Is Metformin Still Top Drug for Type 2 Diabetes?


A new study evaluated the comparative effectiveness and safety of monotherapy and selected metformin-based combinations for type 2 diabetes.

Despite a plethora of newly approved antidiabetic agents, metformin should still be the first-line therapy for patients with type 2 diabetes mellitus (DM), according to a new study.1

“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),” stated the authors, led by Nisa M. Maruthur, MD, of Johns Hopkins University School of Medicine, Baltimore, MD.

They noted that clinicians and patients need updated evidence on the comparative effectiveness and safety of diabetes medications to make informed treatment choices.

The new systematic review updates the comparative effectiveness and safety analysis of antidiabetic agents. New information since the last comprehensive review published in 2011 includes the novel sodium-glucose cotransporter 2 (SGLT-2) inhibitors as well as much more information on the relatively new dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists.

The goal of the study was to evaluate the comparative effectiveness and safety of monotherapy (thiazolidinediones, metformin, sulfonylureas, DPP-4 inhibitors, SGLT-2 inhibitors, and GLP-1 receptor agonists) and selected metformin-based combinations in adults with type 2 diabetes (T2DM).

Maruthur and colleagues conducted a systematic review that identified 179 trials and 25 observational studies of head-to-head monotherapy or metformin-based combinations.

The results show that metformin led to lower cardiovascular mortality than sulfonylureas. The evidence on all-cause mortality, cardiovascular morbidity, and microvascular complications was insufficient or of low strength, they noted.

Reductions in hemoglobin A1c values were similar across monotherapies and metformin-based combinations. The exception was 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. Weight increased with sulfonylureas, thiazolidinediones, and insulin. Between-group differences were 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.

The review found no increased risk for lactic acidosis with metformin, a rare but serious adverse event. The FDA recently revised2 its warnings regarding the use of metformin, stating it can be used safely in patients with mild impairment in kidney function and in some patients with moderate impairment in kidney function. Previously, the FDA had strongly recommended against metformin use in some patients whose kidneys do not work normally because use of metformin in these patients can increase the risk of lactic acidosis.

One of the strengths of the study is direct comparisons of monotherapies and metformin-based combination therapies for T2DM. The authors noted the systematic review was limited because most of the studies included were short, with limited ability to assess rare safety and long-term clinical outcomes.

In conclusion, the authors stated: “On the basis of less evidence, results for add-on therapies to metformin were similar to those for monotherapies.”

They suggest that future research should prioritize the effects of diabetes medications on long-term mortality, cardiovascular mortality and morbidity, microvascular outcomes, and rare, serious adverse events.



1. Maruthur NM, et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med.  19 April 2016.

2. FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. 20 April 2016.

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