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Metformin

Metformin Hydrochloride

Glucophage Glumetza Fortamet Riomet

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Updated: October 17, 2025

Overview

Metformin is an oral antihyperglycemic drug primarily used for the treatment of type 2 diabetes mellitus. It's often a first-line medication due to its effectiveness, relatively low cost, and generally good safety profile. Metformin improves glycemic control by decreasing hepatic glucose production, increasing insulin sensitivity, and modestly reducing intestinal glucose absorption. Beyond diabetes, metformin is increasingly being investigated for its potential benefits in other conditions like polycystic ovary syndrome (PCOS), prediabetes, and even certain cancers, though these uses are often off-label and require further research. It does not typically cause hypoglycemia when used alone. It’s important to note that while metformin is generally well-tolerated, it can cause gastrointestinal side effects and carries a risk of lactic acidosis in specific patient populations. Careful patient selection and monitoring are crucial for safe and effective use.

Drug Class

Biguanide antihyperglycemic agent. Therapeutic category: Antidiabetic

Mechanism of Action

Metformin exerts its primary antihyperglycemic effect by decreasing hepatic glucose production. It achieves this by inhibiting gluconeogenesis and glycogenolysis. It also increases insulin sensitivity in peripheral tissues (muscle) improving glucose uptake and utilization. Additionally, metformin modestly reduces intestinal glucose absorption. At a molecular level, metformin activates AMP-activated protein kinase (AMPK), an enzyme that plays a crucial role in regulating cellular energy balance. AMPK activation leads to decreased expression of genes involved in gluconeogenesis and increased expression of genes involved in glucose uptake. Metformin also affects the gut microbiome, potentially contributing to its glucose-lowering effects.

Pharmacokinetics

Absorption: Metformin is absorbed from the small intestine, with incomplete absorption (approximately 50-60%). Absorption is saturable, meaning that higher doses may result in decreased absorption and increased gastrointestinal side effects. Distribution: Metformin distributes widely throughout the body but does not bind significantly to plasma proteins. It does not readily cross the blood-brain barrier. Metabolism: Metformin is not metabolized by the liver. It is excreted unchanged in the urine. Excretion: Primarily excreted unchanged by the kidneys through glomerular filtration and tubular secretion. Renal function is a key determinant of metformin clearance. Half-life: Approximately 1.5-3 hours. However, the duration of action is longer due to tissue accumulation.

Pharmacodynamics

Metformin lowers both basal and postprandial plasma glucose levels. It does not stimulate insulin secretion and therefore does not cause hypoglycemia when used alone. It improves insulin sensitivity, allowing the body to use insulin more effectively. Metformin can also have favorable effects on lipid metabolism, potentially reducing triglycerides and LDL cholesterol.

Indications

• Type 2 Diabetes Mellitus: As monotherapy or in combination with other oral antidiabetic agents, to improve glycemic control in adults and children 10 years and older. • Polycystic Ovary Syndrome (PCOS): Off-label use to improve insulin sensitivity, reduce androgen levels, and potentially restore ovulation in women with PCOS. • Prediabetes: Off-label use to prevent or delay the onset of type 2 diabetes in individuals with impaired glucose tolerance.

Contraindications

Absolute: • Severe renal impairment (eGFR < 30 mL/min/1.73m²) • Acute or unstable congestive heart failure • Metabolic acidosis, including diabetic ketoacidosis • Severe hepatic impairment • Acute or chronic metabolic acidosis Relative: • Moderate renal impairment (eGFR 30-45 mL/min/1.73m²): Use with caution and dose adjustment. • History of lactic acidosis • Conditions predisposing to hypoxia (e.g., respiratory failure, severe infection)

Dosage & Administration

Type 2 Diabetes Mellitus: Initial dose: Typically 500 mg once or twice daily with meals. Maintenance dose: Gradually increase the dose in 500 mg increments weekly, as tolerated, to a maximum recommended daily dose of 2000 mg, divided into multiple doses. Extended-release formulations (Glumetza, Fortamet): May be administered once daily with the evening meal. The total daily dose should not exceed 2000mg. Polycystic Ovary Syndrome (PCOS): Dosing varies widely, typically starting with 500 mg once daily and gradually increasing to 1500-2000 mg daily, divided into multiple doses.

Special Populations

Pediatric: Can be used in children 10 years and older, starting with low doses and titrating gradually. Geriatric: Use with caution due to age-related decline in renal function. Monitor renal function closely and adjust dosage accordingly. Renal impairment: Contraindicated with eGFR < 30 mL/min/1.73m². Avoid use with eGFR 30-45 mL/min/1.73m². Dose adjustment and close monitoring are essential for those with mild to moderate impairment. Hepatic impairment: Use with caution, as hepatic impairment can increase the risk of lactic acidosis. Avoid use in severe hepatic impairment.

Adverse Effects

Common (>10%): • Gastrointestinal disturbances (nausea, vomiting, diarrhea, abdominal pain, loss of appetite): These are the most common side effects and are often transient. Taking metformin with meals can help minimize these effects. • Metallic taste Serious (<1%): • Lactic acidosis: A rare but life-threatening complication, particularly in patients with renal impairment, liver disease, or heart failure. • Vitamin B12 deficiency: Long-term metformin use can interfere with vitamin B12 absorption.

Drug Interactions

• Cimetidine: May increase metformin concentrations by reducing renal tubular secretion. • Furosemide: Can increase metformin concentrations. • Alcohol: Increases the risk of lactic acidosis. • Contrast agents (iodinated): May temporarily impair renal function and increase the risk of lactic acidosis. Discontinue metformin before or at the time of contrast administration and for 48 hours afterward. • Drugs that affect renal function: NSAIDs, ACE inhibitors, ARBs can potentially increase metformin levels.

Warnings & Precautions

• Lactic Acidosis: A rare but serious metabolic complication that can occur in patients with impaired renal function, liver disease, heart failure, or those who consume excessive alcohol. Symptoms include weakness, muscle pain, difficulty breathing, and abdominal pain. Immediate medical attention is required. • Hypoglycemia: Rarely causes hypoglycemia when used alone, but the risk increases when combined with other antidiabetic agents (e.g., sulfonylureas, insulin). • Vitamin B12 Deficiency: Long-term use may lead to vitamin B12 deficiency, particularly in individuals with pre-existing risk factors. Periodic monitoring of B12 levels may be warranted.

Pregnancy & Lactation

Pregnancy: Metformin crosses the placenta. While studies have not shown a definitive risk, it’s generally recommended to use insulin as the preferred treatment for gestational diabetes. FDA Pregnancy Category B. Lactation: Metformin is excreted in human milk. The American Academy of Pediatrics considers metformin compatible with breastfeeding, but potential effects on the infant are unknown.

Monitoring Parameters

• Renal function (serum creatinine, eGFR): Monitor regularly, especially in patients with renal impairment. • Liver function tests (LFTs): Assess baseline and periodically during treatment, especially in patients with liver disease. • Hemoglobin A1c (HbA1c): Monitor glycemic control every 3-6 months. • Vitamin B12 levels: Consider periodic monitoring, especially with long-term use.

Patient Counseling

• Take metformin with meals to minimize gastrointestinal side effects. • Be aware of the symptoms of lactic acidosis and seek immediate medical attention if they occur. • Inform healthcare providers about all medications and supplements being taken. • Discuss potential for vitamin B12 deficiency with your doctor. • Maintain a healthy diet and exercise program as part of your diabetes management plan.

Storage & Stability

Store at room temperature (20-25°C or 68-77°F) away from moisture and heat. Keep container tightly closed.

Clinical Pearls

• Starting with a low dose and titrating slowly can significantly reduce gastrointestinal side effects. • Consider extended-release formulations for improved tolerability and adherence. • Always assess renal function prior to initiating metformin and monitor periodically. • Metformin is weight neutral or may even promote modest weight loss, unlike some other antidiabetic agents.

References

• American Diabetes Association. Standards of Medical Care in Diabetes—2023. Diabetes Care. 2023;46(Supplement 1):S1-S264. • Kirpichnikova, D., & McFarlane, S. I. (2016). Metformin: An update. British journal of diabetes & vascular disease, 16(4), 183–188. • Salpeter, S. R., Buckley, L. P., & Grey, A. (2013). Vitamin B12 deficiency in patients taking metformin. Archives of internal medicine, 173(4), 356–357.