Metformin remains the foundation of therapy for type 2 diabetes mellitus (T2DM), although combination regimens are often introduced when glycemic targets are not achieved. Balancing clinical effectiveness with treatment costs has become increasingly important, particularly in resource-limited settings. A systematic review published in the Journal of Diabetes Research evaluated the efficacy, safety, and cost-utility of dipeptidyl peptidase-4 (DPP-4) inhibitor and metformin combination therapy compared with metformin alone and other combination approaches.

The review identified 35 eligible studies through searches of PubMed, Scopus, Cochrane, ClinicalTrials.gov, and Google Scholar. Studies were selected based on predefined criteria, and data were extracted and synthesized following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance. The analysis included comparisons with other commonly used therapies, including sodium-glucose cotransporter-2 (SGLT-2) inhibitors, sulfonylureas, glucagon-like peptide-1 (GLP-1) receptor agonists, insulin, and thiazolidinediones.

Across studies, DPP-4 inhibitor and metformin combinations demonstrated glycemic efficacy comparable to metformin monotherapy. However, metformin alone showed greater cost-effectiveness, particularly during initial treatment. When monotherapy did not achieve targets, the relative effectiveness of add-on therapies varied depending on patient characteristics and treatment goals, and some individuals required triple therapy. Cost-utility differed across treatment combinations and healthcare settings.

These findings indicate that while combination therapies offer glycemic benefits, cost considerations remain central when selecting treatment strategies, particularly in settings with limited resources.