Introduction
Xigduo XR is a fixed-dose combination medication containing dapagliflozin and metformin hydrochloride extended-release. It represents an important therapeutic option in the management of type 2 diabetes mellitus, combining two complementary mechanisms of action to improve glycemic control. This combination therapy addresses multiple pathophysiological defects in type 2 diabetes while offering the convenience of once-daily dosing.
Mechanism of Action
Xigduo XR exerts its glucose-lowering effects through two distinct mechanisms:
Dapagliflozin: A selective sodium-glucose cotransporter 2 (SGLT2) inhibitor that reduces renal glucose reabsorption in the proximal tubule, promoting glucosuria and thereby lowering plasma glucose concentrations. This insulin-independent mechanism results in the excretion of approximately 70-90 grams of glucose daily at maximum therapeutic doses. Metformin hydrochloride: An biguanide that decreases hepatic glucose production (gluconeogenesis), reduces intestinal glucose absorption, and improves peripheral glucose uptake and utilization by increasing insulin sensitivity. The extended-release formulation provides sustained plasma concentrations over 24 hours.The combination provides complementary mechanisms that address both fasting and postprandial hyperglycemia through different physiological pathways.
Indications
Xigduo XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both dapagliflozin and metformin is appropriate.
Specific clinical scenarios include:- Patients inadequately controlled on metformin alone
- Patients inadequately controlled on dapagliflozin alone
- Patients switching from separate components of dapagliflozin and metformin
- Initial pharmacotherapy for patients with HbA1c significantly above target
Dosage and Administration
Initial Dose: Individualized based on current regimen, renal function, and glycemic control Usual Maintenance Dose: Once daily with evening meal Maximum Recommended Dose: Dapagliflozin 10 mg/metformin 2000 mg daily Dosage Forms Available:- 5 mg/500 mg dapagliflozin/metformin HCl extended-release tablets
- 5 mg/1000 mg dapagliflozin/metformin HCl extended-release tablets
- 10 mg/500 mg dapagliflozin/metformin HCl extended-release tablets
- 10 mg/1000 mg dapagliflozin/metformin HCl extended-release tablets
- Renal impairment: Contraindicated in patients with eGFR <30 mL/min/1.73m²
- eGFR 30-45 mL/min/1.73m²: Not recommended for initiation - eGFR 45-60 mL/min/1.73m²: Monitor frequently
- Hepatic impairment: Use with caution; contraindicated in hepatic disease
- Elderly: Use with caution due to increased risk of adverse reactions
- Pediatric: Safety and effectiveness not established
Pharmacokinetics
Absorption:- Dapagliflozin: Rapid absorption with Tmax of 2 hours; bioavailability ~78%
- Metformin XR: Extended release with Tmax of 7 hours; bioavailability ~50-60%
- Dapagliflozin: Protein binding ~91%; Vd ~118 L
- Metformin: Minimal protein binding; Vd ~654 L
- Dapagliflozin: Primarily via UGT1A9 to inactive metabolites
- Metformin: No significant hepatic metabolism
- Dapagliflozin: Renal (75%) and fecal (21%) excretion; t½ ~12.9 hours
- Metformin: Renal excretion unchanged; t½ ~6.5 hours
Contraindications
1. Severe renal impairment (eGFR <30 mL/min/1.73m²) 2. Acute or chronic metabolic acidosis, including diabetic ketoacidosis 3. History of hypersensitivity reaction to dapagliflozin, metformin, or any component 4. Acute congestive heart failure requiring pharmacological treatment 5. Severe hepatic impairment 6. Conditions associated with hypoxemia or dehydration
Warnings and Precautions
Lactic Acidosis: Rare but serious metabolic complication with metformin; risk factors include renal impairment, congestive heart failure, advanced age, and dehydration Volume Depletion: SGLT2 inhibitors may cause intravascular volume contraction; monitor for signs and symptoms of hypotension Ketoacidosis: Reports of euglycemic diabetic ketoacidosis; monitor for metabolic acidosis in appropriate clinical scenarios Acute Kidney Injury: Cases reported with SGLT2 inhibitors; monitor renal function periodically Urosepsis and Pyelonephritis: Serious urinary tract infections reported Hypoglycemia: Risk increased when used with insulin or insulin secretagogues Genital Mycotic Infections: Higher incidence with SGLT2 inhibitors Vitamin B12 Deficiency: Long-term metformin use associated with reduced B12 absorption Fournier's Gangrene: Rare but serious necrotizing fasciitis of the perineum reportedDrug Interactions
Strongly Interacting Medications:- Carbonic anhydrase inhibitors (topiramate, zonisamide): Increased risk of lactic acidosis
- Alcohol: Excessive consumption potentiates metformin's effect on lactate metabolism
- Cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin): May reduce metformin clearance
- Diuretics: May enhance volume depletion effects
- Insulin/insulin secretagogues: Increased hypoglycemia risk
- Contrast media: Temporary discontinuation may be necessary
- Drugs affecting renal function: May require dosage adjustment
Adverse Effects
Very Common (>10%):- Gastrointestinal disturbances (nausea, vomiting, diarrhea, abdominal pain)
- Headache
- Genital mycotic infections
- Urinary tract infections
- Increased urination
- Back pain
- Dyslipidemia
- Constipation
- Fatigue
- Dizziness
- Hypoglycemia (when combined with other agents)
- Lactic acidosis
- Diabetic ketoacidosis
- Acute kidney injury
- Severe urinary tract infections
- Hypersensitivity reactions
- Fournier's gangrene
- Vitamin B12 deficiency
Monitoring Parameters
Baseline Assessment:- Comprehensive metabolic panel (including renal and hepatic function)
- HbA1c
- Complete blood count
- Volume status assessment
- Urinalysis
- Renal function (eGFR) every 3-6 months
- HbA1c every 3 months until stable, then every 6 months
- Blood glucose self-monitoring
- Signs/symptoms of volume depletion
- Genital hygiene and signs of infection
- Vitamin B12 levels annually in high-risk patients
- Weight and blood pressure
- Symptoms of hypoglycemia
- Signs of urinary or genital infections
- Symptoms of volume depletion (thirst, dizziness, weakness)
Patient Education
Key Points for Safe Use:- Take once daily with the evening meal to reduce gastrointestinal effects
- Swallow tablets whole; do not crush, chew, or split
- Maintain adequate hydration
- Recognize symptoms of hypoglycemia (sweating, shaking, hunger, confusion)
- Report symptoms of urinary tract infections (painful urination, frequency) or genital infections (itching, discharge)
- Immediately report symptoms of lactic acidosis (muscle pain, breathing difficulty, stomach pain, dizziness, slow heartbeat)
- Avoid excessive alcohol consumption
- Inform all healthcare providers about Xigduo XR use before procedures
- Temporary discontinuation may be required before radiologic studies with contrast
- Regular follow-up with healthcare provider is essential
- Not for treatment of type 1 diabetes
- Does not replace lifestyle modifications including diet and exercise
References
1. FDA Prescribing Information: Xigduo XR (dapagliflozin and metformin HCl extended-release) tablets. 2023. 2. American Diabetes Association. Standards of Medical Care in Diabetes—2023. Diabetes Care. 2023;46(Suppl 1):S1-S291. 3. Davies MJ, et al. Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2022;45(11):2753-2786. 4. Qiu R, et al. Dapagliflozin and metformin combination therapy for type 2 diabetes mellitus. Expert Opin Pharmacother. 2021;22(13):1665-1674. 5. Scheen AJ. Dapagliflozin/metformin fixed-dose combination therapy for the treatment of type 2 diabetes. Expert Opin Pharmacother. 2020;21(5):531-541. 6. ClinicalTrials.gov: Studies on dapagliflozin-metformin combination therapy. 7. Package inserts for individual components (Farxiga and Glucophage XR).