Comparative safety of dipeptidyl peptidase-4 inhibitors and sudden cardiac arrest and ventricular arrhythmia: Population-based cohort studies

Comparative safety of dipeptidyl peptidase-4 inhibitors and sudden cardiac arrest and ventricular arrhythmia: Population-based cohort studies

Ghadeer K. Dawwas, Sean Hennessy, Colleen M. Brensinger, Rajat Deo, Warren B. Bilker, Samantha E. Soprano, Neil Dhopeshwarkar, James H. Flory, Zachary T. Bloomgarden, Christina L. Aquilante, Stephen E. Kimmel, Charles E. Leonard

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 1.24–3.25). However, in Optum data, this finding was not present (aHR, 0.79; 0.41–1.51). Further, we found no association between linagliptin (vs. sitagliptin) and SCA/VA (aHR, 0.65; 0.36–1.17). We found discordant results regarding the association between SCA/VA with saxagliptin compared to 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.

 

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  CPeRT members develop real-world evidence about the health effects of medications and other medical products, and prepare the next generation of pharmacoepidemiology leaders. CPeRT is an academic partner to the Food and Drug Administration (FDA)-funded Sentinel Initiative. CPeRT members are also editors of the journal Pharmacoepidemiology and Drug Safety, and the books Pharmacoepidemiology, 6th edition and Textbook of Pharmacoepidemiology, 3rd edition.   

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