Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes

Background: Clinicians and patients need updated evidence on the comparative effectiveness and safety of diabetes medications to make informed treatment choices. Purpose: To evaluate the comparative effectiveness and safety of monotherapy (thiazolidinediones, metformin, sulfonylureas, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium–glucose cotransporter 2 [SGLT-2] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists) and selected metformin-based combinations in adults with type 2 diabetes. Data Sources: English-language studies from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, indexed from inception through March 2015 (MEDLINE search updated through December 2015). Study Selection: Paired reviewers independently identified 179 trials and 25 observational studies of head-to-head monotherapy or metformin-based combinations. Data Extraction: Two reviewers independently assessed study quality and serially extracted data and graded the strength of evidence. Data Synthesis: Cardiovascular mortality was lower for metformin versus sulfonylureas; the evidence on all-cause mortality, cardiovascular morbidity, and microvascular complications was insufficient or of low strength. Reductions in hemoglobin A1c values were similar across monotherapies and metformin-based combinations, except that DPP-4 inhibitors had smaller effects. Body weight was reduced or maintained with metformin, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors and increased with sulfonylureas, thiazolidinediones, and insulin (between-group differences up to 5 kg). Hypoglycemia was more frequent with sulfonylureas. Gastrointestinal adverse events were highest with metformin and GLP-1 receptor agonists. Genital mycotic infections were increased with SGLT-2 inhibitors. Limitation: Most studies were short, with limited ability to assess rare safety and long-term clinical outcomes. Conclusion: The evidence supports metformin as first-line therapy for type 2 diabetes, given its relative safety and beneficial effects on hemoglobin A1c, weight, and cardiovascular mortality (compared with sulfonylureas). On the basis of less evidence, results for add-on therapies to metformin were similar to those for monotherapies. Primary Funding Source: Agency for Healthcare Research and Quality.