J Am Board Fam Med: first published as 10.3122/jabfm.2013.02.120174 on 7 March 2013. Downloaded from CLINICAL REVIEW An Evidence-Based and Practical Approach to Using Bydureon™ in Patients With Type 2 Diabetes Nathan A. Painter, PharmD, CDE, Candis M. Morello, PharmD, CDE, Renu F. Singh, PharmD, CDE, BCACP, and Sarah E. McBane, PharmD, CDE, BCPS Glucagon-like peptide (GLP)-1 agonists are one of the newer classes of medications for use in type 2 diabetes. There are currently three GLP-1 agonists on the market: exenatide twice daily, liraglutide, and exenatide extended release (ER). Exenatide ER is a new weekly formulation of exenatide. Exenatide ER reduces glycosylated hemoglobin by 1.6%, with fewer gastrointestinal side effects compared with twice- daily exenatide. Like other GLP-1 agonists, exenatide ER can be used in combination with metformin, sulfonylureas, or thiazolidinediones. Patients should be assessed for risk of pancreatitis and renal im- pairment. Education about proper administration technique is vital with the novel delivery system. Pre- scribers may also consider the use of exenatide ER to improve medication adherence in patients who have successfully tolerated exenatide twice daily or use in patients who have gastrointestinal side effects with exenatide twice daily. Exenatide is a reasonable option that can be added to the regimen of a pa- tient with type 2 diabetes. (J Am Board Fam Med 2013;26:203–210.) Keywords: Chronic Disease, Diabetes Mellitus, Drugs, Evidence-based Medicine, Pharmacology, Pharmacotherapy It is estimated that nearly 26 million Americans and an eventual decline in ␤-cell function. In addi- have diabetes mellitus, with type 2 diabetes mellitus tion to lifestyle changes, metformin is considered accounting for nearly 90% of all diabetes cases.1 In first-line therapy for the treatment of type 2 diabe- a recent study, less than half of patients with type 2 tes, but many patients will require multiple medi- diabetes who started taking insulin as monotherapy cations to achieve adequate glycemic control.3,4 or in combination with other medications for dia- Glucagon-like peptide-1 (GLP-1) and glucose- betes achieved an glycosylated hemoglobin (A1c) dependent insulinotropic peptide are regulatory http://www.jabfm.org/ level of Ͻ7% within 9 months.2 Patients achieving peptides called incretins, which are secreted by the an A1c Ͻ7% were more likely to have started the intestines in response to food intake. GLP-1 helps study with lower A1c levels.2 Achieving glycemic maintain glucose homeostasis by enhancing glu- goals can be challenging, which highlights the need cose-dependent insulin secretion, suppressing glu- for a multifaceted approach that includes interpro- cagon release, slowing gastric emptying, decreasing fessional care. food intake, and increasing satiety. Physiologic on 1 October 2021 by guest. Protected copyright. Type 2 diabetes is characterized by a deficiency GLP-1 has a very short half-life and is degraded by in insulin production, peripheral insulin resistance, dipeptidyl peptidase-4 (DPP-4) in 1.5 to 2 min- impaired regulation of hepatic glucose production, utes.5 Several medications affect this pathway. Ex- enatide and liraglutide are GLP-1 receptor agonists that mimic the physiologic action of endogenous This article was externally peer reviewed. GLP-1 (Table 1). Submitted 3 July 2012; revised 2 November 2012; ac- DPP-4 inhibitors also are a class of medications cepted 7 November 2012. From the University of California, San Diego, Skaggs that affect the incretin system (Table 1). Patients School of Pharmacy and Pharmaceutical Sciences, San Di- with diabetes often have a diminished GLP-1 re- ego (NAP, CMM, RFS, SEM), and the Veterans Affairs San Diego Healthcare System, San Diego, CA (CMM). sponse that correlates with insulin resistance. By Funding: none. blocking the enzyme that breaks down GLP-1 and Conflict of interest: none declared. Corresponding author: Nathan A. Painter, 9500 Gilman Dr, MC other incretins, endogenous GLP-1 has a more 0675, La Jolla, CA 92093-0675 (E-mail: [email protected]). pronounced effect. Although DPP-4 inhibitors doi: 10.3122/jabfm.2013.02.120174 Using Bydureon™ in Patients with Type 2 Diabetes 203 J Am Board Fam Med: first published as 10.3122/jabfm.2013.02.120174 on 7 March 2013. Downloaded from Table 1. Food and Drug Administration–Approved Incretins and Clinical Effects as Monotherapy6–11 GLP-1 Agonists or Analogs DPP-4 Inhibitors Exenatide ER Exenatide Liraglutide Sitagliptin Saxagliptin Linagliptin (Bydureon) (Byetta) (Victoza) (Januvia) (Onglyza) (Tradjenta) Route SQ SQ SQ Oral Oral Oral Dosing frequency Once a week Twice a day Daily Daily Daily Daily Change in A1c, % Ϫ1.6 Ϫ0.9 Ϫ1.1 Ϫ0.5 Ϫ0.5 Ϫ0.4 Change in weight, kg Ϫ2.0 Ϫ2.5 Ϫ1.9 Ϫ1.5 Ϫ1.1 Ϫ1.0 Hypoglycemia ϮϮϮ—— — Adverse GI effects ϩϩϩϩϩ—— — Approximate monthly cost of therapy ($),12 370 360 520 260 260 280 ER, extended release; GLP, glucagon-like peptide; DPP, dipeptidyl peptidase; GI, gastrointestinal; SQ, subcutaneously. have the advantage of being oral agents, they do not these agents received exenatide ER or exenatide cause weight loss and have a modest glucose-low- twice daily for 30 weeks.15 At the conclusion of ering effect.5 the trial, subjects receiving exenatide ER experienced GLP-1 agonists have a longer half-life than en- a significantly greater reduction in A1c than those taking dogenous GLP-1 because of structural differences exenatide twice daily (Ϫ1.9% and Ϫ1.5% respectively; and other chemical modifications. Exenatide ex- P ϭ .0023). Weight loss was similar between both tended-release (exenatide ER; Bydureon, Amylin groups, but the patients receiving exenatide ER experi- Pharmaceuticals, Inc., San Diego, CA) uses a pro- enced less nausea. Similar results were noted in the prietary controlled release formulation (Medisorb DURATION-5, where more than 250 patients (al- microspheres) to provide a continuous amount of ready taking metformin, sulfonylurea, thiazolidin- exenatide over a 7-day period.13,14 All GLP-1 ago- edione, or a combination of these medications) nists have been shown to improve glycemic control with a baseline A1c of 8.4% were randomized to and promote weight loss, but they can cause signif- exenatide ER or exenatide twice daily and followed icant nausea and gastrointestinal (GI) adverse ef- for 24 weeks. Subjects taking exenatide ER experi- fects as they slow gastric emptying. enced a 1.6% lowering of A1c (P Ͻ .0001) and a The U.S. Food and Drug Administration origi- 35-mg/dL decrease in fasting plasma glucose (P ϭ nally approved twice-daily exenatide in April 2005. .0008) compared with 0.9% and 12 mg/dL, respec- http://www.jabfm.org/ Exenatide ER was approved in January 2012 as tively, for exenatide twice daily. Subjects taking monotherapy or in combination with other medi- exenatide ER experienced a small reduction in sys- cations for the treatment of type 2 diabetes. Diabe- tolic blood pressure (BP) (Ϫ2.9 mm Hg) but a tes Therapy Utilization: Researching Changes in slight increase in diastolic BP (0.2 mm Hg) com- HBA1C, Weight, and Other Factors Through Inter- pared with exenatide twice daily (Ϫ1.2 mm Hg vention with Exenatide Once Weekly (DURATION) is systolic BP; Ϫ0.1 mm Hg diastolic BP). Small but on 1 October 2021 by guest. Protected copyright. a series of clinical trials designed to compare exenatide statistically significant improvements were re- ER with other medications to treat type 2 diabetes that ported in total cholesterol and low-density lipopro- are already on the market. These data and results tein levels (P Ͻ .01). Subjects randomized to ex- from other trials, as well as some of the implications enatide ER experienced a reduction in weight to clinical practice, are discussed herein. (Ϫ2.3 kg; P ϭ .01) compared with those taking exenatide twice daily (1.4 kg).16 Clinical Effects of Exenatide ER Compared with exenatide twice daily, exenatide ER Exenatide ER Compared With Metformin has demonstrated improvements in glycemic con- Although numerous controlled clinical trials have trol, cardiovascular parameters, weight, and nausea. demonstrated the efficacy of exenatide twice daily In DURATION-1, patients with a baseline A1c of and exenatide ER compared with or in combination 8.3% who were taking metformin, a sulfonylurea, with other diabetes medications, few controlled tri- thiazolidinedione, or any combination of 2 of als have evaluated the efficacy of exenatide ER in 204 JABFM March–April 2013 Vol. 26 No. 2 http://www.jabfm.org J Am Board Fam Med: first published as 10.3122/jabfm.2013.02.120174 on 7 March 2013. Downloaded from combination with metformin. In a small, random- comparison of liraglutide 1.8 mg daily and ex- ized, placebo-controlled, phase 2 trial, 2 doses of enatide ER showed that patients receiving ex- exenatide ER were studied to assess glucose control enatide ER experienced an A1c change of Ϫ1.3% and body weight in 45 subjects with type 2 diabetes. compared with Ϫ1.5% for liraglutide at 6 months. All subjects who had received exenatide in previous Patients experienced more GI adverse effects with trials were excluded. Treatment with the same dose liraglutide compared with exenatide ER: nausea, of metformin throughout the study period was per- 20.4% versus 9.4%; diarrhea, 13.1% versus 6.1%; mitted. Exenatide ER was administered subcutane- and vomiting, 10.7% versus 3.7%, respectively.19 ously once weekly for 15 weeks, followed by a 12-week safety observation period. Compared with Exenatide ER in Combination With Oral Diabetes a baseline A1c of 8.5%, at 15 weeks both doses Medications resulted in a statistically significant (P Ͻ .05) Exenatide ER has been used in combination with change in A1c of Ϫ1.7%. Reduction of A1c was many oral diabetes medications and has been observed at week 3, the first data point measure- shown to improve glycemic control.