Dapagliflozin + Metformin

Usage

• Dapagliflozin + Metformin is prescribed as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It’s also used to lower the risk of hospitalization for heart failure in patients with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors. Additionally, it’s indicated to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in patients with heart failure with reduced ejection fraction, and to lower the risk of worsening of kidney disease, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in patients with chronic kidney disease. It is not indicated for type 1 diabetes.
• Pharmacological Classification: Antidiabetic combination; SGLT2 inhibitor + Biguanide
• Mechanism of Action: Dapagliflozin inhibits sodium-glucose co-transporter 2 (SGLT2) in the kidneys, increasing urinary glucose excretion and lowering blood glucose levels. Metformin decreases hepatic glucose production, reduces intestinal glucose absorption, and improves insulin sensitivity.

Alternate Names

• While there isn’t a true “alternate name,” Dapagliflozin and Metformin are often referred to as an “SGLT2 inhibitor/Biguanide combination.”
• Brand Names: Xigduo XR, Xigduo.

How It Works

• Pharmacodynamics: Dapagliflozin works independently of insulin to promote urinary glucose excretion. Metformin reduces hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. The combination has additive effects on lowering blood glucose.
• Pharmacokinetics:
  • Dapagliflozin: Orally administered dapagliflozin is rapidly absorbed, achieving peak plasma concentrations within 2 hours. It is approximately 91% protein-bound, primarily to albumin. It is mainly metabolized via glucuronidation by uridine 5’-diphospho-glucuronosyltransferase (UGT)1A9, with a minor contribution from CYP2C9. It is eliminated through both urinary and fecal excretion, mostly as metabolites.
  • Metformin: Metformin is absorbed slowly and incompletely from the gastrointestinal tract after oral administration. It is minimally protein-bound and distributes widely to tissues. It is not metabolized and is eliminated primarily through renal excretion.
• Mode of Action: Dapagliflozin inhibits SGLT2 in the renal proximal tubules, preventing glucose reabsorption and leading to glucosuria. Metformin’s precise mechanism is unclear but involves inhibition of mitochondrial respiratory chain complex 1, activation of AMP-activated protein kinase (AMPK), and possibly changes in gut microbiota.
• Receptor Binding/Enzyme Inhibition: Dapagliflozin specifically targets SGLT2. Metformin’s action involves multiple pathways, including AMPK activation and modulation of mitochondrial function.
• Elimination Pathways: Dapagliflozin is primarily excreted via urine (75%) and feces (21%), primarily as dapagliflozin 3-O-glucuronide. Metformin is excreted unchanged in the urine.

Dosage

Standard Dosage

Adults:

• Initial dose: Dapagliflozin 5 mg + Metformin 500 mg or 1000 mg orally once daily with a meal, or as directed by the physician.
• Maintenance dose: May be adjusted based on efficacy and tolerability up to a maximum of Dapagliflozin 10 mg + Metformin 2000 mg per day. If taking an evening dose of metformin XR, skip the last dose before starting the combination therapy. For patients requiring 5 mg dapagliflozin and 2000 mg metformin extended release, use two of the 2.5 mg dapagliflozin / 1000 mg metformin XR tablets.

Children:

• Not recommended for use in children under 18 years of age.

Special Cases:

• Elderly Patients: Initiate and titrate cautiously due to potential age-related decline in renal function. Monitor renal function closely.
• Patients with Renal Impairment: Contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²). Not recommended for initiation in patients with eGFR <45 mL/min/1.73 m². Maximum daily dose for eGFR 30 - 45 mL/min/1.73 m² is 10 mg dapagliflozin and 1000 mg metformin.
• Patients with Hepatic Dysfunction: Not recommended in patients with hepatic impairment due to the presence of metformin.
• Patients with Comorbid Conditions: Assess for volume depletion before initiating therapy and correct if present. Use with caution in patients with a history of heart failure.

Clinical Use Cases

Dapagliflozin + Metformin is not typically indicated for the acute medical settings listed below.

• Intubation: Not applicable.
• Surgical Procedures: Temporarily discontinue before surgeries or procedures requiring iodinated contrast media.
• Mechanical Ventilation: Not applicable.
• Intensive Care Unit (ICU) Use: Not typically used.
• Emergency Situations: Not applicable.

Dosage Adjustments

• Adjust dosage based on renal function and individual patient response.

Side Effects

Common Side Effects:

• Genital mycotic infections (e.g., vulvovaginitis, balanitis)
• Urinary tract infections
• Nasopharyngitis
• Nausea, diarrhea
• Increased urination
• Headache, back pain

Rare but Serious Side Effects:

• Diabetic ketoacidosis (DKA)
• Lactic acidosis (with Metformin)
• Severe hypoglycemia (especially with insulin or sulfonylurea co-administration)
• Acute kidney injury
• Necrotizing fasciitis of the perineum (Fournier’s gangrene)
• Serious hypersensitivity reactions (angioedema, anaphylaxis)

Long-Term Effects:

• Vitamin B12 deficiency (with Metformin)
• Fractures (with Metformin)

Adverse Drug Reactions (ADR):

• Any signs of DKA, lactic acidosis, urosepsis or pyelonephritis, severe hypoglycemia or hypersensitivity should be immediately investigated and the drug discontinued if deemed to be causative.

Contraindications

• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• End-stage renal disease or patients on dialysis
• History of serious hypersensitivity to either drug component
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis
• Type 1 Diabetes

Drug Interactions

• Insulin and other antidiabetic agents (additive hypoglycemic effects)
• Carbonic anhydrase inhibitors (e.g., topiramate, acetazolamide; increased risk of DKA)
• Diuretics, especially loop diuretics (increased risk of Metformin-related lactic acidosis due to potential for decreased renal function)
• Cationic drugs (e.g., cimetidine) (reduced renal clearance of Metformin)
• Alcohol (increased risk of lactic acidosis)

Pregnancy and Breastfeeding

• Pregnancy: Not recommended, especially during the second and third trimesters. May cause fetal harm.
• Breastfeeding: Not recommended. Metformin is present in human milk and it is unknown if dapagliflozin is present in human milk.

Drug Profile Summary

• Mechanism of Action: SGLT2 inhibition (Dapagliflozin), reduced hepatic glucose production, decreased intestinal glucose absorption, and increased insulin sensitivity (Metformin).
• Side Effects: Genital mycotic infections, urinary tract infections, nasopharyngitis, nausea, diarrhea, increased urination. Serious effects: DKA, lactic acidosis, acute kidney injury.
• Contraindications: Severe renal impairment, end-stage renal disease, hypersensitivity, metabolic acidosis.
• Drug Interactions: Insulin, sulfonylureas, other antidiabetic agents, diuretics, alcohol.
• Pregnancy & Breastfeeding: Not recommended.
• Dosage: Adults: Initial: Dapagliflozin 5 mg + Metformin 500 mg or 1000 mg once daily, Max: Dapagliflozin 10 mg + Metformin 2000 mg daily.
• Monitoring Parameters: eGFR, blood glucose, HbA1c, signs of volume depletion, ketones, serum lactate, vitamin B12 levels.

Popular Combinations

• Dapagliflozin + Metformin is frequently used as a standalone combination. When combined with other agents, insulin or sulfonylureas are often added.

Precautions

• General Precautions: Monitor renal function (eGFR) before initiation, at least annually, and more frequently in at-risk populations (elderly). Assess volume status and correct volume depletion before initiating treatment. Monitor for signs of DKA and lactic acidosis.
• Specific Populations:
  • Pregnant Women: Avoid use, particularly in the second and third trimesters.
  • Breastfeeding Mothers: Avoid use.
  • Children & Elderly: Not recommended for children under 18. Use with caution in the elderly, initiating at lower doses and titrating carefully.
  • Menstruating Individuals: This combination may restore ovulation in some premenopausal anovulatory women and increase the risk of unintended pregnancy.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Dapagliflozin + Metformin?

A: The initial dosage is typically Dapagliflozin 5 mg + Metformin 500 or 1000 mg once daily. The maximum daily dose is Dapagliflozin 10 mg + Metformin 2000 mg.

Q2: How does Dapagliflozin + Metformin differ from other antidiabetic medications?

A: This combination includes drugs from two distinct antidiabetic classes, targeting different mechanisms to improve glycemic control. It offers renal and cardiovascular benefits lacking in some other agents.

Q3: What are the major side effects to be aware of?

A: The most frequent side effects are genital mycotic infections and urinary tract infections. Serious but rare side effects are DKA, lactic acidosis, and acute kidney injury.

Q4: Can Dapagliflozin + Metformin be used in patients with renal impairment?

A: It’s contraindicated in severe renal impairment (eGFR <30 mL/min/1.73 m²). Dosage adjustments are necessary in moderate impairment, and initiation isn’t recommended with an eGFR <45 mL/min/1.73 m².

Q5: What are the key drug interactions?

A: Interactions can occur with insulin, sulfonylureas, other antidiabetic agents, carbonic anhydrase inhibitors, diuretics, and alcohol, potentially leading to hypoglycemia or lactic acidosis.

Q6: Can this combination be used during pregnancy or breastfeeding?

A: It’s generally not recommended during pregnancy, especially in the second and third trimesters, and during breastfeeding due to potential risks to the fetus or infant.

Q7: What monitoring parameters are crucial for patients taking Dapagliflozin + Metformin?

A: Close monitoring of renal function (eGFR), blood glucose, HbA1c, volume status, signs of dehydration, ketones, serum lactate, and vitamin B12 levels are essential.

Q8: What patient education points are essential when prescribing this medication?

A: Patients should be educated on signs/symptoms of hypoglycemia, hyperglycemia, urinary tract infections, genital mycotic infections, DKA, and lactic acidosis. Stress the importance of adherence to diet and exercise, regular monitoring, and reporting any unusual symptoms.

Q9: Are there any specific precautions for elderly patients?

A: Yes, elderly patients should be started on lower doses and titrated carefully with close monitoring of renal function due to the increased risk of age-related renal impairment and potential for lactic acidosis.