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Vasoactive peptide-induced angioedema may occur not only in ACEIs but also in DPP-4Is. This study evaluated the association between DPP-4Is and angioedema, including cases with and without the concomitant use of ACEIs. When we stratified the data according to age group and sex, we detected a signal for the female subset, three female age groups with patients aged60s, and the group of males in their 40s. ON excluding ACEI users from the whole dataset, we only detected a signal for females in their 60s and males aged80years. Individually, signals for saxagliptin and sitagliptin, which were detected when the whole dataset was analyzed, disappeared when we excluded ACEI users. Notably, linagliptin was the only DPP-4I where a signal was detected in females regardless of age and concomitant ACEI use.

From the stratified analysis in our study, the number of detected signals for DPP-4Iassociated angioedema was more in the female groups than in the male groups (Fig.1, Table 2) and more in the elderly groups than in the middle-adulthood groups (Fig.1, Table 2). Generally, the incidence of drug-induced angioedema has been reported as higher in females25, 26, and older age has been associated with a higher incidence of angioedema27, which supports our results.

A previous study using pharmacovigilance databases also reported the association between DPP-4I and angioedema28, 29. Lepelley et al. evaluated the association of an increased angioedema reporting risk using the World Health Organizations pharmacovigilance database, reporting that exposure to DPP-4I alone was not associated with a disproportionality signal for angioedema28. Moreover, in another study using the Japanese Adverse Drug Event Report database, the authors also performed a disproportionality analysis to evaluate DPP-4I/ACEI-induced angioedema and concluded that DPP-4I tended to have different effects on the onset of angioedema from ACEI in clinical practice, because an inverse association of DPP-4I with angioedema was found. The difference in the conclusion could be attributed to the use of different pharmacovigilance databases, which include information on different races. Additionally, although the adverse event (angioedema) was defined according to MedDRA in both cases, there was a slight difference in the selection of PTs. Moreover, our study classified the data in more detail by stratification according to age and sex.

Some case reports have suggested that linagliptin can cause acute renal failure with hypotension and hyperkalemia when added to the treatment regimens of patients already receiving ACEIs30, 31. Moreover, a recent in silico and in vivo study reported that many DPP-4Is, including linagliptin, could potentially inhibit ACE in concentrations close to those required for DPP-4 inhibition32. These results suggest that linagliptin can inhibit two enzymes, both of which contribute to BK and SP degradation, and it may be reasonable to assume that linagliptin causes angioedema.

Conversely, it was also reported that sitagliptin inhibits both DPP-4 and ACE32, despite the detection of a limited signal for sitagliptin in our study (Tables 2 and 3). A possible explanation may be the different pharmacokinetics of these drugs. In other words, since the more complete or sustained ACE inhibition seen with the longer-acting agents may be detrimental33, DPP-4Is are suggested to inhibit ACEs for a longer-acting duration and also be more likely to cause angioedema than shorter-acting agents. The half-life of linagliptin and sitagliptin is 104113h34 and 914h35, respectively. Further studies are necessary to determine whether such inhibitory effects occur in clinical settings.

It has been proposed that patients with a history of ACEI-induced angioedema are at risk for recurrent angioedema with DPP-4Is36. This may be explained by reports that the enzymatic activity of DPP-4 is innately reduced in the sera of such patients compared with the sera of ACEI-treated patients without angioedema37,38,39. Furthermore, the concentrations of enzymes involved in BK and SP degradation were reported to have drastically reduced compared with the reference range for at least a year after inhibition by DPP-4Is and ACEIs37, 40. Therefore, the recurrence of angioedema in patients with such a history warrants additional care, given the possible inhibition of BK and SP degradation, even without DPP-4Is and ACEIs administration.

This study suggests that the use of DPP-4Is, even in the absence of concomitant ACEI use, is associated with angioedema in clinical practice. To determine whether this is a class effect of DPP-4I, further studies are essential. In any case, clinicians should be aware of the possible association as seen in this study.

Although the analysis of a spontaneous report is a valuable method for identifying signals, there are potential limitations of such databases that may have affected the interpretation of our findings. First, adverse events are not always induced by medication. Second, angioedema is influenced by many confounding factors, such as comorbidities including chronic heart failure or coronary artery disease4, 5; the concomitant administration of drugs other than ACEIs, such as angiotensin receptor blockers, antibiotics, and nonsteroidal anti-inflammatory drugs41; and smoking5, 6, which we did not take into consideration in this study. Although the incidence of angioedema has been reported to be lower in patients with diabetes mellitus4, 6, we had to include such patients because DPP-4Is are used to treat diabetes mellitus in clinical practice. Third, as mentioned above, duplicate reports for the same case could be included in spontaneous reporting systems, and, conversely, underreporting may occur. Fourth, data are missing and drug names are frequently misspelled in the FAERS database. Additionally, concerning data mining techniques, given that control populations are not included in spontaneous reporting systems, disproportionality-based signals indicate an increased risk of adverse event reporting, not the risk of the adverse events.

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Pharmacovigilance study of the association between dipeptidyl peptidase4 inhibitors and angioedema using the FDA Adverse Event Reporting System...