Cardiovascular Safety of Incretin-Based Therapies in Type 2 Diabetes: Systematic Review of Integrated Analyses and Randomized Controlled Trials

Fig. 1. Individual flow diagrams of included studies. Search #1 = alogliptin OR linagliptin OR saxagliptin OR sitagliptin OR vildagliptin OR “dipeptidyl peptidase-4 inhibitors” OR “DPP-4 inhibitors” OR gliptins; Search #2 = “pooled analysis” OR “comprehensive analysis” OR “meta-analysis” OR “integrated analysis” OR “systematic review” OR “systematic assessment” OR “indirect comparison”; Search #3 = cardiovascular; Search #4 = exenatide OR liraglutide OR albiglutide OR taspoglutide OR dulaglutide OR lixisenatide OR semaglutide OR “glucagon-like peptide-1 receptor agonists” OR GLP-1; Search #5 = randomized OR randomised OR randomly; Search #6 = cardiovascular or heart [field: Title/abstract]. *Included one pairwise and network meta-analysis. CV cardiovascular, DPP-4 dipeptidyl peptidase-4, GLP-1 glucagon-like peptide-1, RCTs randomized controlled trials, T2DM type 2 diabetes mellitus

Fig. 2. Risk of a MACE: a pooled analyses of patient-level data for specific DPP-4 inhibitors, b meta-analyses of trial-level data for specific DPP-4 inhibitors, and c meta-analyses of trial-level data for DPP-4 inhibitors as a drug class. MACEs were defined differently in each analysis (see Table 2). CI confidence interval, DPP-4 dipeptidyl peptidase-4, HR hazard ratio, OR odds ratio, RR risk ratio. aVildagliptin 50 mg once daily and twice daily. bAll included studies. The principal analysis excluded seven studies that did not report events. cUpper 95% CI not shown. dDPP-4 inhibitor monotherapy versus metformin monotherapy. eDPP-4 inhibitor plus metformin versus metformin monotherapy. fDPP-4 inhibitors versus sulfonylureas

Fig. 3. Risk of a CV event with GLP-1 receptor agonist according to integrated analyses of patient- and trial-level data. AEs adverse events, CI confidence interval, CV cardiovascular, GLP-1 glucagon-like peptide-1, HR hazard ratio, MACE major adverse cardiac events, OR odds ratio, RR risk ratio. aPrimary endpoint: MACE composite endpoint or hospital admission for unstable angina [53]. bSecondary endpoint: MACE composite endpoint only [53]. cSecondary MACE composite endpoint, which included all relevant CV AEs [i.e., all terms of the primary MACE endpoint plus terms for arrhythmia, heart failure (with or without hospitalization), and mechanical-related events] [51]