Dapagliflozin - Drug Monograph

Introduction

Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor approved by the FDA in 2014 for the management of type 2 diabetes mellitus. More recently, it has received additional indications for heart failure and chronic kidney disease. As a novel antidiabetic agent, dapagliflozin represents a paradigm shift in diabetes management by targeting renal glucose reabsorption rather than insulin secretion or sensitivity.

Mechanism of Action

Dapagliflozin selectively inhibits sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules. SGLT2 is responsible for approximately 90% of glucose reabsorption in the kidneys. By blocking this transporter, dapagliflozin reduces renal glucose reabsorption and increases urinary glucose excretion, resulting in lower blood glucose levels. This insulin-independent mechanism also promotes osmotic diuresis and mild natriuresis, contributing to blood pressure reduction and potential cardiovascular benefits.

Indications

• Type 2 Diabetes Mellitus: As an adjunct to diet and exercise to improve glycemic control
• Heart Failure with Reduced Ejection Fraction (HFrEF): To reduce the risk of cardiovascular death and hospitalization for heart failure in adults with HFrEF
• Chronic Kidney Disease: To reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with CKD at risk of progression
• Heart Failure with Preserved Ejection Fraction (HFpEF): To reduce the risk of cardiovascular death and hospitalization for heart failure in adults with HFpEF

Dosage and Administration

• Renal impairment: Not recommended when eGFR is persistently below 25 mL/min/1.73m² for heart failure indication or below 20 mL/min/1.73m² for CKD indication
• Hepatic impairment: No dosage adjustment necessary
• Elderly: No dosage adjustment necessary, but consider increased risk of volume depletion
• Pediatric: Safety and effectiveness not established

Pharmacokinetics

• Absorption: Rapidly absorbed with peak plasma concentrations achieved within 2 hours under fasting conditions
• Distribution: Protein binding approximately 91%, primarily to albumin
• Metabolism: Primarily metabolized via UGT1A9 to inactive metabolites
• Elimination: Half-life approximately 12.9 hours; primarily excreted renally (75%) and fecally (21%)
• Bioavailability: 78% following oral administration

Contraindications

• History of serious hypersensitivity reaction to dapagliflozin
• Patients with type 1 diabetes mellitus
• Patients with diabetic ketoacidosis
• Severe renal impairment (eGFR <25 mL/min/1.73m² for heart failure indication; <20 mL/min/1.73m² for CKD indication)
• End-stage renal disease patients on dialysis

Warnings and Precautions

• Volume depletion: May cause symptomatic hypotension, particularly in elderly patients and those on diuretics
• Ketoacidosis: Reports of euglycemic diabetic ketoacidosis have occurred
• Acute kidney injury: Monitor renal function, particularly during initiation
• UTIs and genital infections: Increased risk of urinary tract and genital mycotic infections
• Hypoglycemia: Risk increased when used with insulin or insulin secretagogues
• Necrotizing fasciitis of the perineum (Fournier's gangrene): Rare but serious reports
• Lower limb amputations: Increased risk observed in some clinical trials

Drug Interactions

• Diuretics: Increased risk of volume depletion and hypotension
• Insulin and insulin secretagogues: Increased risk of hypoglycemia (dose reduction may be needed)
• Digoxin: Monitoring recommended due to potential increase in digoxin exposure
• Positive urine glucose tests: Will test positive due to mechanism of action
• Lithium: May decrease lithium concentrations; increased monitoring recommended

Adverse Effects

• Female genital mycotic infections (8-11%)
• Urinary tract infections (5-7%)
• Nasopharyngitis (6-7%)
• Increased urination (6-8%)

• Ketoacidosis
• Acute kidney injury
• Urosepsis and pyelonephritis
• Hypersensitivity reactions
• Volume depletion
• Fournier's gangrene

Monitoring Parameters

• Glycemic control: HbA1c, fasting glucose
• Renal function: Serum creatinine, eGFR at baseline and periodically
• Volume status: Blood pressure, signs/symptoms of volume depletion
• Infections: Monitor for genital and urinary tract infections
• Electrolytes: Particularly in patients prone to imbalances
• Ketones: In patients with signs/symptoms of metabolic acidosis
• Foot exams: Regular examination for sores, ulcers, or infections

Patient Education

• Take medication once daily with or without food
• Maintain adequate hydration to prevent volume depletion
• Recognize symptoms of genital infections (itching, discharge, odor) and report promptly
• Monitor for symptoms of urinary tract infections (painful urination, frequency)
• Be aware of potential for positive urine glucose tests
• Recognize symptoms of ketoacidosis (nausea, vomiting, abdominal pain, fatigue, difficulty breathing)
• Practice good foot care and report any foot sores or infections
• Inform all healthcare providers about dapagliflozin use
• Do not stop diabetes medications without medical supervision

References

1. FDA Prescribing Information: Farxiga (dapagliflozin). 2023 2. Wiviott SD, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380(4):347-357 3. McMurray JJV, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008 4. Heerspink HJL, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446 5. American Diabetes Association. Standards of Medical Care in Diabetes—2023. Diabetes Care. 2023;46(Suppl 1) 6. Zinman B, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128 7. ClinicalTrials.gov: DAPA-HF, DAPA-CKD, DECLARE-TIMI 58 trials