Metformin

Usage

• Metformin is primarily used to treat type 2 diabetes mellitus, particularly in overweight or obese individuals. It helps control blood sugar levels. It can be used as monotherapy or in combination with other oral antidiabetic agents or insulin.

• It also has off-label uses, such as treatment of polycystic ovary syndrome (PCOS) and prediabetes.

• Pharmacological Classification: Biguanide, Antihyperglycemic

• Mechanism of Action: Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Alternate Names

• No commonly used alternate names.

• Brand Names: Glucophage, Glucophage XR, Glumetza, Riomet, Fortamet.

How It Works

• Pharmacodynamics: Metformin’s primary effect is to lower blood glucose levels. It doesn’t stimulate insulin secretion but rather enhances insulin action in peripheral tissues, reducing insulin resistance. It also modestly reduces intestinal glucose absorption and suppresses hepatic glucose production.

• Pharmacokinetics:

  • Absorption: Absorbed from the gastrointestinal tract, with bioavailability of approximately 50-60%. Food reduces the extent and slightly delays absorption.
  • Distribution: Distributes widely to body tissues but does not significantly bind to plasma proteins.
  • Metabolism: Not metabolized in the liver.
  • Elimination: Excreted unchanged primarily by the kidneys. The plasma elimination half-life is approximately 6.2 hours.

• Mode of Action: The exact mechanism is not fully understood, but it appears to involve activation of AMP-activated protein kinase (AMPK), leading to a cascade of effects that improve insulin signaling and glucose metabolism in the liver, muscle, and other tissues.

• Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Primarily exerts its effects through AMPK activation rather than direct receptor binding or enzyme inhibition. Does not modulate neurotransmitters.

• Elimination Pathways: Primarily renal excretion.

Dosage

Standard Dosage

Adults:

• Immediate-Release: Initial dose is 500 mg two times a day or 850 mg once a day, taken with meals. Increase by 500 mg weekly or 850 mg every two weeks, as needed and tolerated. Maximum daily dose is 2550 mg, usually taken in divided doses two or three times daily.
• Extended-Release: Initial dose is typically 500 mg once daily with the evening meal. Dosage can be increased by 500 mg weekly as needed, up to a maximum of 2000 mg per day.

Children (10 years and older):

• Immediate-Release: Starting dose is 500 mg twice a day, given with meals. Increase by 500 mg weekly as needed and tolerated, to a maximum of 2000 mg per day in divided doses.
• Extended-Release: Not approved for pediatric use.

Special Cases:

• Elderly Patients: Start with a low dose and titrate cautiously, considering age-related decline in renal function. Avoid the maximum dose in many cases.
• Patients with Renal Impairment: Contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²). Dose adjustments are required for moderate impairment, based on the individual patient’s GFR and creatinine clearance.
• Patients with Hepatic Dysfunction: Use with caution due to increased risk of lactic acidosis. The manufacturer generally recommends avoiding metformin in patients with hepatic impairment.
• Patients with Comorbid Conditions: Assess for risk factors of lactic acidosis, such as heart failure or hypoxia.

Clinical Use Cases

Metformin’s use is primarily focused on chronic management of type 2 diabetes and is generally not indicated in acute clinical settings like intubation, surgical procedures, mechanical ventilation, ICU, or emergency situations such as status epilepticus or cardiac arrest.

Dosage Adjustments

Dosage adjustments are based on renal function, age, and individual patient response. Monitoring of blood glucose levels and renal function is important during titration.

Side Effects

Common Side Effects

• Gastrointestinal disturbances: diarrhea, nausea, vomiting, stomach upset, flatulence, metallic taste in mouth.

Rare but Serious Side Effects

• Lactic acidosis (a rare but severe metabolic complication): symptoms include malaise, myalgia, respiratory distress, somnolence, hypotension, hypothermia.

Long-Term Effects

• Vitamin B12 deficiency (may occur with prolonged use): can cause anemia and peripheral neuropathy.

Adverse Drug Reactions (ADR)

• Lactic acidosis, severe gastrointestinal symptoms requiring hospitalization.

Contraindications

• Severe renal impairment (eGFR < 30 mL/min/1.73 m²).
• Hypersensitivity to metformin.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
• Hepatic impairment or liver disease.
• Conditions that predispose to tissue hypoxia (e.g., heart failure, acute myocardial infarction).

Drug Interactions

• Drugs that decrease renal function: Can increase risk of metformin accumulation and lactic acidosis (e.g., NSAIDs, radiocontrast agents, some diuretics, cimetidine).
• Cationic drugs: Can compete with metformin for renal tubular transport (e.g., vandetanib, ranolazine, dolutegravir).
• Drugs that increase blood glucose: Can reduce metformin efficacy (e.g., corticosteroids, atypical antipsychotics, thiazide diuretics).
• Alcohol: Increases the risk of lactic acidosis.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Previously Category B, now not assigned a category by the FDA. Data suggests no increased risk of major birth defects or miscarriage, but insulin is often preferred.
• Breastfeeding: Metformin is excreted in breast milk in small amounts. Most data suggests it is safe for use during breastfeeding, but caution is advised, particularly for newborns or premature infants and in mothers with renal impairment. Neonatal blood glucose should be monitored.

Drug Profile Summary

• Mechanism of Action: Improves insulin sensitivity, reduces hepatic glucose production, and decreases intestinal glucose absorption.
• Side Effects: Primarily gastrointestinal (diarrhea, nausea, vomiting). Rarely, lactic acidosis.
• Contraindications: Renal impairment, metabolic acidosis, hepatic disease, hypersensitivity.
• Drug Interactions: Drugs affecting renal function, cationic drugs, drugs affecting blood glucose, alcohol.
• Pregnancy & Breastfeeding: Generally considered safe but use with caution; monitor neonate.
• Dosage: Variable, depending on formulation, age, renal function, and response.
• Monitoring Parameters: Blood glucose, renal function (eGFR, creatinine), vitamin B12 levels (with long-term use).

Popular Combinations

• Metformin is frequently combined with other antidiabetic medications, such as sulfonylureas (e.g., glipizide), DPP-4 inhibitors (e.g., sitagliptin), SGLT2 inhibitors (e.g., canagliflozin), and insulin. These combinations offer synergistic effects on blood glucose control.

Precautions

• General Precautions: Assess renal function before initiating therapy and periodically during treatment. Monitor for signs of lactic acidosis.
• Specific Populations: As detailed in the Dosage section.
• Lifestyle Considerations: Advise patients to maintain a healthy diet, engage in regular exercise, and limit alcohol intake.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Metformin?

A: Dosage varies depending on the patient’s age, renal function, and individual response. See detailed dosage information above.

Q2: What are the common side effects of Metformin?

A: The most common side effects are gastrointestinal, including diarrhea, nausea, vomiting, and abdominal discomfort. These often improve over time or with dose adjustments.

Q3: What is the most serious side effect of Metformin?

A: Lactic acidosis, although rare, is the most serious side effect. Patients should be educated on the symptoms and seek immediate medical attention if they occur.

Q4: Can Metformin be used during pregnancy?

A: While generally considered safe in pregnancy, insulin is often preferred, particularly in the later stages. The decision to use Metformin should be made on a case-by-case basis after discussing the risks and benefits with the patient.

Q5: Can Metformin be used during breastfeeding?

A: Metformin does pass into breast milk in small amounts, but it’s generally considered safe. Monitor the infant for any unusual signs or symptoms.

Q6: What are the contraindications to using Metformin?

A: Metformin is contraindicated in individuals with severe renal impairment, hepatic disease, metabolic acidosis, and hypersensitivity to the drug.

Q7: How does Metformin interact with alcohol?

A: Concurrent alcohol consumption can increase the risk of lactic acidosis and should be avoided or limited while taking Metformin.

Q8: What should I monitor in patients on long-term Metformin therapy?

A: Monitor renal function, vitamin B12 levels, and HbA1c for efficacy. Also, educate patients on the signs and symptoms of lactic acidosis.

Q9: What are the typical drug combinations involving Metformin?

A: Metformin is often combined with other antidiabetic agents like sulfonylureas, DPP-4 inhibitors, and insulin to achieve better glycemic control.