Dapagliflozin

Usage

Dapagliflozin is prescribed for:

• Type 2 Diabetes Mellitus (T2DM): As an adjunct to diet and exercise to improve glycemic control in adults and children 10 years and older.
• Heart Failure (HF): To reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adults with HF (with reduced or preserved ejection fraction).
• Chronic Kidney Disease (CKD): To reduce the risk of sustained eGFR decline, end-stage kidney disease (ESKD), cardiovascular death, and hospitalization for heart failure in adults with CKD at risk of progression.

Pharmacological Classification: Sodium-glucose co-transporter 2 (SGLT2) inhibitor.

Mechanism of Action: Dapagliflozin inhibits SGLT2 in the kidneys, blocking glucose reabsorption and increasing urinary glucose excretion, thereby lowering blood glucose levels.

Alternate Names

International Nonproprietary Name (INN): Dapagliflozin

Brand Names: Farxiga, Forxiga (EU), Xigduo (in combination with metformin), Qtern (in combination with saxagliptin)

How It Works

Pharmacodynamics: Dapagliflozin primarily lowers blood glucose levels by increasing urinary glucose excretion. It has a mild diuretic effect and can also reduce blood pressure. It doesn’t stimulate insulin secretion or increase insulin sensitivity.

Pharmacokinetics:

• Absorption: Dapagliflozin is well-absorbed orally, with bioavailability of 78%. Food can delay absorption but doesn’t significantly affect overall exposure.
• Metabolism: Primarily metabolized to dapagliflozin 3-O-glucuronide, an inactive metabolite. Dapagliflozin is a substrate for uridine 5’-diphospho-glucuronosyltransferase (UGT)1A9 and a weak substrate for P-glycoprotein (P-gp) transporter.
• Elimination: Primarily excreted in the urine (75%) and feces (21%), mostly as the inactive metabolite. Elimination half-life is about 12.8 hours.

Mode of Action: Dapagliflozin selectively inhibits SGLT2 in the renal proximal tubule. SGLT2 is responsible for the majority of glucose reabsorption from the glomerular filtrate. By inhibiting SGLT2, dapagliflozin prevents glucose reabsorption, leading to increased urinary glucose excretion and lower blood glucose levels.

Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Dapagliflozin’s primary mechanism is through SGLT2 inhibition. It does not directly bind to other receptors, inhibit enzymes, or modulate neurotransmitters.

Elimination Pathways: Primarily renal excretion, both as unchanged drug and as dapagliflozin 3-O-glucuronide.

Dosage

Standard Dosage

Adults:

• T2DM: Initial: 5 mg orally once daily; may increase to 10 mg once daily for additional glycemic control.
• HF & CKD: 10 mg orally once daily.

Children (T2DM, ≥10 years):

• Initial: 5 mg orally once daily; may increase to 10 mg once daily for additional glycemic control.
• Safety and efficacy in children <10 years haven’t been established.

Special Cases:

• Elderly Patients (≥65 years): No dosage adjustment based on age alone, but consider renal function and volume depletion risk. Initiation not recommended for those ≥75 years due to limited data.
• Patients with Renal Impairment:
  • eGFR ≥45 mL/min/1.73 m²: No dosage adjustment.
  • eGFR 25 to <45 mL/min/1.73 m²: For T2DM, not recommended. For HF and CKD, no dosage adjustment.
  • eGFR <25 mL/min/1.73 m²: Initiation not recommended. Patients with HF or CKD may continue at 10 mg/day to reduce the risk of progression, but with careful monitoring.
  • ESRD/Dialysis: Contraindicated.
• Patients with Hepatic Dysfunction:
  • Mild or moderate: No dosage adjustment.
  • Severe: Start with 5 mg; if tolerated, may increase to 10 mg.
• Patients with Comorbid Conditions: Individualize dosage based on patient’s specific conditions (e.g., diabetes, cardiovascular disease).

Clinical Use Cases

Dapagliflozin’s clinical use is centered around chronic conditions like T2DM, HF, and CKD. It is not indicated for acute situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations (e.g., cardiac arrest). Temporarily discontinue for at least 3 days before major surgery. Resume when patient is clinically stable and oral intake is resumed.

Dosage Adjustments

Dose adjustments may be necessary based on renal function, hepatic dysfunction, and other patient-specific factors. Close monitoring for adverse events is essential, especially during dose adjustment.

Side Effects

Common Side Effects:

• Genital mycotic infections (vulvovaginitis, balanitis)
• Urinary tract infections (UTIs)
• Increased urination (polyuria), including nocturia
• Nasopharyngitis
• Back pain

Rare but Serious Side Effects:

• Diabetic ketoacidosis (DKA), particularly in T1DM or patients with predisposing factors
• Dehydration, including hypotension and orthostatic hypotension
• Acute kidney injury
• Necrotizing fasciitis of the perineum (Fournier’s gangrene)

Long-Term Effects:

• Potential for bone fractures with long-term use

Adverse Drug Reactions (ADR):

• Angioedema
• Hypersensitivity reactions

Contraindications

• Hypersensitivity to dapagliflozin
• Type 1 diabetes mellitus
• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• End-stage renal disease (ESRD)
• Patients on dialysis

Drug Interactions

• Diuretics: Increased risk of dehydration and hypotension.
• Insulin and Insulin Secretagogues (e.g., sulfonylureas): Increased risk of hypoglycemia.
• CYP450 Inducers/Inhibitors: Minimal interaction via CYP450 pathway. Dapagliflozin is primarily metabolized by UGT1A9.
• Other Medications: Potential interactions with medications that lower blood pressure or affect renal function should be monitored.

Pregnancy and Breastfeeding

• Pregnancy: Not recommended during the second and third trimesters. Limited data in first trimester. Use with caution.
• Breastfeeding: Not recommended due to potential risk to the infant.

Drug Profile Summary

• Mechanism of Action: SGLT2 inhibitor; increases urinary glucose excretion, lowers blood glucose.
• Side Effects: UTIs, genital mycotic infections, increased urination, nasopharyngitis, back pain. Serious side effects include DKA, dehydration, kidney injury.
• Contraindications: Type 1 diabetes, severe renal impairment/ESRD/dialysis, hypersensitivity.
• Drug Interactions: Diuretics, insulin/sulfonylureas, other antihypertensives.
• Pregnancy & Breastfeeding: Not recommended.
• Dosage: T2DM: 5-10 mg once daily; HF/CKD: 10 mg once daily.
• Monitoring Parameters: Renal function (eGFR, creatinine), blood glucose, blood pressure, ketones (especially in patients at risk of DKA), electrolytes.

Popular Combinations

• Metformin: Dapagliflozin + metformin (Xigduo) is a common combination for T2DM. It offers synergistic effects on glycemic control.
• Saxagliptin: Dapagliflozin + saxagliptin (Qtern) is another combination for T2DM.

Precautions

• Monitor renal function, blood glucose, blood pressure, and electrolytes.
• Assess for risk factors for DKA and monitor ketones if needed.
• Ensure adequate hydration.
• Educate patients about signs and symptoms of side effects.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Dapagliflozin?

A: For T2DM: Initial dose 5 mg once daily, may increase to 10 mg. HF/CKD: 10 mg once daily. Pediatric (≥10 years, T2DM): 5 mg once daily, may increase to 10 mg.

Q2: How does Dapagliflozin work?

A: It inhibits SGLT2 in the kidneys, blocking glucose reabsorption and increasing urinary glucose excretion.

Q3: What are the common side effects of Dapagliflozin?

A: Genital mycotic infections, UTIs, increased urination, nasopharyngitis, back pain.

Q4: Is Dapagliflozin safe in pregnancy?

A: Not recommended during the second and third trimesters. Use with caution in the first trimester.

Q5: Can Dapagliflozin be used in patients with renal impairment?

A: Dosage adjustments or avoidance may be necessary depending on the degree of impairment. It’s contraindicated in severe renal impairment, ESRD, and patients on dialysis.

Q6: What are the serious side effects of Dapagliflozin?

A: DKA (especially in patients with T1DM or predisposing factors), dehydration, acute kidney injury, Fournier’s gangrene.

Q7: How should Dapagliflozin be taken?

A: Orally, once daily, with or without food.

Q8: Does Dapagliflozin interact with other medications?

A: Yes. It can interact with diuretics, insulin/insulin secretagogues, and some antihypertensives. Provide a complete medication history to your doctor before starting Dapagliflozin.

Q9: What should be monitored in patients taking Dapagliflozin?

A: Renal function (eGFR, creatinine), blood glucose, blood pressure, ketones (especially in patients at risk for DKA) and electrolytes.