Navigating GLP-1 RA Therapy

The gut has long been recognized as a key portal to enhancing human health. The discovery of the incretin effect led to studies on glucagon-like peptide-1 receptor agonists (GLP-1 RAs). The GLP-1 RA pharmacologic class of medications has revolutionized the treatment of type 2 diabetes mellitus (T2DM) and obesity. These unique drugs have been successful in treating both conditions for many people, though they have also created significant controversy and media attention. Nurses and other healthcare professionals must possess a thorough understanding of these medications to accurately assess, advise, prescribe (if applicable), and evaluate GLP-1 RA use for each patient.

Obesity is defined as having a body mass index (BMI) of 30.0 kilogram per square meter (kg/m²) or higher, and severe obesity is described as having a BMI of 40.0 kg/m² or higher. In the United States, the prevalence of obesity is reported at a staggering 100 million adults with obesity and 22 million adults with severe obesity (Centers for Disease Control and Prevention [CDC], 2024). It is well established that obesity and severe obesity are linked to several chronic health conditions, including T2DM and cardiovascular disease.

Of the one in nine adults worldwide living with diabetes, 90-95% are living with T2DM. The International Diabetes Federation (IDF) forecasts that by 2050, the prevalence will increase by 46%, increasing the prevalence to over 850 million people (IDF, n.d.). An association has been found that non-Hispanic black individuals, Hispanic individuals, and those with a high school diploma or lower education level have higher rates of both obesity and T2DM (IDF, n.d.).

Historically, many pharmacological and non-pharmacological interventions have been used to treat both diabetes and obesity to improve health outcomes. Until the release of GLP-1 RA medications, there were few pharmacologic therapy options to treat these chronic diseases. GLP-1 RAs are now a sought-after choice in the treatment of both T2DM and obesity.

Though the GI mechanisms of action are similar for all GLP-1 RA pharmacological agents, the United States Food and Drug Administration (FDA) approval, administration, dosing, and pharmacokinetics differ. All approved agents are to be used in conjunction with lifestyle interventions and typically are part of a multimodal treatment plan. Here, we will review the currently FDA-approved drugs in the United States.

Adverse reactions when taking GLP-1 RAs can range from mild to life-threatening. Here we will discuss several adverse reactions. Please refer to each drug's prescribing information for drug-specific adverse reactions and frequencies.

Allergic or hypersensitivity-type reactions have occurred. Rare cases of anaphylaxis and angioedema have been reported. Antibodies against GLP-1 RAs have also been reported. Injection site reactions are more common in this drug class than compared to insulin and are typically mild, though they can progress to cellulitis, abscess, and necrosis.

Due to the mechanism of action, the most common side effects from GLP-1 RAs occur in the GI system. GI symptoms include nausea, vomiting, diarrhea, constipation, and abdominal pain. Proper dose titration can help to lower GI side effects. In some cases, slower dose titration can help minimize GI adverse reactions. Mild GI symptoms have been shown to improve over time. Though appetite loss is a positive benefit of this drug class, it can be extreme, leading to starvation ketosis, inappropriate weight loss, and worsening renal function secondary to dehydration.

Acute pancreatitis, elevated pancreatic enzymes, and other pancreas-related risks have been studied regarding GLP-1 RAs. There has been a slight increase in the risk of acute pancreatitis. However, further studies have not identified causation or a higher risk compared to other oral agents, such as sulfonylureas. There have been reports of elevated pancreatic enzyme levels when monitored using a GLP-1 RA. This did not appear to predict episodes of acute pancreatitis. Ongoing studies are continuing to evaluate if there is an increased risk of pancreatic cancer or neuroendocrine tumors related to GLP-1 RA use. To date, no causal relationships have been noted (Ghusn & Hurtado, 2024).

Additional GI side effects include gallbladder and biliary disease. This includes cholecystitis and acute cholelithiasis. The most significant risk appears to be associated with the use of high-dose GLP-RAs for weight management. Risk was also related to the duration of therapy, with longer duration having the highest risk (Ghusn & Hurtado, 2024).

Hypoglycemia is a potential adverse reaction when added to agents with a known hypoglycemia risk, such as insulin, sulfonylureas, and meglitinides. There is a minimal risk of hypoglycemia when using GLP-1 RAs alone or with other low hypoglycemia risk agents.

The risk of acute kidney injury is low and has been noted to be secondary to severe GI symptoms resulting in dehydration. Case reports have also indicated an increase in acute kidney injury risk with severe GI symptoms and the use of other medications with a known acute kidney injury risk, including diuretics and angiotensin-converting enzyme (ACE) inhibitors.

Tachycardia has been noted as an adverse reaction to GLP-1 RAs. These events have not been deemed serious. Case reports have required discontinuation of the drug, particularly in individuals with heart failure, as an increased cardiac demand from tachycardia could result in adverse cardiac outcomes (Calderon et al., 2022).

The risk of medullary thyroid carcinoma and multiple endocrine neoplasia type 2 remains controversial. In rodent studies during drug development, a dose-dependent and treatment-dependent increase in thyroid C-cell tumors was observed. This did not appear to occur in primate studies. There have been case studies of medullary thyroid carcinoma; however, currently, there is no statistically significant increase in humans, although studies are still ongoing (Ghusn & Hurtado, 2024; Pasternak et al., 2024).

There has been controversy as to the risk of increased depression, suicidal ideation, or death by suicide in those taking GLP-1 RA (Salvo & Faillie, 2024). Research has currently not identified an increased risk of worsening mental health or suicide. Although more research is needed in this area, healthcare providers must be vigilant to monitor patients for any worsening mental health or suicidal ideation (Ueda et al., 2024).

Worsening diabetic retinopathy has been noted with the use of subcutaneous semaglutide. Though the exact mechanism is not clear, previous evidence has indicated that a rapid improvement of glycemic control can worsen preexisting diabetic retinopathy. The risk of worsening diabetic retinopathy appears to be dependent on patient characteristics, degree of retinopathy, and glycemic control (Dungan & DeSantis, 2025; Joo et al., 2024).

GLP-1 RAs have general contraindications and cautions, though some specific agents have additional recommendations. Please refer to each drug's prescribing information for exact contraindications and warnings (Kindel et al., 2024).

• As with any pharmacologic agent, the drug class is contraindicated in individuals who have experienced a previous hypersensitivity reaction, including anaphylaxis or angioedema.
• Due to preclinical studies with GLP-1 RAs, it is contraindicated to use these agents with a personal or family history of medullary thyroid carcinoma and multiple endocrine neoplasia type 2.
• In individuals with existing chronic kidney disease and those with a risk of acute kidney injury, caution should be used when starting and escalating doses of GLP-1 RAs.
• GLP-1 RA use is not recommended for those with preexisting severe constipation or gastroparesis.
• Caution must be used in those using GLP-1 RAs while taking oral medications with a narrow therapeutic window due to the altered gastric emptying, which may require more frequent monitoring.
• Aspiration risk during anesthesia and deep sedation is thought to be increased due to slowed gastric emptying with GLP-1 RAs. Consideration for holding GLP-1 RAs prior to anesthesia or deep sedation must be done in collaboration with the anesthesia team.
• GLP-1 RAs are not approved and are not indicated for use in pregnancy or glycemic control in type 1 diabetes.

There are numerous barriers to the use of GLP-1 RA medications. Cost has become a significant barrier, with the average cost of these agents ranging from $900 to over $1300 per month. Even with adequate health insurance, the out-of-pocket costs are often unaffordable (Klein, 2024). Pharmaceutical companies are exploring possibilities for lower-cost options.

Adverse reactions are another barrier to the use of GLP-1 RAs. Even with slow titration and dietary modifications, some individuals suffer severe GI upset or other adverse events, making this class of medication intolerable. Patient education is essential when starting these agents, as it provides patients with knowledge of possible adverse reactions and guidance on when to seek medical attention for severe adverse reactions.

Recent drug shortages have also become a barrier to the use of GLP-1 RAs. Many of these agents have had sporadic shortages, causing interruptions in therapy. Due to the barrier of drug shortages, compounded and counterfeit GLP-1 RAs have been marketed to patients as alternatives.

Sustained weight loss and improved glycemic control from the use of GLP-1 RAs have multiorgan benefits as previously noted. Significant weight loss and loss of lean muscle mass can, unfortunately, harm bone density and muscle strength. As GLP-1 RAs are not approved for use in pregnancy and have a long half-life, preconception planning is imperative, as these should be stopped several months before planning pregnancy (Ducker, 2024). Although this medication class has been approved for adults since 2005, long-term data in children is still ongoing.

As previously mentioned, cost and drug shortages have created challenges to stable ongoing use of GLP-1 RAs. This risk led to the introduction of compounded and counterfeit GLP-1 RAs to the market, creating further confusion and risk. FDA-approved drugs undergo multiple safety and quality checks throughout the manufacturing process. A pharmacist modifies compounded medications to create a customized drug. Counterfeit medications are illegal copies of FDA-approved drugs. Both compounded and counterfeit GLP-1 RAs carry the risks of inaccurate dosing, unproven additives, improper dosing, and the risk of contamination. Counterfeit medications also have the risk of harmful ingredients and may even lack the active GLP-1 ingredient. It is currently recommended to use only FDA-approved GLP-1 RA agents for the treatment of obesity and T2DM (FDA, 2025).

The key to successful GLP-RA therapy starts with nurses providing effective patient education. Education on the proper administration of oral semaglutide is essential to drug effectiveness and patient compliance. If not taken properly, the effect of oral semaglutide is minimal due to reduced absorption.

Teaching proper injection technique is vital to ensure the drug is administered correctly. Subcutaneous GLP-1 RA injections can be given in the abdomen, thigh, or upper arm. The pens used to administer the injections vary between each drug, making instruction and return demonstration important in the education process. To ensure proper administration, advise patients to avoid areas of scars, stretch marks, or any compromised skin. Instruct patients to rotate injection sites to avoid the buildup of scar tissue over time. Demonstration pens and pads help use the teach-back method to determine if the patient understood the instructions. Safe sharps disposal is another topic to address during patient education. Used pens, vials, or needles, depending on the agent, must be disposed of in an approved sharps container or an approved household container. Sharps should never be disposed of in the trash.

Nurses also must instruct patients about potential side effects. Side effects such as nausea, GI upset, and appetite loss are typically transient and are best mitigated by eating slowly, limiting the size of meals, and avoiding high-fat foods (Gorgojo-Martínez et al., 2022). GI side effects can also be reduced by slowing the titration of the medication. Nurses must also educate on signs and symptoms of severe adverse reactions, such as dehydration, acute pancreatitis, or worsening diabetic retinopathy, and provide clear steps to seek medical care if these were to occur.

Nurses also assist in developing alternative plans to manage drug shortages. During drug shortages, patients may need to use alternate dosing strategies or lower the dose of the GLP-RA to extend the time to the next refill. Depending on insurance coverage and cost, nurses may need to assist patients in switching to a different GLP-1 RA agent. Some patients may need to stop GLP-RA therapy and use an alternate glycose-lowering pharmacotherapy until the shortage has ended and the GLP-1 RA can be reinitiated (Whitley et al., 2023). When starting GLP-1 RA therapy, nurses are vital in assisting patients in finding which GLP-1 RA is on formulary to help reduce out-of-pocket costs. This alone can help improve compliance.

The discovery of the incretin effect has led to the development of the revolutionary GLP-1 RA class of medications. Primary for treating obesity and T2DM, tirzepatide is also FDA-approved to treat obstructive sleep apnea. GLP-1 RAs have multiorgan benefits that extend beyond weight loss and improved glycemic control. The available GLP-1 RAs have similar mechanisms of action and adverse events. Through patient assessments, nurses can identify and address cautions or contraindications when prescribing these pharmacologic agents. Nurses play a vital role in providing proper education to enhance drug effectiveness, manage expectations, and mitigate side effects.

Cassandra is a 64-year-old female seen today in the outpatient clinic for follow-up. She has a past medical history of:

• T2DM
• Obesity
• Hypertension
• Myocardial infarction at the age of 60
• Osteoarthritis 
• Hyperlipidemia

She is following up in the clinic today after starting tirzepatide three months ago. She has been titrated up to the 5 mg weekly dose. Since starting this current dose, she reports weight loss and "better blood sugar numbers" compared to three months ago. She also complains that giving the injection in her abdomen makes her anxious and asks where else she can give the injection. She tells you she typically will have some leaking at the injection site after she gives the injection.

Today's lab results and vital signs:

• Fasting blood sugar: 98 mg/deciliter (dL) (previously 115 mg/dL)
• Hemoglobin A1c: 6.8% (previously 8.0%)
• GFR: 92 mL/minute/1.73 m²
• Liver function tests: within normal limits
• Electrolytes: within normal limits
• Blood pressure: 118/67 millimeters of mercury (mmHg), heart rate: 72 beats per minute, respiratory rate: 22, pulse ox: 99% on room air
• Weight: 200 pounds (previously 225 pounds)

She is happy with her weight loss and glycemic control, although she reports experiencing nausea anytime she tries to eat. Due to nausea, she is skipping meals and not exercising because she does not have energy. She denies any fever, chest pain, abdominal pain, constipation, or diarrhea. Her physical exam is within normal limits. After obtaining the history and physical exam, you formulate an education plan for Cassandra.

You focus on the most important points that arose during the visit, which include her side effect of nausea, which is causing her to skip meals, lack of physical activity, and injection site concerns.

You educate Cassandra on the mechanism of action of the GLP-1 RA pharmacological class and the etiology behind her symptoms of nausea. You explain that skipping meals is not recommended, but instead recommend she try smaller, low-fat meals while trying to eat more slowly. She is also instructed to call the office if she has continued nausea even after implementing these diet modifications.

Next, you discuss how skipping meals has led to decreased energy consumption, resulting in decreased physical activity. If the diet modifications are successful, she should expect to have more energy to get back to her previous exercise routine. Again, she is educated to call the office if this does not improve.

Additionally, her injection concerns are common when using subcutaneous GLP-1 RA agents. You review the tirzepatide instructions for use with her. You show her that tirzepatide can be given in the abdomen, thighs, or the backs of the arms. You have her demonstrate an injection with a demonstration pen. You realize she immediately removes the pen from the injection pad. Per the instructions for use, you review with her that she will need to hold the pen against her body for ten seconds before removing it. She is educated to call the office if she continues to have any difficulty with giving the injection or if she continues to have any leakage from the injection site.

You call Cassandra in six weeks to check in and ask if she has any concerns. She reports that with the recommended diet modifications, her nausea is now gone, and she is back to walking regularly. She is now injecting in the thigh and holding the pen for at least ten seconds before removing it. She reports she has only had one further episode of leaking from the injection site and is now very happy with her treatment plan.

• Calderon, A., Santos, A., & Luo, H. (2022). Mechanism Behind GLP1RA-Induced Refractory Tachycardia: A Case and Literature Review. Endocrine Practice, 28(12). S7-10. Visit Source.
• Centers for Disease Control and Prevention (CDC). (2024). Adult Obesity Facts. Centers for Disease Control and Prevention. Visit Source.
• Davis, E. M., & Sandoval, D. A. (2020). Glucagon-Like Peptide-1: Actions and Influence on Pancreatic Hormone Function. Comprehensive Physiology, 10(2), 577. Visit Source.
• Diz-Chaves, Y., Mastoor, Z., Spuch, C., González-Matías, L. C., & Mallo, F. (2022). Anti-Inflammatory Effects of GLP-1 Receptor Activation in the Brain in Neurodegenerative Diseases. International Journal of Molecular Sciences, 23(17), 9583. Visit Source.
• Ducker, D. J. (2024). Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity. Diabetes Care, 47(11),1873–1888. Visit Source.
• Dungan, K. & DeSantis, A. (2025). Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus. UpToDate. Visit Source.
• Ghusn, W., & Hurtado, M. D. (2024). Glucagon-like Receptor-1 agonists for obesity: Weight loss outcomes, tolerability, side effects, and risks. Obesity Pillars, 12, 100127. Visit Source.
• Gorgojo-Martínez, J. J., Mezquita-Raya, P., Carretero-Gómez, J., Castro, A., Cebrián-Cuenca, A., de Torres-Sánchez, A., García-de-Lucas, M. D., Núñez, J., Obaya, J. C., Soler, M. J., Górriz, J. L., & Rubio-Herrera, M. Á. (2022). Clinical Recommendations to Manage Gastrointestinal Adverse Events in Patients Treated with Glp-1 Receptor Agonists: A Multidisciplinary Expert Consensus. Journal of Clinical Medicine, 12(1), 145. Visit Source.
• Hullon, D., Subeh, G. K., Volkova, Y., Janiec, K., Trach, A., & Mnevets, R. (2025). The role of glucagon-like peptide-1 receptor (GLP-1R) agonists in enhancing endothelial function: a potential avenue for improving heart failure with preserved ejection fraction (HFpEF). Cardiovascular Diabetology, 24(1), 70. Visit Source.
• International Diabetes Federation (IDF). (n.d.). Facts & figures. International Diabetes Federation. Visit Source.
• Joo, J. H., Sharma, N., Shaia, J., Wu, A. K., Skugor, M., Singh, R. P., & Rachitskaya, A. V. (2024). The Effect of Glucagon-Like Peptide-1 Receptor Agonists on Diabetic Retinopathy at a Tertiary Care Center. Ophthalmology Science, 4(6), 100547. Visit Source.
• Kindel, T. L., Wang, A. Y., Wadhwa, A., Schulman, A. R., Sharaiha, R. Z., Kroh, M., Ghanem, O. M., Levy, S., Joshi, G. P., LaMasters, T. L., American Gastroenterological Association, American Society for Metabolic and Bariatric Surgery, American Society of Anesthesiologists, International Society of Perioperative Care of Patients with Obesity, & Society of American Gastrointestinal and Endoscopic Surgeons. (2024). Multisociety clinical practice guidance for the safe use of glucagon-like peptide-1 receptor agonists in the perioperative period. Surgery for Obesity and Related Diseases, 20(12), 1183-1186. Visit Source.
• Klein, H. E. (2024). Most Insured Adults Still Have to Pay at Least Part of the Cost of GLP-1 Drugs. American Journal of Managed Care. Visit Source.
• Novo Nordisk. (2024). Rybelsus: Prescribing information. Novo Nordisk. Visit Source.
• Novo Nordisk. (2025). FDA approves Ozempic® (semaglutide) as the only GLP-1 RA to reduce the risk of worsening kidney disease and cardiovascular death in adults with type 2 diabetes and chronic kidney disease. Novo Nordisk. Visit Source.
• Pasternak, B., Wintzell, V.,Hviid, A., Eliasson B,, Gudbjörnsdottir, S., Jonasson, C., Hveem, K., Svanström, H., Melbye, M., & Ueda, P. (2024). Glucagon-like peptide 1 receptor agonist use and risk of thyroid cancer: Scandinavian cohort study. BMJ, 385, e078225. Visit Source.
• Rosenberg, J., Jacob, J., Desai, P., Park, J., Donovan, L., & Kim, J. Y. (2021). Incretin Hormones: Pathophysiological Risk Factors and Potential Targets for Type 2 Diabetes. Journal of Obesity & Metabolic Syndrome, 30(3), 233-247. Visit Source.
• Salvo, F., & Faillie, J. (2024). GLP-1 receptor agonists and suicidality—Caution is needed. JAMA Netw Open, 7(8), e2423335. Visit Source.
• Ueda, P., Söderling, J., Wintzell, V., Svanström, H., Pazzagli, L., Eliasson, B., Melbye, M., Hviid, A., & Pasternak, B. (2024). GLP-1 Receptor Agonist Use and Risk of Suicide Death. JAMA internal medicine, 184(11), 1301–1312. Visit Source.
• UpToDate Lexidrug. (n.d.-a). Dulaglutide: Drug information. UpToDate. Visit Source.
• UpToDate Lexidrug. (n.d.-b). Exenatide: Drug information. UpToDate. Visit Source.
• UpToDate Lexidrug. (n.d.-c). Liraglutide: Drug information. UpToDate. Visit Source.
• UpToDate Lexidrug. (n.d.-d). Lixisenatide (United States and Canada: Not available): Drug information. UpToDate. Visit Source.
• UpToDate Lexidrug. (n.d.-e). Semaglutide: Drug information. UpToDate. Visit Source.
• UpToDate Lexidrug. (n.d.-f). Tirzepatide: Drug information. UpToDate. Visit Source.
• U.S. Food and Drug Administration (FDA). (2024). FDA Approves First Medication for Obstructive Sleep Apnea. U.S. Food and Drug Administration. Visit Source.
• U.S. Food and Drug Administration (FDA). (2025). FDA’s Concerns with Unapproved GLP-1 Drugs Used for Weight Loss. Visit Source.
• Whitley, H. P., Trujillo, J. M., & Neumiller, J. J. (2023). Special Report: Potential Strategies for Addressing GLP-1 and Dual GLP-1/GIP Receptor Agonist Shortages. Clinical Diabetes: A Publication of the American Diabetes Association, 41(3), 467-473. Visit Source.
• Yu, J. H., Park, S. Y., Lee, D. Y., Kim, N. H., & Seo, J. A. (2022). GLP-1 receptor agonists in diabetic kidney disease: Current evidence and future directions. Kidney Research and Clinical Practice, 41(2), 136-149. Visit Source.
• Zhao, X., Wang, M., Wen, Z., Lu, Z., Cui, L., Fu, C., Xue, H., Liu, Y., & Zhang, Y. (2021). GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects. Frontiers in Endocrinology, 12, 721135. Visit Source.
• Zheng, Z., Zong, Y., Ma, Y., Tian, Y., Pang, Y., Zhang, C., & Gao, J. (2024). Glucagon-like peptide-1 receptor: Mechanisms and advances in therapy. Signal Transduction and Targeted Therapy, 9(1), 1-29. Visit Source.