What is the recommended initiation protocol for Xigduo (dapagliflozin and metformin)?

Initiating Xigduo (Dapagliflozin/Metformin) Therapy

For patients with type 2 diabetes, Xigduo (dapagliflozin/metformin) should be initiated at the lowest available dose of 5 mg dapagliflozin/500 mg metformin extended-release once daily with the evening meal, followed by gradual dose titration to minimize gastrointestinal side effects. 1, 2

Initial Assessment Before Starting Xigduo

Before initiating Xigduo, perform the following assessments:

• Assess renal function (eGFR)

  • Xigduo is not recommended for glycemic control if eGFR <45 ml/min/1.73 m² 1
  • Dapagliflozin component may be continued for cardiovascular and kidney benefits if eGFR falls below 25 ml/min/1.73 m² 3, 1

• Assess volume status

  • Correct volume depletion before initiating therapy 1
  • SGLT2 inhibitors may cause hypovolemia, especially in patients with reduced kidney function 3

Dosing Protocol

1. Initial dose: Start with Xigduo 5/500 mg once daily with the evening meal 1, 2

2. Titration schedule:

   • Increase by 500 mg metformin every 7 days 4
   • Target dose: Dapagliflozin 10 mg/Metformin 2000 mg daily (divided if needed) 2
   • For patients with eGFR 30-44 ml/min/1.73 m², halve the metformin dose 3, 4

3. Administration timing:

   • Take with food to reduce gastrointestinal side effects 4
   • Extended-release formulation allows for once-daily dosing 4, 5

Special Considerations

Renal Function

• eGFR ≥45 ml/min/1.73 m²: Standard dosing
• eGFR 30-44 ml/min/1.73 m²: Reduce metformin to maximum 1000 mg daily; dapagliflozin 10 mg daily can be used 3
• eGFR <30 ml/min/1.73 m²: Contraindicated for metformin; dapagliflozin not recommended for initiation but may be continued if already started 3, 1

Monitoring Requirements

• Monitor renal function:

  • At baseline
  • Every 3-6 months if eGFR <60 ml/min/1.73 m² 3
  • More frequently during illness or when starting medications that affect kidney function

• Monitor for side effects:

  • Genital mycotic infections (6-14.6% risk with SGLT2 inhibitors vs. 1-5.1% with placebo) 3, 6
  • Urinary tract infections (8-13.3% risk) 6
  • Signs of ketoacidosis (nausea, vomiting, abdominal pain, malaise, shortness of breath) 1
  • Volume depletion symptoms (dizziness, orthostatic hypotension) 3

Potential Adverse Effects and Management

• Gastrointestinal effects (common with metformin):

  • Often transient and resolve within 1-2 weeks 3
  • Taking with food and slow titration minimizes these effects 4

• Genital mycotic infections (increased with dapagliflozin):

  • Daily hygiene measures may reduce risk 3
  • Most infections are easily treated with standard therapy 3

• Hypoglycemia risk:

  • Low when used alone but may increase if combined with insulin or sulfonylureas 3, 6
  • Consider reducing doses of these agents when adding Xigduo 3

• Diabetic ketoacidosis:

  • May occur with minimal to no elevation in blood glucose 3, 1
  • Higher risk in insulin-dependent patients 3
  • Temporarily discontinue before major surgery (at least 3 days prior) 1

Clinical Pearls

• The combination of dapagliflozin and metformin can result in greater HbA1c reductions (up to 2%) than either agent alone 2

• Fixed-dose combination improves medication adherence compared to taking individual components separately 7, 5

• Additional benefits beyond glycemic control include:

  • Weight reduction (2-3 kg) 5
  • Modest blood pressure reduction (3-5 mmHg systolic) 5
  • Cardiovascular and renal benefits 3

• Monitor vitamin B12 levels in patients on metformin for more than 4 years 3

• Initial "eGFR dip" of 3-5 ml/min/1.73 m² is common and generally returns to baseline within weeks 3