What is Xigduo?
Xigduo is a fixed-dose combination oral medication containing dapagliflozin (an SGLT2 inhibitor) and metformin, used for the treatment of type 2 diabetes mellitus. 1, 2
Mechanism of Action
The combination provides complementary glucose-lowering effects through two distinct pathways:
Dapagliflozin blocks the sodium-glucose cotransporter-2 (SGLT2) in the kidney, preventing reabsorption of filtered glucose and increasing urinary glucose excretion, thereby lowering blood glucose levels independently of insulin secretion or sensitivity 3, 4
Metformin decreases hepatic glucose production and improves insulin sensitivity, primarily targeting insulin resistance 5, 4
Clinical Efficacy
The combination of dapagliflozin and metformin demonstrates robust glycemic control:
Glycemic reduction: Achieves HbA1c reductions of up to 2% when used as combination therapy 6, 7
Weight loss: Produces 2-3 kg weight reduction, a significant advantage over many other diabetes medications 6, 7
Blood pressure: Provides modest systolic blood pressure reductions of 3-5 mmHg 6, 7
Sustained efficacy: Long-term extension studies demonstrate maintained glycemic control and weight reduction for up to 2-4 years 3
Cardiovascular and Renal Benefits
Beyond glucose control, the dapagliflozin component provides proven cardiovascular and kidney protection:
Dapagliflozin has demonstrated benefits in reducing heart failure hospitalizations and slowing chronic kidney disease progression 5
The American Diabetes Association 2025 guidelines recommend SGLT2 inhibitors like dapagliflozin for patients with type 2 diabetes who have established cardiovascular disease, heart failure, or chronic kidney disease, independent of baseline HbA1c 5
KDIGO 2022 guidelines recommend SGLT2 inhibitors be initiated when eGFR ≥20 mL/min/1.73 m² and continued until dialysis or transplantation 5
Dosing and Administration
Available as extended-release (XR) formulation that can be administered once daily, improving medication adherence 6
The glucose-lowering effect of dapagliflozin is minimal at eGFR <45 mL/min/1.73 m², but should be continued for cardiovascular and kidney benefits until dialysis or transplantation 5
Metformin is contraindicated when eGFR <30 mL/min/1.73 m² 5, 8
Safety Profile and Adverse Effects
The combination is generally well tolerated with specific considerations:
Low hypoglycemia risk: Unlike sulfonylureas or insulin, this combination carries minimal risk of hypoglycemia when used without these agents 5, 7
Genital mycotic infections: More frequent with dapagliflozin than placebo; mitigate risk with genital hygiene and avoid in high-risk individuals 5, 3
Urinary tract infections: Reported more frequently in some studies with dapagliflozin 3, 7
Diabetic ketoacidosis (DKA): Rare risk in type 2 diabetes, including euglycemic DKA; discontinue 3-4 days before scheduled surgery, during critical illness, or prolonged fasting 5, 8
Volume depletion: Monitor volume status and blood pressure, particularly when ill or fasting; adjust other volume-contracting agents as needed 5
Metformin-related: Gastrointestinal side effects can be mitigated with slow dose titration, extended-release formulations, and administration with food; monitor for vitamin B12 deficiency 5
Fournier gangrene: Rare necrotizing fasciitis of the perineum; requires prompt treatment if suspected 5
Clinical Positioning
Current guidelines position this combination prominently in type 2 diabetes management:
The American College of Physicians recommends metformin as first-line monotherapy, with addition of a second agent when glycemic targets are not met 5
The 2025 ADA Standards of Care recommend initial combination therapy for patients presenting with HbA1c 1.5-2.0% above target 5
For patients with established cardiovascular disease, heart failure, or chronic kidney disease, SGLT2 inhibitors should be part of the glucose-lowering regimen independent of HbA1c and independent of metformin use 5
Practical Advantages
The fixed-dose combination offers several real-world benefits:
Improved adherence: Single-pill combination reduces pill burden and improves patient compliance compared to taking medications separately 2, 6
Complementary mechanisms: Addresses multiple pathophysiologic defects in type 2 diabetes simultaneously 4, 7
Favorable tolerability profile: Neutral-to-positive effects on weight and low hypoglycemia risk make it well-suited for long-term use 7