This review aims to compare the efficacy, safety, and cost-effectiveness of DPP-4 inhibitors with metformin/metformin with other combinations and metformin alone.<h4>Methods</h4>A literature search was performed through databases including PubMed, Scopus, Cochrane, clinicaltrials.gov, and Google Scholar using specific keywords on "type 2 diabetes mellitus management," "metformin," "DPP-4 inhibitors," "safety," and "efficacy." The retrieved studies were screened and selected according to eligibility criteria, followed by data extraction and critical appraisal. This evidence concerns the gene DPP4 and diabetes mellitus.