Cardiovascular safety of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus

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Johns Hopkins University
Objective: The proposed study will examine the association between the dipeptidyl peptidase-4 inhibitors (DPP-4i) drug class and the risk of major adverse cardiovascular events (MACE) in patients with diabetes. Methods: In the surveillance portion of this dissertation, we utilized the Food and Drug Administration’s Adverse Events Reporting System (FAERS) to conduct a Bayesian disproportionality analysis on reports for MACE associated with DPP-4i, to assess the association of DPP-4i with a cardiovascular subset of reports to the full database. These associations were quantified using the posterior distribution of the empirical Bayes lower bound (EB05) of the relative reporting ratio, among high- and low- risk populations. Next for the longitudinal analyses, we conducted retrospective, time to first MACE analyses of data from Truven Marketscan Commercial Claims and Encounters to compare new users of DPP-4i versus sulfonylurea and DPP-4i versus metformin. This association was measured using propensity score weighted Cox proportional hazards models, adjusted for baseline demographics, comorbidities, and concomitant medications. Propensity score weights, based on baseline clinical characteristics and concomitant medications, were calculated using a generalized boosted logistic regression model. This analysis was repeated in both individuals with established cardiovascular and/or kidney disease (high-risk cohort), as well as in individuals without these medical conditions (low-risk cohort). Results: In the surveillance study, there was a safety signal for heart failure with linagliptin (EB05=2,782.47) and saxagliptin (EB05=2.40), myocardial infarction with alogliptin (EB05=290.11), and cerebral infarction with sitagliptin (EB05=2.80) in the cardiovascular subset of reports. Eight of fourteen possible MACE events had a percent positive agreement ≥50% for a drug-event safety signal in both the cardiovascular subset and the full dataset. Overall, the cardiovascular subset elicited 11 more safety signals for DPP-4i than the full dataset. In the longitudinal analysis of low-risk individuals, DPP-4i use was associated with lower risk for MACE than sulfonylurea use (adjusted Hazard Ratio (aHR)=0.87; 95% Confidence Interval (CI): [0.78, 0.98]), and no increased risk for MACE compared to metformin use (aHR=1.07; 95% CI: [0.97, 1.18]). Risk for acute myocardial infarction (aHR=0.70; 95% CI: [0.51, 0.96]), stroke (aHR=0.57; 95%CI: [0.41, 0.79]), and heart failure (aHR=0.57; 95% CI: 0.41, 0.79) with DPP-4i was lower compared to sulfonylureas. In the longitudinal analysis of high-risk individuals, DPP-4i was associated with lower risk for MACE than sulfonylurea (aHR=0.84; 95% CI: [0.7, 0.9]), and with no increased risk for MACE compared to metformin (aHR=1.07; 95% CI: [1.0, 1.2]). Conclusions: This dissertation confirms the evidence that DPP-4i carry less risk for MACE compared to sulfonylureas in new users of antihyperglycemic therapy for type 2 diabetes. Additionally, DPP-4i and metformin are similar in risk of MACE. While the surveillance data showed a signal for heart failure with some DPP-4i, further prospective analyses of longitudinal data did not lead to evidence to support the drug label warning for increased risk of heart failure among high-risk patients with the use of DPP-4i.
Dipeptidyl peptidase-IV inhibitors, drug-related side effects and adverse reactions, heart failure, pharmacovigilance, pharmacoepidemiology