[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Original Investigation
September 19, 2019

Association of Treatment With Metformin vs Sulfonylurea With Major Adverse Cardiovascular Events Among Patients With Diabetes and Reduced Kidney Function

Author Affiliations
  • 1Veteran Administration Tennessee Valley VA Health Care System Geriatric Research Education Clinical Center, Nashville
  • 2Department of Medicine, Vanderbilt University Medical Center, Nashville
  • 3Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee
  • 4Department of Health Policy, Vanderbilt University Medical Center, Nashville, Tennessee
JAMA. 2019;322(12):1167-1177. doi:10.1001/jama.2019.13206
Key Points

Question  Is there an association between treatment with metformin vs sulfonylureas and major adverse cardiovascular events (MACE) among patients with diabetes and reduced kidney function?

Findings  In this retrospective cohort study of 49 478 patients with diabetes and reduced kidney function, the incidence of MACE for those treated with metformin vs sulfonylurea monotherapy was 23.0 per 1000 person-years vs 29.2 per 1000 person-years, a difference that was statistically significant.

Meaning  Monotherapy treatment with metformin, compared with a sulfonylurea, was associated with a lower risk of MACE among patients with diabetes and reduced kidney function.


Importance  Before 2016, safety concerns limited metformin use in patients with kidney disease; however, the effectiveness of metformin on clinical outcomes in patients with reduced kidney function remains unknown.

Objective  To compare major adverse cardiovascular events (MACE) among patients with diabetes and reduced kidney function who continued treatment with metformin or a sulfonylurea.

Design, Setting, and Participants  Retrospective cohort study of US veterans receiving care within the national Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016. There were 174 882 persistent new users of metformin and sulfonylureas who reached a reduced kidney function threshold (estimated glomerular filtration rate <60 mL/min/1.73 m2 or creatinine ≥1.4 mg/dL for women or ≥1.5 mg/dL for men). Patients were followed up from reduced kidney function threshold until MACE, treatment change, loss to follow-up, death, or study end (December 2016).

Exposures  New users of metformin or sulfonylurea monotherapy who continued treatment with their glucose-lowering medication after reaching reduced kidney function.

Main Outcomes and Measures  MACE included hospitalization for acute myocardial infarction, stroke, transient ischemic attack, or cardiovascular death. The analyses used propensity score weighting to compare the cause-specific hazard of MACE between treatments and estimate cumulative risk accounting for the competing risks of changing therapy or noncardiovascular death.

Results  There were 67 749 metformin and 28 976 sulfonylurea persistent monotherapy users; the weighted cohort included 24 679 metformin and 24 799 sulfonylurea users (median age, 70 years [interquartile range {IQR}, 62.8-77.8]; 48 497 men [98%]; and 40 476 white individuals [82%], with median estimated glomerular filtration rate of 55.8 mL/min/1.73 m2 [IQR, 51.6-58.2] and hemoglobin A1c level of 6.6% [IQR, 6.1%-7.2%] at cohort entry). During follow-up (median, 1.0 year for metformin vs 1.2 years for sulfonylurea), there were 1048 MACE outcomes (23.0 per 1000 person-years) among metformin users and 1394 events (29.2 per 1000 person-years) among sulfonylurea users. The cause-specific adjusted hazard ratio of MACE for metformin was 0.80 (95% CI, 0.75-0.86) compared with sulfonylureas, yielding an adjusted rate difference of 5.8 (95% CI, 4.1-7.3) fewer events per 1000 person-years of metformin use compared with sulfonylurea use.

Conclusions and Relevance  Among patients with diabetes and reduced kidney function persisting with monotherapy, treatment with metformin, compared with a sulfonylurea, was associated with a lower risk of MACE.