Cardiovascular Safety of Metformin and Sulfonylureas

Study Questions:

What is the association of metformin and sulfonylureas with cardiovascular events in patients with different cardiovascular risk profiles indicated by N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels?


A total of 2,024 patients with diabetes mellitus were included in this observational study. The primary endpoint was defined as a combination of cardiovascular events and death. Association of metformin and sulfonylureas was assessed using Cox regression models. Possible differences of these associations in patients with different NT-proBNP levels were studied by stratifying and through interaction analysis.


During a median follow-up of 60 months, the primary endpoint occurred in 522 (26%) patients. The median age was 63 years. A Cox regression analysis was adjusted for site of treatment, concomitant medication, age, gender, body mass index, glycated hemoglobin, duration of diabetes, glomerular filtration rate, cholesterol, and history of smoking and cardiac disease. Metformin was associated with a decreased risk in the cohort with elevated NT-proBNP ≥300 pg/ml (hazard ratio, 0.70; p = 0.014) and a similar association was found for the interaction between metformin and NT-proBNP (p = 0.001). There was neither an association for sulfonylureas nor a significant interaction between sulfonylureas and NT-proBNP.


The authors concluded that metformin is associated with beneficial cardiovascular outcomes in patients with diabetes only when (sub)clinical cardiovascular risk defined by NT-proBNP levels is present.


This study reports a significant and independent association of metformin treatment with improved outcome in patients at an increased cardiovascular risk identified by NT-proBNP levels ≥300 pg/ml, which was also confirmed in an interaction analysis. There was no such association in low-risk patients identified by NT-proBNP values <300 pg/ml. Sulfonylureas were not associated with differences in all-cause mortality and cardiovascular events in adjusted models and interaction analysis. Future trials focusing on pre-existing (sub)clinical cardiovascular risk may be useful for a more personalized/targeted therapeutic approach where certain treatment options are recommended for either low- or high-risk populations.

Clinical Topics: Anticoagulation Management, Diabetes and Cardiometabolic Disease, Prevention

Keywords: Biological Markers, Cardiovascular Diseases, Diabetes Mellitus, Hemoglobin A, Glycosylated, Metabolic Syndrome X, Metformin, Natriuretic Peptide, Brain, Peptide Fragments, Primary Prevention, Risk Factors, Sulfonylurea Compounds

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