Swapping Metformin for Sulfonylureas Boosts CV Risk in Type 2 Diabetes, Study Finds

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Sulfonylureas are an older class of type 2 diabetes therapy but remain the most commonly prescribed antidiabetic drug after metformin.

Patients taking metformin for type 2 diabetes (T2D) who switch to a sulfonylurea are at increased cardiovascular (CV) risk, according to findings reported Wednesday. The long-term study found that the links to heart attacks and death were driven by trading metformin for a sulfonylurea, not by adding sulfonylureas to metformin.

Clinical guidelines typically call for patients newly diagnosed with T2D to start with metformin, and to add therapies if they are unable to achieve glycemic control, or change drugs if they cannot tolerate metformin. Sulfonylureas were introduced in the 1950s, and a popular third-generation therapy, glimepiride, arrived in 1995.

In recent years, new classes including dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium glucose co-transporter-2 (SGLT2) inhibitors, have arrived, including several that have been shown to offer cardioprotective benefits. As the researchers noted, however, sulfonylureas remain the commonly prescribed treatment for T2D if patients cannot sufficiently lower their glycated hemoglobin (A1C) on metformin alone.


Researchers led by Antonios Douros, MD, PhD, of the Lady Davis Institute at Jewish General Hospital in Montreal, Canada, matched records from healthcare databases in the United Kingdom with diagnostic codes to examine what happened to 77,138 people with T2D who started taking metformin between 1993 and 2013. About one-third (25,699 people) either added or switched to a sulfonylurea.

To see the effect on all-cause mortality, the researchers examined results for 23,592 patients who added or switched to sulfonylureas, matched with 23,592 who stayed on metformin alone. Matched cohorts of a similar size also examined the effect of adding or switching sulfonylureas on hospital admission for myocardial infarction, hospital admission for ischemic stroke, CV death, and severe hypoglycemia.

Results showed:

  • Using sulfonylureas as a second-line treatment after metformin—either adding or switching—was associated with a 26% increased risk of heart attack, a 24% increased risk of stroke, and a 28% increase of death from any cause.
  • Sulfonylureas, either added or switched with metformin, were associated with a nearly 8 times greater risk of severe hypoglycemia.
  • Switching to sulfonylureas from metformin was associated with 51% higher risk of a heart compared, compared with adding the drug to metformin.
  • Risk of both CV death (22%) and all-cause mortality (23%) were higher when patients switched drugs, compared with adding sulfonylureas to metformin.

“In line with current recommendations on the treatment of type 2 diabetes, continuing metformin when introducing sulfonylureas is safer than switching,” the authors concluded.


Douros A, Dell’Aniello S, Yu OHY, Filion KB, Azoulay L, Suissa S. Sulfonylureas as second-line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycemic events: population based cohort. BMJ. 2018;362:k2693. doi:10.1136/bmjk2693.