org/doi/10.1073/pnas.2415550121#:~:text=%E2%80%9CIncretine%E2%80%9D%20would%20remain%20undiscovered%20until,source%20of%20glucagon%2Dproducing%20cells.

  • Mojsov, S., Weir, G. C., & Habener, J. F. (1986). Insulinotropic action of glucagon-like peptide-I (7-37) at physiological concentrations in the perfused rat pancreas. Journal of Clinical Investigation, 78(1), 140-146.

  • Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet. 1987 Dec 5;2(8571):1300-4. doi: 10.1016/s0140-6736(87)91194-9. PMID: 2890903.

  • Thorens B. Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8641-5. doi: 10.1073/pnas.89.18.8641. PMID: 1326760; PMCID: PMC49976.

  • Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007 Oct;87(4):1409-39. doi: 10.1152/physrev.00034.2006. PMID: 17928588

  • Pi-Sunyer, X., Astrup, A., Fujioka, K., Greenway, F., Halpern, A., Krempf, M., Lau, D. C. W., le Roux, C. W., Violante Ortiz, R., Jensen, C. B., & Wilding, J. P. H., for the SCALE Obesity and Prediabetes NN8022-1839 Study Group. (2015). A randomized, controlled trial of 3.0 mg of liraglutide in weight management. New England Journal of Medicine, 373(1), 11–22. https://doi.org/10.1056/NEJMoa1411892

  • Garvey, W.T., Batterham, R.L., Bhatta, M. et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med 28, 2083–2091 (2022). https://doi.org/10.1038/s41591-022-02026-4

  • Alexander, J. T., Staab, E. M., Wan, W., Franco, M., Klittler, A., Sikandari, M. R., Bolen, S., Maruthur, N. M., Huang, E. S., Phillipson, L. H., Wynn, A. N., Thomas, C. C., Peytinoğlu, M., Press, V. G., Tung, E. L., Gunter, K., Bindon, B., Jumamil, S., & Latif, N. (2021). The longer-term benefits and harms of glucagon-like peptide-1 receptor agonists: A systematic review and meta-analysis. Journal of General Internal Medicine, 37(2), 415–438. https://doi.org/10.1007/s11606-021-07015-9       

  • Garvey, W. T., Batterham, R. L., Bhatta, M., Buscemi, S., Chou, S. H., Dicker, D., … Wilding, J. P. H. (2022). Two-year effects of semaglutide in adults with overweight or obesity (STEP 5). Nature Medicine, 28, 2083–2091. https://doi.org/10.1038/s41591-022-02026-4 Nature+1

  • Gerstein, H. C., Colhoun, H. M., Dagenais, G. R., Diaz, R., Lakshmanan, M., Pais, P., … REWIND Investigators. (2019). Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND). The Lancet, 394(10193), 121–130. https://doi.org/10.1016/S0140-6736(19)31149-3 PubMed

  • Lincoff, A. M., Brown-Frandsen, K., Colhoun, H. M., Deanfield, J., Emerson, S. S., Esbjerg, S., … SELECT Trial Investigators. (2023). Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). New England Journal of Medicine, 389(24), 2221–2232. https://doi.org/10.1056/NEJMoa2307563 PubMed

  • Marso, S. P., Daniels, G. H., Brown-Frandsen, K., Kristensen, P., Mann, J. F. E., Nauck, M. A., … LEADER Trial Investigators. (2016a). Liraglutide and cardiovascular outcomes in type 2 diabetes (LEADER). New England Journal of Medicine, 375(4), 311–322. https://doi.org/10.1056/NEJMoa1603827 PubMed

  • Marso, S. P., Bain, S. C., Consoli, A., Eliaschewitz, F. G., Jódar, E., Leiter, L. A., … SUSTAIN-6 Investigators. (2016b). Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6). New England Journal of Medicine, 375(19), 1834–1844. https://doi.org/10.1056/NEJMoa1607141 PubMed

  • Perkovic, V., Kline, G. A., Li, Q., Mahaffey, K. W., Neal, B., Ruilope, L. M., … FLOW Trial Investigators. (2024). Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes (FLOW). New England Journal of Medicine, 390, 2043–2056. https://doi.org/10.1056/NEJMoa2403347 PubMed

  • Rubino, D., Abrahamsson, N., Davies, M., Hesse, D., Greenway, F. L., Jensen, C., … Wilding, J. P. H. (2021). Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity (STEP 4). JAMA, 325(14), 1414–1425. https://doi.org/10.1001/jama.2021.18383 JAMA Network+1

  • Wilding, J. P. H., Batterham, R. L., Calanna, S., Davies, M., Van Gaal, L. F., Lingvay, I., … Kushner, R. F. (2022). Weight regain and cardiometabolic effects after withdrawal of semaglutide: STEP-1 extension. Diabetes, Obesity and Metabolism, 24(8), 1553–1564. https://doi.org/10.1111/dom.14725

  • Berg, S., Stickle, H., Rose, S. J., & Nemec, E. C. (2025). Discontinuing glucagon-like peptide-1 receptor agonists and body habitus: A systematic review and meta-analysis. Obesity Reviews, 26(8), e13929. https://doi.org/10.1111/obr.13929         

Alina Schmidt
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