First-Line Drug for Type 2 Diabetes
Metformin is the first-line pharmacologic agent for type 2 diabetes mellitus and should be initiated at diagnosis alongside lifestyle modifications, unless contraindicated. 1, 2, 3
Why Metformin is First-Line
The American Diabetes Association explicitly recommends metformin as the preferred initial pharmacologic agent for type 2 diabetes and should be continued as long as tolerated and not contraindicated. 1, 2
Metformin reduces cardiovascular events and mortality risk—the UKPDS demonstrated a 36% relative risk reduction in all-cause mortality and 39% reduction in myocardial infarction. 4
Metformin is effective (reduces HbA1c by approximately 1.4-1.5%), safe, economical, and achieves glycemic control without weight gain or significant hypoglycemia risk. 2, 5, 4
Compared to sulfonylureas as first-line therapy, metformin demonstrates superior effects on HbA1c, weight, and cardiovascular mortality. 2
Practical Dosing Strategy
Start metformin at 500 mg once or twice daily with meals to minimize gastrointestinal side effects. 1
Titrate by 500 mg increments every 7 days until reaching the target dose of 1000 mg twice daily (2000 mg total daily), which is the maximum recommended dose for most patients. 1
Extended-release formulations can be dosed once daily with the evening meal, improving adherence while providing equivalent efficacy. 1
If gastrointestinal side effects occur during titration, decrease to the previous lower dose and attempt advancement later. 1
Critical Renal Function Considerations
For eGFR ≥60 mL/min/1.73 m²: Continue standard dosing up to 2000 mg daily. 1
For eGFR 45-59 mL/min/1.73 m²: Consider dose reduction in patients at high risk of lactic acidosis. 1
For eGFR 30-44 mL/min/1.73 m²: Reduce dose to 1000 mg daily (half the standard dose). 1
For eGFR <30 mL/min/1.73 m²: Discontinue metformin entirely. 1
Monitor eGFR at least annually in patients with normal renal function, and every 3-6 months when eGFR <60 mL/min/1.73 m². 1
When to Consider Alternatives or Add-On Therapy
For patients with established atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease: Add an SGLT2 inhibitor or GLP-1 receptor agonist with proven cardiovascular benefit to metformin. 6, 3
The ESC guidelines recommend that patients with established ASCVD should be treated with an SGLT2 inhibitor or GLP-1 receptor agonist, typically in addition to metformin. 6
If glycemic targets are not achieved after 3 months at maximum tolerated metformin dose, add a second agent rather than delaying intensification. 1
For patients who cannot tolerate metformin, consider DPP-4 inhibitors (low hypoglycemia risk, weight neutral), SGLT2 inhibitors (cardiovascular and renal benefits), or GLP-1 receptor agonists (high efficacy, weight loss) based on patient-specific factors. 7
Important Safety Monitoring
Check vitamin B12 levels periodically, especially in patients treated with metformin for more than 4 years or those with anemia or peripheral neuropathy. 1, 2
Temporarily discontinue metformin before procedures using iodinated contrast, during hospitalizations, and when acute illness may compromise renal or liver function. 1
Metformin is contraindicated in patients with hypovolemia, sepsis, liver insufficiency, respiratory insufficiency, or acute heart failure due to increased lactic acidosis risk. 8
Common Pitfalls to Avoid
Do not delay metformin initiation—it should be started at diagnosis, not after lifestyle modifications have "failed." 2
Do not avoid metformin in patients with mild-to-moderate renal impairment (eGFR 30-60 mL/min/1.73 m²) with appropriate dose adjustment. 1, 8
Do not discontinue metformin when adding other agents, including insulin, as long as it remains tolerated and not contraindicated. 1
Gastrointestinal side effects are common but usually resolve with gradual titration or switching to extended-release formulations—do not abandon metformin prematurely. 1, 8