Continuing Education Activity

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 as monotherapy or in combination with other diabetic medications.

Objectives:

• Describe the therapeutic mechanism of action of exenatide.
• Discuss exenatide's place in a diabetic therapy regimen, including administration and dosing options.
• Review the adverse event profile of exenatide.
• Outline interprofessional team strategies for improving care coordination and communication to advance diabetes management and improve outcomes using a GLP-1 receptor agonist like exenatide.

Indications

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; although, it is not recommended as a first-line therapy to treat diabetes. Clinical trials have shown that exenatide can be safe as either monotherapy or in combination with metformin. Clinical trials have also demonstrated exenatide's ability to lower HbA1c and postprandial blood glucose in patients with type 2 diabetes mellitus.[1] 

Exenatide received approval in 2005, after evaluation for its safety and efficacy. All studies included patients treated with either diet, exercise, metformin, sulfonylureas, or a combination of these agents. Research has shown that weekly administration of exenatide results in more significant reductions in both plasma glucose and HbA1c than twice-daily administration.[2]

As of 2018, the American Diabetes Association suggests adding GLP-1 receptor agonists if appropriate fasting glucose levels are attainable using a titration of basal insulin.[3] The current HbA1c goal for most adults with type 2 diabetes mellitus is less than 7%, with variations based on comorbidities.[4]

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 to have similar cardiovascular protection when compared to the placebo. These studies have also demonstrated the added benefits of exenatide, including weight loss, reduction in systolic blood pressure, and slight reductions in cholesterol levels.[5]

Mechanism of Action

Exenatide is a GLP-1 receptor agonist released from the gut and acts to increase glucose-dependent insulin secretion from pancreatic beta cells, suppress glucagon secretion, delay gastric emptying, and reduce food intake. The binding of the drug to pancreatic GLP-1 receptors mediates these actions.

The incidence of hypoglycemia is lower with exenatide than other diabetic therapies due to the glucose-dependent release of insulin. Administration of exenatide has shown restoration in the insulin response that is usually defective in type 2 diabetic patients. Researchers also observed the prolonged release of insulin in response to elevated glucose levels was also observed in patients treated with exenatide.

Treatment with exenatide leads to the decreased release of glucagon during hyperglycemic periods, which reduces hepatic glucose output as well as decreases insulin demand. Delayed gastric emptying decreases the rate at which glucose arrives in the bloodstream.

The release of insulin and the suppression of glucagon occur during hyperglycemic and euglycemic conditions. Exenatide reduces the likelihood of a hypoglycemic episode when administered to a diabetic patient when used by itself. If combining exenatide with other medications that cause hypoglycemia, there is an increased likelihood of a hypoglycemic event.[1] There is inadequate research to suggest the safety and efficacy of exenatide with prandial insulin. The use of exenatide should not replace insulin in patients requiring such treatment, as in Type 1 diabetics. 

Administration

Exenatide is available as an immediate-release solution and extended-release suspension for subcutaneous administration. The administration of these injections should be in the thigh, abdomen, or upper arm. Additionally, patients should receive instruction to use a different injection site for each dose to prevent infection. 

Immediate-Release

The immediate-release formulation of exenatide is available in prefilled pens containing 250 mcg/mL in two different package sizes: 1.2 mL prefilled pen with a 5 mcg/dose and 2.4 mL 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 most substantial meals of the day. Doses should be administered at least 6 hours apart and not after meals.

Extended-Release

The extended-release formulation 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.

Adverse Effects

Clinical trials have shown the most common adverse effect to be nausea. This side effect was dose-dependent and decreased with continued usage of the medication.[1] Studies have shown that weekly administration of exenatide results in less nausea than twice-daily exenatide.[2] Other manufacturers reported adverse effects, including vomiting, diarrhea, hypoglycemia, headache, dizziness, injection-site pruritus, injection-site nodules, and dyspepsia. It is also important to note that the class of GLP-1 analogs can induce pancreatitis. Also, exenatide is a class C teratogen and should not be used in pregnancy. If a female is pregnant or actively seeking to get pregnant, she should be switched to insulin as insulin does not cross the placenta and will not interfere with the fetus's development. 

Contraindications

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. Avoid using exenatide in patients with a personal or familial history of medullary thyroid carcinoma. The extended-release formulation of exenatide has a black box warning concerning medullary thyroid carcinoma since treatment in mice has resulted in tumor formation. It is currently unknown if exenatide results in the same outcome in humans. Therefore, patients should receive counsel 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, the recommendation is that patients with severe gastrointestinal disease avoid using this medication.

Monitoring

Patients taking exenatide should continue monitoring serum glucose concentrations as well as HbA1c twice yearly. Monitoring also should include renal function, weight, triglycerides, and monitoring for signs or symptoms of pancreatitis or gallbladder disease.[6]

Toxicity

According to the manufacturer, severe overdose has been shown to induce severe nausea, vomiting, and rapidly declining blood glucose concentrations. If an overdose occurs, clinicians should initiate appropriate supportive treatment. However, several case reports have recorded only gastrointestinal symptoms and little to no hypoglycemia.

Enhancing Healthcare Team Outcomes

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 a first-line therapy to treat diabetes. Clinical trials have shown exenatide to be safe and effective when used as either monotherapy or in combination with other diabetic medications. Clinical trials have demonstrated exenatide's ability to lower HbA1c and postprandial blood glucose in patients with type 2 diabetes mellitus.[7][8][9]

While the drug is relatively safe, it is also expensive. The interprofessional healthcare team, including clinicians, mid-level providers, nurses, and pharmacists, should regularly educate patients on the importance of exercise and lowering body weight, which helps lower blood glucose and decreases the need for pharmacological agents. The patient should also be informed regarding the signs of adverse events so they can contact their clinician. The pharmacist can verify dosing and perform medication reconciliation to check for potential drug-drug interactions. It is essential to treat the underlying cause of the disease with lifestyle changes, with medication as an adjunct. Using interprofessional strategies will improve therapeutic results with exenatide and decrease adverse events. [Level 5]