Keith R. Campbell, PharmD, MBA, CDE Distinguished Professor in Diabetes Care and Pharmacotherapy, Department of Pharmacotherapy, Washington State University College of Pharmacy, Pullman, Washington
Michael E. Cobble, MD, FNLA Director, Canyons Medical Center, Sandy, Utah, Adjunct Faculty, University of Utah School of Medicine, Salt Lake City, Utah
Timothy S. Reid, MD Department of Family Medicine, Mercy Diabetes Center, Janesville, Wisconsin
Mansur E. Shomali, MD, CM Clinical Associate Professor of Medicine, University of Maryland School of Medicine, Associate Medical Director, Diabetes and Endocrine Center, Union Memorial Hospital, Baltimore, Maryland
References
It is important to note that the incidence of mild to moderate hypoglycemia is increased in patients treated concomitantly with a GLP-1 agonist or DPP-4 inhibitor and a sulfonylurea. In 1 trial, 14% to 36% of patients treated with a combination of exenatide and a maximally effective dose of a sulfonylurea (glimepiride, glipizide, glyburide, chlorpropamide, tolazamide) reported mild to moderate hypoglycemia compared with 3% of those administered a placebo and a sulfonylurea.47 A trial involving the addition of saxagliptin to glyburide found that 13% to 15% of patients treated daily with glyburide 7.5 mg and saxagliptin 2.5 mg or 5 mg reported mild to moderate hypoglycemia compared with 10% of patients treated with glyburide 10 mg to 15 mg alone.23 For this reason, consideration should be given to reducing the dose of a sulfonylurea or secretagogue when combined with a GLP-1 agonist or DPP-4 inhibitor.33-35
Because of their low incidence of hypoglycemia, the American Diabetes Association/European Association for the Study of Diabetes panel recommends GLP-1 agonists for patients for whom hypoglycemia is particularly undesirable, such as those who perform manual labor, drive a vehicle for a living, or operate heavy or dangerous machinery.48 In fact, the US Federal Aviation Administration lists the GLP-1 agonists and DPP-4 inhibitors as allowable medications for aviators.49 This recommendation is particularly appropriate for the building contractor in Case 1.
Nausea
Transient nausea is the most common GI side effect associated with GLP-1 agonists, occurring in up to 57% of patients treated with exenatide in clinical trials6,30 and 29% treated with liraglutide.4 Diarrhea and vomiting also occurred, although rates were similar to rates with initiation of metformin. The high occurrence of transient nausea in these trials prompted investigators to implement a dose escalation strategy33,34 (see “Patient education and self-management” article in this supplement). Since adoption of this strategy, a comparative trial of exenatide and liraglutide found that nausea occurred in 28% of patients treated with exenatide and in 26% treated with liraglutide.12 Nausea was generally transient, so that by Week 6 of therapy, 16% of patients treated with exenatide and 8% with liraglutide experienced nausea,12 and by Week 26, 9% of exenatide-treated patients and 3% of liraglutide-treated patients continued to experience nausea.12
Of patients treated with the DPP-4 inhibitor sitagliptin, nausea has occurred in 1% to 2% com pared with 1% of those receiving placebo.18,43 In patients treated with saxagliptin, nausea has occurred in 2% to 4% compared with 8% of those receiving placebo.21
Acute pancreatitis
Acute pancreatitis has been observed in clinical trials and/or identified in postmarketing reports involving exenatide,33 liraglutide,34 and sitagliptin.36 Determining whether there is a true association of these agents with acute pancreatitis or this is just coincidental has been difficult, partly because patients with T2DM have a 2.8-fold greater risk of pancreatitis compared with nondiabetic subjects.50 A review of health insurance transactions with 1-year follow-up (June 2005 through June 2008) involving approximately 88,000 patients (exenatide, n=27,996; sitagliptin, n=16,276; approximately equal numbers of matched comparators) showed that the relative risk of pancreatitis was statistically the same with exenatide, sitagliptin, metformin, and glyburide.51
In its ongoing review, the FDA has required the manufacturers of exenatide and sitagliptin to modify product labeling regarding the risk of acute pancreatitis and to conduct additional animal studies.52 As part of the January 2010 approval of liraglutide, the FDA required the manufacturer to perform mechanistic studies in animals and to conduct an epidemiologic evaluation using a large insurance claims database.52 In the interim, exenatide, liraglutide, and sitagliptin should be used cautiously,34,35 if at all, in people with a history of pancreatitis.33 Furthermore, educating patients about the signs and symptoms of pancreatitis, including how to differentiate it from the transient nausea commonly observed with these agents, is critical. Patients at risk of developing acute pancreatitis (eg, due to excess alcohol consumption or gallstones) should not receive an incretin-based therapy. Therapy should be changed if a patient develops acute pancreatitis while using a GLP-1 agonist or DPP-4 inhibitor.
Hypersensitivity
Hypersensitivity reactions have been experienced by some patients treated with exenatide,33 liraglutide,34 sitagliptin,35 or saxagliptin.36 Postmarketing reports have described serious hypersensitivity reactions (anaphylaxis, angioedema) with exenatide.33 In clinical trials, 0.8% of patients treated with liraglutide and 0.4% treated with comparator agents experienced an immunogenic reaction, generally urticaria.34 With sitagliptin, anaphylaxis, angioedema, or exfoliative dermatitis, including Stevens-Johnson syndrome, typically occurs within 3 months but may occur after the first dose. Hypersensitivity events, such as urticaria and facial edema, were shown to occur in 1.5% of patients treated with saxagliptin 2.5 mg, 1.5% of those treated with saxagliptin 5 mg, and 0.4% of those receiving placebo. None of the events necessitated hospitalization or were life-threatening.36 If a hypersensitivity reaction occurs, treatment should be discontinued.
