Glucagon-like peptide-1 receptor agonists (GLP-1 agonists) are a newer class of medications that are US Food and Drug Administration (FDA)-approved to manage type 2 diabetes and obesity in conjunction with diet and lifestyle changes.1 GLP-1 agonists affect glycemic control and body weight by increasing insulin production and release in a glucose-dependent manner; decreasing glucagon secretion; delaying gastric emptying; and increasing satiety.1,2
In addition to being effective treatments, these medications have a low overall risk of severe adverse effects.2 This article covers the indications, dosing regimens, and adverse effects of GLP-1 agonists.
The following GLP-1 agonists are FDA-approved 3-12:
As a class, GLP-1 agonists are approved to treat type 2 diabetes mellitus and obesity. However, because each medication in this class is indicated for 1 or more specific conditions, GLP-1 agonists should not be used interchangeably.3-12
Most formulations — Trulicity, Bydureon, Byetta, Victoza, Ozempic, Rybelsus, and Mounjaro — are indicated as supplemental treatments, along with diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus.3-6,8,10,11 In addition, Trulicity and Victoza are indicated to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus.3,6 GLP-1 agonists are not a substitute for insulin and should not be prescribed to patients diagnosed with type 1 diabetes mellitus.3-12
Saxenda, Wegovy, and Zepbound are indicated to reduce excess body weight and sustain reduced body weight when used in conjunction with diet and exercise.7,9,12 Saxenda and Wegovy are approved for patients age 12 years and older, while Zepbound is approved for adults.7,9,12 In addition, Wegovy is approved to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus with overweight or obesity.9
All FDA-approved GLP-1 agonists are available as a subcutaneous injection; semaglutide is also available as an oral tablet (Rybelsus).10 All GLP-1 agonists are available as a long-acting formulation, and exenatide is also available in a short-acting formulation (Byetta).5 They can be used in combination with basal insulin therapy.1
Given their equivalent or even superior effect on glycemic control relative to other treatments and low risk for adverse reactions, GLP-1 agonists are a primary treatment option for type 2 diabetes, particularly in patients at risk for or presenting with cardiovascular disease.1,2 Their safety profile and broad receptor distribution have led researchers to investigate their use for conditions beyond diabetes and obesity, such as Parkinson’s disease and Alzheimer’s disease; some clinical trials and preclinical studies have produced promising initial results.13
Although all GLP-1 agonists reduce blood glucose concentrations, the dosing regimens, cost, effectiveness, and frequency and severity of adverse effects vary by agent. Factors to consider before prescribing a GLP-1 agonist include the following:
Drawbacks to GLP-1 agonists that might limit patients’ ability to adhere to treatment are the cost, the periodic unavailability of certain medications due to limited supplies, the need to be administered via subcutaneous injection (except for Rybelsus), and the relatively frequent occurrence of gastrointestinal distress as an adverse effect.2 Some evidence suggests that gradual increases in dosage can minimize the risk of developing gastrointestinal adverse effects.13
GLP-1 agonists imitate the endogenous GLP-1 incretin hormone produced in the intestines in response to food intake.14 GLP-1 receptors are present in multiple organs, including the pancreas, nervous system, stomach, heart, and other cardiovascular tissues.13,15 In the pancreas, GLP-1 agonists stimulate glucose-mediated insulin production and release, induce pancreatic beta-cell proliferation, and reduce beta-cell apoptosis.15 Because the function of GLP-1 agonists is correlated with blood glucose concentrations, the risk of hypoglycemic events with them is minimal.15 Due to resistance to degradation, they also have a longer half-life than endogenous incretins.14
In the stomach, GLP-1 agonists slow gastric emptying.15 GLP-1 receptors are broadly distributed throughout the brain and generally induce satiety and reduced food intake.13 GLP-1 agonists reduce the progression of cardiovascular disease through several mechanisms, including by reducing the production of reactive oxygen species and endothelin, and lowering activation of platelets and other immune response cells.16 Collectively, these effects increasing vasodilation.16
The Table outlines dosing and administration of the FDA-approved GLP-1 agonists.3-12 For those agents approved for both obesity and type 2 diabetes, the dosing schedule and maximum dosage differ for each condition. For most GLP-1 agonists, the recommended treatment regimen starts with a subtherapeutic dose to reduce the risk of adverse effects, followed by incremental dose increases until the treatment is effective.
GLP-1 = glucagon-like peptide-1; T2DM = type 2 diabetes mellitus.
a Use the upper arm, thigh, or abdomen for all subcutaneous injections. Rotate sites between every injection.If a dose is missed, see the FDA-approved prescribing information for guidance.
From the FDA-approved prescribing information for each medication.3-12
Common adverse effects of GLP-1 agonists include the following 3-12:
Increases in the incidence of pancreatitis have been observed with all GLP-1 agonists; if pancreatitis is suspected, the GLP-1 agonist should be discontinued.3-12 Hypersensitivity, including anaphylaxis, has been observed in patients using GLP-1 agonists, and the medication should be halted if a patient develops allergic symptoms.3-12 In patients using exenatide, clinicians have identified the emergence of antibodies to the medication after initial use, which may exacerbate hypersensitive reactions.4,5 Because they may cause acute kidney injury or worsen renal impairment in patients with chronic kidney disease, renal function should be monitored in all patients.3-12
In non-human trials, exenatide, liraglutide, and semaglutide were associated with an increased risk of thyroid C-cell tumor proliferation; the risk in humans is unknown.4-10 GLP-1 agonists have been associated with a slight increase in acute gallbladder disease and (when used in higher doses to treat obesity) with suicidal ideation and minor increases in heart rate.3-12
When taken concomitantly with insulin or sulfonylureas, GLP-1 agonists increase the risk of hypoglycemic events.3-12 Because they slow gastric emptying, they may also affect the rate of absorption of oral medications that are administered at the same time.3-12
Before beginning any GLP-1 agonist treatment plan, clinicians should instruct patients to consult the FDA-approved patient labeling (the Medication Guide and Instructions for Use) for the specific medication they are being prescribed.
Effective type 2 diabetes and obesity management necessitates adjustments to diet and lifestyle in concert with pharmaceutical treatments.17 Patients should be encouraged to work with dieticians, diabetes educators, and other health care professionals to maintain a healthy lifestyle and receive consistent monitoring and education.
Coverage in mainstream press has led to widespread interest in GLP-1 agonists, and patients commonly ask about these medications, particularly for weight loss. Endocrinology Advisor offers a Patient Fact Sheet, How Do GLP-1 Receptor Agonists, Like Ozempic or Mounjaro Work? that summarizes in non-clinical terms what patients need to know about these medications.
1. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art. Mol Metab. 2021;46:101102. doi:10.1016/j.molmet.2020.101102
2. Antza C, Nirantharakumar K, Doundoulakis I, Tahrani AA, Toulis KA. The development of an oral GLP-1 receptor agonist for the management of type 2 diabetes: Evidence to date. Drug Des Devel Ther. 2019;13:2985-2996. doi:10.2147/DDDT.S166765
3. Trulicity. Prescribing information. Eli Lilly and Company; 2022. Accessed October 1, 2024. https://www.frankenthalerfoundation.org
4. Bydureon. Prescribing information. AstraZeneca Pharmaceuticals; 2018. Accessed October 1, 2024.https://www.frankenthalerfoundation.org
5. Byetta. Prescribing information. AstraZeneca Pharmaceuticals; 2022. Accessed October 1, 2024. https://www.frankenthalerfoundation.org
6. Victoza. Prescribing information. Novo Nordisk; 2023. Accessed October 1, 2024. https://www.frankenthalerfoundation.org
7. Saxenda. Prescribing information. Novo Nordisk; 2023. Accessed October 1, 2024. https://www.frankenthalerfoundation.org
8. Ozempic. Prescribing information. Novo Nordisk; 2023. Accessed October 1, 2024. https://www.frankenthalerfoundation.org
9. Wegovy. Prescribing information. Novo Nordisk; 2024. Accessed October 1, 2024. https://www.frankenthalerfoundation.org
10. Rybelsus. Prescribing information. Novo Nordisk; 2024. Accessed October 1, 2024. https://www.frankenthalerfoundation.org
