Medicine & USMLE

Second-Gen Sulfonylureas

Diabetes Drugs (Old)
  1. Insulin Preparations
  2. Metformin
  3. Glitazones / Thiazolidinediones
  4. First-Gen Sulfonylureas
  5. Second-Gen Sulfonylureas
  6. Meglitinides
  7. GLP-1 Analogs
  8. DPP-4 Inhibitors
  9. alpha-Glucosidase Inhibitors
  10. Pramlintide


Second-generation sulfonylureas include the drugs glyburide, glimeperide, and glipizide; and they are used in the management of type II diabetes. They work by closing the potassium channels of the islets of langerhans in the pancreas, causing an influx of calcium, depolarizing the beta cells and releasing insulin. Since sulfonylureas increase the total amount of active insulin in the body, one important side effect to note is hypoglycemia, which is especially common in people with kidney failure.

Key Points

  • Second-Generation Sulfonylureas
    • Drugs
      • Glyburide
      • Glipizide
      • Glimeperide
    • Mechanism
      • Close ATP-dependent potassium channels
      • → beta cell depolarization
      • → calcium influx
      • → insulin release
        • So C-peptide levels also increase
          • C-peptide is also in beta cell vesicles
          • This gives us a way to differentiate between endogenous and exogenous insulin exposure (esp. relevant in factitious hypoglycemia)
    • Clinical Use
      • Type II diabetes
        • Requires some islet function, so not useful in type I DM
    • Adverse Effects
      • Hypoglycemia
        • Insulin drives sugar into cells, which removes glucose from the bloodstream. If too much insulin is present, too much glucose can be driven into cells and blood glucose levels can get too low.
      • Weight gain
        • I like to think of this as insulin driving sugar into cells and fattening them up
      • Side effects are worse in kidney disease
        • Sulfonylureas are renally-excreted, so in CKD patients they accumulate and can lead to worse side effects
        • Diabetes can cause kidney disease
        • The one to really watch out for is hypoglycemia
      • Sulfa allergies
        • Obvious because "sulfa" is in the drug class’ name
        • Symptoms range from mild to life-threatening
          • E.g. fever, urticaria (hives), Stevens-Johnson syndrome, etc.