DPP-4 inhibitors and angioedema: a cause for concern?

Abstract

INTRODUCTION Medications are frequently associated with angioedema, a leading cause of hospitalizations for hypersensitivity reactions in the United States.1 Antihypertensives, likely angiotensin-converting enzyme inhibitors (ACEI), are the most commonly identified class, accounting for approximately 1 in 4 of these hospitalizations.1 A progressive rise has been noted in the prevalence of ACEI-associated angioedema, which is most likely a consequence of increased utilization. Dipeptidyl peptidase IV inhibitors (DPP-4I) are often used concurrently with ACEI, and this combination may increase the potential for development of angioedema. A new class of medications, the DPP-4I, was introduced to the United States market in 2006 for the management of type 2 diabetes. This class has interesting physiologic effects and mechanisms that also may increase the possibility of hypersensitivity reactions. Sitagliptin (Januvia) was the first medication approved, followed in 2009 by saxagliptin (Onglyza). In 2007, postmarketing reports of hypersensitivity reactions with sitagliptin, including angioedema, prompted warnings and labeling changes.2 The labeling for saxagliptin also reports hypersensitivity reactions that occurred in pre-approval clinical trials.3 The most recent treatment algorithm published by the American College of Endocrinology promotes the use of DPP-4I as a first-line option for management of type 2 diabetes mellitus (DM).4 This recommendation will likely result in increased utilization of this class of medications, which may potentially lead to increased reports of hypersensitivity reactions. With hypertension (HTN) as a common comorbidity of DM, many patients will likely be managed with both ACEI and DPP-4I. Thus, in DM patients with HTN who develop angioedema, there may be significant potential for incorrectly attributing the reaction solely to ACEI or angiotensin receptor blocker (ARB) therapy. Currently, few data are available to confirm the clinical impact and associations of DPP-4I and angioedema, including any additive or synergistic angioedema risk in patients taking both ACEI/ ARB and DPP-4I.