Glucagon-like Peptide-1 Receptor Agonists

Continuing Education Activity

Glucagon-like peptide-1 agonists are a class of medications utilized in the treatment of type 2 diabetes and obesity. This activity will highlight the indications, mechanism of action, administration, adverse effect profile, and contraindications for these drugs. The use of an interprofessional team of nurses, primary care providers, pharmacists, as well as endocrinologists remains pertinent to care for patients prescribed this class of medications.


  • Review the mechanism of action of GLP-1 receptor agonists.
  • Identify the contraindications and adverse effects of GLP-1 receptor agonists.
  • Outline the methods of administration for GLP-1 analogs and the clinical monitoring necessary for patients prescribed GLP-1 receptor agonists.
  • Explain the importance of collaboration and communication among an interprofessional healthcare team to improve outcomes for patients receiving GLP-1 agonists.


Glucagon-like peptide-1 (GLP-1) agonists represent a class of medications used in the treatment of type 2 diabetes mellitus in adults. Examples of drugs in this class include exenatide, lixisenatide, liraglutide, albiglutide, dulaglutide, and semaglutide. According to the American Diabetes Association, metformin remains the preferred first-line therapy for the treatment of type 2 diabetes. However, the addition of a GLP-1 analog should be considered in patients with a contraindication or intolerance to metformin, in patients with a hemoglobin A1c greater than 1.5% over target, or in patients who do not reach their target A1c in three months particularly in patients with atherosclerosis, heart failure, or chronic kidney disease.[1][2][3][4] Furthermore, high dose liraglutide is FDA approved as a pharmacologic treatment for obesity or can be prescribed to overweight patients with comorbidities. The utilization of GLP-1 analogs is an object of research with favorable hemoglobin A1c results and weight loss results in patients with type-1 diabetes mellitus. Of note, higher costs, as well as tolerability, remain significant barriers in prescribing these medications.[5][6][7][8]

Mechanism of Action

Glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GIP), both incretin hormones inactivated by dipeptidyl peptidase-4 (DPP-4), stimulate insulin secretion after an oral glucose load via the incretin effect. In type 2 diabetes, this process can become blunted or even be absent; however, the utilization of pharmacological levels of GLP-1 can revive insulin excretion. The benefits of this form of therapy to treat type 2 diabetes include delayed gastric emptying and inhibiting the production of glucagon from pancreatic alpha cells if blood sugar levels are high. Furthermore, GLP-1 receptor agonists can decrease pancreatic beta-cell apoptosis while promoting their proliferation.

This class of medications has also shown to promote an average weight loss of 2.9 kilograms when compared to placebo in addition to lowering both systolic and diastolic blood pressure and total cholesterol. 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. Other functions of GLP-1 include increased glucose uptake in the muscles, decreased glucose production in the liver, neuroprotection, and increased satiety due to direct actions on the hypothalamus. GLP-1 analogs have also exhibited lower all-cause mortality as well as a hemoglobin A1c reduction of about one percent compared to control groups in patients with type-2 diabetes mellitus.[9][10][11][12][13][14][15][16][8]


Many formulations of GLP-1 agonists, all of which historically were injectable and administered subcutaneously due to poor oral bioavailability, can be prescribed in the United States. Lixisenatide and liraglutide dosing are once-daily, albiglutide, dulaglutide, and semaglutide dosing are once weekly, and exenatide comes as either as a twice-daily or a once-weekly injection. Recently, the FDA approved an oral formulation of semaglutide. Researchers have suspended trials investigating taspoglutide as a novel GLP-1 analog due to gastrointestinal side effects and hypersensitivity reactions.

Depending on the drug prescribed, the medication may come as a single- or multi-dose pen and may require a separate prescription for needles with various needle gauge requirements. Patients have shown improved satisfaction with once-weekly exenatide compared to a twice-daily regimen, and studies have demonstrated their preferences for narrow needles. However, concerns regarding compliance with a once-weekly as opposed to a daily regimen have also been raised. GLP-1 analogs, combined with long-acting insulin in a single injection, have also been introduced to the pharmaceutical market. This regimen potentially provides synergism with insulin lowering fasting and post-absorptive blood sugars and GLP-1 agonists targeting postprandial blood sugars. This strategy may lower the risk of hypoglycemia due to less reliance on bolus and even basal insulin and may offset potential weight gain experienced with insulin.[17][18][19][20][8][21][22]

Adverse Effects

The most frequently exhibited side effects from GLP-1 agonists include nausea, vomiting, and diarrhea that could lead to an acute kidney injury due to volume contraction. Dizziness, mild tachycardia, infections, headaches, and dyspepsia may also occur. Patients should receive education that this class of drugs increases satiety and transient, mild nausea may occur if they attempt to eat while feeling full. Increasing the dosage of these medications should occur slowly if nausea is present. Injection-site pruritus and erythema are also common, most notably with the longer-acting medications in this class.

A low risk of minor episodes of hypoglycemia does remain; however, research has not described any major hypoglycemic episodes at this time. Patients can form antibodies to particular GLP-1 analogs that could affect the efficacy of these medications, particularly with exenatide. This immunogenicity could lead to injection site reactions and even potential anaphylaxis. Studies have shown these adverse effects typically lead to an overall low rate of discontinuation at around ten percent. Combination therapy with GLP-1 agonists and dipeptidyl peptidase-4 inhibitors is not a current recommendation due to statistically insignificant glycemic improvement and enhanced hypoglycemic effects. The interactions between GLP-1 agonists and other oral anti-diabetic medications remain unclear.[9][23][11][19][24][25][8][26]


In terms of contraindications to utilizing GLP-1 agonists, hypersensitivity, as well as pregnancy, should prohibit prescribing this class of medications. A form of contraception is the recommendation 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. Concern for long-term consequences on the thyroid gland with the use of GLP-1 agonists has been a topic of investigation. In rodent models, liraglutide stimulated calcitonin release and led to hyperplasia of thyroid gland C-cells and tumors. The effects in humans remain unclear, with further investigations being necessary. Consequently, GLP-1 agonists are not recommended in patient populations with a personal or family history significant for multiple endocrine neoplasia 2A, multiple endocrine neoplasia 2B, or medullary thyroid cancer.

While the mechanism remains largely unknown, acute pancreatitis, including potentially fatal hemorrhagic and necrotizing types, has been noted in users of GLP-1 analogs. Whether a causal relationship exists between GLP-1 analogs and pancreatitis or pancreatic cancer is unknown at this time. Nonetheless, GLP-1 agonists should not be prescribed in patients with a history of pancreatitis and should be discontinued in those who develop pancreatitis while taking this medication.[27][28][19][29][24][30][31]


GLP-1 analogs are principally renally eliminated. Dosing adjustments of GLP-1 agonists are not necessary due to 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 this patient population. Dosing increases of twice-daily exenatide in patients 70 years and older merit evaluation of the potential risks and benefits.

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, patients require monitoring for hypoglycemia. A decrease in the insulin dose may even become necessary, depending on the GLP-1 analog selected. 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 this medication by delaying gastric emptying. Healthcare providers should also monitor patients taking GLP-1 agonists for signs and symptoms consistent with pancreatitis. The FDA currently has recommended against routinely monitoring calcitonin levels for medullary thyroid cancer.[29][24][8]


Research into GLP-1 analog overdoses remains limited. Reports exist of symptoms such as nausea, vomiting, diarrhea, excessive belching, and abdominal pain as a result of a toxic ingestion of medication within this class; however, no serious complications, such as pancreatitis or hypoglycemia, have been noted in case studies. Treatment comprises of supportive care, including antiemetics to control excessive nausea and vomiting.[25][32]

Enhancing Healthcare Team Outcomes

The treatment of both type 2 diabetes and obesity should involve an interprofessional team, including a primary care provider, diabetes educator, pharmacist, and possibly an endocrinologist. Providers and pharmacists n collaborate on the decision to try a GLP-1 agonist and include a complete medication review in their decision.

Clinicians, pharmacists, and nursing should all educate patients on potential side effects and drug interactions of GLP-1 agonist therapy, and patients should have regular follow-up appointments with their primary care provider to monitor blood glucose levels, weight, kidney function, as well as for signs and symptoms consistent with pancreatitis. Nursing can be particularly helpful in this monitoring, and report any concerns to the prescriber and/or pharmacist. A cohesive interprofessional team approach can further the goal of GLP-1 therapy should highlight maximizing blood sugar control and weight loss while minimizing potential adverse reactions. [Level 5]

Article Details

Article Author

Logan Collins

Article Editor:

Ryan Costello


6/23/2020 10:54:30 AM



Hunt B,Malkin SJP,Moes RGJ,Huisman EL,Vandebrouck T,Wolffenbuttel B, Once-weekly semaglutide for patients with type 2 diabetes: a cost-effectiveness analysis in the Netherlands. BMJ open diabetes research     [PubMed PMID: 31641522]


Burcelin R,Gourdy P, Harnessing glucagon-like peptide-1 receptor agonists for the pharmacological treatment of overweight and obesity. Obesity reviews : an official journal of the International Association for the Study of Obesity. 2017 Jan;     [PubMed PMID: 27636208]


Gourgari E,Wilhelm EE,Hassanzadeh H,Aroda VR,Shoulson I, A comprehensive review of the FDA-approved labels of diabetes drugs: Indications, safety, and emerging cardiovascular safety data. Journal of diabetes and its complications. 2017 Dec;     [PubMed PMID: 28939018]


9. Pharmacologic Approaches to Glycemic Treatment: {i}Standards of Medical Care in Diabetes-2019{/i}. Diabetes care. 2019 Jan;     [PubMed PMID: 30559235]


8. Obesity Management for the Treatment of Type 2 Diabetes: {i}Standards of Medical Care in Diabetes{/i}-{i}2019{/i}. Diabetes care. 2019 Jan;     [PubMed PMID: 30559234]


Janzen KM,Steuber TD,Nisly SA, GLP-1 Agonists in Type 1 Diabetes Mellitus. The Annals of pharmacotherapy. 2016 Aug;     [PubMed PMID: 27252246]


Sanford M, Dulaglutide: first global approval. Drugs. 2014 Nov;     [PubMed PMID: 25367716]


Hinnen D, Glucagon-Like Peptide 1 Receptor Agonists for Type 2 Diabetes. Diabetes spectrum : a publication of the American Diabetes Association. 2017 Aug;     [PubMed PMID: 28848315]


Vilsbøll T,Christensen M,Junker AE,Knop FK,Gluud LL, Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ (Clinical research ed.). 2012 Jan 10;     [PubMed PMID: 22236411]


Davidson MH, Cardiovascular effects of glucagonlike peptide-1 agonists. The American journal of cardiology. 2011 Aug 2;     [PubMed PMID: 21802579]


Garber AJ, Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. Diabetes care. 2011 May;     [PubMed PMID: 21525469]


Gallwitz B, GLP-1 agonists and dipeptidyl-peptidase IV inhibitors. Handbook of experimental pharmacology. 2011;     [PubMed PMID: 21484567]


Okerson T,Chilton RJ, The cardiovascular effects of GLP-1 receptor agonists. Cardiovascular therapeutics. 2012 Jun;     [PubMed PMID: 21167014]


Zheng SL,Roddick AJ,Aghar-Jaffar R,Shun-Shin MJ,Francis D,Oliver N,Meeran K, Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis. JAMA. 2018 Apr 17;     [PubMed PMID: 29677303]


Monami M,Marchionni N,Mannucci E, Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials. European journal of endocrinology. 2009 Jun;     [PubMed PMID: 19318378]


Seufert J,Gallwitz B, The extra-pancreatic effects of GLP-1 receptor agonists: a focus on the cardiovascular, gastrointestinal and central nervous systems. Diabetes, obesity     [PubMed PMID: 24373150]


Eng C,Kramer CK,Zinman B,Retnakaran R, Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet (London, England). 2014 Dec 20;     [PubMed PMID: 25220191]


Christensen M,Knop FK, Once-weekly GLP-1 agonists: How do they differ from exenatide and liraglutide? Current diabetes reports. 2010 Apr;     [PubMed PMID: 20425571]


Madsbad S, Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists. Diabetes, obesity     [PubMed PMID: 26511102]


Gupta V, Glucagon-like peptide-1 analogues: An overview. Indian journal of endocrinology and metabolism. 2013 May;     [PubMed PMID: 23869296]


Urquhart L, FDA new drug approvals in Q3 2019. Nature reviews. Drug discovery. 2019 Oct;     [PubMed PMID: 31673140]


Husain M,Birkenfeld AL,Donsmark M,Dungan K,Eliaschewitz FG,Franco DR,Jeppesen OK,Lingvay I,Mosenzon O,Pedersen SD,Tack CJ,Thomsen M,Vilsbøll T,Warren ML,Bain SC, Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. The New England journal of medicine. 2019 Aug 29;     [PubMed PMID: 31185157]


Trujillo JM,Nuffer W,Ellis SL, GLP-1 receptor agonists: a review of head-to-head clinical studies. Therapeutic advances in endocrinology and metabolism. 2015 Feb;     [PubMed PMID: 25678953]


Unger JR,Parkin CG, Glucagon-like peptide-1 (GLP-1) receptor agonists: Differentiating the new medications. Diabetes therapy : research, treatment and education of diabetes and related disorders. 2011 Mar;     [PubMed PMID: 22127767]


Filippatos TD,Panagiotopoulou TV,Elisaf MS, Adverse Effects of GLP-1 Receptor Agonists. The review of diabetic studies : RDS. 2014 Fall-Winter;     [PubMed PMID: 26177483]


Nauck MA,Stewart MW,Perkins C,Jones-Leone A,Yang F,Perry C,Reinhardt RR,Rendell M, Efficacy and safety of once-weekly GLP-1 receptor agonist albiglutide (HARMONY 2): 52 week primary endpoint results from a randomised, placebo-controlled trial in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetologia. 2016 Feb;     [PubMed PMID: 26577795]


Bjerre Knudsen L,Madsen LW,Andersen S,Almholt K,de Boer AS,Drucker DJ,Gotfredsen C,Egerod FL,Hegelund AC,Jacobsen H,Jacobsen SD,Moses AC,Mølck AM,Nielsen HS,Nowak J,Solberg H,Thi TD,Zdravkovic M,Moerch U, Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010 Apr;     [PubMed PMID: 20203154]


Anderson SL,Trujillo JM, Association of pancreatitis with glucagon-like peptide-1 agonist use. The Annals of pharmacotherapy. 2010 May;     [PubMed PMID: 20371755]


Prasad-Reddy L,Isaacs D, A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs in context. 2015;     [PubMed PMID: 26213556]


Elashoff M,Matveyenko AV,Gier B,Elashoff R,Butler PC, Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011 Jul;     [PubMed PMID: 21334333]


Gier B,Butler PC,Lai CK,Kirakossian D,DeNicola MM,Yeh MW, Glucagon like peptide-1 receptor expression in the human thyroid gland. The Journal of clinical endocrinology and metabolism. 2012 Jan;     [PubMed PMID: 22031513]


Elmehdawi RR,Elbarsha AM, An accidental liraglutide overdose: case report. The Libyan journal of medicine. 2014;     [PubMed PMID: 24461534]