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. 1
Primary Mechanisms
- Metformin reduces hepatic glucose production through inhibition of the mitochondrial respiratory chain complex I, which alters cellular energy metabolism 2, 3
- It inhibits fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, which contributes significantly to its therapeutic action 4
- Metformin non-competitively inhibits mitochondrial glycerophosphate dehydrogenase, resulting in an altered hepatocellular redox state that reduces conversion of lactate and glycerol to glucose 5
- With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease 1
Effects on Glucose Metabolism
- Metformin lowers both basal and postprandial plasma glucose levels 1
- It typically reduces HbA1c by 1.0-1.5 percentage points when used as monotherapy 6
- Unlike insulin secretagogues (sulfonylureas), metformin does not increase the risk of hypoglycemia when used alone 6
- Metformin is generally considered weight-neutral or may promote modest weight loss, in contrast to many other glucose-lowering medications 6
Clinical Pharmacokinetics
- The absolute bioavailability of metformin is approximately 50-60% under fasting conditions 1
- Metformin is negligibly bound to plasma proteins and has a plasma elimination half-life of approximately 6.2 hours 1
- Steady-state plasma concentrations are reached within 24-48 hours and are generally less than 1 μg/mL 1
- Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism 1
Secondary Mechanisms and Emerging Concepts
- Metformin may improve obesity-induced meta-inflammation through direct and indirect effects on tissue-resident immune cells in metabolic organs 2
- The gastrointestinal tract plays a role in metformin action through modulation of glucagon-like peptide 1 and alterations in gut microbiota composition 2
- Recent research suggests metformin may have effects on the intestinal bile acid pool, which could contribute to its glucose-lowering properties 2
Clinical Implications of Mechanism
- Metformin is the preferred initial pharmacologic agent for treatment of type 2 diabetes due to its efficacy, safety profile, and potential cardiovascular benefits 6
- The drug can be safely used in patients with estimated glomerular filtration rate ≥30 mL/min/1.73 m² but is contraindicated in advanced renal insufficiency due to risk of lactic acidosis 6
- Gastrointestinal side effects are common but can be mitigated by gradual dose titration and/or using extended-release formulations 6, 1
- Long-term use of metformin may be associated with vitamin B12 deficiency, suggesting periodic testing of vitamin B12 levels, especially in patients with anemia or peripheral neuropathy 6
By targeting multiple aspects of glucose metabolism, particularly hepatic glucose production, metformin effectively improves glycemic control without increasing insulin secretion or causing weight gain, making it an ideal first-line therapy for type 2 diabetes.