QUESTION In adults with type 2 diabetes mellitus, are dipeptidyl peptidase-4 (DPP-4) inhibitors, alone or combined with metformin, effective and safe for glycemic control compared with metformin alone or combined with other hypoglycemic drugs? REVIEW SCOPE Included studies compared DPP-4 inhibitors with metformin monotherapy, or DPP-4 inhibitors plus metformin with other hypoglycemic drugs (a sulfonylurea, basal insulin, pioglitazone, or a glucagon-like peptide [GLP]-1 agonist) plus metformin for ≥ 12 weeks in patients> 18 years of age with type 2 diabetes mellitus, and reported glycated hemoglobin (HbA1c) levels. Exclusion criteria were studies of rosiglitazone and hypoglycemic drugs not widely adopted in clinical practice (α-glucosidase inhibitors, glinides, amylin agonists), and pregnancy. Outcomes included changes in HbA1c levels and body weight, and adverse events. REVIEW METHODS MEDLINE, EMBASE/Excerpta Medica, Cochrane Library (all to 2011); conference abstracts from 3 professional associations (2009 and 2010); pharmaceutical company Web sites; ClinicalTrials.gov; and ClinicalStudyResults.org were searched for published and unpublished randomized controlled trials (RCTs). 27 reports of 19 RCTs (n = 13 881) met the selection criteria. 16 reports had adequate randomization, and 10 had adequate allocation concealment. Overall risk for bias for the primary outcome was low in 3 reports, unclear in 9, high in 14, and not assessed in 1. MAIN RESULTS DPP-4 inhibitor monotherapy resulted in smaller reductions in HbA1c than did metformin alone or than metformin plus a sulfonylurea or a GLP-1 agonist (Table). DPP-4 inhibitors increased weight compared with metformin alone or metformin plus a GLP-1 agonist but reduced weight compared with metformin plus a sulfonylurea or pioglitazone (Table). DPP-4 inhibitors plus metformin had a lower risk for serious adverse events than did metformin plus pioglitazone (relative risk reduction 53%, 95% CI 18 to 73) but did not differ from metformin plus a sulfonylurea or GLP-antagonist. CONCLUSION In adults with type 2 diabetes mellitus, dipeptidyl peptidase-4 (DPP-4) inhibitor monotherapy is less effective than metformin monotherapy for reducing HbA1c levels, and DPP-4 inhibitors plus metformin are less effective than metformin plus a sulfonylurea or a GLP-1 agonist.DPP-4 inhibitors vs metformin (met) alone or DPP-4 inhibitors plus metformin vs metformin plus a sulfonylurea, pioglitazone, or a GLP-1 agonist in type 2 diabetes*OutcomesComparisonsNumber of trials (n)WMD (95% CI)†Change in HbA1c (%)DPP-4 vs met7 (3237)0.20 (0.08 to 0.32)DPP-4 + met vs met + sulfonylurea6 (7291)0.07 (0.03 to 0.11)DPP-4 + met vs met + pioglitazone3 (1021)0.09 (-0.07 to 0.24)DPP-4 + met vs met + GLP-1 agonist2 (766)0.49 (0.31 to 0.67)Change in body weight (kg)DPP-4 vs met5 (2306)1.50 (0.90 to 2.11)DPP-4 + met vs met + sulfonylurea4 (5349)-1.92 (-2.34 to -1.49)DPP-4 + met vs met + pioglitazone2 (901)-2.96 (-4.13 to -1.78)DPP-4 + met vs met + GLP-1 agonist2 (277)1.56 (0.94 to 2.18)*DPP = dipeptidyl peptidase; GLP-1 = glucagon-like peptide-1; HbA1c = hemoglobin A1c; WMD = weighted mean difference; other abbreviations defined in Glossary. WMD based on a random-effects model.†Values> 0 favor comparators.