Glucagon-Like Peptide-1 Agonists (GLP-1)

By Paul Gilbert, MD, Internal Medicine Residency Class of 2025

Note: This is a series called “Clinical Pearls,” where physicians will share treatment tips for specific conditions. Interested in contributing to this series? Please contact HonorHealth’s Marketing Manager, Kevin Wyne, at [email protected]. 

Summary Points:

• GLP1RAs significantly reduce the rate of major adverse cardiovascular events in patients with Type 2 Diabetes, chronic kidney disease, and overweight patients with cardiovascular disease.
• Symptomatic side effects are predominantly gastrointestinal-related but generally improve. Severe adverse effects include acute kidney injury, gallbladder disease, hypersensitivity reactions.
• Patients with gastroparesis or advanced kidney disease can use GLP1RAs (predominantly long-acting forms) although this is a relative contraindication to use.
• GLP/GIP agonists (tirzepatide) have greater weight loss effects/hgb A1c reduction in comparison to GLP1RAs – studies comparing cardioprotective effects are ongoing.
• History of pancreatitis, pregnancy/breastfeeding, personal/family history of MEN 2A/2B or medullary thyroid cancer are all contraindications to prescribing.
• Rebound weight gain upon discontinuation of GLP1RA has been shown to occur – education and emphasis on lifestyle modification prior to discontinuation is important for effective long-term weight management strategies.

Glucagon-like peptide-1 (GLP-1) is an incretin which slows gastric emptying, enhances glucose-dependent insulin secretion, and reduces postprandial glucagon levels. Glucagon like peptide-1 receptor agonists (GLP1RAs) utilize this to great effect, leading to improved glycemic control with no increased risk of hypoglycemia. GLP1RAs are hypothesized to have additional anti-inflammatory effects beyond improved glycemic control, although this is less robustly studied. GLP1RAs have been shown to decrease rates of major adverse cardiac events (MACE) in patients with Type 2 Diabetes Mellitus (T2DM), a leading cause of death in this population1. Meta-analysis has shown that in patients with T2DM and chronic kidney disease, GLP1RAs lower rates of all-cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney disease progression2. The American Diabetes Association, the American Association of Clinical Endocrinology, and American College of Cardiology recommend use of GLP1RAs in patients with T2DM or those are at high risk for clinical cardiovascular disease, heart failure, or diabetic kidney disease3.

More recently, GLP1RA has shown cardioprotective effects use in overweight patients with cardiovascular disease without diabetes showed significant reductions in cardiovascular events4. GLP1RAs have also been linked to symptom palliation and improvement of exercise function in patients with obesity and heart failure with preserved ejection fraction (HFpEF)4. GLP1RAs are currently being studied in patients with peripheral artery disease and Alzheimer’s (STRIDE and EVOKE trials respectively).

Current GLP1RAs with proven cardiovascular benefits include semaglutide (Ozempic, Wegovy), liraglutide (Victoza, Saxenda), and dulaglutide (Trulicity). Of those, semaglutide and dulaglutide have weekly dosing regimens.

Tirzepatide (Mounjaro, Zepbound) is a dual incretin receptor agonist, affecting both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, which was approved for treatment of T2DM by the FDA in May 2022. This has been shown to have more potent weight loss effects in comparison to treatment with GLP1RAs5. Further studies are in place to assess treatment efficacy of GIP/GLP1RAs versus GLP1RAs with respect to relative rates of MACE6. Additionally, triple agonist therapy involving GLP/GIP and glucagon receptor agonist (retatrutide, Eli Lilly) has recently entered phase 3 testing7.
GLP1RAs must be started and titrated slowly to mitigate risk of adverse side effects. The most common adverse side effects of GLP1RAs are gastrointestinal symptoms such as nausea, abdominal pain, vomiting, dehydration. More serious side effects include acute kidney injury, development of gallbladder disease, allergic reactions. Use of GLP1RAs significantly affects gastric emptying and should be discontinued prior to obtaining certain diagnostic testing or surgical procedures.
Patients with advanced chronic kidney disease (eGFR <30) and gastroparesis can use certain GLP1RAs with caution and close specialist monitoring; patient education on symptoms of dehydration is needed to reduce risk of kidney injury. GLP1RA use is contraindicated with prior history of pancreatitis, pregnancy and breastfeeding. Use of GLP1RAs in patients with personal or family history of multiple endocrine neoplasia (2A/2B) or medullary thyroid cancer is contraindicated due to concern of cancer risk.

References:

1. GLP1RAs in Clinical Practice: Therapeutic Advances and Safety Perspectives. American College of Cardiology. Accessed June 20, 2024. https://www.acc.org/Latest-in-Cardiology/Articles/2024/04/15/11/19/http%3a%2f%2fwww.acc.org%2fLatest-in-Cardiology%2fArticles%2f2024%2f04%2f15%2f11%2f19%2fGLP1RAs-in-Clinical-Practice
2. Palmer SC, Tendal B, Mustafa RA, et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ. Published online January 13, 2021:m4573. doi:10.1136/bmj.m4573
3. Marx N, Husain M, Lehrke M, Verma S, Sattar N. GLP-1 Receptor Agonists for the Reduction of Atherosclerotic Cardiovascular Risk in Patients With Type 2 Diabetes. Circulation. 2022;146(24):1882-1894. doi:10.1161/CIRCULATIONAHA.122.059595
4. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563
5. Lin F, Yu B, Ling B, et al. Weight loss efficiency and safety of tirzepatide: A Systematic review. Roggen I, ed. PLOS ONE. 2023;18(5):e0285197. doi:10.1371/journal.pone.0285197
6. Nicholls SJ, Bhatt DL, Buse JB, et al. Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events in participants with type 2 diabetes and atherosclerotic cardiovascular disease: SURPASS‐CVOT design and baseline characteristics. Am Heart J. 2024;267:1-11. doi:10.1016/j.ahj.2023.09.007
7. Rosenstock J, Frias J, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. The Lancet. 2023;402(10401):529-544. doi:10.1016/S0140-6736(23)01053-X

HonorHealth does not endorse, advocate or verify the views or information presented in this article. Any views expressed in this article are solely the views of the author, and information is provided on as “as is” basis with no representation or warranty that it is accurate or up to date. This publication is intended for medical professionals only. Readers retain full responsibility for the care and treatment of patients and should use professional judgment when considering the information presented.