Healthcare providers in almost any setting are likely to encounter patients with diabetes. The 2024 National Diabetes Statistics Report shows that approximately 38.1 million adults in the United States (US), or 14.7% of the population, had diabetes in the most recent analysis (2021).¹ In the report, 8.7 million adults (22.8% of adults with diabetes) met the laboratory criteria for diabetes (an HbA1C serum level of >6.4%) but were either unaware or did not report having the condition.^1-3 The prevalence of diabetes increases significantly with age, with about 30% of individuals aged 65 and older living with the disease.¹ 

Glucagon-like peptide-1 (GLP-1) agonists (an agonist is a chemical substance that binds to a cell receptor and causes a biological response) are a class of medications used to manage type 2 diabetes mellitus (DMII) and obesity. These drugs work by lowering blood glucose levels and helping regulate metabolism and blood sugar control for people with DMII.^3,4 GLP-1 receptor agonists are a proven, effective therapy for managing DMII, though they do come with potential side effects that patients should be educated on before starting. According to the American Diabetes Association’s (ADA) 2022 Standards of Medical Care, these medications help lower HbA1C levels and offer additional benefits such as weight loss. Both American and European guidelines advocate for their use before insulin therapy when metformin alone does not help the patient achieve blood sugar management targets (typically <7% HbA1C levels for people with DMII).^2,3 With increasing use in the patient population, healthcare practitioners should know about this medication’s use, efficacy, side effects, and considerations when patients ask. 

GLP-1 Receptor Agonist Mechanisms and Effects 

How GLP-1 Medications Works

GLP-1 is a naturally occurring hormone in the body. Primarily produced by L-cells (cells that secrete hormones that regulate appetite) in the small intestine and colon, smaller amounts of GLP-1 are also produced in the pancreas and central nervous system. This hormone plays a key role in regulating blood sugar, appetite, and digestion. GLP-1 triggers the pancreas to release insulin, which lowers blood sugar levels and prevents the release of glucagon (a hormone that helps regulate blood sugar levels). This process of suppressing glucagon helps regulate blood sugar levels in the body.^4-6 Synthetic versions of GLP-1 are available as Food and Drug Administration (FDA)-approved medications both in injectable and (more recently) oral form, used for treating DMII and obesity by mimicking the effects of the natural hormone.^2,5-7 

GLP-1 improves blood sugar control due to a combination of related factors. First, it regulates glucose by stimulating insulin release while inhibiting the release of glucagon (a hormone that stimulates the liver to produce glucose) from the pancreas.^4,5 Glucose is more effectively taken into the cells for energy, lessening the need for higher insulin levels and decreasing insulin resistance. In this way, GLP-1 can lessen the desire for food. It also helps control appetite by signaling the brain to reduce hunger and slow stomach emptying, helping clients feel full for longer. 

GLP-1 Medication Efficacy 

Between 2012 and 2014, three weight loss medications (extended-release phentermine/topiramate, liraglutide, and naltrexone ER/bupropion) were approved by the FDA for weight management. These medications met the FDA’s efficacy standards in phase 3 clinical trials, where participants lost an average of 5% of their body weight or 35% more weight loss than those in the placebo group.⁸ In June 2021, the FDA approved a GLP-1 receptor agonist (semaglutide) for weight management. The phase 3 trials for semaglutide showed nearly double the weight loss compared to previously approved obesity treatments.⁸ 

There have been many large-scale studies on GLP-1 medications. One example of the type of studies and their outcomes is the SURPASS-1 study, conducted from June 2019 to October 2020 in 52 medical research centers worldwide (including India, Japan, Mexico, and the US, among many others). The 40-week double-blind, randomized control trial assessed the efficacy, safety, and tolerability of tirzepatide, a GLP-1 receptor agonist, in patients with DMII who had inadequate blood sugar control through diet and exercise. The study found that the medication used once a week led to dose-dependent weight loss ranging from 7 to 9.5 kg. The most commonly reported side effects were mild to moderate gastrointestinal (GI) issues: nausea (12-18%), diarrhea (12-14%), and vomiting (2-6%). Importantly, no cases of severe or clinically significant hypoglycemia were observed during the study, a common concern for patients and healthcare providers alike.⁹ 

Challenges and Considerations for Patients 

GI side effects are most common when starting treatment or increasing the dosage of GLP-1 medications. These side effects are not thought to be directly related to how GLP-1 affects digestion but are more likely due to interactions with brain receptors.⁶ It signals through receptors in the brainstem responsible for regulating appetite and gut function, indicating a sense of fullness, which in turn slows gastric emptying. However, these parts of the brain can cause GI side effects like nausea, vomiting, diarrhea, and constipation.¹⁰ Data from clinical trials has shown that a large percentage of patients may experience GI problems; some cite up to 85% of patients.¹¹ These symptoms often reduce or disappear over time, even if treatment continues. The occurrence and severity of side effects can vary based on the specific type of GLP-1 medication, its dose, how long-acting it is, and whether it is combined with other drugs like metformin or insulin. Some patients may need to discontinue GLP-1 medications due to GI side effects at lower doses, but others may tolerate higher doses without experiencing side effects. 

Healthcare providers (especially those who prescribe or help manage these types of medications through diet and lifestyle) should be prepared to answer questions about how common side effects are, when they’re most likely to happen, and how to manage them with diet and lifestyle changes if needed. Guidelines developed by a multidisciplinary team of experts advise changes such as following a low-fat diet, avoiding spicy foods or foods with high amounts of added sugar, keeping a food diary to monitor symptoms to make connections, eating small, frequent meals, and eating slowly.¹¹ Protein intake is especially important to maintain muscle mass and prevent losing lean body tissue as the patient loses weight.¹² Some patients on these medications exhibit poor diet quality and low food intake, putting them at risk of deficiencies in protein, fiber, vitamins, and minerals.¹² Healthcare providers can advise their clients using this expert guidance if they’re experiencing symptoms after starting GLP-1 medications. 

Takeaways for Healthcare Providers 

Healthcare providers should stay informed about the increasing use of GLP-1 receptor agonists in managing DMII and obesity, given the high prevalence of these conditions. Studies show that these medications are highly effective at lowering HbA1C levels and supporting weight loss, making them a valuable treatment option. Providers should be prepared to discuss common side effects, such as GI issues, and advise patients on diet and lifestyle adjustments to mitigate discomfort and increase medication tolerance. By staying updated on new therapies, providers can offer tailored, evidence-based care to improve glycemic control and quality of life for their patients. 

References:

1. Centers for Disease Control. National Diabetes Statistics Report. https://www.cdc.gov/diabetes/php/data-research/index.html. Published May 15, 2024. Accessed October 10, 2024.
2. King A, Miller EM. Glucagon-Like Peptide 1 Receptor Agonists Have the Potential to Revolutionize the Attainment of Target A1C Levels in Type 2 Diabetes—So Why Is Their Uptake So Low? Clin Diabetes. 2023; 41 (2): 226–238.
3. Collins L, Costello RA. Glucagon-Like Peptide-1 Receptor Agonists. [Updated 2024 Feb 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551568/
4. Cornell S. A review of GLP‐1 receptor agonists in type 2 diabetes: a focus on the mechanism of action of once‐weekly agents. Journal of clinical pharmacy and therapeutics. 2020;45:17-27.
5. Müller TD, Finan B, Bloom SR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72-130.
6. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes–state-of-the-art. Molecular metabolism. 2021;46:101102.
7. Jensterle M, Rizzo M, Haluzík M, Janež A. Efficacy of GLP-1 RA approved for weight management in patients with or without diabetes: a narrative review. Advances in therapy. 2022;39(6):2452-67.
8. Popoviciu MS, Păduraru L, Yahya G, Metwally K, Cavalu S. Emerging role of GLP-1 agonists in obesity: a comprehensive review of randomised controlled trials. International journal of molecular sciences. 2023;24(13):10449.
9. Rosenstock, J, Wysham, C, Frías, J.P, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): A double-blind, randomised, phase 3 trial. Lancet. 2021; 398:143–155.
10. Wharton S, Davies M, Dicker D, et al. Managing the gastrointestinal side effects of GLP-1 receptor agonists in obesity: recommendations for clinical practice. Postgraduate medicine. 2022;134(1):14-9.
11. Gorgojo-Martínez JJ, Mezquita-Raya P, Carretero-Gómez J, et al. Clinical Recommendations to Manage Gastrointestinal Adverse Events in Patients Treated with Glp-1 Receptor Agonists: A Multidisciplinary Expert Consensus. J Clin Med. 2022;12(1):145.
12. Christensen S, Robinson K, Thomas S, Williams DR. Dietary intake by patients taking GLP-1 and dual GIP/GLP-1 receptor agonists: A narrative review and discussion of research needs. Obesity Pillars. 2024:100121.