Mechanism of Action of Metformin
Metformin primarily works by decreasing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization, without stimulating insulin secretion. 1
Primary Mechanisms
- Metformin decreases hepatic glucose production (gluconeogenesis) through several pathways, which is its primary glucose-lowering effect 1, 2
- It reduces intestinal absorption of glucose, limiting postprandial glucose excursions 1
- Metformin improves insulin sensitivity by increasing peripheral glucose uptake and utilization in skeletal muscle and adipose tissue 1
- Unlike insulin secretagogues, metformin does not increase insulin secretion - insulin levels remain unchanged or may decrease during treatment 3, 1
Molecular Targets and Cellular Effects
- At clinically relevant concentrations (50-100 μM), metformin inhibits mitochondrial glycerophosphate dehydrogenase, altering the hepatocellular redox state 4
- This redox-dependent mechanism reduces the conversion of lactate and glycerol to glucose, thereby decreasing hepatic gluconeogenesis 5
- Metformin also inhibits fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, through AMP-mediated regulation 6
- The drug affects the cytosolic redox state, inhibiting gluconeogenesis from lactate and glycerol but not from pyruvate and alanine 5
Clinical Pharmacology
- Metformin has an oral bioavailability of approximately 50-60% under fasting conditions 1
- Peak plasma concentrations are reached within 24-48 hours at steady state and are generally <1 μg/mL 1
- The drug is negligibly bound to plasma proteins and is excreted unchanged in urine without undergoing hepatic metabolism 1
- Food decreases and slightly delays metformin absorption, reducing peak plasma concentration by about 40% 1
Clinical Effects and Safety Profile
- Metformin typically reduces HbA1c by 1.0-1.5 percentage points when used as monotherapy 7
- Unlike insulin secretagogues, metformin does not increase the risk of hypoglycemia when used alone 7, 3
- Metformin is generally weight-neutral or may promote modest weight loss, unlike many other glucose-lowering medications 7
- The principal side effects are gastrointestinal intolerance (bloating, abdominal discomfort, diarrhea), which can be mitigated by gradual dose titration 8
- Long-term use may be associated with vitamin B12 deficiency, suggesting periodic testing of vitamin B12 levels 8, 7
Important Considerations
- Metformin can be safely used in patients with estimated glomerular filtration rate ≥30 mL/min/1.73 m² 8, 7
- The main toxicity concern with metformin overdose or accumulation (particularly in renal dysfunction) is lactic acidosis, not hypoglycemia 3
- Combination therapy with insulin or insulin secretagogues increases the risk of hypoglycemia, not metformin alone 3