Oral Hypoglycemics I
Sulfonylureas · Meglitinides · Metformin
Secretagogue Mechanism: K-ATP Channel Closure
Drug binds SUR-1 subunit
→
K-ATP channel closes
→
Membrane depolarizes
→
Ca² influx
→
Insulin secreted
Applies to both sulfonylureas and meglitinides. Occurs independent of blood glucose — hence hypoglycemia risk.
Class Comparison
ClassExamplesDosingHypo RiskKey Notes
Sulfonylureas Glipizide, glyburide, glimepiride Once–twice daily High Weight gain; avoid glyburide in elderly/CKD; secondary failure over time
Meglitinides Repaglinide, nateglinide With each meal Moderate Skip dose if skipping meal; CYP3A4 substrate; gemfibrozil interaction with repaglinide
Metformin (biguanide) Metformin Twice–three times daily None First-line; weight neutral; hold if eGFR <30; monitor vitamin B12
Metformin Mechanism
  • Inhibits mitochondrial complex I in hepatocytes
  • Raises AMP-to-ATP ratio → activates adenosine monophosphate-activated protein kinase
  • Suppresses gluconeogenic enzymes → less hepatic glucose output
  • Improves peripheral insulin sensitivity (secondary effect)
  • No effect on insulin secretion → no hypoglycemia as monotherapy
Safety: Metformin Contraindications
  • eGFR <30 mL/min: contraindicated (lactic acidosis risk)
  • eGFR 30–45: use with caution, reduce dose
  • Hold before IV contrast if eGFR <30 or high risk
  • Acute heart failure or myocardial infarction: hold
  • Long-term use: monitor vitamin B12 (absorption reduced)
  • GI side effects: start low, titrate slowly, take with food
UKPDS Evidence: Metformin Cardiovascular Benefit
United Kingdom Prospective Diabetes Study (UKPDS 34): Metformin-treated overweight type 2 diabetes mellitus patients had significant reductions in myocardial infarction and all-cause mortality compared with conventional treatment — not seen with sulfonylureas or insulin at equivalent glycemic control. Suggests a cardiovascular benefit beyond glucose lowering. Supports metformin as first-line therapy for most type 2 diabetes mellitus patients.