What is the first-line drug for type 2 diabetes mellitus (DM2)?

First-Line Drug for Type 2 Diabetes Mellitus (DM2)

Metformin is the first-line pharmacologic therapy for type 2 diabetes when lifestyle modifications have failed to adequately control hyperglycemia. 1

Rationale for Metformin as First-Line Therapy

Metformin offers several advantages as first-line therapy:

• Effective at lowering A1C (can reduce A1C by approximately 1.5%) 2
• Weight neutral or modest weight loss (vs. weight gain with many alternatives) 2, 3
• Low risk of hypoglycemia 1, 3
• Inexpensive and widely available 1
• Long-term cardiovascular benefits demonstrated in clinical trials 3
• Reduces risks of microvascular complications, cardiovascular events, and death 4

Dosing and Administration

• Initial dose: 500mg once or twice daily with food 1
• Gradual titration to minimize gastrointestinal side effects 1
• Available in immediate-release (twice daily) or extended-release (once daily) formulations 4, 5
• Extended-release formulation may improve GI tolerability and adherence 5

Contraindications and Precautions

• Contraindicated in severe renal impairment (eGFR <30 mL/min/1.73 m²) 4, 1
• Use caution in patients with impaired hepatic function or heart failure 4
• May need to temporarily discontinue during procedures, hospitalizations, or acute illness 4
• Monitor vitamin B12 levels in long-term users 4, 1

When Metformin May Not Be Sufficient as Monotherapy

1. High baseline A1C: Patients with A1C ≥9.0% have low probability of achieving near-normal targets with monotherapy 4

2. Significant hyperglycemia at presentation: For patients with:

   • Dramatic hyperglycemia (>300-350 mg/dL)
   • A1C ≥10-12%
   • Significant hyperglycemic symptoms
   • Insulin therapy should be strongly considered from the outset 4

3. Presence of catabolic features or ketonuria: Insulin therapy is mandatory 4

Second-Line Therapy Options (When Metformin Is Insufficient)

When A1C is ≥1.5% above the individualized glycemic goal, consider:

• SGLT2 inhibitors: Preferred for patients with or at high risk for heart failure or kidney disease 1
• GLP-1 receptor agonists: Especially for patients with established cardiovascular disease 1
• Avoid concurrent use of DPP-4 inhibitors with GLP-1 RAs due to lack of additional glucose lowering 4

Special Considerations

• Older adults: Consider medication classes with low risk of hypoglycemia; simplification of complex treatment plans may be necessary 4
• Cardiovascular disease: Add SGLT2 inhibitor or GLP-1 receptor agonist with proven cardiovascular benefit 1
• Heart failure or kidney disease: SGLT2 inhibitors are preferred 1

Monitoring and Follow-Up

• Reassess HbA1c in 3 months to evaluate treatment effectiveness 1
• Monitor renal function regularly, especially in patients at risk for kidney disease 1
• Check vitamin B12 levels in long-term metformin users 4, 1

Metformin remains the cornerstone of type 2 diabetes management due to its proven efficacy, safety profile, and cost-effectiveness, despite the emergence of newer agents with cardiovascular and renal benefits.