Metformin

Mechanism

Pharmacological Class and Group

Oral antihyperglycemic agent of the Biguanide class (synthetic derivative of galegin from the plant Galega officinalis).

Mechanism of Action

Metformin is a positively charged hydrophilic compound at physiological pH. Its entry into the target cell (mainly hepatocytes and immunocytes) is actively mediated by organic cation transporters (mainly OCT1). Once in the cellular cytosol, its molecular target is Complex I of the mitochondrial electron transport chain (NADH:ubiquinone oxidoreductase).

Intracellular Molecular Mechanism

1. Mild and transient inhibition of mitochondrial Complex I: Selectively blocks electronic flow, decreasing proton translocation and altering the electrochemical gradient. This results in a reduction in the synthesis of adenosine triphosphate (ATP) and an increase in cytosolic adenosine monophosphate (AMP):

Ratio ↑ ([AMP])/([ATP]) and ↑ ([ADP])/([ATP])

2. Activation of AMPK (AMP-activated protein kinase): The increase in AMP promotes allosteric binding to the regulatory domain of AMPK, inducing a conformational change that favors the phosphorylation of its Thr172 residue by the LKB1 kinase. Phosphorylated AMPK turns off energy-consuming processes (gluconeogenesis, lipid synthesis) and activates catabolic pathways (glycolysis, beta-oxidation of fatty acids).

3. Inhibition of Hepatic Gluconeogenesis: AMPK phosphorylates and inactivates the transcriptional coactivators CRTC2 and the histone deacetylase HDAC4/5, preventing the transcription of the genes that encode phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Likewise, it directly allosterically inhibits fructose-1,6-bisphosphatase-1 (FBPase-1) through increasing cellular AMP.

4. Inhibition of the Mitochondrial Glycerol-3-Phosphate Dehydrogenase Shuttle (mGPD): By decreasing the activity of mGPD, the conversion of lactate and glycerol into glucose is blocked, altering the cellular redox state (increased NADH/NAD+ ratio in the cytosol) and drastically limiting the contribution of gluconeogenic substrates.

Pharmacokinetics

High Resolution Pharmacokinetics

• Routes of administration: Oral only (immediate or extended release tablets).
• Absorption and Bioavailability: Bioavailability of 50-60%. Absorption occurs mainly in the duodenum and jejunum by saturable active transport. Food delays and slightly reduces the peak maximum concentration (C_max).
• Distribution: Apparent volume of distribution (V_d) of 654 ± 358 L. It does not bind to circulating plasma proteins. Preferential accumulation in salivary glands and wall of the gastrointestinal tract.
• Metabolism: It is not metabolized in the liver. It is not a substrate for cytochrome P450 (CYP450) enzymes.
• Excretion and Elimination: Exclusive renal excretion by glomerular filtration and active tubular secretion mediated by OCT2 and MATE1/MATE2-K. Renal clearance exceeds normal GFR (renal Acl ≈ 400 mL/min).
• Half-life (t_1/2): Plasma half-life 4 to 6 hours; erythrocyte terminal elimination half-life of approximately 17.6 hours.

Indicators and dose

Clinical Indications and Off-Label Uses

• Type 2 Diabetes Mellitus: First-line drug of choice, both in monotherapy and in combined oral or injectable therapy.
• Pre-diabetes and impaired fasting glucose (off-label): Especially in patients with a body mass index (BMI) 35 kg/m², age < 60 years or women with a history of gestational diabetes.
• Polycystic Ovary Syndrome (PCOS) (off-label): For the management of insulin resistance, reduction of hyperandrogenism, regulation of menstrual cycles and induction of ovulation.
• Weight gain induced by atypical antipsychotics (off-label): Mitigation of secondary metabolic dysfunction in psychiatric patients.

Dosage and Clinical Adjustment

Adjustment in Kidney Failure:

• eGFR ≥ 45 to 59 mL/min/1.73 m²: Continue usual therapy. Annual monitoring of kidney function.
• eGFR 30 to 44 mL/min/1.73 m²: Mandatory dose reduction to 50% (maximum 1000 mg/day). Do not start new treatment in this range. Monitor kidney function every 3 months.
• eGFR < 30 mL/min/1.73 m²: Absolute contraindication. Remove the drug immediately.

Adjustment in Liver Failure: Avoid its use due to the lower capacity to metabolize lactates by the cirrhotic or severely dysfunctional liver.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Known hypersensitivity to metformin.
• Severe renal failure: Estimated Glomerular Filtration Rate (eGFR) < 30 mL/min/1.73 m² (due to cumulative risk of toxicity).
• Acute or chronic metabolic acidosis of any etiology (including diabetic ketoacidosis).
• Acute conditions prone to cellular hypoperfusion: Cardiogenic shock, septic shock, severe dehydration, unstable acute heart failure.

Relative Contraindications

• eGFR between 30 and 45 mL/min/1.73 m² (requires mandatory dose reduction of 50%).
• Moderate to severe hepatic impairment or chronic active alcoholism (increased risk of lactic acidosis due to ineffective lactate clearance).
• Concomitant use of iodinated contrast media (requires prior suspension and reevaluation of renal function).

Adverse Effects (ADR) and Specific Toxicity

• Very common (>10%): Dose-dependent gastrointestinal disorders (osmotic diarrhea, nausea, vomiting, flatulence, crampy abdominal pain, metallic taste). They are usually mitigated by slow dose titration and administration with food.
• Frequent (1%-10%): Headache, asthenia, dizziness. Vitamin B12 (cobalamin) malabsorption: Competitively interferes with the ileal intrinsic factor receptor that depends on positively charged calcium. It can induce megaloblastic anemia and peripheral neuropathy after prolonged exposure (>5 years).
• Very rare (<0.01%): Lactic acidosis (approximate incidence rate of 3 to 5 cases per 100,000 patient-years).

Critical Toxicity: Metformin-Associated Lactic Acidosis (MALA)

In patients with renal failure or severe tissue hypoxia, metformin accumulation exacerbates anaerobic lactate production by inhibiting oxidative phosphorylation. The accumulated lactate exceeds the hepatic clearance capacity of the Cori shuttle:

Metformin accumulation mGPD inhibition Blockade Lactic gluconeogenesis Metabolic acidemia with elevated GAP anion

It presents with dyspnea (Kussmaul respiration), nonspecific abdominal pain, hypothermia, refractory bradycardia and cardiovascular collapse. The treatment of choice for clinical suspicion with serum lactate levels > 5 mmol/L and pH < 7.35 is urgent hemodialysis with bicarbonate to remove the drug and correct the acidemia.

Drug Interactions of Clinical Relevance

• OCT2 / MATE inhibitors (Dolutegravir, Cimetidine, Ranolazine, Vandetanib): They decrease renal secretion of metformin, increasing its plasma area under the curve (AUC) and the risk of lactic acidosis. They require monitoring and possible dose adjustment.
• Intravascular iodinated contrast media: May induce contrast nephropathy with secondary acute renal failure and systemic accumulation of metformin. The drug should be discontinued 48 hours before or at the time of the study, and resumed only after normal renal function is established 48 hours later.
• Drugs that alter blood glucose (Corticosteroids, thiazide diuretics, beta-2 agonists): They can antagonize the hypoglycemic effect of metformin.

Safety in Pregnancy and Breastfeeding

• Pregnancy: FDA Category B. It crosses the placental barrier freely, reaching fetal concentrations similar to maternal concentrations. Long-term clinical trials (MiG trial) have not demonstrated teratogenicity or major adverse effects on embryonic development. However, insulin remains the gold standard of choice in gestational diabetes.
• Breastfeeding: Compatible. It is excreted in human milk in trace amounts (relative milk dose rate < 1%). No adverse effects have been reported in infants.