What is the mechanism of action and administration for metformin (biguanide)

Mechanism of Action and Administration of Metformin

Metformin improves glucose tolerance in type 2 diabetes by decreasing hepatic glucose production, decreasing intestinal glucose absorption, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization. 1

Mechanism of Action

Metformin works through several key mechanisms:

1. Primary mechanisms:

   • Reduces hepatic glucose output (primary effect)
   • Decreases intestinal absorption of glucose
   • Improves peripheral insulin sensitivity
   • Does not increase insulin secretion (insulin levels remain unchanged or decrease)

2. Molecular targets:

   • Inhibits mitochondrial complex I in the liver, which alters energy metabolism
   • Affects cAMP and protein kinase A signaling pathways that respond to glucagon
   • Stimulates 5'-AMP-activated protein kinase (AMPK), which improves insulin sensitivity primarily through modulation of lipid metabolism

Administration and Dosing

• Available forms:

  • Immediate-release tablets (twice-daily dosing)
  • Extended-release tablets (once-daily dosing)

• Dosing considerations:

  • Start with low dose and gradually titrate to minimize gastrointestinal side effects
  • Immediate-release: Typically started at 500mg twice daily with meals
  • Extended-release: Can be given once daily
  • Bioavailability: 40-60% with oral administration 2
  • Absorption is complete within 6 hours of ingestion
  • No plasma protein binding
  • No metabolism (excreted unchanged in urine)

Clinical Effects and Benefits

• Reduces A1C levels by approximately 1.5 percentage points as monotherapy 3
• Weight neutral or modest weight loss (unlike many other diabetes medications) 3
• Does not cause hypoglycemia when used as monotherapy
• Reduces risks of microvascular complications, cardiovascular events, and death 3
• More effective than DPP-4 inhibitors in lowering A1C and weight when used as monotherapy 3

Safety Considerations

• Renal function:

  • Safe to use with eGFR ≥30 mL/min/1.73 m² 3
  • Contraindicated when eGFR <30 mL/min/1.73 m² due to risk of lactic acidosis
  • Use with caution in patients with eGFR 30-45 mL/min/1.73 m² due to risk of periodic decreases in eGFR

• Common side effects:

  • Gastrointestinal intolerance (bloating, abdominal discomfort, diarrhea)
  • Can be mitigated by gradual dose titration and/or using extended-release formulation 3

• Important monitoring:

  • Periodic testing of vitamin B12 levels due to increased risk of deficiency with long-term use 3
  • Monitor for worsening symptoms of neuropathy which may be related to B12 deficiency 3

Special Considerations

• Lactic acidosis is a rare but serious complication, primarily occurring with renal failure 3
• No metabolites or conjugates have been identified 2
• Plasma elimination half-life after oral administration is between 4.0 and 8.7 hours 2
• Emerging evidence suggests the gut may be an important site of action in addition to the liver 4
• Should be temporarily discontinued for patients undergoing angiography with iodinated contrast agents 3

By understanding metformin's mechanism of action and proper administration, clinicians can optimize its use to improve glycemic control while minimizing adverse effects, ultimately reducing morbidity and mortality in patients with type 2 diabetes.