Biguanides (Metformin) in Type 2 Diabetes Management
First-Line Therapy Recommendation
Metformin is the optimal first-line pharmacologic agent for type 2 diabetes unless contraindicated, and should be initiated at or soon after diagnosis when lifestyle interventions alone are insufficient to achieve glycemic targets. 1
Mechanism and Clinical Efficacy
Metformin reduces blood glucose through three primary mechanisms: decreasing hepatic glucose production, reducing intestinal glucose absorption, and enhancing peripheral insulin sensitivity without stimulating insulin secretion 2, 3
Metformin typically reduces HbA1c by 1.0% to 1.5% compared to placebo, making it highly effective for glycemic control 4
Unlike insulin secretagogues, metformin does not cause hypoglycemia when used as monotherapy and carries minimal risk of this complication 1, 5
Cardiovascular and Metabolic Benefits
Metformin is associated with reduced major cardiovascular events and demonstrated a 36% reduction in all-cause mortality and 39% reduction in myocardial infarction in the UKPDS, establishing cardiovascular benefits beyond glucose lowering 5
The drug improves lipid profiles by decreasing LDL cholesterol and triglyceride levels 4, 6
Metformin is weight neutral or promotes modest weight reduction, a critical advantage over many other diabetes medications 4, 7
Dosing and Administration Strategy
Start with 500 mg once or twice daily with meals, then gradually titrate upward over 2-4 weeks to minimize gastrointestinal side effects 4, 8
Extended-release formulations improve tolerability by reducing gastrointestinal symptoms while maintaining equivalent efficacy 4, 8
Maximum effective doses typically range up to 2000-2550 mg daily, though absorption decreases with higher doses 2
Absolute Contraindications
Do not prescribe metformin in patients with:
Severe renal impairment (eGFR <30 mL/min/1.73 m²) due to lactic acidosis risk 4, 8, 2
Acute or chronic metabolic acidosis, including diabetic ketoacidosis 2
Acute congestive heart failure requiring pharmacologic treatment 2
Hypoxemic conditions or severe infections 4
History of hypersensitivity to metformin 2
Renal Function Monitoring and Dose Adjustment
Dose reduction is required when eGFR falls to 30-45 mL/min/1.73 m², and metformin must be discontinued if eGFR drops below 30 mL/min/1.73 m² 4, 8
Regular monitoring of renal function is mandatory, particularly in patients with borderline kidney function or those at risk for deterioration 8
In patients over 80 years of age, do not initiate metformin unless renal function has been verified as normal 2
Managing Common Side Effects
Gastrointestinal intolerance:
Abdominal discomfort, bloating, nausea, and diarrhea occur commonly but can be mitigated through gradual dose titration 4, 8
Always administer metformin with meals to reduce GI symptoms 2
Switch to extended-release formulations if standard formulations are not tolerated 4, 8
Vitamin B12 deficiency:
Long-term metformin use may cause vitamin B12 deficiency, requiring periodic monitoring especially in patients with anemia or peripheral neuropathy 4, 8
Supplement with vitamin B12 if deficiency is detected 8
Lactic Acidosis Risk
Lactic acidosis is rare (less than 1 case per 100,000 treated patients) when contraindications are respected 5
Temporarily discontinue metformin before procedures involving iodinated contrast agents or surgery where oral intake will be restricted, then restart only after confirming normal renal function 2
Avoid metformin in patients with conditions predisposing to lactic acidosis: severe dehydration, sepsis, acute myocardial infarction, or excessive alcohol use 2
When to Escalate Beyond Metformin Monotherapy
If baseline HbA1c is ≥9.0%, consider starting combination therapy immediately as monotherapy has low probability of achieving near-normal targets 1
If HbA1c is ≥10.0-12.0% with hyperglycemic symptoms, plasma glucose >300-350 mg/dL, or any ketonuria is present, initiate insulin therapy immediately (with or without metformin) 1
After metformin, add 1-2 additional oral or injectable agents based on patient-specific factors, aiming to minimize side effects 1
Special Populations
In premenopausal anovulatory women, metformin may restore ovulation and lead to unintended pregnancy; counsel accordingly 2
Metformin effectively lowers glucose in children ages 10-16 years with type 2 diabetes, though it has not been studied in children under 10 years 2
Safety during pregnancy and breastfeeding is not fully established; discuss alternative glucose control strategies with pregnant or nursing patients 2