Efficacy and Safety of Dipeptidyl Peptidase-4 Inhibitors in Combination with Metformin

Use of dipeptidyl peptidase-4 (DPP-4) inhibitors is prevalent for the treatment of type 2 diabetes since they have fewer adverse effects compared with other non-insulin medications currently available; however, as monotherapy, the glycosylated hemoglobin (HbA1c)-lowering power of these agents is moderate. The aim of this article is to evaluate the current literature regarding the safety and efficacy of DPP-4 inhibitors in combination with metformin. A literature search was conducted through MEDLINE (from 1950 to October 2012), PubMed (from 1966 to October 2012), EMBASE (from 1966 to October 2012), and International Pharmaceutical Abstracts (from 1970 to October 2012) using the search terms "sitagliptin," "linagliptin," "alogliptin," "vildagliptin," "saxagliptin," and "metformin." Studies that did not evaluate the DPP-4 inhibitors in combination with metformin and those that were not phase 3, were excluded. Many of the studies evaluated DPP-4 inhibitors in combination with metformin versus glucagon-like peptide-1 (GLP-1) agonists, placebo, DPP-4 inhibitors as monotherapy, thiazolidinediones, and sulfonylureas. The results of these noninferiority trials were that DPP-4 inhibitors as a whole are noninferior to either each other or other agents except for GLP-1 agonists. Also, in superiority studies, GLP-1 agonists proved to have greater HbA1c lowering. In summary, DPP-4 inhibitors play a vital role in the treatment of diabetes. They have relatively limited adverse effects, especially regarding hypoglycemia. DPP-4 inhibitors in combination with metformin are generally well tolerated and are available as combination products to reduce pill burden and enhance compliance. The limitations to DPP-4 inhibitors are the lack of outcomes data and more limited HbA1c lowering than other medications currently approved for the treatment of type 2 diabetes. However, as previously stated, thiazolidinediones, glinides, sulfonylureas, pramlinitide, and GLP-1 agonists are all quite beneficial in HbA1c lowering but are not without major adverse effects. Therefore, DPP-4 inhibitors have a vital role as an oral add-on agent for the treatment of type 2 diabetes.