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Diabetes Watch

Understanding the Glucagon-like Peptide-1 Receptor Agonist Medications for Diabetes

January 2023

An estimated 1.4 million Americans are diagnosed with diabetes every year, according to the American Diabetes Association, and metformin remains the preferred first-line therapy for treating type 2 diabetes.1,2 Glucagon-like peptide-1 (GLP-1) agonists (also known as GLP-1 receptor agonists [RAs], incretin mimetics, or GLP-1 analogs) represent a class of medications used to treat type 2 diabetes mellitus and obesity in adults.2 GLP-1 medications were initially approved by the Food and Drug Administration (FDA) in 2005.3 Examples of drugs in this class include exenatide (Byetta), lixisenatide (Adlixin), liraglutide (Saxenda), albiglutide (Tanzium), dulaglutide (Trulicity), and semaglutide (Ozempic and Rybelsus).2,3

Consideration of a glucagon-like peptide-1 receptor agonist (GLP-1) analog is appropriate for patients with a contraindication or intolerance to metformin.2 Additionally, these GLP-1 medications may come into play for patients with a hemoglobin A1c greater than 1.5% over target, or in patients who do not reach their target A1c in 3 months, particularly those with comorbidities such as atherosclerosis, heart failure, or chronic kidney disease.2

What Are GLP-1 Agonists?

Glucagon-like peptide (GLP-1) is a type of hormone known as an incretin that’s lower than normal in type 2 diabetes.2 GLP-1 receptor agonists belong to a class of medications known as incretin mimetics. The GLP-1 receptor agonists have many effects: helping to control appetite and blood sugar levels, facilitating the pancreas’ release of the optimal amount of insulin, which transports glucose to tissues in the body to be used for energy, and slowing the rate at which food leaves the stomach, which helps to control post-prandial blood sugar levels. GLP-1 agonists work on different organs throughout the body.2–6

Other functions of GLP-1 medications include increased muscle glucose uptake, decreased liver glucose production, neuroprotection, and increased satiety due to direct actions on the hypothalamus.2 GLP-1 analogs also exhibit lower all-cause mortality as well as hemoglobin A1c reduction of about 1 percent when compared to control groups in patients with type-2 diabetes.2

Studies have shown that this class of medications also promotes an average weight loss of 2.9 kilograms when compared to placebo.2 In 2014, liraglutide became the first GLP-1 agonist to be FDA-approved for weight management in obese patients without diabetes.7 Furthermore, GLP-1 agonists lowering both systolic and diastolic blood pressure and total cholesterol.2 In terms of cardiovascular effects, GLP-1 agonists can improve left ventricular ejection fraction, myocardial contractility, coronary blood flow, cardiac output, and endothelial function while reducing infarction size and overall risks for a cardiovascular event.2

Most GLP-1 receptor agonist medications are injectable, and may be short- or long-lasting. GLP-1 receptor agonist injections are subcutaneous inserted into the fatty tissue just below the surface of the skin. Below is a summary of commonly prescribed GLP-1 receptor agonists and their administration:2–5,8

  • dulaglutide—0.75–1.5 mg subcutaneous injection once weekly
  • albiglutide—30-50 mg subcutaneous injection once weekly
  • liraglutide—1.2–1.8 mg subcutaneous injection daily
  • 3 mg subcutaneous injection daily for weight loss
  • exenatide—5-10 mcg subcutaneous injection twice a day
  • exenatide extended release (Bydureon)—2 mg subcutaneous injection weekly
  • lixisenatide—10–20 mcg  subcutaneous injection daily
  • semaglutide—0.25 mg subcutaneous injection once weekly for 4 weeks (Ozempic)
  • semaglutide—3 mg orally once a day for 30 days; then 7 mg orally once a day (Rybelsus)
  • tirzepatide (Mounjaro) injection—2.5 mg injected subcutaneously once weekly

What Do We Know About the Impact of These Medications?

The combination of (basal) insulin with a GLP-1 receptor agonist can be a highly effective treatment even for advanced stages of type 2 diabetes. It should only be used in patients needing a combination of two injectables, especially considering the potential costs of such a combination. When a GLP-1 receptor agonist is added to (basal) insulin, the combination is as effective as an intensified (basal bolus) insulin regimen in terms of HbA1c control. However, it also comes with a much lower risk of hypoglycemia and weight gain. When adding insulin to a GLP-1 medication, it helps control fasting plasma glucose. In combination with post-prandial effects of GLP-1 drugs (decelerating gastric emptying, stimulating insulin, or suppressing glucagon secretion), this provides an excellent forecast to achieve the target ranges for fasting, post-prandial, and overall glycemic control.2–5,8

GLP-1 agonist medications are generally safe, effective, and have relatively few side effects. However, it is important to be familiar with the most common adverse effects of these drugs. GLP-1 agonists’ major side effects include nausea, vomiting, and diarrhea. These particular symptoms affect 10 to 40 percent of patients, and could lead to an acute kidney injury due to volume contraction. Other potential side effets could include dizziness, mild tachycardia, infections, headaches, and dyspepsia.2–5,8

When Should GLP-1 Medications Be Avoided?

Contraindications to utilizing GLP-1 agonists include hypersensitivity and pregnancy. Some form of contraception is recommended with GLP-1 agonists in women of childbearing age. Additionally, patients with severe gastrointestinal diseases such as gastroparesis and inflammatory bowel disease should avoid GLP-1 analogs. Lastly, GLP-1 agonists are not recommended in patient populations with a personal or family history significant for conditions such as multiple endocrine neoplasia 2A, multiple endocrine neoplasia 2B, or medullary thyroid cancer.2–5,8

GLP-1 analogs principally undergo renal elimination. Dosing adjustments of GLP-1 agonists are not necessary for hepatic or mild renal impairment. Moderate renally impaired patients, on the other hand, should avoid weekly exenatide, and dosing escalations should be considered carefully in patients on twice daily exenatide. Likewise, lixisenatide use requires caution in moderate renal impairment. Dosing increases of twice daily exenatide for patients 70 years and older merit close evaluation of the potential risks and benefits.2–5,8

Patients with severe renal dysfunction should not take GLP-1 agonists. If a GLP-1 agonist is added to a regimen already consisting of a sulfonylurea or long-acting insulin, these patients require monitoring for hypoglycemia. A decrease in the insulin dose may even become necessary. As in most cases, patients taking GLP-1 analogs should periodically have their hemoglobin A1c measured and have their glycemic patterns examined. The clinician should follow the international normalized ratio (INR) in patients prescribed warfarin, as a GLP-1 agonist may alter the absorption of warfarin.2–5,8

Concluding Thoughts

To date, there are published results from 9 phase III randomized trials that directly compare different pairs of GLP-1 receptor agonists. Of the GLP-1 receptor agonists in the head-to-head trials, exenatide twice daily and liraglutide were the most common comparators. In all the head-to-head trials, the GLP-1RAs studied led to notable reductions in HbA1c. As a class, the GLP-1RAs have all been shown to have a weight-reduction effect, and this effect is significantly greater than is typically seen with most other therapeutic classes.5

Structural differences between the various GLP-1RAs result in unique clinical profiles; these treatments, therefore, differ from each other substantially with respect to glycemic control, effects on weight, and safety and tolerability. Patient preference should be an important element of the treatment decision.

Dr. Smith is a practicing podiatrist and pharmacist in Ormond Beach, FL. He is a frequent author and lecturer on opioid mitigation, infection control and other foot and ankle topics.

References
1.    American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S90-S102. https://doi.org/10.2337/dc19-S009
2.    Collins L, Costello RA. Glucagon-like peptide-1 receptor agonists. [Updated 2022 May 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.
3.    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.
4.    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.
5.    Htike ZZ, Zaccardi F, Papamargaritis D, Webb DR, Khunti K, Davies MJ. Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: A systematic review and mixed-t reatment comparison analysis. Diabetes Obes Metab. 2017;19(4):524-536.
6.    Madsbad S. Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists. Diabetes Obes Metab. 2016;18(4):317-332.
7.    Isaacs D, Prasad-Reddy L, Srivastava SB. Role of glucagon-like peptide 1 receptor agonists in management of obesity. Am J Health Syst Pharm. 2016 Oct 1;73(19):1493-507.
8.    Htike ZZ, Zaccardi F, Papamargaritis D, Webb DR, Khunti K, Davies MJ. Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: A systematic review and mixed-treatment comparison analysis. Diabetes Obes Metab. 2017;19(4):524-536.

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