optimizing the clinical use of the glp-1 receptor agonist ... · 46 diabetes spectrum volume umber...

46 Diabetes Spectrum Volume 26, Number 1, 2013

Pharmacy and Therapeutics

Optimizing the Clinical Use of the GLP-1 Receptor Agonist Exenatide Once WeeklySusan LaRue, RD, CDE, Steven C. Brunell, PhD, Mary Beth DeYoung, PhD, Laura B. Hieronymus, MSEd, RN, BC-ADM, CDE, Edward Bezarro, RPh, and Steve Chen, MD

Type 2 diabetes is a progressive disease involving multiple metabolic defects that requires timely interven-tion targeted to individual patients’ therapeutic challenges. Current guidelines recommend that the medications used to achieve glycemic goals must be individualized for each patient with type 2 diabetes.1

Although many medications improve control of hyperglycemia in patients with type 2 diabetes, all have limitations. For example, metformin monotherapy is associ-ated with decreased effectiveness over time;2 sulfonylureas are associ-ated with hypoglycemia and weight gain;3 thiazolidinediones are associ-ated with fractures, congestive heart failure, and edema;3,4 and insulin is associated with hypoglycemia and increased body weight and generally requires an increase in frequency of self-monitoring of blood glucose.5

In addition to the limitations of the medications themselves, patients may have difficulty adher-ing to diabetes medication dosing regimens.6 Medication acceptance and adherence have been shown to be influenced by regimen complex-ity.7 Moreover, studies conducted in patients with osteoporosis or depres-sion found improved adherence with once-weekly oral medications, compared to more frequently dosed oral medications.8,9

Although there has not yet been a study to assess adherence among patients who receive exenatide once-weekly injections versus those who receive more frequently dosed injections, there is the potential that a once-weekly diabetes treatment regimen could improve adherence because fewer injections are required.

A need exists for diabetes medica-tions that improve glycemic control without some of the side effects common in other drugs and that may improve patient adherence.

One medication that has dem-onstrated improvements in glycemic control and may positively influence patient adherence is an extended-release formulation of exenatide that is dosed every 7 days (exenatide once weekly). This medication is a line extension to exenatide twice daily, a glucagon-like peptide-1 (GLP-1) receptor agonist that has been avail-able in the United States since 2005. This review provides background information on GLP-1 and exena-tide and presents information from clinical studies that may be useful for clinicians and their patients with type 2 diabetes.

What Is GLP-1?GLP-1 is a glucoregulatory hor-mone secreted by intestinal cells after eating. GLP-1 enhances glucose-dependent insulin secretion, suppresses inappropriate postpran-dial 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 dif-ferent ways. DPP-4 inhibitors (e.g., sitagliptin, saxagliptin, and lina-gliptin) 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

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Pharmacy and TherapeuticsPharmacy and Therapeutics

effects similar to those of native GLP-1.

What Is Exenatide?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 post-prandial 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 admin-istered by patients as a subcutaneous injection. After administration, the microspheres are hydrolyzed, releas-ing 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 exena-tide achieved with exenatide once weekly appears to improve glyce-mic 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 base-line 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 signifi-cantly 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 post-prandial glucose levels were observed with both therapies, exenatide twice daily primarily decreased postpran-dial glucose levels, whereas exenatide once weekly primarily decreased fasting glucose levels.

Efficacy of Exenatide Once WeeklyThe 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 pro-gram. 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, improve-ment in A1C of ~ 1.5 percentage points (mean baseline values of 8.3–8.5% across studies) and reduc-tion in body weight of ~ 2.5 kg were seen with exenatide once weekly treatment in patients treated with a variety of concomitant antihyper-glycemic treatment regimens (68% were on metformin monotherapy).21 Results of the DURATION stud-ies 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 improve-ments in A1C and body weight, exenatide once weekly was associ-ated with greater improvements in systolic blood pressure and LDL cho-lesterol than many of the comparator medications (Figure 2).

Patients display continued respon-siveness 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

Safety and Tolerability of Exenatide Once WeeklyIn general, the most common adverse events reported during treat-ment 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 medi-cally assisted (major) hypoglycemia events reported for exenatide once weekly in the DURATION studies. The incidence of minor hypogly-cemia events was low in patients receiving exenatide once weekly, and this incidence was higher among patients who were taking a concomi-tant 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 antihypergly-Figure 1. Continuous release of exenatide once weekly from microspheres.12



cemic 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 subcutane-ous 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 formula-tion.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-con-trolled 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 exena-tide. 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 antihy-perglycemic 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 recom-mended that exenatide once weekly be promptly discontinued and not restarted.15

Studies in animals have shown that exposure to exenatide was asso-ciated 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 stud-ies 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 contraindi-cated in patients with a personal or family history of medullary thyroid cancer or in patients with mul-

Figure 2. Summary of DURATION development program select efficacy results: absolute difference in change in A1C, body weight, systolic blood pressure, and LDL cholesterol between exenatide once weekly and comparators.


Pharmacy and TherapeuticsPharmacy and Therapeutics

tiple 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 stud-ies 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 exena-tide 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 appar-ent 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

Patient Selection 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 dis-ease. 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 con-trol their diabetes with metformin monotherapy.

Exenatide once weekly can be used as an adjunct to nutrition and exercise or to metformin, a sulfo-nylurea, a thiazolidinedione, or a

Figure 3. Summary of DURATION development program select safety results: absolute difference in the incidence of minor hypoglycemia, nausea, and adverse events leading to withdrawal between exenatide once weekly and comparators.



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, dura-tions of diabetes, and races; in both sexes; and in those using a variety of background medications,21,29 indicat-ing that a wide variety of patients can benefit from exenatide once weekly therapy. It may be particu-larly 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 con-comitant 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 exena-tide once weekly is started) or who have severe gastrointestinal disease (e.g., gastroparesis).15

Dosing Exenatide Once WeeklyEach 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 associ-ated with unsuccessful preparation or dose delivery included skipping pages, skipping information, and not completing a step because the previ-ous 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

Patient EducationSetting 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 sul-fonylurea if used in combination with exenatide once weekly to reduce the risk of hypoglycemia.

• Patients should be counseled that, because of the pharmaco-kinetic 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 exena-tide 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 sub-cutaneously at a 90º angle for most patients (or as otherwise recommended based on clinical judgment and individual patient profile).

• Appropriate subcutaneous injec-tion 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 dis-continue exenatide once weekly

Figure 4. Primary steps to prepare a dose of exenatide once weekly: a) connect, b) shake, and c) inject.

a b c



and immediately seek medical advice if a hypersensitivity reac-tion 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 con-tinuing dosing every 7 days using the new dosing day.

• Patients should be encouraged to maintain proper meal planning and recommended physical activ-ity and exercise and to continue taking all of their other medica-tions as prescribed.

ConclusionsGLP-1 receptor agonists such as exenatide once weekly are recom-mended 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 improve-ment 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 sulfo-nylurea. 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 realis-tic expectations when prescribing exenatide once weekly treatment.

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

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L: Pharmacokinetics and pharmacodynam-ics of exenatide extended-release after single and multiple dosing. Clin Pharmacokinet 50:65–74, 201114Blevins T, Pullman J, Malloy J, Yan P, Taylor K, Schulteis C, Trautmann M, Porter L: DURATION-5: exenatide once weekly resulted in greater improvements in glyce-mic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab 96:1301–1310, 201115Amylin Pharmaceuticals: BYDUREON (exenatide extended-release for injectable suspension) prescribing information. Amylin Pharmaceuticals, Inc., San Diego, Calif., 201216Drucker D, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, Porter L, Group D-S: Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomized, open-label, non-inferiority study. Lancet 372:1240–1250, 200817Bergenstal RM, Wysham C, MacConell L, Malloy J, Walsh B, Yan P, Wilhelm K, Malone J, Porter LE: Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet 376:431–439, 201018Diamant M, Van Gaal L, Stranks S, Northup J, Cao D, Taylor K, Trautmann M: Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet 375:2234–2243, 201019Russell-Jones D, Cuddihy RM, Hanefeld M, Kumar A, Gonzalez JG, Chan M, Wolka AM, Boardman MK: Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as mono-therapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care 35:252–258, 201220Buse JB, Nauck MA, Forst T, Sheu WHH, Hoogwerf BJ, Shenouda SK, Heilmann CR, Boardman MK, Fineman M, Porter L, Schernthaner G: Efficacy and safety of exena-tide once weekly versus liraglutide in subjects with type 2 diabetes (DURATION-6): a randomised, open-label study. Diabetologia 54:S38, 201121Stonehouse A, Walsh B, Cuddihy R: Exenatide once-weekly clinical develop-ment: safety and efficacy across a range of background therapies. Diabetes Technol Ther 13:1063–1069, 201122Taylor K, Gurney K, Han J, Pencek R, Walsh B, Trautmann M: Exenatide once weekly treatment maintained improvements in glycemic control and weight loss over 2 years. BMC Endocr Disord 11:1–9, 201123Shive MS, Anderson JM: Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv Drug Deliv Rev 28:5–24, 1997



24Noel RA, Braun DK, Patterson RE, Bloomgren G: Increased risk of acute pancre-atitis and biliary disease observed in patients with type 2 diabetes: a retrospective, cohort study. Diabetes Care 32:834–838, 200925Girman CJ, Kou TD, Cai B, Alexander CM, O’Neill EA, Williams-Herman DE, Katz L: Patients with type 2 diabetes mellitus have higher risk for acute pancreatitis compared with those without diabetes. Diabetes Obes Metab 12:766–771, 201026Garg R, Chen W, Pendergrass M: Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin: a retrospective obser-vational pharmacy claims analysis. Diabetes Care 33:2349–2354, 201027Dore DD, Bloomgren GL, Wenten M, Hoffman C, Clifford CR, Quinn SG, Braun DK, Noel RA, Seeger JD: A cohort study of acute pancreatitis in relation to exenatide use. Diabetes Obes Metab 13:559–566, 201128Fineman MS, Mace KF, Diamant M, Darsow T, Cirincione BB, Booker Porter TK, Kinninger LA, Trautmann ME: Clinical relevance of anti-exenatide antibodies: safety, efficacy and cross-reactivity with long-term

treatment. Diabetes Obes Metab 14:546–554, 201229Blickensderfer A, Pencek R, Li Y, Brunell S, Anderson PW: Exenatide once weekly: a retrospective analysis of pooled exenatide clinical trial efficacy data stratified by race, age, duration of diabetes, BMI and gender. Diabetologia 54:S315, 201130Lorenzi G, Schreiner B, Osther J, Boardman M: Application of adult-learning principles to patient instructions: a usability study for exenatide once-weekly injection device. Clinical Diabetes 28:157–162, 201031Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR: Management of hyperglycemia in type 2 diabetes: a patient-centered approach: posi-tion Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 35:1364–1379, 2012

Susan LaRue, RD, CDE, is a principal specialist in Advocacy/

Education; Steven C. Brunell, PhD, is a medical writer in Medical Disclosures; Mary Beth DeYoung, PhD, is an associate director of Medical Disclosures; Laura B. Hieronymus, MSEd, RN, BC-ADM, CDE, is a senior specialist in Medical Relations & Information; Edward Bezarro, RPh, is director of Medical Relations & Information; and Steve Chen, MD, is medical director of Medical Research & Development at Amylin Pharmaceuticals, Inc., in San Diego, Calif.

Note of disclosure: All of the authors are employees of and stock shareholders in Amylin Pharmaceuticals, Inc., which manufactures exenatide once weekly and exenatide twice daily.

optimizing the clinical use of the glp-1 receptor agonist ... · 46 diabetes spectrum volume umber...

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