Association Between Intensification of Metformin Treatment With Insulin vs Sulfonylureas and Cardiovascular Events and All-Cause Mortality Among Patients With Diabetes

Study Questions:

In a population of patients with type 2 diabetes mellitus on metformin, what is the comparative difference in time to acute myocardial infarction (AMI), stroke, or death in those who intensify their therapy with insulin versus a sulfonylurea?


This was a retrospective cohort study of patients from the Veterans Health Administration who were initially treated with metformin from 2001 to 2009, and who subsequently added either insulin or sulfonylurea (the exposures of interest) as cotherapies. The primary composite outcome was AMI, stroke hospitalization, or all-cause death.


Fifty-nine percent (43,345/72,868) of metformin patients intensified their therapy with either insulin or a sulfonylurea. Following treatment intensification, median follow-up was 14 months. For the primary outcome, there were 172 vs. 634 events among patients who added insulin vs. sulfonylureas, respectively (42.7 vs. 32.8 events per 1,000 person-years; adjusted hazard ratio [aHR], 1.30; 95% confidence interval [CI], 1.07-1.58; p = 0.009). This was driven by all-cause mortality. At 1 year, median glycated hemoglobin level declined to 7% among metformin and insulin users, and 6.9% among metformin and sulfonylurea users.


In patients with type 2 diabetes mellitus on metformin, the addition of insulin compared to a sulfonylurea was associated with an increased risk of all-cause mortality and nonfatal cardiovascular outcomes.


While there may be consensus that metformin is first-line therapy for type 2 diabetes mellitus in appropriately selected patients, there is less agreement or evidence to inform the best add-on therapy for those inadequately controlled with metformin monotherapy. The authors’ findings of an increased risk associated with metformin and insulin cotherapy, compared to metformin and sulfonylurea cotherapy, certainly warrants further study, but corroborates observations by others in the literature. Intensification of metformin with insulin seems to offer no incremental benefit (any may be harmful), compared to the addition of a sulfonylurea, and should perhaps be avoided in select circumstances when there are other options for add-on therapy.

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