Correspondence Cardiovascular safety of incretin-based therapy for type 2 diabetes: A meta-analysis of randomized trials Ahmed N. Mahmoud a,1 , Marwan Saad b , Hend Mansoor c , Akram Y. Elgendy a , Amr F. Barakat d , Ahmed Abuzaid e , Amgad Mentias f , Islam Y. Elgendy a, ⁎ ,1,2 a Department of Medicine, University of Florida, Gainesville, FL, United States b Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United States c Department of Pharmaceutical Outcomes and Policy, University of Florida, Gainesville, FL, United States d Department of Medicine, Cleveland Clinic Foundation, Cleveland, OH, United States e Department of Medicine, Jefferson University Hospital/Christiana Care Health System, Newark, DE, United States f Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United States article info Article history: Received 26 August 2016 Received in revised form 25 November 2016 Accepted 17 December 2016 Available online xxxx Keywords: Incretins Meta-analysis Mortality Heart failure Myocardial infarction Stroke The evaluation of the cardiovascular safety of pharmacological agents for diabetes has been mandated by the United States Food and Drug Administration for the past decade. The cardiovascular safety of incretin-based therapy (i.e., glucagon like peptide-1 [GLP-1] agonists and dipeptidyl peptidase-4 [DPP-4] inhibitors) has been a subject of many recent trials [1]. Among these trials, some had suggested that saxagliptin was associated with an increased risk of heart failure hospi- talization [2], while other trials demonstrated a reduction in the risk of cardiovascular events, namely with liraglutide and semaglutide [3,4]. Therefore, we aimed to conduct a meta-analysis of randomized trials to evaluate the cardiovascular safety of incretin-based therapy in type 2 diabetes. Electronic databases were searched for randomized clinical trials that compared any incretin-based therapy with placebo in patients with type 2 diabetes. We mandated that the included trials had eval- uated cardiovascular events as the primary outcome. Outcomes of interest included all-cause mortality, cardiovascular mortality, hos- pitalization for heart failure, myocardial infarction, and stroke. A fixed effects Peto's model was used for the estimation of summary odds ratios (ORs), given the rare incidence of these outcomes. Het- erogeneity was assessed by I 2 statistics. Publication bias was evaluat- ed by Egger's test. A confidence interval (CI) was set at 95%, and P-value b 0.05 was adopted for statistical significance. Subgroup analysis was performed according to the type of incretin-based therapy (i.e., GLP-1 agonist and DPP-4 inhibitors) for the various outcomes. Analysis for in- teraction between the subgroups was evaluated using an inverse vari- ance fixed-effects model. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for this analysis. A total of six trials with 55,248 patients were included (Table 1) [2–7]. Two trials (Saxagliptin Assessment of Vascular Outcomes Record- ed in patients with diabetes mellitus [SAVOR]–Thrombolysis in Myocar- dial Infarction [TIMI]–53 and Trial Evaluating Cardiovascular Outcomes with Sitagliptin [TECOS]) enrolled patients with type 2 diabetes and established cardiovascular disease [2,5], two trials (Evaluation of LIXisenatide in Acute coronary syndrome [ELIXA], and EXamination of cArdiovascular outcoMes with alogliptIN versus Standard of CarE [EX- AMINE]), included patients with recent acute coronary syndrome [6, 7], while the Liraglutide Effect and Action in Diabetes: Evaluation of car- diovascular outcome Results (LEADER) and the Semaglutide and Car- diovascular Outcomes in Patients with Type 2 Diabetes (SUSTAIN-6) trials recruited patients either with established cardiovascular disease or risk factors only [3,4]. The mean follow-up was 32 months. Compared with placebo, incretin-based therapy was associated with a similar risk of all-cause mortality (OR 0.97, 95% CI 0.91–1.04, P = 0.41, I 2 = 44%), cardiovascular mortality (OR 0.95, 95% CI 0.87–1.03, P = 0.21, I 2 = 46%), myocardial infarction (OR 0.95, 95% CI 0.88–1.03, P = 0.18, I 2 = 15%), heart failure hospitalization (OR 1.04, 95% CI 0.95–1.13, P = 0.44, I 2 = 44%), and stroke (OR 0.94, 95% CI 0.84–1.05, P = 0.30, I 2 = 30%). Subgroup analysis demonstrated a reduction in the risk of all- cause mortality with GLP-1 agonists (OR 0.89, 95% CI 0.80–0.99, P = 0.03), but not with DPP-4 inhibitors (OR 1.03, 95% CI 0.94–1.12, P = International Journal of Cardiology xxx (2016) xxx–xxx ⁎ Corresponding author at: Department of Medicine, Division of Cardiovascular Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610, United States. E-mail address: islam.elgendy@medicine.ufl.edu (I.Y. Elgendy). 1 Both authors equally contributed to this paper. 2 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. IJCA-24291; No of Pages 3 http://dx.doi.org/10.1016/j.ijcard.2016.12.113 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved. Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard Please cite this article as: A.N. Mahmoud, et al., Cardiovascular safety of incretin-based therapy for type 2 diabetes: A meta-analysis of randomized trials, Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.12.113