Dapagliflozin

1. Drug Name

• Generic Name: Dapagliflozin

• Brand Names: Farxiga, Forxiga (varies by region)

2. Drug Classification

• Class: Antidiabetic Agent

• Subclass: Sodium-glucose co-transporter 2 (SGLT2) Inhibitor

3. Mechanism of Action

Dapagliflozin is a selective inhibitor of the sodium-glucose co-transporter 2 (SGLT2) located in the proximal renal tubules. SGLT2 is responsible for reabsorbing glucose from the urine back into the bloodstream. By inhibiting this transporter, dapagliflozin reduces the renal reabsorption of glucose, leading to increased urinary excretion of glucose (glucosuria) and a reduction in blood glucose levels.

This action is independent of insulin secretion or sensitivity, making it effective in patients with both insulin-sensitive and insulin-resistant forms of type 2 diabetes. Additionally, by lowering blood glucose levels, dapagliflozin helps in reducing hemoglobin A1c (HbA1c) levels without significant risk of hypoglycemia.

Dapagliflozin also has effects beyond glucose control, including reducing blood pressure and promoting weight loss, which can be beneficial for patients with type 2 diabetes and those with heart failure or chronic kidney disease (CKD).

4. Pharmacokinetics

• Absorption: Dapagliflozin is well absorbed after oral administration, with a bioavailability of approximately 78%. Peak plasma concentrations are reached within 1 hour of dosing.

• Distribution: The volume of distribution (Vd) is approximately 118 L, indicating wide distribution throughout the body. Dapagliflozin is 91% protein-bound in plasma.

• Metabolism: Dapagliflozin is extensively metabolized in the liver, mainly via UGT1A9-mediated glucuronidation to an inactive metabolite. A small proportion of the drug is metabolized via CYP3A4, but this is not considered a major pathway.

• Excretion: The elimination half-life of dapagliflozin is approximately 13 hours. It is excreted primarily in the urine (approximately 75%) and to a lesser extent in the feces.

• Special Considerations:

  • Renal Impairment: Dapagliflozin is contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease.

  • Hepatic Impairment: Dose adjustments are not necessary in mild to moderate hepatic impairment, but caution is advised in severe hepatic impairment.

5. Indications

• Primary Indications:

  • Type 2 Diabetes Mellitus: Dapagliflozin is indicated as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes, either as monotherapy or in combination with other antidiabetic agents (e.g., metformin, sulfonylureas, insulin).

  • Heart Failure (HFrEF and HFpEF): Dapagliflozin is used to reduce the risk of hospitalization for heart failure and cardiovascular death in adults with heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF).

  • Chronic Kidney Disease (CKD): Dapagliflozin is indicated to reduce the risk of kidney function decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in patients with chronic kidney disease (CKD), especially those with albuminuria.

• Off-label Uses:

  • May be used off-label for weight management in obese patients with or without diabetes, due to its ability to promote weight loss through increased glucosuria.

• Specific Populations: Dapagliflozin is particularly beneficial in patients with type 2 diabetes who also have cardiovascular disease, heart failure, or chronic kidney disease.

6. Dosage and Administration

• Adult Dosing:

  • For Type 2 Diabetes Mellitus: 5 mg once daily in the morning, with or without food. The dose may be increased to 10 mg once daily depending on the patient's response and tolerability.

  • For Heart Failure and Chronic Kidney Disease: 10 mg once daily.

• Renal Impairment Dosing:

  • eGFR <30 mL/min/1.73 m²: Contraindicated.

  • eGFR ≥30 mL/min/1.73 m²: No dose adjustment needed.

• Pediatric Dosing: Dapagliflozin is not approved for use in children under 18 years of age.

• Administration: Can be taken with or without food, preferably in the morning.

7. Contraindications

• Absolute Contraindications:

  • Severe renal impairment (eGFR <30 mL/min/1.73 m²), end-stage renal disease, or dialysis.

  • Hypersensitivity to dapagliflozin or any of its components.

• Relative Contraindications:

  • History of severe hypersensitivity reactions (e.g., anaphylaxis, angioedema).

  • Caution in patients with a history of diabetic ketoacidosis (DKA), as SGLT2 inhibitors may increase the risk of ketoacidosis, particularly in insulin-treated patients.

8. Warnings and Precautions

• Volume Depletion and Hypotension: Dapagliflozin can lead to dehydration and hypotension, particularly in patients with low blood pressure, elderly individuals, and those on diuretics. Proper hydration should be ensured, and blood pressure should be monitored.

• Diabetic Ketoacidosis (DKA): SGLT2 inhibitors, including dapagliflozin, have been associated with an increased risk of DKA, even in the absence of significantly elevated blood glucose levels. It is important to monitor for symptoms of ketoacidosis (e.g., nausea, vomiting, abdominal pain, shortness of breath).

• Acute Kidney Injury (AKI): Dapagliflozin may cause or worsen kidney function decline, particularly in patients with pre-existing renal disease or those who are volume-depleted. Renal function should be monitored regularly.

• Urinary Tract Infections (UTIs) and Genital Infections: Increased risk of UTIs and genital mycotic infections (e.g., yeast infections) has been reported. Patients should be advised to report any symptoms of these infections.

• Bone Fractures: There is a potential risk of bone fractures with long-term use of dapagliflozin, possibly due to decreased bone mineral density. Bone health should be monitored.

9. Adverse Effects

• Common Adverse Effects (≥10%):

  • Urinary tract infections (UTIs).

  • Genital infections (e.g., candidiasis).

  • Increased urination.

  • Thirst and dehydration.

• Less Common but Clinically Significant Side Effects:

  • Diabetic ketoacidosis (DKA), especially in insulin-treated patients.

  • Acute kidney injury (AKI), particularly in patients with renal impairment.

  • Hypotension and volume depletion.

• Rare/Serious Adverse Reactions:

  • Serious allergic reactions, including anaphylaxis and angioedema.

  • Necrotizing fasciitis of the perineum (Fournier's gangrene).

  • Bone fractures with long-term use.

10. Drug Interactions

• Major Drug Interactions:

  • Diuretics (e.g., furosemide, hydrochlorothiazide): Increase the risk of dehydration, hypotension, and kidney injury. Careful monitoring is required.

  • ACE inhibitors/Angiotensin II Receptor Blockers (ARBs): Concomitant use may increase the risk of hypotension, dehydration, and kidney impairment. Monitor renal function and blood pressure.

  • Insulin and Insulin Secretagogues: Co-administration may increase the risk of hypoglycemia. Blood glucose levels should be monitored, and insulin dose adjustments may be necessary.

• Food Interactions: Dapagliflozin can be taken with or without food. No significant food-drug interactions are known.

• Lab Test Interactions: Dapagliflozin may cause increased levels of serum creatinine, potentially indicating a decline in renal function. It can also increase uric acid levels.

11. Clinical Pharmacology

• Pharmacodynamics: Dapagliflozin works by inhibiting SGLT2, reducing glucose reabsorption in the kidneys and promoting glucosuria. This leads to a reduction in blood glucose levels without significant risk of hypoglycemia.

• Additional Pharmacological Effects: Dapagliflozin reduces blood pressure, promotes modest weight loss, and has beneficial effects on kidney function, especially in patients with CKD. It also has a protective effect on the heart, reducing hospitalizations for heart failure.

12. Special Populations

• Pregnancy: Category C. Dapagliflozin should only be used during pregnancy if the potential benefits justify the potential risks to the fetus. Insulin is preferred for managing blood glucose in pregnant women.

• Lactation: Dapagliflozin is excreted in breast milk, but its effects on a nursing infant are unknown. Caution should be exercised when using dapagliflozin in breastfeeding women.

• Geriatrics: Elderly patients may be more susceptible to volume depletion, hypotension, and renal impairment. Dose adjustments may be necessary.

• Renal and Hepatic Dysfunction: Dapagliflozin is contraindicated in severe renal impairment (eGFR <30 mL/min/1.73 m²). No dose adjustments are necessary for mild to moderate renal impairment or hepatic dysfunction.

13. Therapeutic Uses

• Type 2 Diabetes Mellitus: Dapagliflozin is used as an adjunct to diet and exercise to improve blood glucose control, either as monotherapy or in combination with other antidiabetic agents.

• Heart Failure (HFrEF and HFpEF): Used to reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure.

• Chronic Kidney Disease: Dapagliflozin is used to reduce the risk of disease progression in patients with chronic kidney disease, especially those with albuminuria.

14. Monitoring and Follow-Up

• Recommended Lab Tests: Renal function (serum creatinine, eGFR), blood glucose levels, HbA1c, blood pressure.

• Patient-Reported Symptoms: Monitor for signs of dehydration, hypotension, UTI, genital infections, and symptoms of DKA.

• Monitoring of Therapeutic and Toxic Levels: Regular monitoring of kidney function and blood glucose is essential to optimize therapy and reduce risks.

15. Overdose Management

• Symptoms of Overdose: Symptoms may include dehydration, hypotension, and hypoglycemia.

• Treatment Protocols: There is no specific antidote for dapagliflozin overdose. Symptomatic treatment should be provided, including intravenous fluids for dehydration, correction of electrolyte imbalances, and glucose administration if hypoglycemia occurs.

• Supportive Measures: Continuous monitoring of renal function and blood glucose is essential in overdose situations.

16. Patient Counseling Information

• Key Points:

  • Take dapagliflozin as prescribed, with or without food.

  • Be aware of the signs of dehydration (e.g., dizziness, fainting) and urinary tract/genital infections.

  • Seek immediate medical attention if you experience symptoms of DKA (e.g., nausea, vomiting, abdominal pain).

  • Maintain a healthy diet and regular exercise program to optimize blood sugar control.