Metformin

Overview

Metformin is an oral biguanide antihyperglycemic agent and the first-line pharmacologic therapy for type 2 diabetes mellitus (T2DM) worldwide. Unlike many other antidiabetic agents, metformin does not cause hypoglycemia when used as monotherapy, does not induce weight gain, and is associated with improved cardiovascular outcomes. It is also increasingly investigated in polycystic ovary syndrome (PCOS), prediabetes, and other conditions linked to insulin resistance.

Its safety profile is generally favorable, but caution is needed in renal impairment, hepatic disease, and conditions predisposing to hypoxia due to the rare but serious risk of lactic acidosis.

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Pharmacological Class and Formulations

• Class: Biguanide oral antihyperglycemic agent

• ATC code: A10BA02

• Formulations:

  • Immediate-release tablets (500 mg, 850 mg, 1000 mg)

  • Extended-release tablets (500 mg, 750 mg, 1000 mg)

  • Oral solution (100 mg/mL in some regions)

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Mechanism of Action

Metformin lowers blood glucose primarily by reducing hepatic glucose production (gluconeogenesis). Additional mechanisms include:

• Hepatic: Inhibits mitochondrial respiratory chain complex I → decreased ATP → increased AMP → activation of AMP-activated protein kinase (AMPK) → reduced gluconeogenesis.

• Peripheral: Increases insulin sensitivity in skeletal muscle and adipose tissue → enhanced glucose uptake.

• Gastrointestinal: Slows intestinal absorption of glucose and alters gut microbiota.

Importantly, metformin does not stimulate insulin secretion, reducing the risk of hypoglycemia.

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Pharmacokinetics

• Absorption: 50–60% bioavailability; absorption occurs mainly in small intestine.

• Distribution: Not protein-bound; widely distributed, especially in liver, kidneys, and intestine.

• Metabolism: Not metabolized.

• Excretion: Renally excreted unchanged.

• Half-life: ~6 hours (immediate release); ~17 hours (extended release).

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Clinical Indications

Approved Uses

1. Type 2 diabetes mellitus (T2DM)

   • First-line agent for glycemic control, unless contraindicated.

   • Used alone or in combination with other oral agents or insulin.

2. Type 2 diabetes prevention (prediabetes)

   • Reduces progression to T2DM in high-risk patients (e.g., obesity, impaired glucose tolerance).

Off-label / Additional Uses

• Polycystic ovary syndrome (PCOS): Improves ovulatory function and insulin resistance.

• Gestational diabetes mellitus (GDM): Increasingly used in some regions as alternative to insulin.

• Non-alcoholic fatty liver disease (NAFLD): Investigational role.

• Cancer prevention and longevity research: Ongoing studies.

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Contraindications

• Known hypersensitivity to metformin

• Severe renal impairment (eGFR <30 mL/min/1.73 m²)

• Acute or chronic metabolic acidosis, including diabetic ketoacidosis

• Conditions predisposing to hypoxia or lactic acidosis (e.g., sepsis, shock, acute heart failure, respiratory failure)

• Excessive alcohol intake

• Temporary contraindication: Iodinated contrast imaging procedures in patients with impaired renal function (risk of lactic acidosis)

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Precautions

• Renal impairment:

  • eGFR ≥60: full dose

  • eGFR 45–59: monitor renal function every 3–6 months

  • eGFR 30–44: max dose 500 mg twice daily, reassess risks

  • eGFR <30: contraindicated

• Hepatic impairment: Avoid due to lactic acidosis risk.

• Elderly: Monitor renal function regularly.

• Alcohol: Increases lactic acidosis risk; limit or avoid.

• Surgery / imaging: Temporarily discontinue during procedures with contrast media or prolonged fasting.

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Adverse Effects

Common

• Gastrointestinal upset: nausea, vomiting, diarrhea, abdominal discomfort

• Metallic taste

• Loss of appetite

Less Common

• Vitamin B12 deficiency (long-term use)

• Weight loss

Rare but Serious

• Lactic acidosis: potentially fatal but extremely rare; risk increases in renal/hepatic impairment or tissue hypoxia.

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Drug Interactions

• Iodinated contrast media: increased risk of lactic acidosis; temporarily discontinue.

• Alcohol: increases lactic acidosis risk.

• Cimetidine and some drugs affecting renal tubular transport: reduced clearance of metformin.

• Other antidiabetic agents: may increase risk of hypoglycemia (though metformin alone does not).

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Dosage

Adults (T2DM)

• Immediate-release:

  • Start: 500 mg once or twice daily with meals, or 850 mg once daily.

  • Titrate: Increase by 500 mg weekly or 850 mg every 2 weeks as tolerated.

  • Maintenance: 1500–2000 mg/day in divided doses.

  • Maximum: 2550 mg/day.

• Extended-release:

  • Start: 500 mg once daily with the evening meal.

  • Titrate: Increase by 500 mg weekly as tolerated.

  • Maintenance: 1500–2000 mg once daily.

  • Maximum: 2000–2500 mg/day (depending on brand).

Children (≥10 years, T2DM)

• Start: 500 mg once daily.

• Titrate: Increase by 500 mg weekly as tolerated.

• Maximum: 2000 mg/day in divided doses.

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Monitoring

• Baseline: Renal function, liver function, HbA1c, vitamin B12 (if long-term).

• During therapy:

  • HbA1c every 3–6 months

  • Renal function annually (every 3 months if eGFR 30–60)

  • Vitamin B12 periodically in long-term users or if symptoms of neuropathy/anemia develop.

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Patient Counseling Points

• Take with meals to reduce stomach upset.

• Do not crush or chew extended-release tablets.

• Inform clinician before surgery or imaging requiring contrast dye.

• Avoid excessive alcohol intake.

• Report symptoms of lactic acidosis (fatigue, muscle pain, abdominal pain, rapid breathing).

• Regular follow-up for blood glucose and kidney function is essential.