Exenatide is FDA-indicated to improve glycemic control in adult patients with type 2 diabetes mellitus when used as an adjunct to diet and exercise. It is not recommended as first-line therapy to treat diabetes. However, clinical trials have shown exenatide to be both safe and effective when used either as monotherapy or in combination with metformin with or without a sulfonylurea. Clinical trials have demonstrated exenatide's ability to lower HbA1c and postprandial blood glucose in patients with type 2 diabetes mellitus. 
Exenatide was first approved in 2005 after evaluation of its safety and efficacy in relation to both hyperglycemia and HbA1c in 10 randomized, double-blind, placebo-controlled trials. All studies included patients treated with either diet, exercise, metformin, sulfonylureas, or combinations of those agents. It has been shown that weekly administration of exenatide results in greater reductions in both plasma glucose and HbA1c than twice daily administration. 
In the 2018 update to the Standards of Medical Care in Diabetes, the American Diabetes Association suggests the addition of GLP-1 receptor agonists if appropriate fasting glucose levels have been attained using titration of basal insulin but patient's A1c remains above goal.  The current HbA1c goal for most adults with type 2 diabetes mellitus is less than 7%, with variations based on comorbidities. 
Following the experience with rosiglitazone and its impact on cardiovascular risk, the FDA focused heavily on requiring drug manufacturers to conduct either meta-analyses or post-marketing trials to prove the cardiovascular safety of all new diabetic medications. Such studies involving exenatide have shown the drug to be noninferior to placebo in regards to cardiovascular safety. These studies also have shown the added benefits of exenatide such as weight loss, reduction in systolic blood pressure, and slight reductions in cholesterol levels. 
Exenatide is a first-in-class GLP-1 receptor agonist released from the gut which acts to increase glucose-dependent insulin secretion from pancreatic beta cells, suppress glucagon secretion, delay gastric emptying, and reduce food intake. These actions are mediated by the binding of the drug to pancreatic GLP-1 receptors which increase both synthesis and secretion of insulin from the beta cells.
The incidence of hypoglycemia is lower with exenatide than other diabetes therapies due to the glucose-dependent release of insulin. Administration of exenatide has shown restoration in the first-phase insulin response ordinarily defective in type 2 diabetic patients. This response is characterized by insulin release within 10 minutes of glucose intake. Second-phase insulin response, or the prolonged release of insulin in response to elevated glucose levels, was also increased in patients being treated with exenatide.
Treatment with exenatide leads to the decreased release of glucagon during hyperglycemic periods. This, in turn, reduces hepatic glucose output as well as decreases insulin demand. Delayed gastric emptying decreases the rate at which glucose arrives in the bloodstream.
According to studies, both the release of insulin and suppression of glucagon only occur during hyperglycemic and euglycemic conditions, reducing the likelihood of a hypoglycemic episode following administration of this medication. However, the risk of hypoglycemia is increased when exenatide is administered with antidiabetic medications that cause hypoglycemia such as sulfonylureas, meglitinides, and thiazolidinediones.  There is inadequate research to suggest the safe and efficacious use of exenatide with prandial insulin. Use of exenatide should not replace insulin in patients requiring such treatment.
Exenatide is available as both immediate-release solution and extended-release suspension for subcutaneous administration. Injections should be given in the thigh, abdomen, or upper arm. Patients should be advised to use a different injection site for each dose.
The immediate release formulation of exenatide and is available in prefilled pens containing 250 mcg/mL in two different package sizes: 1.2 mL prefilled pen containing 5 mcg/dose and 2.4mL prefilled pen containing 10 mcg/dose. Doses should be initiated at 5 mcg twice daily within 60 minutes of morning and evening meals. If the response is inadequate after one month of therapy, the dose may be increased to 10 mcg twice daily with the two largest meals of the day. Doses should be administered at least 6 hours apart and not after meals.
The extended-release formulation and is available in both prefilled pens and single-use vials containing 2 mg of the drug. Both formulations require reconstitution before administration. Patients should visually inspect the solution for particulates before injecting.
Clinical trials have shown the most common adverse effect to be nausea, but the incidence was shown to decrease with continued treatment and was dose-dependent.  Studies show that weekly administration of exenatide results in less nausea than twice daily exenatide.  Other manufacturers reported adverse effects including vomiting, diarrhea, hypoglycemia, feeling jittery, headache, dizziness, injection-site pruritus, injection-site nodules, and dyspepsia.
According to the manufacturer, exenatide is contraindicated in patients with a known hypersensitivity to any component of the drug or formulation.
This medication should not be used for the treatment of diabetic ketoacidosis or in type 1 diabetic patients. Exenatide is not recommended for use in end-stage renal disease or severe renal impairment (CrCl less than 30 mL/min).
There is inadequate evidence to support the use of exenatide in patients who are pregnant. Use during pregnancy should be limited to cases where the risk outweighs the benefit. There also is no evidence to support the safety or efficacy of exenatide in pediatric patients.
Patients with a history of pancreatitis should avoid the use of exenatide. In patients with a personal or familial history of medullary thyroid carcinoma, exenatide should be avoided. The extended-release formulation of exenatide has a black box warning concerning medullary thyroid carcinoma since treatment in mice has resulted in the formation of tumors. It is currently unknown if exenatide results in the same outcome in humans. Therefore, patients should be counseled on the symptoms of thyroid tumors, including but not limited to a mass in the neck, dysphagia, dyspnea, or persistent hoarseness.
Due to the prevalence of gastrointestinal adverse events, it is recommended that patients with severe gastrointestinal disease avoid the use of exenatide.
Patients taking exenatide should continue monitoring serum glucose concentrations as well as HbA1c twice yearly if they meet glycemic goals and quarterly when changing therapy or not meeting goals. Monitoring also should include renal function, weight, triglycerides, signs/symptoms of pancreatitis, and signs/symptoms of gallbladder disease. 
According to the manufacturer, severe overdose has been shown to cause severe nausea, vomiting, and rapidly declining blood glucose concentrations. If an overdose occurs, appropriate supportive treatment should be initiated. However, several case reports have recorded only gastrointestinal symptoms and little to no hypoglycemia.