Comparative Efficacy, Safety, and Cost-Utility of DPP-4 Inhibitors and Metformin Combination Therapy in Type 2 Diabetes: A Systematic Review of Real-World Clinical and Economic Outcomes.

introductionThe management of type 2 diabetes with metformin as the first-line therapy has long been established. However, combination therapy of metformin and other oral antidiabetics became necessary to achieve optimal glycemic targets. Recently, the rising cost of these combinations poses a challenge for the healthcare system and patients, particularly in low- and middle-income settings, highlighting the need to balance clinical benefits with economic considerations to ensure access to treatment while maintaining sustainability in patient care. This review aims to compare the efficacy, safety, and cost-effectiveness of DPP-4 inhibitors with metformin/metformin with other combinations and metformin alone.

methodsA 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. The extracted data were synthesized and reported according to the PRISMA guidelines.

resultsThirty-five eligible studies were included in the review. From the studies, oral antidiabetic options apart from DPP-4 inhibitors commonly combined with metformin, either as free or fixed-dose combinations, include SGLT-2 inhibitors, sulfonylureas, GLP-1 receptor agonists, insulin, and thiazolidinediones (TZDs). The efficacy of this drug combination is comparable to that of metformin monotherapy, which is more cost-effective, especially at the beginning of treatment. Where metformin monotherapy fails, the efficacy of an add-on therapy as a second line depends on the specific target and individual patient differences, and even triple therapy may be recommended for some individuals. The cost-effectiveness of each combination depended on the cost-effectiveness model used in the assessment and the nature of the healthcare setting. DISCUSSION: DPP-4 inhibitors/metformin demonstrate significant HbA1c reduction, but their low cost-effectiveness hinders patient adherence compared to metformin monotherapy, free drugs, or other combinations. For that, initiating therapy with cost-effective metformin alone is recommended. Manufacturer-funded trials highlight a potential bias, necessitating independent research validations.