Glucagon-Like Peptide-1 Agonists

Authors: Andrea Nillas, MD, and Brett Roth MD

A 32-year-old female presents with the chief complaint, “I can’t stop vomiting.” The triage note states, “Patient seen here two days ago for same.” Vital signs: Pulse 115 bpm, BP 115/60 mmHg, T 98.8°F, RR 20 rpm, BMI 30 kg/m². On chart review, you notice she does not have any reported past medical history or previous surgeries and has no history of illicit substance use. Her evaluation two days ago included a negative CT with IV contrast of her abdomen and a metabolic panel that was only remarkable for bicarbonate of 19 mEq/L and chloride of 99 mEq/L. Her CBC, UA, lipase, and serum ketones, as well as her liver and renal function panels, were normal. She was treated with ondansetron, one liter of normal saline, and discharged with an “improved” condition.

Upon evaluating the patient today, she appears uncomfortable and notably dehydrated. She is actively vomiting, and an abdominal examination reveals Her laboratory evaluation today reveal a sodium of 142 mEq/L, potassium of 3.0 mEq/L, bicarbonate of 15 mEq/L, chloride of 99 mEq/L, BUN 40, creatinine of 2.1mg/dL, and glucose of 90 mg/dL. Her urinalysis is positive for  . Otherwise, her liver function tests, and lipase are normal. Her urine pregnancy and urine immunoassay drug screen are both negative. She confides that she recently started a new weight loss drug and accidentally administered triple the prescribed weekly dose because she did not understand how to use the injectable pen.

Discussion

Scope of the Problem

Glucagon-like peptide-1 (GLP-1) -agonists have gained popularity over the last decade for treating millions of Americans with type 2 diabetes (T2DM) and obesity. They are attractive primarily because of their beneficial effects on glucose regulation as well as the cardiovascular system.  New indications, beyond those that are FDA approved, are actively being investigated, and with increased utilization, more emergency department visits for drug-GLP-1 agonist-related complications are occurring. Poison center cases involving adverse reactions have reported a 5-fold increase in exposure calls between 2019 and 2023.[1] Despite their efficacy, limitations to access and disadvantages exist, which include serious side effects, costs, and availability.

Understanding GLP-1 and GLP-1 Agonists:

Our understanding of the hormonal regulation of glucose metabolism has advanced well beyond the roles of insulin and glucagon. Endogenous GLP-1 is an incretin (from Latin increta or “augment”) hormone secreted by endocrine cells in the intestinal mucosa. It augments glucose-dependent insulin release, inhibits glucagon release following meals, and slows gastric emptying, thus promoting early satiety. This ultimately delays the absorption of food and slows the release of glucose into the blood.[2] GLP-1 receptors are distributed in the pancreatic beta cells and ducts, gastric mucosa, lungs, heart, kidneys, immune cells, and hypothalamus, contributing to GLP-1s widespread physiological effects.

Exenatide was the first GLP-1 agonist to be developed and was approved in 2005 by the FDA for the treatment of T2DM. It was synthesized from the venom of the Gila monster (Heloderma suspectum), which contained exendin-4, a peptide homologous to mammalian GLP-1 that could bind and activate GLP-1 receptors. [3] Currently available GLP-1 agonists, including exenatide (Byetta, Bydureon), semaglutide (Wegovy, Ozempic, Rybelsus), liraglutide (Saxenda, Victoza), dulaglutide (Trulicity), and tripeptide (Mounjaro), replicate and intensify the effects of native GLP-1, earning them the name incretin mimetics.

Since the creation of exenatide, attempts have been made to structurally modify the GLP-1 peptide to resist rapid degradation by dipeptidyl peptidase-4 (DPP-4) and prolong its systemic circulation. [3] Extended half-lives of GLP-1 agonists ensure sustained effects (e.g., the half-life of semaglutide is 1 week and for liraglutide it is 12 hours, versus minutes for native GLP-1). As such, these medications are administered subcutaneously with durations of action varying from 24 hours to a week.  

Beneficial Effects

Cardiovascular: GLP-1 agonists have demonstrated impressive cardioprotective effects in patients with T2DM and obesity (BMI > 27). Multiple clinical trials have demonstrated their impact on major adverse cardiac events (MACE), including cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke. Most recently, the SELECT trial showed a 20% reduction of MACE in overweight patients treated over 33 months versus placebo. [4,5]

Weight loss: Randomized clinical trials have shown statistically significant weight loss compared to placebo after treatment with higher doses of liraglutide and semaglutide. Studies suggest a 6% and 15% reduction in weight, respectively, over 1-2 years. [6] Therefore, the American Gastroenterological Association currently recommends semaglutide, 2.4 mg injected weekly, as the preferred treatment for obesity in conjunction with lifestyle modifications.  Unfortunately, about 2/3 of patients regain weight if treatment is stopped.[7]

Other Benefits: The American Diabetic Association recommends GLP-1 agonists as first-line therapy to prevent the progression of kidney disease. Additionally, recent studies suggest benefits for the treatment of Alzheimer’s, Parkinson’s, chemical dependency, non-alcoholic fatty liver disease, neuropathy, antipsychotic medication related weight gain, and other disorders. [8,9]

Complications and Adverse Effects

Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain, and constipation account for the vast majority (up to 70%) of reported adverse effects.[9] Severe cases may lead to protracted vomiting similar in presentation to hyperemesis gravidarum or cannabis hyperemesis syndrome. Symptoms are generally associated with higher doses and rapid titration and are more severe within the first four weeks of administration. [10,11] Complications may lead to dehydration, electrolyte disturbances, and acute kidney injury.[12] Gastroparesis and bowel obstruction have been described after longer periods of use.[11] The proposed mechanism for the GI side effects is thought to be reduced gastric emptying. Semaglutide has the highest reported risk of nausea and vomiting compared to liraglutide and dulaglutide.[10]

Pancreatic: As GLP-1 agonists stimulate pancreatic cells, there's a potential risk for the development of pancreatitis, but human studies and meta-analyses have shown conflicting results.[12] Studies suggest a higher risk with liraglutide compared to other options. Both hemorrhagic and necrotizing pancreatitis with deaths are reported.[13]

Hepatobiliary: GLP-1 agonists have been associated with the development of gallstones, inflammation of the gallbladder and bile ducts, elevated liver enzymes, hepatitis, and liver damage. These complications typically arise with higher doses, prolonged therapy (>26 weeks), and with more rapid weight loss. [14]

Metabolic: The likelihood of experiencing hypoglycemia when taking GLP-1 agonists without any accompanying hypoglycemic medications is very low.[9] This is because, in contrast to sulfonylurea and meglitinide medications, GLP-1 agonists are thought to have limited efficacy when the serum glucose concentration is less than 77 mg/dL. [15] However, the concurrent use of a GLP-1 agonist and insulin or a sulfonylurea can induce hypoglycemia, a complication that has been observed in as many as 36% of patients taking both medications. [16] X Unlike GLP-1 agonists, sulfonylureas stimulate insulin secretion independent of glucose concentrations.  Poison center data supports this contention with <5% GLP-1 agonists calls associated with hypoglycemia. [17] Diabetic ketoacidosis is not typically associated with GLP-1 agonists but has been reported after abruptly discontinuing insulin or sulfonylurea therapy when starting a GLP-1 agonist. [18]

Renal:  Reduced oral intake due to nausea, vomiting, and diarrhea may lead to pre-renal acute kidney injury (AKI). Patients with pre-existing kidney disease, high blood pressure, or heart problems are particularly at higher risk.

Ocular:  Vitreous hemorrhage, blindness, or other conditions requiring ophthalmology intervention have been reported among patients taking semaglutide, which may be associated with the degree and rapidity in the lowering of hemoglobin A1C. Oral semaglutide has not been associated with the increased risk of diabetic retinopathy.[10]

Dermatologic: “Ozempic Face” is a cosmetic concern that results in a hollowed-out appearance with increased facial skin folds and sagging. This is thought to occur due to rapid weight loss. Other possible but less common reactions include hypersensitivity reactions, angioedema, skin reactions at injection sites, and bullous pemphigoid.

Current Issues and Challenges with GLP-1 Agonists

Several barriers and limitations exist regarding the monitoring and prescription of GLP-1 agonists.  The inadequate availability and concurrent increase in demand have led to national shortages. Consequently, some patients have outsourced alternative formulations from compounding pharmacies, online sites, foreign supply chains, or medical spas, raising safety concerns. These practices have, in turn, led to variable drug concentrations that result in dosing errors (up to 10-fold) and the use of non-standardized syringes, causing patient confusion and adverse medication effects. [19] In fact, most cases (79.9%) reported to Poison centers between 2017-2022 were associated with therapeutic dosing errors. [11] Additionally, products obtained from non-US or EU pharmacies may contain adulterants, or no GLP-1 agonists at all. Costs have been another concern as patients are often denied coverage or asked to pay up to $1,000 monthly for their medications.  Finally, no standardized or straightforward methods are described to help patients decide how or when to stop taking them.[20]

Conclusion

GLP-1 agonists represent valuable tools for weight management and T2DM treatment. While their mechanisms of action and cardiovascular benefits are well-supported, understanding and actively managing potential complications are crucial for optimizing patient outcomes. Promising research suggests an even broader market for these agents and a need for all physicians to be aware of their potential risks and benefits.

Case Conclusion

You treat your patient with IV saline and anti-emetics.  Afterwards, you provide education on the correct way to use her injectable pen to avoid similar problems in the future and then call the hospitalist for admission.  Diagnosis – Accidental overdose of semaglutide with gastroparesis and hyperemesis.  Over a short hospital course, she recovers completely and can restart her semaglutide at a low dose with proper titration over time. 

Resources

1. Sandhu, G., et al., Prevalence of cannabinoid hyperemesis syndrome and its financial burden on the health care industry. Proc (Bayl Univ Med Cent), 2021. 34(6): p. 654-657.
2. Sorensen, C.J., et al., Cannabinoid Hyperemesis Syndrome: Diagnosis, Pathophysiology, and Treatment-a Systematic Review. J Med Toxicol, 2017. 13(1): p. 71-87.
3. Centers for Disease Control and Prevention. (2021, June 8). Data and statistics. Marijuana and Public Health. https://www.cdc.gov/marijuana/data-statistics.htm Accessed 2/1/2024.
4. Chu, F. and M. Cascella, Cannabinoid Hyperemesis Syndrome, in StatPearls. 2024: Treasure Island (FL).
5. Kim, H.S. and A. Monte, Colorado Cannabis Legalization and Its Effect on Emergency Care. Ann Emerg Med, 2016. 68(1): p. 71-5.
6. Collins, B., et al., "I still partly think this is bullshit": A qualitative analysis of cannabinoid hyperemesis syndrome perceptions among people with chronic cannabis use and cyclic vomiting. Drug Alcohol Depend, 2023. 246: p. 109853.
7. Richards, J.R., et al., Pharmacologic Treatment of Cannabinoid Hyperemesis Syndrome: A Systematic Review. Pharmacotherapy, 2017. 37(6): p. 725-734.
8. Gunasekaran, N., et al., Reintoxication: the release of fat-stored delta (9)-tetrahydrocannabinol (THC) into blood is enhanced by food deprivation or ACTH exposure. Br J Pharmacol,
9. 158(5): p. 1330-7.
10. Aziz, , et al., Topical Capsaicin for Treating Cannabinoid Hyperemesis Syndrome. Case Rep Gastrointest Med, 2020. 2020: p. 8868385.
11. Hashimoto, H., et al., Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol, 2020. 21(2): p. 242-249.
12. Kramer, J., The Surprising Re-emergence of Droperidol. Anesth Prog, 2020. 67(3): p. 125-126.