What are the indications and usage for Farziga (dapagliflozin) in patients with type 2 diabetes?

Indications and Usage for Farziga (Dapagliflozin)

Farziga (dapagliflozin) is FDA-approved for four distinct indications: type 2 diabetes mellitus in adults and pediatric patients ≥10 years, chronic kidney disease with albuminuria, heart failure with reduced ejection fraction (HFrEF), and heart failure with preserved ejection fraction (HFpEF), with cardiovascular and renal benefits extending beyond glycemic control. 1

Type 2 Diabetes Mellitus

Adult Patients

• Dapagliflozin 5-10 mg once daily is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. 1
• It can be used as monotherapy in patients intolerant to metformin or as add-on combination therapy with other glucose-lowering agents including insulin. 2, 3
• The mechanism involves inhibiting renal SGLT-2 cotransporters, preventing glucose and sodium reabsorption and promoting glucosuria, which is independent of insulin secretion or action. 4, 3

Pediatric Patients

• Dapagliflozin is approved for pediatric patients aged 10 years and older with type 2 diabetes as an adjunct to diet and exercise. 1
• Start with 5 mg once daily; patients with HbA1c ≥7% at Week 14 may be uptitrated to 10 mg once daily. 1
• The safety profile in pediatric patients was similar to adults, with efficacy demonstrated in a 26-week placebo-controlled trial with 26-week extension. 1

Important Glycemic Control Limitations

• Do not initiate dapagliflozin for glycemic control when eGFR <45 mL/min/1.73 m², as glucose-lowering efficacy is significantly reduced due to its mechanism of action. 5
• For patients with eGFR ≥45 mL/min/1.73 m², no dose adjustment is required for glycemic control. 5

Chronic Kidney Disease

Dapagliflozin 10 mg once daily is indicated to reduce 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. 1, 6

Patient Selection Criteria

• Initiate in patients with eGFR ≥25 mL/min/1.73 m² (some guidelines support ≥20 mL/min/1.73 m²) and albuminuria (UACR ≥200 mg/g). 5
• Benefits are independent of diabetes status—the DAPA-CKD trial included 67.5% with diabetes and 32.5% without diabetes, with consistent efficacy across both groups. 5

Clinical Evidence

• The DAPA-CKD trial demonstrated a 39% reduction (HR 0.61 [95% CI 0.51-0.72]) in the composite outcome of sustained eGFR decline ≥50%, end-stage kidney disease, or renal/cardiovascular death. 5
• The kidney-specific composite was reduced by 44% (HR 0.56 [95% CI 0.45-0.68]). 5
• Cardiovascular death or hospitalization for heart failure was reduced by 29% (HR 0.71 [95% CI 0.55-0.92]). 5

Continuation Below Initiation Threshold

• If eGFR falls below 25 mL/min/1.73 m² during treatment, continue dapagliflozin 10 mg daily until dialysis is initiated. 5, 1
• An initial reversible eGFR dip of 3-5 mL/min/1.73 m² typically occurs within 1-4 weeks, followed by stabilization and slower long-term decline. 5

Heart Failure with Reduced Ejection Fraction (HFrEF)

Dapagliflozin 10 mg once daily is indicated to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adults with heart failure (NYHA class II-IV) and ejection fraction ≤40%. 6, 1

Clinical Evidence

• The DAPA-HF trial demonstrated a 26% reduction (HR 0.74 [95% CI 0.65-0.85]) in the composite of worsening heart failure or cardiovascular death over 18.2 months. 7, 6
• First worsening heart failure event was reduced by 30% (HR 0.70 [95% CI 0.59-0.83]). 7
• Cardiovascular death was reduced by 18% (HR 0.82 [95% CI 0.69-0.98]). 7
• Benefits were consistent regardless of diabetes status—45% of DAPA-HF participants had type 2 diabetes. 7

Renal Function Considerations

• Dapagliflozin can be initiated if eGFR ≥25 mL/min/1.73 m², with a fixed dose of 10 mg once daily. 5, 6
• The DAPA-HF trial included 1,926 patients with eGFR 30-60 mL/min/1.73 m², with consistent safety and efficacy. 1

Heart Failure with Preserved Ejection Fraction (HFpEF)

Dapagliflozin 10 mg once daily is indicated to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adults with heart failure and ejection fraction >40%. 6, 1

Clinical Evidence

• The DELIVER trial demonstrated an 18% reduction (HR 0.82 [95% CI 0.73-0.92]) in the composite of worsening heart failure or cardiovascular death in 6,263 patients with LVEF >40%. 7, 6
• Approximately 44% of participants had type 2 diabetes, with consistent results regardless of diabetes status. 7
• 76% of DELIVER participants were older than 65 years, demonstrating efficacy in elderly populations. 1

Type 2 Diabetes with Cardiovascular Risk Factors

Dapagliflozin 10 mg once daily is indicated to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. 6, 8

Clinical Evidence

• The DECLARE-TIMI 58 trial enrolled 17,160 patients with type 2 diabetes and either established atherosclerotic cardiovascular disease (n=6,971) or multiple risk factors (n=10,189). 9
• Dapagliflozin reduced hospitalization for heart failure by 27% in this broad population. 6
• In patients with previous myocardial infarction specifically, dapagliflozin reduced MACE by 16% (HR 0.84 [95% CI 0.72-0.99]) with an absolute risk reduction of 2.6%. 10

Dosing Algorithm by Indication

For Glycemic Control

• eGFR ≥45 mL/min/1.73 m²: Start 5 mg once daily; may increase to 10 mg once daily if additional glycemic control needed. 5
• eGFR <45 mL/min/1.73 m²: Do not initiate for glycemic control (ineffective). 5

For Cardiovascular and Renal Protection

• eGFR ≥25 mL/min/1.73 m²: Fixed dose of 10 mg once daily for heart failure or CKD indications, regardless of diabetes status. 5, 6
• eGFR <25 mL/min/1.73 m²: Do not initiate, but may continue 10 mg daily if already on treatment until dialysis. 5, 1

Critical Safety Considerations

Perioperative Management

• Withhold dapagliflozin at least 3 days before major surgery or procedures requiring prolonged fasting to prevent postoperative ketoacidosis. 5, 8
• Resume only after patient is clinically stable and has resumed oral intake. 8

Sick Day Rules

• Temporarily discontinue dapagliflozin during any acute illness, particularly with reduced food/fluid intake, fever, vomiting, or diarrhea. 5
• Monitor for diabetic ketoacidosis even with normal blood glucose levels (euglycemic DKA). 5
• Maintain at least low-dose insulin in insulin-requiring patients even when dapagliflozin is held. 5

Volume Depletion Risk

• Assess volume status before initiation and correct volume depletion if present. 5, 6
• Use caution in patients with low systolic blood pressure, those on diuretics, or elderly patients. 5
• Consider reducing concurrent diuretic doses when initiating dapagliflozin. 5

Common Adverse Effects

• Genital mycotic infections occur in approximately 6% of patients versus 1% on placebo, particularly in women. 5, 2
• Urinary tract infections are more common with dapagliflozin. 5, 4
• Rare but serious: necrotizing fasciitis of the perineum (Fournier gangrene) requires prompt treatment if suspected. 5

Special Populations

Elderly Patients

• No dosage adjustment based on age alone. 1
• Higher proportion of patients ≥65 years experienced hypotension when treated for glycemic control. 1
• In DAPA-HF, 57% were >65 years; in DELIVER, 76% were >65 years; in DAPA-CKD, 42% were >65 years, all with consistent safety and efficacy. 1

Pregnancy and Lactation

• Dapagliflozin use is not recommended during breastfeeding due to potential risk to the developing kidney. 1
• Human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur. 1