Risk for Angioedema With the Use of Dipeptidyl Peptidase 4 Inhibitors: A Population-Based Cohort Study

Dipeptidyl peptidase 4 (DPP4) inhibitors, which are widely used antidiabetic medications, may induce the accumulation of bradykinin and substance P, and thus possibly increase the risk for angioedema.

To assess the risk for angioedema with the use of DPP4 inhibitors compared with other second-line oral antidiabetics (OADs) in patients with type 2 diabetes.

A cohort study was conducted using a nationwide health care data of South Korea (2010-2022). Patients older than 40 years, with type 2 diabetes, initiating DPP4 inhibitors or other second-line OADs were included. The primary outcome was angioedema, and the secondary outcome was serious angioedema. Hazard ratio and rate difference per 1000 person-years between DPP4 inhibitors and other OADs were estimated within a 1:1 propensity score-matched cohort.

This study included 1,410,173 patients initiating DPP4 inhibitors and 966,137 patients initiating other second-line OADs, 99.1% of whom were not using concomitant angiotensin-converting enzyme inhibitor due to prescription patterns in South Korea. Over a 1.5-year mean follow-up, no difference in the risk for angioedema with the use of DPP4 inhibitors versus OADs was observed (0.47 and 0.48 events per 1000 person-years, respectively), with a hazard ratio of 0.99 (95% CI, 0.89 to 1.12) and a rate difference of -0.01 (95% CI, -0.07 to 0.05) per 1000 person-years, respectively. The risk for serious angioedema did not increase (rate difference, -0.001 [95% CI, -0.006 to 0.004]; hazard ratio, 0.73 [95% CI, 0.15 to 3.65].

In this large cohort study, the use of DPP4 inhibitors, with 99.1% of users not on concomitant angiotensin-converting enzyme inhibitor therapy, was not associated with an increased risk for angioedema compared with other second-line OADs. However, further studies are needed to determine this risk in those on angiotensin-converting enzyme inhibitor treatment.