Metformin

Medication Overview

Metformin is a prescription medication primarily prescribed to manage type 2 diabetes. It falls under the class of drugs known as biguanides, which work by reducing the amount of glucose the liver releases into the blood. Metformin also increases insulin sensitivity in the body, helping cells to absorb and utilize glucose more effectively. As such, it plays a crucial role in glycemic control for individuals with diabetes.

Dosage and Administration

Metformin is available in various forms, including tablets and extended-release tablets. The initial recommended dosage for adults typically starts at 500 mg, taken orally twice a day with meals, to minimize gastrointestinal side effects. Depending on the patient’s response and tolerance, healthcare providers may gradually increase the dose, not exceeding 2000 mg per day. Extended-release tablets are usually taken once daily with the evening meal, and dose adjustments are made with careful monitoring of blood glucose levels.

Mechanism of Action

Metformin works through several mechanisms to exert its glucose-lowering effects. It primarily suppresses hepatic glucose production, thereby reducing fasting blood glucose levels. Furthermore, it enhances insulin sensitivity in peripheral tissues, promoting increased glucose uptake by muscle cells. Unlike other diabetes medications, Metformin does not stimulate insulin secretion from the pancreas, thus minimizing the risk of hypoglycemia.

Pharmacokinetics Details

After oral administration, Metformin is absorbed mainly from the small intestine. The bioavailability of Metformin tablets is approximately 50-60%. It is widely distributed in the body, and the volume of distribution is large, indicating extensive absorption by tissues. Metformin is excreted unchanged in the urine, as it undergoes minimal hepatic metabolism. Its renal clearance far exceeds the glomerular filtration rate, suggesting active tubular secretion.

Off-Label Uses of Metformin

Polycystic Ovary Syndrome (PCOS)

Metformin is extensively used off-label for PCOS management, particularly in women not planning pregnancy. It improves insulin sensitivity and helps address the underlying insulin resistance present in approximately 60% of PCOS women.

Clinical Benefits:

1. Restores menstrual regularity and improves ovulation rates.
2. Reduces insulin resistance by approximately 40% and decreases mean weight by 5.8%.
3. Helps manage hirsutism, acne, and other hyperandrogenic symptoms.
4. Can be used as first-line therapy or for clomiphene-resistant patients.

Dosing Protocols

The standard dose is 500mg three times daily (1,500mg total), though lower doses may be equally effective. A typical titration schedule begins at 500mg daily, increasing gradually to reduce gastrointestinal side effects:

• Week 1: 250mg once daily
• Week 2: 250mg twice daily
• Week 3: 250mg three times daily
• Week 4: 500mg twice daily
• Week 5: 500mg three times daily
• Week 6: 1g twice daily (target dose)

Studies suggest efficacy is not dose-dependent while side effects are, making lower dosages preferable in clinical practice.

Weight Management

Metformin demonstrates modest but clinically significant weight loss effects in adults with obesity, even without diabetes. The mechanism involves appetite reduction, improved insulin sensitivity, and effects on gut microbiota and leptin levels.

Evidence Base:

• Average weight loss of 5.8kg (13 pounds) compared to placebo groups.
• More effective in individuals with higher insulin resistance levels.
• Long-term studies show sustained weight maintenance benefits over 6-15 years.

Clinical Considerations:

Weight loss effects are typically modest (2-3% of body weight annually) and may cease if medication is discontinued. It’s most effective when combined with lifestyle interventions rather than as monotherapy.

Prediabetes Prevention

Licensed in some regions for diabetes prevention, metformin is recommended for high-risk adults with impaired glucose tolerance who continue progressing despite intensive lifestyle interventions.

Indication Criteria:

• Adult, overweight patients with impaired fasting glucose (5.5-6.9 mmol/L) or HbA1c (42-47 mmol/mol).
• High cardiovascular risk.
• Progression toward diabetes despite 3-6 months of intensive lifestyle changes.
• Unable to participate in lifestyle programmes due to medical reasons.

Dosing: Start with 500mg once daily, titrating gradually to 1,500-2,000mg daily. Monitor with 3-monthly glucose/HbA1c assessments for 6-12 months.

Antipsychotic-Induced Weight Gain

Metformin effectively prevents and treats weight gain associated with second-generation antipsychotics. Meta-analyses demonstrate significant reductions in weight (approximately 5 pounds over 12-16 weeks) and BMI z-scores in both adults and children.

Prevention Protocol:

Recent guidelines recommend starting metformin concurrently with antipsychotics rather than waiting for weight gain to occur. Typical dosing ranges from 500-1,000mg twice daily.

Possible Side Effects

Metformin is generally well-tolerated, but some patients may experience side effects. Common gastrointestinal issues include nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These symptoms are usually transient and may be alleviated by adjusting the dose or administering the medication with meals. Rarely, Metformin can lead to a serious condition called lactic acidosis, characterized by muscle pain and weakness, difficulty breathing, and fatigue.

Drug Interactions to Consider

Patients taking Metformin should be aware of potential drug interactions. Concomitant use with cationic drugs such as cimetidine can reduce the renal clearance of Metformin, potentially increasing the risk of lactic acidosis. Metformin may interact with medications that affect renal function, such as diuretics or nonsteroidal anti-inflammatory drugs (NSAIDs), requiring careful monitoring. Additionally, alcohol consumption can potentiate Metformin’s effects on lactic acidosis, and patients are advised to limit or avoid alcohol intake.

Special Populations Advisory

Caution is advised when prescribing Metformin to certain populations. Elderly patients, particularly those with compromised renal function, may require dosage adjustments due to decreased drug clearance. In pediatric patients over ten years of age, Metformin is approved, although doses should be tailored based on weight and glycemic response. In individuals with hepatic impairment, Metformin use is generally not recommended due to the increased risk of lactic acidosis.

Monitoring and Laboratory Tests

Regular monitoring of blood glucose levels is essential in patients taking Metformin to ensure therapeutic efficacy. Hemoglobin A1c tests may be conducted every three to six months to evaluate long-term glycemic control. Renal function should be assessed prior to initiation and periodically thereafter, with particular attention to patients at risk of renal impairment. Vitamin B12 levels may also be monitored, as long-term Metformin use can interfere with B12 absorption.

Storage and Stability

Metformin should be stored at room temperature, away from excess heat and moisture to maintain its stability and effectiveness. The medication should be kept in its original container with the lid tightly closed and out of reach of children. Patients should be instructed to check expiration dates and dispose of expired or unused medication according to local regulations to prevent inadvertent consumption.

Patient Counseling Information

Patients should be counseled on the importance of adhering to their prescribed dosing schedule to achieve optimal blood glucose control. They should report any unusual symptoms, such as lactic acidosis signs or persistent gastrointestinal disturbances, to their healthcare provider promptly. Patients should also be informed about the possible need for dietary modifications to complement their diabetes management regimen and the role Metformin plays in an overall treatment plan.