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Table 1

Arguments for and against the modern sulfonylureas

For the prosecutionFor the defenseEvidence yet to be presented
Ischemic preconditioning Tolbutamide and glyburide interfere with ischemic preconditioning Gliclazide, glipizide, and glimepiride do not alter ischemic preconditioning  
Hypoglycemia Hypoglycemia and weight gain occur with all sulfonylureas Gliclazide, glipizide, and glimepiride cause less hypoglycemia than glyburide  
Observational studies Cardiovascular risk is higher with sulfonylureas vs. comparators in some studies Cardiovascular risk is mainly higher vs. metformin, which decreases risk Studies with better design to limit bias 
Randomized studies Short-term mortality was increased with tolbutamide in UGDP Long-term mortality was decreased with glyburide, chlorpropamide, and glipizide in UKPDS CAROLINA (glimepiride vs. linagliptin) 
GRADE (glimepiride vs. other second-line agents) 
For the prosecutionFor the defenseEvidence yet to be presented
Ischemic preconditioning Tolbutamide and glyburide interfere with ischemic preconditioning Gliclazide, glipizide, and glimepiride do not alter ischemic preconditioning  
Hypoglycemia Hypoglycemia and weight gain occur with all sulfonylureas Gliclazide, glipizide, and glimepiride cause less hypoglycemia than glyburide  
Observational studies Cardiovascular risk is higher with sulfonylureas vs. comparators in some studies Cardiovascular risk is mainly higher vs. metformin, which decreases risk Studies with better design to limit bias 
Randomized studies Short-term mortality was increased with tolbutamide in UGDP Long-term mortality was decreased with glyburide, chlorpropamide, and glipizide in UKPDS CAROLINA (glimepiride vs. linagliptin) 
GRADE (glimepiride vs. other second-line agents) 

The modern sulfonylureas—gliclazide, glipizide, and glimepiride—are accused of “increased risk of cardiovascular mortality.” The table summarizes the main arguments for prosecution and defense, including evidence from studies of older sulfonylureas.

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