For patients with type 2 diabetes, metformin reduces the relative risk of cardiovascular-related mortality by 30% to 40% more than sulfonylureas, according to a meta-analysis published in the Annals of Internal Medicine.

“Metformin looks like a clear winner,” said Nisa Maruthur, MD, MHS, assistant professor of medicine at the Johns Hopkins University School of Medicine. “This is likely the biggest bit of evidence to guide treatment of type 2 diabetes for the next 2 to 3 years.”

This review provides an update to 2 previous analyses, the most recent of which was published in 2011. Since then, more than 100 new studies have compared the efficacy of blood sugar-reducing drugs, and several new drugs have been introduced.

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The study compared the efficacy 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 several metformin-based combinations in adults with type 2 diabetes.

The researchers used data from 204 studies (179 trials and 25 observational studies) that compared monotherapies or metformin-based combination therapies. The studies were identified from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from inception through March 2015 (with the MEDLINE search extended through December 2015).

After analyzing the data, the researchers found that cardiovascular mortality was lower in patients who used metformin compared with those who used sulfonylureas, but the evidence on all-cause mortality, cardiovascular morbidity, and microvascular complications was insufficient or low strength.

All monotherapies and metformin-based combinations resulted in similar reductions in HbA1c values except for DPP-4 inhibitors, which resulted in smaller reductions. Metformin, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors reduced or maintained body weight; sulfonylureas, thiazolidinediones, and insulin increased body weight. Sulfonylureas had the highest rates of hypoglycemia; metformin and GLP-1 receptor agonists had the highest rates of gastrointestinal adverse events; and SGL-2 inhibitors increased the risk of genital mycotic infections.

The results align with current recommendations of metformin as first-line therapy for type 2 diabetes. However, the researchers note that there is less certainty when clinicians and patients need to add a second medication to be used in combination with metformin.

“The medications all have different benefits and side effects, so the choice of second-line medications must be based on an individual patient’s preferences,” said Dr Maruthur.

Most of the included studies had follow-up periods of less than 2 years, so the researchers were unable to assess rare safety and long-term clinical outcomes.


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