Comparative Safety of Dipeptidyl Peptidase-4 Inhibitors and Sudden Cardiac Arrest and Ventricular Arrhythmia: Population-Based Cohort Studies

Abstract

In vivo studies suggest that arrhythmia risk may be greater with less selective dipeptidyl peptidase-4 inhibitors, but evidence from population-based studies is missing. We aimed to compare saxagliptin, sitagliptin, and linagliptin with regard to risk of sudden cardiac arrest (SCA)/ventricular arrhythmia (VA). We conducted high-dimensional propensity score (hdPS) matched, new-user cohort studies. We analyzed Medicaid and Optum Clinformatics separately. We identified new users of saxagliptin, sitagliptin (both databases), and linagliptin (Optum only). We defined SCA/VA outcomes using emergency department and inpatient diagnoses. We identified and then controlled for confounders via a data-adaptive, hdPS approach. We generated marginal hazard ratios (HRs) via Cox proportional hazards regression using a robust variance estimator while adjusting for calendar year. We identified the following matched comparisons: saxagliptin vs. sitagliptin (23,895 vs. 96,972) in Medicaid, saxagliptin vs. sitagliptin (48,388 vs. 117,383) in Optum, and linagliptin vs. sitagliptin (36,820 vs. 78,701) in Optum. In Medicaid, use of saxagliptin (vs. sitagliptin) was associated with an increased rate of SCA/VA (adjusted HR (aHR), 2.01, 95% confidence interval (CI) 1.24-3.25). However, in Optum data, this finding was not present (aHR, 0.79, 95% CI 0.41-1.51). Further, we found no association between linagliptin (vs. sitagliptin) and SCA/VA (aHR, 0.65, 95% CI 0.36-1.17). We found discordant results regarding the association between SCA/VA with saxagliptin compared with sitagliptin in two independent datasets. It remains unclear whether these findings are due to heterogeneity of treatment effect in the different populations, chance, or unmeasured confounding.

Figure 1

Kaplan–Meier curves depicting the proportion free of sudden cardiac arrest / ventricular arrhythmia (SCA/VA) events among new users of dipeptidyl peptidase-4 inhibitors in Medicaid Optum databases in the matched cohort. (a) Kaplan-Meier curves depicting the proportion free of SCA/VA events among new users of saxagliptin vs. sitagliptin in Medicaid database (P value based on stratified log-rank test P = 0.007). (b) Kaplan–Meier curves depicting the proportion free of SCA/VA events among new users of saxagliptin vs. sitagliptin in Optum database (P value based on stratified log-rank test P = 0.8093). (c) Kaplan–Meier curves depicting the proportion free of SCA/VA events among new users of linagliptin vs. sitagliptin in Optum database (P value based on stratified log-rank test P = 0.586). CI, confidence interval; HR, hazard ratio.