Dapagliflozin

• Type 2 diabetes mellitus glycemic control
• Heart failure with reduced ejection fraction
• Chronic kidney disease progression prevention
• Cardiovascular risk reduction in diabetes
• Reducing hospitalization for heart failure

Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that has revolutionized the treatment of type 2 diabetes, heart failure, and chronic kidney disease. By blocking glucose reabsorption in the kidneys, it provides multiple cardiometabolic benefits beyond glucose control, including cardiovascular protection, renal preservation, and modest weight loss.

Mechanism of Action

Dapagliflozin selectively inhibits SGLT2, the primary transporter responsible for reabsorbing approximately 90% of filtered glucose in the proximal renal tubule. By blocking this transporter, dapagliflozin causes the excretion of approximately 70 grams of glucose per day in the urine, lowering blood glucose levels through an insulin-independent mechanism. This glucosuria also results in an osmotic diuresis and natriuresis, which contributes to blood pressure reduction and volume effects that benefit heart failure patients.

Beyond glucose effects, SGLT2 inhibition provides cardiorenal protection through multiple mechanisms including improved cardiac energetics, reduced preload and afterload, decreased inflammation, and favorable effects on kidney hemodynamics that reduce hyperfiltration and slow progression of kidney disease.

Available Formulations

Dapagliflozin (Farxiga) is available as tablets in 5 mg and 10 mg strengths. It is also available in fixed-dose combinations with metformin (Xigduo XR) and saxagliptin (Qtern) for patients requiring combination therapy for diabetes management.

FDA-Approved Indications

Dapagliflozin has received FDA approval for multiple conditions, reflecting its broad cardiometabolic benefits. These indications include improving glycemic control in adults with type 2 diabetes mellitus, reducing the risk of hospitalization for heart failure in adults with type 2 diabetes and cardiovascular disease or multiple cardiovascular risk factors, reducing the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure with reduced ejection fraction (HFrEF), and reducing the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression.

Dosing Guidelines

For type 2 diabetes, the recommended dose is 10 mg once daily in the morning, taken with or without food. For heart failure, the dose is 10 mg once daily. For chronic kidney disease, the dose is also 10 mg once daily. No dose adjustment is needed for mild to moderate hepatic impairment. The medication should be initiated only when eGFR is 25 mL/min/1.73m² or higher, though it may be continued at lower levels once started.

Clinical Trial Evidence

The cardiovascular and renal benefits of dapagliflozin have been demonstrated in landmark clinical trials. The DECLARE-TIMI 58 trial showed reduced hospitalization for heart failure in patients with type 2 diabetes. The DAPA-HF trial demonstrated significant reductions in cardiovascular death and heart failure hospitalization in patients with HFrEF, regardless of diabetes status. The DAPA-CKD trial showed remarkable renal protection in patients with chronic kidney disease, leading to early trial termination due to overwhelming efficacy.

Important Safety Considerations

While generally well-tolerated, dapagliflozin carries important safety considerations. Diabetic ketoacidosis, including euglycemic DKA with normal glucose levels, can occur and requires heightened awareness. Genital mycotic infections (yeast infections) are common due to glucosuria. Rare but serious cases of necrotizing fasciitis of the perineum (Fournier's gangrene) have been reported. Volume depletion and hypotension may occur, particularly in elderly patients or those on diuretics. Patients should be educated about these risks and advised to maintain adequate hydration.

Drug Interactions and Monitoring

Diuretics may increase the risk of volume depletion when combined with dapagliflozin. Insulin and insulin secretagogues may need dose reduction to prevent hypoglycemia. Regular monitoring of renal function, potassium, and volume status is recommended. Patients should be counseled about symptoms of ketoacidosis and instructed to hold the medication during periods of reduced oral intake or acute illness.

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