New Once-Weekly Exenatide for Type 2 Diabetes

When exenatide for once-weekly injection (Bydureon^®)  (exenatide QW)¹ became available for clinical use in early 2012, it was a much anticipated addition to the arsenal of treatments currently used to manage type 2 diabetes mellitus (T2DM). Exenatide QW joins other FDA-approved glucagon-like peptide-1 (GLP-1) receptor agonists-exenatide twice-daily (Byetta^®, approved 2005)² and liraglutide (Victoza^®, approved 2010)³-and offers numerous benefits over its comparators.⁴ GLP-1 receptor agonists have multiple mechanisms of action, including stimulation of glucose-dependent insulin secretion, suppression of glucagon secretion, slowing of gastric emptying, and increasing satiety. In addition to these effects, exenatide QW offers the potential for increased adherence and possibly greater efficacy over other therapies for T2DM.^5-11

Exenatide QW is administered as a 2-mg dose SC.¹  Onset of action is approximately 2 to 4 weeks, with steady state achieved by week 7 when beneficial effects on fasting blood glucose (FBG), post-prandial blood glucose (PPBG), and A1C are seen.¹ In head-to-head trials, exenatide QW lowered A1C more effectively than exenatide twice-daily (−0.7% treatment difference, P < .0001), sitagliptin (−0.4% treatment difference, P < .001), and insulin glargine (−0.16% treatment difference, P = .0003). The once-weekly formulation was deemed non-inferior to metformin (−0.04% treatment difference).^5-10 Against its once-daily comparator liraglutide, exenatide QW did not prove to be non-inferior in reducing A1C values.¹¹ Weight loss among patients taking exenatide QW was slightly greater than that for patients receiving exenatide twice-daily (−0.95 kg treatment difference). Once-daily liraglutide resulted in a larger reduction in weight than did exenatide QW (0.9-kg treatment difference).^10,11

Adverse-effect profiles
Exenatide QW, when compared with its GLP-1 agonist competitors, has shown fewer overall adverse effects than once-daily liraglutide and twice-daily exenatide.^10,11  The most common adverse effects associated with this class of drugs are nausea, diarrhea, and injection site reactions.^1,12,13  Nausea and diarrhea typically subside over time. That said, in some clinical trials these adverse events have resulted in nonadherence and discontinuation of therapy.^5-13

Once-weekly exenatide is associated with significantly less nausea than exenatide twice-daily and liraglutide, with twice as many patients experiencing gastrointestinal adverse effects with liraglutide therapy.¹¹

Proceed with caution in some patients 
In general, clinicians should avoid use of GLP-1 receptor agonists in patients with severe gastrointestinal disorders such as gastroparesis.^1,12,13 All of the available GLP-1 receptor agonists carry a Black Box Warning for risk of thyroid C-cell tumors (observed in laboratory animals) and warnings regarding risk of acute pancreatitis.^1-3 The professional prescribing information recommends that use of these agents be avoided in patients with a personal or family history of medullary thyroid carcinoma or a personal history of multiple endocrine neoplasia syndrome type 2.^1-3 Other therapies for T2DM also should be considered for patients with a personal history of pancreatitis.^1,12,13

On the basis of the results of recent trials, in most cases exenatide QW provides similar if not greater reduction in A1C, FBG, and PPBG compared with other commonly used therapies for T2DM.^5-11 GLP-1 receptor agonists offer many benefits, including weight loss and low risk of hypoglycemia. Guidelines published by the American Diabetes Association and European Association for the Study of Diabetes¹⁴ and by the American Association of Clinical Endocrinologists and American College of Endocrinology¹⁵ recognize that GLP-1 receptor agonists are appropriate second-line agents and useful first-line agents when metformin is contraindicated.

Overall GLP-1 agonists are promising agents for the treatment of T2DM because of their multiple salutary mechanisms of action, associated weight loss, and low risk of hypoglycemia. Exenatide QW offers the additional benefits of less frequent dosing and fewer gastrointestinal adverse effects. See the Table for details on dosing and average A1C reduction.

References
1. Bydureon (exenatide) [package insert]. San Diego, CA: Amylin Pharmaceuticals, Inc. 2012.
2. Byetta (exenatide) [package insert]. San Diego, CA: Amylin Pharmaceuticals, Inc; September 2010.
3. Victoza (liraglutide) [package insert]. Bagsvrd, Denmark: Novo Nordisk A/S; May 18, 2011.
4. FDA.org [homepage on the Internet]. Silver Spring, MD: US Food and Drug Administration.  http://www.fda.org. 
5. Buse JB, Drucker DJ, Taylor KL, et al; DURATION-1 Study Group. DURATION-1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care. 2010;33:1255-1261. http://care.diabetesjournals.org/content/early/2010/03/04/dc09-1914.full.pdf+html.  Accessed June 20, 2012.
6. Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomized, open-label, non-inferiority study. Lancet. 2008;372:1240-1250.
7. Wysham C, Bergenstal R, Malloy J, et al. DURATION-2: efficacy and safety of switching from maximum daily sitagliptin or pioglitazone to once-weekly exenatide. Diabet Med. 2011;28:705-714.
8. Diamant M, Van Gaal L, Stranks S, et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomized trial. Lancet. 2010;375:2234-2243.
9. Russell-Jones D, Cuddihy RM, Hanefeld M, et al. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-nave patients with type 2 diabetes (DURATION-4). Diabetes Care. 2012;35:252-258.
10. Blevins T, Pullman J, Malloy J, et al. DURATION-5: exenatide once weekly resulted in greater improvement in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011;96:1301-1310.
11. Buse JB, Nauck, MA, Forst T, et al. Efficacy and safety of exenatide once weekly versus liraglutide in subjects with type 2 diabetes (DURATION-6): a randomised, open-label study. In: Program and abstracts of 47th Annual Meeting of the European Association for the Study of Diabetes; September 13-16, 2011; Lisbon, Portugal. Abstract 75.
12. Micromedex® Healthcare Series [Internet database]. Greenwood Village, CO: Thomson Micromedex. http://www.micromedex.com/support/quick_reference/qr/hcs_online_qrc.pdf. Accessed July 30, 2012.
13. Lexi-Comp^TM Online [Internet database]. Hudson, OH: 1978-3909 Lexi-Comp, Inc. http://www.lexi.com/institutions/online.jsp?id=databases. Accessed July 30, 2012.
14. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: A patient centered approach. Diabetes Care. Published online ahead of print, April 19, 2012.   http://care.diabetesjournals.org/content/early/2012/04/19/dc12-0413.full.pdf.  Accessed June 20, 2012.
15. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologist/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009;15:540-559.