What is the second-line oral medication for a patient with type 2 diabetes (T2D) already on metformin?

Second-Line Oral Medication for Type 2 Diabetes After Metformin

For patients with type 2 diabetes already on metformin, an SGLT2 inhibitor or GLP-1 receptor agonist with demonstrated cardiovascular benefit should be added as the second-line medication, especially for those with established cardiovascular disease, heart failure, or chronic kidney disease. 1

Decision Algorithm for Second-Line Therapy

For Patients with Established Cardiovascular Disease:

1. First choice: SGLT2 inhibitor (empagliflozin or canagliflozin)

   • Reduces cardiovascular death by 38% (empagliflozin) 2
   • Reduces major adverse cardiovascular events by 14% 2
   • Reduces hospitalization for heart failure 1
   • Reduces progression of kidney disease 1

2. Alternative: GLP-1 receptor agonist with proven CV benefit

   • Consider if SGLT2 inhibitor is contraindicated or not tolerated
   • Particularly beneficial for patients with atherosclerotic cardiovascular disease 1

For Patients without Established Cardiovascular Disease:

The 2018 ACC Expert Consensus Decision Pathway recommends considering the following factors when selecting a second-line agent 1:

• Cardiovascular risk factors
• Risk of hypoglycemia
• Impact on weight
• Cost
• Side effect profile
• Patient preferences

Specific SGLT2 Inhibitor Options

Empagliflozin has shown significant cardiovascular benefits in the EMPA-REG OUTCOME trial:

• Available in 10mg and 25mg daily doses
• Reduces CV death by 38% and all-cause mortality by 32% 2
• Improves glycemic control, reduces body weight, and lowers blood pressure 3
• Well-tolerated when added to metformin 4

Canagliflozin is another option:

• Available in 100mg and 300mg daily doses
• FDA approved to reduce risk of CV death in adults with T2D and CV disease 1

Dosing Considerations

• For empagliflozin: Start with 10mg daily, may increase to 25mg if needed 1
• For canagliflozin: Start with 100mg daily, may increase to 300mg if eGFR ≥60 mL/min/1.73m² 1

Renal Function Considerations

• SGLT2 inhibitors require dose adjustment based on renal function:
  • Empagliflozin: Do not initiate if eGFR <45 mL/min/1.73m² 1
  • Canagliflozin: Do not exceed 100mg daily if eGFR 45-59 mL/min/1.73m² 1
  • CV benefit appears to persist down to eGFR of 30 mL/min/1.73m² 1

Common Side Effects and Precautions

• Genital mycotic infections (more common with SGLT2 inhibitors) 2
• Urinary tract infections 3
• Volume depletion (monitor blood pressure)
• Rare but serious: diabetic ketoacidosis, Fournier's gangrene

Special Populations

Older Adults:

SGLT2 inhibitors may be particularly beneficial for older patients with T2D:

• Oral administration is convenient 1
• Cardiovascular benefits are similar or greater in older patients 1
• Low risk of hypoglycemia compared to sulfonylureas 1

Patients with Chronic Kidney Disease:

• SGLT2 inhibitors reduce risks of CKD progression and cardiovascular events 1
• GLP-1 RAs are an alternative that may slow CKD progression 1

Important Caveats

1. Avoid SGLT2 inhibitors in patients with history of genital mycotic infections or at high risk for urinary tract infections
2. Use caution in elderly patients at risk for volume depletion or falls
3. Temporary discontinuation may be needed during acute illness or procedures
4. Monitor renal function periodically, especially in at-risk patients

By following this evidence-based approach to selecting a second-line medication after metformin, clinicians can optimize both glycemic control and cardiovascular/renal outcomes in patients with type 2 diabetes.