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]

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]

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]