What is metformin used for in the treatment of type 2 diabetes?

Metformin in Type 2 Diabetes Treatment

Metformin is the recommended first-line pharmacologic agent for type 2 diabetes mellitus when combined with lifestyle modifications, reducing HbA1c by approximately 1.0-1.5% while offering cardiovascular benefits, weight neutrality, and minimal hypoglycemia risk. 1, 2

Primary Mechanism and Clinical Effects

Metformin works through three distinct mechanisms that collectively improve glycemic control without stimulating insulin secretion 3, 4:

• Decreases hepatic glucose production (primary effect) 3, 4
• Reduces intestinal glucose absorption 3, 4
• Enhances peripheral insulin sensitivity by increasing glucose uptake and utilization in muscle and other tissues 3, 4

The American Diabetes Association endorses metformin as first-line therapy based on its robust efficacy profile, typically achieving HbA1c reductions of 1.0-1.5% compared to placebo 1, 2. This glucose-lowering effect occurs without increasing endogenous insulin secretion, which explains why hypoglycemia is rare with monotherapy 2, 4.

Key Clinical Advantages

Metabolic Benefits

• Weight neutral or promotes modest weight loss, unlike sulfonylureas or insulin which cause weight gain 1, 2, 5
• Improves lipid profiles by reducing LDL cholesterol and triglyceride levels 1, 2, 5
• Does not cause hypoglycemia when used as monotherapy, eliminating the need for frequent finger-stick glucose monitoring 6, 2

Cardiovascular Protection

The American College of Cardiology notes that metformin reduces major cardiovascular events and mortality in patients with type 2 diabetes 1, 2. The landmark UKPDS study demonstrated a 36% reduction in all-cause mortality and 39% reduction in myocardial infarction in obese patients treated with metformin 7.

Special Population Benefits

In adolescents with type 2 diabetes, metformin offers practical advantages over insulin 6:

• Oral administration improves adherence compared to injections 6
• May normalize menstrual cycles in females with polycystic ovary syndrome, though this increases fertility and requires contraception counseling 6
• Requires less instruction time for busy practitioners 6

Dosing and Administration

Starting and Titration

• Initial dose: 500 mg once or twice daily with meals 1, 8
• Gradual titration over 2-4 weeks to minimize gastrointestinal side effects 8
• Target dose: up to 2000 mg daily (divided doses for immediate-release; once-daily for extended-release) 3
• Extended-release formulations provide similar efficacy with improved GI tolerability and once-daily dosing 1, 2, 3

Renal Dosing Adjustments

Metformin is primarily eliminated unchanged through renal filtration 3:

• eGFR ≥45 mL/min/1.73 m²: No dose adjustment needed 2
• eGFR 30-45 mL/min/1.73 m²: Dose reduction required; maximum 1000 mg daily 1, 2
• eGFR <30 mL/min/1.73 m²: Contraindicated due to lactic acidosis risk 1, 8, 3

Contraindications and Precautions

Absolute Contraindications

Metformin is contraindicated in 6, 1, 3:

• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Known hepatic disease
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis
• Hypoxemic conditions (severe heart failure, respiratory failure)
• Severe infections or sepsis
• Alcohol abuse

Temporary Discontinuation Required

Stop metformin 6, 3:

• Before procedures with iodinated contrast agents (restart 48 hours after if renal function stable)
• During acute illness with dehydration, hypoxemia, or sepsis
• Perioperatively when oral intake is restricted

Critical pitfall: The FDA warns that lactic acidosis, though rare (<1 per 100,000 patients), is a medical emergency requiring immediate hospitalization 3, 7. Risk increases dramatically with renal impairment, making regular renal function monitoring essential 8.

Common Side Effects and Management

Gastrointestinal Intolerance

The most frequent adverse effects are GI-related (bloating, abdominal discomfort, diarrhea) 1, 8:

• Mitigation strategy: Start with 500 mg once or twice daily with food, increase gradually over 2-4 weeks 8
• Alternative formulation: Switch to extended-release if standard formulation not tolerated 1, 8
• Most GI symptoms resolve with continued use and dose titration 8, 4

Vitamin B12 Deficiency

Long-term metformin use is associated with vitamin B12 deficiency 1, 2, 8:

• Monitor B12 levels periodically, especially in patients with anemia or peripheral neuropathy 8
• Supplement if deficiency detected 8

Combination Therapy Considerations

When metformin monotherapy fails to achieve glycemic targets after 3-6 months 6:

• Add a second agent rather than discontinuing metformin 2
• Continue metformin when combining with insulin, SGLT2 inhibitors, or GLP-1 receptor agonists if not contraindicated 2
• For patients with established cardiovascular disease, heart failure, or chronic kidney disease, consider adding SGLT2 inhibitors or GLP-1 receptor agonists with proven cardiovascular benefits 2

Important caveat: The TODAY trial revealed that metformin monotherapy alone is inadequate for sustained glycemic control in the majority of youth with type 2 diabetes, requiring early intensification with additional agents 6.

Pharmacokinetics

• Bioavailability: Approximately 50-60% under fasting conditions 3
• Time to steady state: 24-48 hours 3
• Peak concentration: 7 hours (median) for extended-release formulation 3
• Metabolism: Not metabolized; excreted unchanged in urine 3
• Food effect: Decreases Cmax by 40% and AUC by 25%, but improves GI tolerability 3