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
additional safety investigations
The FDA has required additional safety investigations for liraglutide, saxagliptin, and sitagliptin. These investigations will address observations made during preclinical and clinical evaluation, as well as the new standards adopted by the agency in December 2008 regarding cardiovascular safety for all new glucose-lowering agents.53
Thyroid cancer
Rodent studies have suggested that liraglutide in doses many times those utilized in humans is associated with an increased risk of preneoplastic lesions that can lead to C-cell hyperplasia and medullary thyroid cancer, which occurs rarely in humans.52 Thyroid tumors have also been observed in rodents administered native GLP-154 or exenatide33 but not sitagliptin35 or saxagliptin.36 A slight increase in calcitonin, a marker for medullary cancer, which remained well within the normal reference range, was observed during Phase 3 clinical trials in patients treated with liraglutide compared with controls. There were no cases of medullary thyroid cancer in the liraglutide trials, including one that involved more than 2 years of follow-up. Based on this evidence, the FDA determined that the risk of thyroid cancer among humans treated with liraglutide is low. The effects may be due to species-specific differences in GLP-1 receptor expression and action in the thyroid, as 20 months of liraglutide at >60 times the human exposure level did not lead to C-cell hyperplasia in monkeys.55 The FDA has required the manufacturer to conduct additional animal studies, however, and to establish a cancer registry to monitor the annual incidence of medullary thyroid cancer over the next 15 years.52 In addition, the prescribing information for liraglutide carries a boxed warning describing the rodent findings and the risk of medullary thyroid cancer.34 Liraglutide is also contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia syndrome type 2.34
Cardiovascular risk
The clinical evaluation of liraglutide and saxagliptin was completed prior to December 2008, when the FDA adopted the new cardiovascular safety standards for new antidiabetic drugs. Analyses of data from Phase 2 and 3 clinical trials indicate that liraglutide meets the new 2008 standard for ruling out an unacceptable increase in cardiovascular risk.52 While the overall rates of cardiovascular events were low in preapproval clinical trials, the more stringent criteria for postapproval evaluations were not met. Consequently, the FDA has required postapproval clinical trials of cardiovascular safety with liraglutide52 and saxagliptin.
Summary
The overall safety profiles of GLP-1 agonists and DPP-4 inhibitors are favorable, with a low incidence of hypoglycemia. This attribute, along with their weight and cardiovascular benefits, particularly with the GLP-1 agonists, make them appropriate choices in our 3 patient cases. Ongoing safety investigations with GLP-1 agonists and DPP-4 inhibitors will provide further clarity to the complete safety profiles of these agents.
