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Second Generation Sulfonylurea

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Second Generation Sulfonylurea, Sulfonylurea Drug Interactions Causing Hypoglycemia, Sulfonylurea

  • See Also
  1. First Generation Sulfonylurea
  2. Oral Hypoglycemic Agents
  3. Glipizide
  4. Glyburide
  5. Glimepiride
  1. Better effect in lean patients
  2. Consider when Hemoglobin A1C <9%
  3. Second-line to Metformin in most patients
  4. Consider as first-line in specific cohorts
    1. Consider when post-prandial Glucose 200 to 300 mg/dl
    2. Consider when Type II with Polyuria, polydipsia
  • Contraindications
  1. Sulfa Allergy (applies to Sulfonylureas)
  2. Renal and liver dysfunction
    1. Use caution with Sulfonylureas (especially Glyburide)
    2. Repaglinide or Nateglinide may be preferred here
    3. Avoid most Sulfonylureas when GFR <60 ml/min (higher risk of Hypoglycemia)
      1. GlipizideHalf-Life is not impacted by lower GFR and is safer to use in low GFR
  3. Avoid Glyburide in cardiovascular disease (and in general due to Hypoglycemia risk)
    1. Glimepiride and Glipizide do not appear to increase risk
  • Mechanism
  1. Sulfonylureas trigger Insulin release from pancreatic beta cells
    1. Sulfonylureas stimulate Potassium channel closure on pancreatic beta cell surface
    2. Secretagogues do NOT burn out the beta cells sooner
  2. Sulfonylureas may also increase tissue Insulin sensitivity
  • Dosing
  • Pearls
  1. Use Long acting agents
  2. Increase dose every 1-2 weeks until adequate response
  3. No response in 25-30% of Type II Diabetics
  4. Never combine secretagogues
    1. They all have same site of activity
    2. If one does not work, then all will not work
  1. Glimepiride (Amaryl)
    1. Start: 1-2 mg orally daily taken orally with breakfast
    2. Usual: 4 mg orally daily
    3. Maximum: 8 mg orally daily (doses above 4 mg daily, are unlikely to offer benefit)
    4. Advantages
      1. More rapid onset with longer duration
      2. Lower Incidence of Hypoglycemia than Glyburide, but greater risk than Glipizide
      3. Risk of Hypoglycemia increases with lower GFR
      4. Preferred of class for Coronary Artery Disease
  1. Glipizide (Glucotrol)
    1. Start: 5 mg orally daily
    2. Usual: 10-20 mg orally daily
    3. Maximum: 20 mg orally twice daily
  2. Glipizide Extended Release (Glucotrol XL)
    1. Start: 5 mg orally daily taken 30 minutes before breakfast
    2. Usual: 5-10 mg orally daily
    3. Maximum: 20 mg orally daily
      1. Doses above 10 mg daily ER, are unlikely to offer benefit (divide twice daily if used)
    4. Advantages: Least expensive Sulfonylurea
    5. Disadvantages: Extended release may increase Hypoglycemia risk when compared with immediate release
  1. Precautions
    1. Glipizide may be preferred instead due to increased risks of Hypoglycemia associated with Glyburide, Glimepiride
      1. Other agents are generic (no cost advantage to Glyburide)
    2. Glyburide has been associated with worse cardiovascular outcomes in patients presenting for emergent PCI
      1. Jørgensen (2011) Int J Cardiol 152:327-331 [PubMed]
    3. Glyburide appears to predispose to more severe Hypoglycemia than the other Second Generation Sulfonylureas
      1. Avoid in older adults
      2. Glyburide should be avoided in renal dysfunction where GFR <50-60 mL/min (increases hypglycemia risk)
      3. Glyburide should be avoided in severe hepatic dysfunction (increases Hypoglycemia risk)
      4. Gangji (2007) Diabetes Care 30:389-94 [PubMed]
  2. Glyburide (DiaBeta, Micronase)
    1. Start: 2.5 to 5 mg orally daily with breakfast
    2. Usual: 5-20 mg orally daily
    3. Maximum: 20 mg orally daily
  3. Glyburide Micronized (Glynase, PresTab)
    1. Start: 1.5 to 3 mg orally daily with breakfast
    2. Usual: 3-12 mg orally daily
    3. Maximum: 12 mg orally daily
  • Adverse Effects
  1. See Sulfonylurea Poisoning
  2. Hemolytic Anemia in G6PD Deficiency Risk
  3. Weight gain
  4. Hypoglycemia
    1. Higher risk of severe Hypoglycemia with Glyburide than other Sulfonylureas
    2. Hypoglycemia risk increases with lower GFR
    3. See Drug Interactions below for concurrent agents that increase Hypoglycemia risk
  5. Cardiovascular Disease does not appear to be at increased risk with Sulfonylureas
    1. Early studies had suggested possible increased Cardiovascular Risk
    2. Sulfonylureas appear to be neutral in their Cardiovascular Risk effects
    3. Contrast with GLP-1 Agonists and SGLT2 Inhibitors which reduce Cardiovascular Risk
    4. (2019) presc lett 26(12): 71
  • Safety
  1. Unknown safety in Lactation
  2. Unknown safety in pregnancy
    1. Discontinue at least 2 weeks before delivery
  • Drug Interactions
  • Increased risk of Hypoglycemia with Sulfonylureas
  1. Chloramphenicol
  2. Clarithromycin
  3. Fibrates
  4. Fluconazole
  5. Fluoroquinolones (esp. Gatifloxacin)
  6. H2 Receptor Antagonists
  7. Miconazole
  8. Phenylbutazone
  9. Sulfonamide
  10. Verapamil
  11. References
    1. Kabbara (2015) Ther Clin Risk Manag 11: 639–647 [PubMed]
    2. May (2016) Ther Adv Endocrinol Metab 7(2): 69–83 [PubMed]
  • Efficacy
  1. Lower Hemoglobin A1C 0.8 to 1.5%
  2. Do not affect all-cause mortality
  • References
  1. (2017) Presc Lett 25(1): 1-2
  2. Defronzo (1999) Ann Intern Med 131:281-303 [PubMed]
  3. Gangji (2007) Diabetes Care 30:389-94 [PubMed]
  4. Luna (1999) Prim Care 26:895-915 [PubMed]
  5. Vaughan (2024) Am Fam Physician 109(4): 333-42 [PubMed]