Background: The first treatment approach for type 2 diabetes mellitus is lifestyle change and metformin, but it is usually not enough. The anti-hyperglycemic classes of sulfonylureas and dipeptidyl peptidase-4 (DPP-4) inhibitors are considered second-line of treatment, since they show similar efficacy effect. Due to this fact, we performed a meta-analysis for safety profile to comprehend which treatment has lower adverse events. Methods: PUBMED and EMBASE databases were searched from inception until July 2017 to retrieve RCT studies comparing DPP-4 inhibitors and sulfonylureas treatments in adult type 2 diabetes patients. There was no language restriction. We extracted and combined data from studies comparison that reported safety profile and weight change. A random effect, meta-analytic model was applied in all calculations. Cochrane collaboration tool was used to assess quality and bias of the included studies. Findings: Of 1,472 articles identified in our search and screened for eligibility, 36 studies comparing DPP-4 inhibitors and sulfonylureas were identified. DPP-4 inhibitors in combination with metformin had less overall adverse events (RR: 0*90; 95% CI, 0*86-0*94; p<0*0001; I2=83%; 17 studies), cardiovascular events (RR: 0*54; 95% CI, 0*37-0*79; p=0*002; I2=0%; 6 studies), hypoglycemia (RR: 0*17; 95% CI, 0*13-0*22; p≤0*00001; I2=76%; 17 studies) and severe hypoglycemia events (RR: 0*10; 95% CI, 0*05-0*19; p≤0*00001; I2=0%; 12 studies). The mean difference of the weight change was 1*92 kg in favor of DPP-4 inhibitors in combination with metformin in relation to sulfonylureas in combination with metformin. Monotherapy with DPP-4 inhibitors also had less rates of hypoglycemia (RR: 0*31; 95% CI, 0*24-0*41; p≤0*00001; I2=0%; 8 studies) and severe hypoglycemia events (RR: 0*26; 95% CI, 0*10-0*66; p=0*004; I2=0%; 8 studies) and patients did not gain 1*19 kg. Interpretation: These results suggest better safety profile for DPP-4 inhibitors than sulfonylureas for both comparisons, and it is more notable when the treatment regimen includes metformin. Trial Registration for Meta-Analysis: Trial registered in PROSPERO (CRD42017075823). Funding Statement: This study was funded by Takeda Pharmaceuticals, Brazil. Declaration of Interests: DF reports grants from Takeda Distribuidora Ltda., during the conduct of the study. MCMF reports grants from Takeda Distribuidora Ltda. during the conduct of the study; he is scientific director from AxiaBio Life Sciences International, a consultancy company that provides various work to distinct healthcare stakeholders, including Takeda Distribuidora Ltda; and he is employed by Sao Paulo Federal University as professor, outside the submitted work. GML has nothing to discosure. FGE has nothing to disclosure. Ethics Approval Statement: We conducted the systematic review and meta-analysis in accordance with recommendations from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The study protocol was registered in PROSPERO (CRD42017075823).