CONCOMITANT USE OF DPP4 INHIBITORS AND RAAS INHIBITORS AND RISK OF ANGIOEDEMA: A RETROSPECTIVE COHORT STUDY
Author(s)
Amina Alkhalaf, PharmD, MS, Kamika Reynolds, MS, PhD, Kimberly O’Malley, MS, Chintan Dave, PharmD, PhD;
Center for Health Outcomes, Policy, and Economics, Ernest Mario College of Pharmacy, Piscataway, NJ, USA
Center for Health Outcomes, Policy, and Economics, Ernest Mario College of Pharmacy, Piscataway, NJ, USA
OBJECTIVES: Given shared bradykinin-mediated pathways and accumulating case-reports, we evaluated whether the concomitant use of DPP4i with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) was associated with an increased risk of angioedema.
METHODS: We conducted an active comparator new user cohort study using Medicare fee-for-service data (2013-2021), including patients with type 2 diabetes newly initiating an DPP4i versus SGLT2i. Patients were subsequently classified into three mutually exclusive strata based on concomitant RAAS inhibitor use: i) DPP4i or SGLT2i plus ACEi, ii) DPP4i or SGLT2i plus ARB, and iii) DPP4i or SGLT2i without ACEi or ARB. Within each stratum, inverse probability of treatment weighting was applied to balance baseline characteristics between treatment groups. The outcome was an angioedema event, identified by ICD-9-CM/ICD-10-CM codes, and a weighted Cox proportional model was used to estimate adjusted hazard ratios (95% CI).
RESULTS: In the ACEi stratum (N=207,583; mean [SD] age, 73.9 [6.5] years; 48.2% female), DPP4i initiation was associated with 17% higher risk of angioedema compared to SGLT2i: HR 1.17 (95% CI: 0.93-1.46), although this association did not reach statistical significance. In the ARB stratum (N=170,752; mean [SD] age, 74.7 [6.6] years; 55.9% female), DPP4i initiation was associated with a significantly higher risk of angioedema SGLT2i: HR 1.70 (1.19-2.42), while in the non-RAAS inhibitor stratum (N=145,756; mean [SD] age, 75.3 [7.3] years; 53.2% female), DPP4i initiation was associated with an elevated but statistically non-significant risk of angioedema (HR 1.38, 95% CI 0.95-2.00).
CONCLUSIONS: In this cohort study, initiation of DPP4, particularly among patients receiving concomitant ARB therapy, was associated with higher risk of angioedema. A numerical increase in risk was also observed among DPP4i users not using RAAS inhibitors. These findings highlight a potential safety signal, and suggest that increased clinical vigilance may be warranted when initiating DPP4i in older adults.
METHODS: We conducted an active comparator new user cohort study using Medicare fee-for-service data (2013-2021), including patients with type 2 diabetes newly initiating an DPP4i versus SGLT2i. Patients were subsequently classified into three mutually exclusive strata based on concomitant RAAS inhibitor use: i) DPP4i or SGLT2i plus ACEi, ii) DPP4i or SGLT2i plus ARB, and iii) DPP4i or SGLT2i without ACEi or ARB. Within each stratum, inverse probability of treatment weighting was applied to balance baseline characteristics between treatment groups. The outcome was an angioedema event, identified by ICD-9-CM/ICD-10-CM codes, and a weighted Cox proportional model was used to estimate adjusted hazard ratios (95% CI).
RESULTS: In the ACEi stratum (N=207,583; mean [SD] age, 73.9 [6.5] years; 48.2% female), DPP4i initiation was associated with 17% higher risk of angioedema compared to SGLT2i: HR 1.17 (95% CI: 0.93-1.46), although this association did not reach statistical significance. In the ARB stratum (N=170,752; mean [SD] age, 74.7 [6.6] years; 55.9% female), DPP4i initiation was associated with a significantly higher risk of angioedema SGLT2i: HR 1.70 (1.19-2.42), while in the non-RAAS inhibitor stratum (N=145,756; mean [SD] age, 75.3 [7.3] years; 53.2% female), DPP4i initiation was associated with an elevated but statistically non-significant risk of angioedema (HR 1.38, 95% CI 0.95-2.00).
CONCLUSIONS: In this cohort study, initiation of DPP4, particularly among patients receiving concomitant ARB therapy, was associated with higher risk of angioedema. A numerical increase in risk was also observed among DPP4i users not using RAAS inhibitors. These findings highlight a potential safety signal, and suggest that increased clinical vigilance may be warranted when initiating DPP4i in older adults.
Conference/Value in Health Info
2026-05, ISPOR 2026, Philadelphia, PA, USA
Value in Health, Volume 29, Issue S6
Code
EPH91
Topic
Epidemiology & Public Health
Topic Subcategory
Safety & Pharmacoepidemiology
Disease
SDC: Cardiovascular Disorders (including MI, Stroke, Circulatory), SDC: Diabetes/Endocrine/Metabolic Disorders (including obesity)