Optimizing the Clinical Use of the GLP-1 Receptor Agonist Exenatide Once Weekly

GLP-1 is a glucoregulatory hormone secreted by intestinal cells after eating. GLP-1 enhances glucose-dependent insulin secretion, suppresses inappropriate postprandial glucagon secretion, slows gastric emptying, and increases satiety. However, native GLP-1 has a half-life of ~ 1.5–2 minutes because it is rapidly deactivated by the enzyme dipeptidyl peptidase-4 (DPP-4). Currently available diabetes drugs affect the GLP-1 system in two different ways. DPP-4 inhibitors (e.g., sitagliptin, saxagliptin, and linagliptin) inhibit the enzyme DPP-4, thereby increasing the amount of time native GLP-1 remains active. GLP-1 receptor agonists that have a longer half-life than native GLP-1 (e.g., exenatide and liraglutide) bind to GLP-1 receptors and produce effects similar to those of native GLP-1.

Exenatide is a synthetic peptide that binds to and activates GLP-1 receptors, stimulating the same glucoregulatory actions as GLP-1. The origin of exenatide is the peptide exendin-4, a salivary secretion from the lizard Heloderma suspectum (Gila monster) that was found to be similar to GLP-1.¹⁰  Exenatide is the synthetic form of exendin-4. Exenatide twice daily, administered within 60 minutes before the two main meals of the day, decreases A1C primarily by lowering postprandial glucose levels. It is approved for the treatment of type 2 diabetes as monotherapy, in combination with various oral antihyperglycemic agents, and as an add-on therapy to insulin glargine.¹¹ 

Exenatide once weekly is made from the identical active ingredient as exenatide twice daily, except that the exenatide is encapsulated in 0.1-mm microspheres. The microspheres are made of the same material as dissolvable sutures, and similar microspheres are used in multiple other medications that have been approved by the U.S. Food and Drug Administration.

Exenatide once weekly is administered by patients as a subcutaneous injection. After administration, the microspheres are hydrolyzed, releasing exenatide in a controlled manner (Figure 1).¹²  Improvements in blood glucose levels are apparent after ~ 2 weeks of therapy, and reductions in A1C are apparent as early as 4 weeks after therapy initiation, with the full effect achieved in ~ 9 weeks.^13,14 

Continuous exposure to exenatide achieved with exenatide once weekly appears to improve glycemic control in a manner somewhat different from that of intermittent exposure to exenatide achieved with exenatide twice daily. For example, after 14 weeks of treatment, the least squares mean change from baseline postprandial glucose level was significantly greater with exenatide twice daily (−126 mg/dl) than with exenatide once weekly (−96 mg/dl).¹⁵  On the other hand, the mean change in fasting plasma glucose was significantly greater with exenatide once weekly (−25 mg/dl) than it was with exenatide twice daily (−5 mg/dl) after 24 weeks of treatment.¹⁵  Although improvements in fasting and postprandial glucose levels were observed with both therapies, exenatide twice daily primarily decreased postprandial glucose levels, whereas exenatide once weekly primarily decreased fasting glucose levels.

The efficacy of exenatide once weekly was evaluated in the Diabetes Therapy Utilization: Researching Changes in HBA1C, Weight, and Other Factors Through Intervention with Exenatide Once Weekly (DURATION) clinical study program. In this series of studies, exenatide once weekly was compared to exenatide twice daily, sitagliptin, pioglitazone, metformin, insulin glargine, and liraglutide.^14,16–20 

Across these studies, improvement in A1C of ~ 1.5 percentage points (mean baseline values of 8.3–8.5% across studies) and reduction in body weight of ~ 2.5 kg were seen with exenatide once weekly treatment in patients treated with a variety of concomitant antihyperglycemic treatment regimens (68% were on metformin monotherapy).²¹  Results of the DURATION studies showed that exenatide once weekly was associated with a greater improvement in A1C and a larger reduction in body weight than were most of the comparator medications (Figure 2). In addition to improvements in A1C and body weight, exenatide once weekly was associated with greater improvements in systolic blood pressure and LDL cholesterol than many of the comparator medications (Figure 2).

Patients display continued responsiveness to exenatide once weekly after long-term exposure. Significant improvements from baseline were maintained after 2 years with regard to A1C (−1.7 percentage points) and body weight (−2.6 kg).²² 

In general, the most common adverse events reported during treatment with exenatide once weekly in the DURATION studies were gastrointestinal in nature, such as nausea (range 8–26%), diarrhea (range 7–18%), and vomiting (range 4–11%).^14,16–20  Events of nausea were generally mild or moderate in intensity and typically resolved with continued use. There were no medically assisted (major) hypoglycemia events reported for exenatide once weekly in the DURATION studies. The incidence of minor hypoglycemia events was low in patients receiving exenatide once weekly, and this incidence was higher among patients who were taking a concomitant sulfonylurea (0.88 events per patient-year) than among patients who were not (0.14 events per patient-year) (data on file, Amylin Pharmaceuticals, Inc.). Results of the DURATION studies showed that, compared to other antihyperglycemic medications, exenatide once weekly was generally associated with similar rates of hypoglycemia (one notable exception is insulin glargine, which had a much higher rate of hypoglycemia), a higher incidence of nausea, and a slightly higher rate of withdrawal because of adverse events (Figure 3).

Injection-site reactions (e.g., injection-site pruritus), although common with exenatide once weekly, were generally mild in intensity and resolved with continued treatment in clinical studies.¹⁶  In addition to these adverse reactions, health care professionals should be aware that small, asymptomatic subcutaneous injection-site nodules (typically 0.5–0.75 cm in diameter) are very common with exenatide once weekly treatment.¹²  These nodules are consistent with the known reactions to the polymer microsphere formulation.²³  That is, after injection of the microspheres, a local inflammatory response is expected. These injection-site nodules are not allergic reactions. Injection-site nodules associated with exenatide once weekly were reported by 80% of patients in a placebo-controlled study.¹²  In that study, nodules resolved unremarkably in all but two patients, who experienced delayed resolution (one of whom withdrew from the study).

Acute pancreatitis has been reported in postmarketing data in some patients who used exenatide. Of note, patients with type 2 diabetes are at a two- to threefold greater risk of acute pancreatitis than are patients without diabetes.^24–26  Pharmacoepidemiology studies in patients with type 2 diabetes reported that exenatide twice daily was associated with similar risks of pancreatitis as were other antihyperglycemic medications.^26,27  In a pooled analysis of eight exenatide once weekly phase 3 studies, the rate of pancreatitis was 0.3% in patients treated with exenatide once weekly and 0.2% in patients treated with a comparator drug (data on file, Amylin Pharmaceuticals, Inc.). Because exenatide has not been studied in patients with a history of pancreatitis, it is not recommended for use in these patients.¹⁵  If a patient who is using exenatide once weekly develops pancreatitis, it is recommended that exenatide once weekly be promptly discontinued and not restarted.¹⁵ 

Studies in animals have shown that exposure to exenatide was associated with thyroid C-cell tumors.¹⁵  However, there was no evidence of an increased risk of C-cell thyroid hyperplasia, adenoma, or carcinoma in the exenatide clinical studies program or in postmarketing surveillance. Overall, thyroid cancer is very rare in patients treated with exenatide (< 0.01%) (data on file, Amylin Pharmaceuticals, Inc.). But the exenatide once weekly trials were likely not of sufficient length for C-cell thyroid hyperplasia to emerge. Exenatide once weekly is contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia syndrome type 2.

There is a theoretical question whether prolonged exposure to exenatide during treatment with exenatide once weekly—as opposed to acute exposure during treatment with exenatide twice daily—could be associated with an increased risk for prolonged adverse events. However, the results of two controlled studies that compared exenatide once weekly to exenatide twice daily (DURATION 1 and 5) showed that the safety profile of exenatide once weekly was consistent with that of exenatide twice daily,^14,16  and the rates of withdrawal because of adverse events were similar with these two formulations of exenatide (Figure 3).

As with any other therapeutic peptide, antibodies against exenatide may form. Results of a pooled analysis showed that antibodies to exenatide were more common in patients who received exenatide once weekly than in patients who received exenatide twice daily.²⁸  Low-titer anti-exenatide antibodies occurred in 32% of exenatide twice daily patients and 45% of exenatide once weekly patients but had no apparent effect on efficacy. Higher-titer anti-exenatide antibodies occurred in 5% of exenatide twice daily patients and 12% of exenatide once weekly patients. Although increased antibody titer was associated with decreased efficacy among those patients who had high-titer anti-exenatide antibodies, approximately half of those patients (49.3%) had a change in A1C of at least −0.5%. Overall, mean A1C changes were −1.6% in antibody-negative patients and −1.3% in antibody-positive patients. Adverse event rates were similar in antibody-negative and antibody-positive patients other than a higher incidence of injection-site reactions among antibody-positive patients. No anaphylactic reactions were reported.²⁸ 

The American Diabetes Association's 2012 position statement on the management of hyperglycemia in type 2 diabetes¹  is an important step forward in the treatment of the disease. In this statement, patients and clinicians are described as partners in deciding the most appropriate treatment plan to safely achieve and maintain glycemic control. GLP-1 receptor agonists are recommended as one option for patients with type 2 diabetes who have failed to control their diabetes with metformin monotherapy.

Exenatide once weekly can be used as an adjunct to nutrition and exercise or to metformin, a sulfonylurea, a thiazolidinedione, or a combination of these oral agents to improve glycemic control in adults with type 2 diabetes.¹⁵  Studies have shown that exenatide once weekly improved glycemic control and decreased body weight in adult patients of various ages, BMIs, durations of diabetes, and races; in both sexes; and in those using a variety of background medications,^21,29  indicating that a wide variety of patients can benefit from exenatide once weekly therapy. It may be particularly helpful in patients for whom weight loss and reduced incidence of hypoglycemia are important. Exenatide once weekly should not be used in patients who are taking concomitant insulin therapy (although exenatide twice daily is indicated for use with insulin glargine),¹¹  have severe renal impairment, or have end-stage renal disease. It should be used with caution in patients who have had a renal transplant (in patients with moderate renal failure, caution should be taken when exenatide once weekly is started) or who have severe gastrointestinal disease (e.g., gastroparesis).¹⁵ 

Each dose of exenatide once weekly is supplied in a single-dose tray that contains a syringe prefilled with diluent, a vial that contains the medication (a dry powder), a vial connector, and two 23-gauge, 5/16-inch custom needles (one is a spare). To prepare and deliver a dose, patients should a) connect the syringe to the vial using the vial connecter and inject the diluent into the vial, b) shake vigorously until there are no clumps or white powder visible, and then c) draw the suspension into the syringe and inject (Figure 4).

The results of a usability study showed that the majority of first-time users of the drug (88%) were able to administer a dose using only the printed instructions supplied with the drug with no prior education or training. Common factors associated with unsuccessful preparation or dose delivery included skipping pages, skipping information, and not completing a step because the previous step was incomplete.³⁰ 

Exenatide once weekly can be taken at any time of day without regard to meals. Patients who miss a dose should take the missed dose as soon as possible, provided the next regularly scheduled dose is at least 3 days later, and then resume their normal injection schedule. If the next scheduled dose is < 3 days later, these patients should not administer the missed dose and instead should take the next regularly scheduled dose.¹⁵ 

Setting realistic expectations can help support patient success. Below are some key education points for patients using exenatide once weekly that may be useful for health care professionals.

• Exenatide once weekly is not insulin and should not be used in place of insulin.

• Exenatide once weekly should be stored in the refrigerator (36–46°F); if needed, such as when traveling, the single-dose tray may be kept out of the refrigerator for up to 4 weeks at a temperature of 68–77°F.

• Patients should be advised to disclose if they are pregnant or planning to become pregnant.

• Clinicians may consider decreasing a patient's dose of sulfonylurea if used in combination with exenatide once weekly to reduce the risk of hypoglycemia.

• Patients should be counseled that, because of the pharmacokinetic properties of exenatide once weekly, a small transient increase in fasting blood glucose that lasts about 2 weeks is normal when switching from exenatide twice daily to exenatide once weekly; fasting blood glucose will improve in 2–4 weeks.

• Patients should be advised to schedule the injection of exenatide once weekly with a recurring weekly event such as a television program or a recurring meeting.

• Patients should follow the product's Instructions for Use each time exenatide once weekly is used.

• Exenatide once weekly should be injected immediately after mixing to ensure a proper dose.

• The injection of exenatide once weekly should be given subcutaneously at a 90° angle for most patients (or as otherwise recommended based on clinical judgment and individual patient profile).

• Appropriate subcutaneous injection sites for exenatide once weekly are the upper arm, thigh, or abdomen; the same body area can be used on a weekly basis, but it is important to choose a different injection site within the selected area.

• Small, asymptomatic injection-site nodules are expected with the use of exenatide once weekly. These nodules slowly disappear over the course of several weeks.

• Nausea is common with the initiation of exenatide once weekly treatment, but it is generally mild or moderate in intensity, and it typically resolves with continued use.

• Patients should report any symptoms related to potential thyroid tumors (e.g., lump in the neck area, hoarseness, dysphagia, or dyspnea).

• Patients should be advised to discontinue exenatide once weekly and immediately seek medical advice if a hypersensitivity reaction or symptoms of pancreatitis occur.

• The dosing day can be changed by administering exenatide once weekly on the new day, provided that it is at least 3 days after the last routine dose and then continuing dosing every 7 days using the new dosing day.

• Patients should be encouraged to maintain proper meal planning and recommended physical activity and exercise and to continue taking all of their other medications as prescribed.

GLP-1 receptor agonists such as exenatide once weekly are recommended as a potential second-line therapy after metformin for the management of type 2 diabetes because of their efficacy, low risk of hypoglycemia, and association with weight loss.³¹  Exenatide once weekly is currently the only medication available for once weekly treatment of hyperglycemia.

In clinical studies, exenatide once weekly was associated with improvement in A1C of ~ 1.5 percentage points and reduction in body weight of ~ 2.5 kg. Hypoglycemia was uncommon with exenatide once weekly but was more frequent when used concomitantly with a sulfonylurea. The most common adverse events associated with exenatide once weekly were gastrointestinal in nature.

The patient education points included in this article will aid health care professionals in setting realistic expectations when prescribing exenatide once weekly treatment.

Financial support for this article was provided by Amylin Pharmaceuticals, Inc.