Metformin Advanced Drug Monograph

Metformin Report

Name: Metformin Name (English): Metformin DrugBank ID: DB00331 Type: Small Molecule CAS Number: 657-24-9

General Information: Metformin is an oral antihyperglycemic agent of the biguanide class, primarily used in the management of type 2 diabetes mellitus. It is often considered the first-line medication for this condition, especially in overweight individuals. Metformin can also be used off-label for insulin resistance in polycystic ovary syndrome (PCOS).

Pharmacology: Metformin works by:

• Decreasing hepatic glucose production.
• Increasing insulin sensitivity in peripheral tissues.
• Improving glucose uptake and utilization.
• Increasing GDF15 secretion, which reduces appetite and caloric intake.

Indications:

• Type 2 diabetes mellitus in adults and pediatric patients ≥10 years old, as an adjunct to diet and exercise.
• May be used as a second-line agent for infertility in women with PCOS.
• Investigational use for other conditions such as type 1 diabetes, obesity, and various cancers is ongoing.

Dosage and Administration: Dosage varies depending on the formulation (immediate-release or extended-release) and individual patient needs. It is typically taken with meals to reduce gastrointestinal side effects.

Contraindications:

• Severe renal impairment (eGFR below 30 mL/min/1.73 m²)
• Hypersensitivity to metformin
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis

Warnings and Precautions:

• Lactic Acidosis: A rare but serious, potentially life-threatening condition. Risk is increased in patients with renal impairment, advanced age, liver disease, acute illness, and concomitant use of certain medications.
• Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels. Periodic monitoring of hematologic parameters and vitamin B12 levels is recommended.
• Hypoglycemia: Risk is increased when used in combination with insulin and/or insulin secretagogues. Dose adjustments of these agents may be necessary.

Adverse Reactions: The most common adverse reactions (>5%) include diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.

Drug Interactions: Metformin interacts with a wide range of medications. Clinically significant interactions include:

• Carbonic anhydrase inhibitors (e.g., acetazolamide): Increased risk of lactic acidosis.
• Drugs that reduce metformin clearance (e.g., ranolazine, vandetanib, dolutegravir, cimetidine): May increase metformin accumulation.
• Alcohol: Can potentiate the effect of metformin on lactate metabolism and may increase the risk of hypoglycemia.
• Insulin and insulin secretagogues (e.g., sulfonylureas): Increased risk of hypoglycemia.
• Corticosteroids, thiazide diuretics: May decrease the therapeutic effect of metformin by increasing blood glucose levels.

Chemical Structure: The chemical formula of Metformin is C₄H₁₁N₅, and its molecular weight is approximately 129.16 g/mol. It often used as the hydrochloride salt ($\text{C}4\text{H}{11}\text{N}_5 \cdot \text{HCl}$), which has a CAS number of 1115-70-4. The structure consists of a biguanide moiety with two methyl groups attached to one of the nitrogen atoms.

Pharmacokinetics:

• Absorption: Absorbed primarily in the small intestine.
• Distribution: Widely distributed but does not bind to plasma proteins.
• Metabolism: Not metabolized by the liver and is excreted unchanged in the urine.
• Elimination half-life: Approximately 4-9 hours.

Brand Names: Glucophage, Glumetza, Riomet, Fortamet, and others. It is also available in combination products with other antidiabetic agents.

Regulatory Information: Metformin was first approved in Canada in 1972 and by the FDA in the US in 1995.