Analysis Supports Metformin as First-Line Therapy for Type 2 Diabetes

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, according to a new systematic review and meta-analysis.

“Evidence on the newer versus older diabetes medications continues to amass, and we performed an updated systematic review of the comparative effectiveness and safety of medications for type 2 diabetes in terms of intermediate, long-term, and safety outcomes,” the researchers explained.

They evaluated 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.

The researchers examined current literature for their analysis, with reviewers independently identifying 179 trials and 25 observational studies of monotherapy or metformin-based combinations.

Overall, the researchers found that:

  • Cardiovascular mortality was lower for metformin vs. sulfonylureas.
  • 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.

They said future research should be prioritized to focus on the comparative effects of diabetes medications on long-term mortality; cardiovascular mortality and morbidity; microvascular outcomes; and rare, serious adverse events.

—Mike Bederka


Maruthur NM, Tseng E, Hutfless S, et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis [published online April 19, 2016]. Ann Intern Med. doi:10.7326/M15-2650.