Can metformin, Farxiga (dapagliflozin), and insulin glargine be prescribed together?

Combination Therapy with Metformin, Dapagliflozin, and Insulin Glargine

Yes, metformin, dapagliflozin (Farxiga), and insulin glargine can be safely and effectively prescribed together as a combination therapy for type 2 diabetes. This combination leverages complementary mechanisms of action to achieve glycemic control while providing cardiovascular and renal benefits.

Rationale for Triple Therapy

Metformin as Foundation

• Metformin remains the preferred first-line pharmacological agent for type 2 diabetes 1
• It reduces hepatic gluconeogenesis, improves glucose uptake, and may have protective effects on pancreatic islet cells 2
• Does not cause weight gain and has a low risk of hypoglycemia 2

Adding SGLT2 Inhibitors (Dapagliflozin)

• For patients with established ASCVD, heart failure, or chronic kidney disease, an SGLT2 inhibitor like dapagliflozin is recommended as part of the glucose-lowering plan regardless of A1C level 1
• Provides additional benefits beyond glycemic control:
  • Cardiovascular risk reduction
  • Renal protection
  • Weight loss
  • Low hypoglycemia risk

Adding Insulin Glargine

• When oral agents fail to achieve glycemic targets, basal insulin (like glargine) is an appropriate addition 1
• Particularly indicated when:
  • Blood glucose levels are severely elevated (≥300 mg/dL)
  • A1C >10%
  • Patient has symptoms of hyperglycemia or evidence of catabolism 1

Evidence for Combination Therapy

Metformin + Insulin

• Combination of metformin and insulin improves glycemic control and reduces insulin requirements 3
• The LANMET study showed good glycemic control with insulin glargine plus metformin, with reduced symptomatic hypoglycemia compared to NPH insulin plus metformin 4

Metformin + Dapagliflozin

• The fixed-dose combination provides synergistic effects with complementary mechanisms of action 5
• Results in better glycemic control with potential weight loss and reduced hypoglycemia risk 5

Triple Therapy

• When A1C target is not achieved after approximately 3 months of dual therapy, adding a third agent from another class is appropriate 1
• For patients with established cardiovascular disease or high risk factors, the combination of metformin, SGLT2 inhibitor, and insulin provides comprehensive coverage for glycemic control and cardiovascular protection 1

Dosing and Titration

1. Metformin:

   • Start at low dose (500 mg once or twice daily) and titrate gradually to minimize gastrointestinal side effects
   • Target dose: 2000 mg daily in divided doses
   • Monitor for vitamin B12 deficiency with long-term use 1

2. Dapagliflozin (Farxiga):

   • Typical dose: 10 mg once daily
   • Can be added to existing metformin therapy

3. Insulin Glargine:

   • Starting dose: 10 units per day or 0.1-0.2 units/kg/day 1
   • Titrate by 2-4 units every 3-4 days until fasting glucose target is reached 6
   • Monitor for hypoglycemia, especially during initial titration

Monitoring Recommendations

• Check fasting blood glucose daily during insulin initiation and titration
• Assess A1C after 3 months of therapy
• Monitor for hypoglycemia, especially during insulin dose adjustments
• Assess renal function regularly when using dapagliflozin
• Screen for vitamin B12 deficiency in patients on long-term metformin 1

Potential Pitfalls and Considerations

• Hypoglycemia risk: While metformin and dapagliflozin have low hypoglycemia risk, adding insulin increases this risk. Start with low insulin doses and titrate carefully.
• Volume depletion: SGLT2 inhibitors can cause volume depletion. Ensure adequate hydration, especially in elderly patients.
• Renal function: Both metformin and dapagliflozin require monitoring of renal function. Metformin is safe with eGFR ≥30 mL/min/1.73 m² 1.
• Urinary tract infections: Dapagliflozin may increase risk of genital mycotic infections and UTIs.
• Diabetic ketoacidosis: Rare but serious risk with SGLT2 inhibitors, even with normal blood glucose levels.

Conclusion

The combination of metformin, dapagliflozin, and insulin glargine represents a comprehensive approach to diabetes management that addresses multiple pathophysiological defects. This regimen provides effective glycemic control while offering additional cardiovascular and renal benefits, making it an excellent option for patients with type 2 diabetes who require intensification beyond dual therapy.