Metformin Still Safest for First-Line Therapy in Type 2 Diabetes, Study Finds

Since the study period ended, new results show a long-term cardioprotective benefit for empagliflozin and liraglutide.

When it comes to balancing the need to control blood sugar and while preventing heart attacks and strokes, metformin still works best, according to a giant analysis of more than 200 studies and 1.4 million patients.

The meta-analysis, published Tuesday in Annals of Internal Medicine, found the old stand-by for treating type 2 diabetes (T2D) was safer for the heart than many of its more modern competitors. The results were especially striking when metformin was compared with several commonly used sulfonylureas, according to the abstract.

For the analysis, researchers evaluated data from 179 clinical trials and 25 observational studies of head-to-head monotherapy or metformin-based combinations. They found that cardiovascular mortality was lower for metformin than sulfonylureas, and that reductions in glycated hemoglobin (A1C) were similar across all drugs as monotherapies and metformin combinations, except DPP-4 inhibitors had smaller effects.

According to the abstract, patients lost weight or at least maintained it on metformin, DPP-4 inhibtors, GLP-1 receptor agonists, and SGLT2 inhibitors. Patients gained weight on sulfonylureas, insulin, and thiazolidinediones (TZDs). Hypoglycemia was also more frequent for those taking sylfonylureas.

Of course, most of the newer medications for diabetes are designed to work in combination with metformin, thus increasing glucose control. The last study captured by the meta-analysis was published in March 2015, and since that time results for empagliflozin and liraglutide have been published showing cardiovascular benefits over the long-term.

The researchers noted that many of the trials they examined were short, and did not allow for the time of long-term safety view seen in the more recent data about empagliflozin, an SGLT2 inhibitor, and liraglutide, a GLP-1 receptor agonist. A drug in the TZD class, pioglitazone, has been shown to have a CV benefit, but it causes weight gain and is associated with higher rates of heart failure.


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.

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