Metformin associated with fewer cardiovascular events than sulfonylureas after decline in kidney function

The findings from this retrospective study further support metformin as the first-line treatment to which other diabetes medications are added, even in patients who are in the early stages of chronic kidney disease, an editorial noted.


Patients with diabetes who continued taking either metformin or a sulfonylurea despite developing reduced kidney function had a lower risk of major adverse cardiovascular events (MACE) with metformin, a retrospective cohort study found.

Researchers assessed outcomes of patients in the Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016. There were 174,882 new users of metformin and sulfonylurea monotherapy who continued treatment with their initial glucose-lowering medication after developing reduced kidney function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 or creatinine level ≥1.4 mg/dL for women or ≥1.5 mg/dL for men). Participants were followed from when they hit the reduced kidney function threshold until MACE (e.g., hospitalization for acute myocardial infarction, stroke, transient ischemic attack, or cardiovascular death), treatment change, loss to follow-up, death, or study end (December 2016). Results were published online Sept. 19 by JAMA.

There were 67,749 metformin users and 28,976 sulfonylurea users (54% glipizide, 45% glyburide, and 1% glimepiride). Metformin users were younger than sulfonylurea users (median age, 67 vs. 71 years), had fewer cardiovascular comorbidities, and reached the kidney function threshold in later study years. These differences were minimized in a propensity score-weighted cohort, which included 24,679 metformin and 24,799 sulfonylurea users (median age, 70 years; 98% men; 82% white). At cohort entry, the median eGFR was 55.8 mL/min/1.73 m2 (interquartile range [IQR], 51.6 to 58.2mL/min/1.73 m2), and the median HbA1c level was 6.6% (IQR, 6.1% to 7.2%).

During follow-up (median, 1.0 year for metformin vs. 1.2 years for sulfonylurea), there were 1,048 MACE outcomes (23.0 per 1,000 person-years) among metformin users and 1,394 events (29.2 per 1,000 person-years) among sulfonylurea users. Compared with sulfonylureas, the cause-specific adjusted hazard ratio of MACE for metformin was 0.80 (95% CI, 0.75 to 0.86), yielding an adjusted rate difference of 5.8 (95% CI, 4.1 to 7.3) fewer events per 1,000 person-years of metformin use compared with sulfonylurea use.

The authors noted limitations of the study, such as the fact that the results cannot be generalized to patients who already have a reduced eGFR at the time of therapy initiation. They added that findings may not be representative of the larger population of patients with diabetes and reduced kidney function.

“The study further supports the use of metformin as the first-line treatment to which other diabetes medications are added, even as early chronic kidney disease develops,” an accompanying editorial said.