Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema

Abstract

Dipeptidyl peptidase-IV (DPP-IV) inhibitors decrease degradation of the incretins. DPP-IV inhibitors also decrease degradation of peptides, such as substance P, that may be involved in the pathogenesis of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. This study tested the hypothesis that DPP-IV inhibition affects risk of clinical angioedema, by comparing the incidence of angioedema in patients treated with the DPP-IV inhibitor vildagliptin versus those treated with comparator in Phase III randomized clinical trials. Prospectively defined angioedema-related events were adjudicated in a blinded fashion by an internal medicine adjudication committee and expert reviewer. Concurrent ACE inhibitor or angiotensin receptor blocker exposure was ascertained from case report forms. Study drug exposure was ascertained from unblinded data from phase III studies. Odds ratios and 95% confidence intervals comparing angioedema risk in vildagliptin-treated and comparator-treated patients were calculated for the overall population and for patients taking ACE inhibitors or angiotensin receptor blockers, using both an analysis of pooled data and a meta-analysis (Peto method). Overall, there was no association between vildagliptin use and angioedema. Among individuals taking an ACE inhibitor, however, vildagliptin use was associated with an increased risk of angioedema (14 confirmed cases among 2754 vildagliptin users versus 1 case among 1819 comparator users: odds ratio 4.57 [95% confidence interval 1.57 to 13.28]) in the meta-analysis. Vildagliptin use may be associated with increased risk of angioedema among patients taking ACE inhibitors, although absolute risk is small. Physicians confronted with angioedema in a patient taking an ACE inhibitor and DPP-IV inhibitor should consider this possible drug-drug interaction.

Figure 1

Schematic diagram showing the role of angiotensin-converting enzyme (ACE) and dipeptidyl peptidase-IV (DPP-IV) in the degradation of bradykinin and substance P. Studies in rodents suggest that DPP-IV is the primary enzyme responsible for the inactivation of substance P when ACE is inhibited. The dotted line indicates that bradykinin is already inactivated by aminopeptidase P (APP) before it is degraded further by DPP-IV. CPN indicates carboxypeptidase N; NEP indicates neutral endopeptidase.

Figure 2

Meta-analysis showing the effect of vildagliptin on the risk of angioedema, in all patients, those taking an angiotensin-converting enzyme (ACE) inhibitor concurrently, and those taking an angiotensin-receptor blocker (ARB) concurrently. Data are presented as odds ratios and 95% confidence intervals. Odds ratios were estimated using the Peto method, in which all studies with a comparator treatment arm and an event in at least one arm were included. This analysis was conducted using both fixed effect (Fixed) and random effect (Random) models. * NSI indicates not sufficient information.

Figure 3

Meta-analysis showing the effect of vildagliptin dose on the risk of confirmed cases of angioedema in all patients, in patients taking an angiotensin-converting enzyme inhibitor concurrently (ACE+), and those not taking an ACE inhibitor (ACE-). Data are presented as odds ratios and 95% confidence intervals. Odds ratios were estimated using the Peto method, in which all studies with a comparator treatment arm and an event in at least one arm were included. This analysis was conducted using both fixed effect (Fixed) and random effect (Random) models. The 100mg daily group includes patients receiving vildagliptin 50mg bid and 100mg/d.