What are the indications for Dapagliflozin (Forxiga)?

Dapagliflozin Indications

Dapagliflozin is FDA-approved for four distinct indications: chronic kidney disease at risk of progression, heart failure (both reduced and preserved ejection fraction), reduction of heart failure hospitalization in type 2 diabetes with cardiovascular disease or risk factors, and as adjunctive therapy for glycemic control in type 2 diabetes. 1

FDA-Approved Indications

1. Chronic Kidney Disease (CKD)

• Dapagliflozin 10 mg once daily reduces 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. 1
• Initiate in patients with eGFR ≥25 mL/min/1.73 m² and albuminuria (UACR 200-5000 mg/g), regardless of diabetes status. 2, 3
• The DAPA-CKD trial demonstrated a 39% reduction in the composite outcome of sustained eGFR decline ≥50%, end-stage renal disease, or renal/cardiovascular death (HR 0.61,95% CI 0.51-0.72). 2, 3
• Renal-specific outcomes were reduced by 44% (HR 0.56,95% CI 0.45-0.68). 2, 3
• Do not use in patients with polycystic kidney disease or those requiring/recently receiving immunosuppressive therapy for kidney disease, as dapagliflozin is not expected to be effective. 1

2. Heart Failure

• Dapagliflozin 10 mg once daily reduces the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adults with heart failure. 1
• Effective in both heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). 3
• The DAPA-HF trial showed a 26% reduction in the composite of worsening heart failure or cardiovascular death in HFrEF patients (HR 0.74,95% CI 0.65-0.85). 3
• The DELIVER trial demonstrated an 18% reduction in the composite of worsening heart failure or cardiovascular death in HFpEF patients. 3
• Benefits are independent of diabetes status—dapagliflozin works equally well in patients with and without diabetes. 4, 3

3. Type 2 Diabetes with Cardiovascular Disease or Risk Factors

• Dapagliflozin 10 mg once daily reduces the risk of hospitalization for heart failure in adults with type 2 diabetes and either established cardiovascular disease or multiple cardiovascular risk factors. 1
• The DECLARE-TIMI 58 trial demonstrated a 27% reduction in hospitalization for heart failure in this population. 3

4. Glycemic Control in Type 2 Diabetes

• Dapagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes. 1
• Starting dose: 5 mg once daily, may increase to 10 mg once daily for additional glycemic control. 1
• Critical limitation: Do not initiate for glycemic control if eGFR <45 mL/min/1.73 m², as it is likely ineffective based on its mechanism of action. 1, 2
• Not recommended for type 1 diabetes mellitus. 1

Dosing Algorithm by Indication and Renal Function

For CKD or Heart Failure Indications:

• Fixed dose of 10 mg once daily if eGFR ≥25 mL/min/1.73 m². 2, 3
• Do not initiate if eGFR <25 mL/min/1.73 m², but may continue 10 mg daily if already on treatment until dialysis is required. 2
• No dose adjustment needed based on renal function for cardiovascular/renal protection. 2

For Glycemic Control in Type 2 Diabetes:

• Start 5 mg once daily if eGFR ≥45 mL/min/1.73 m², may increase to 10 mg once daily. 1
• Do not initiate if eGFR <45 mL/min/1.73 m² for glycemic control—it won't work effectively. 1, 2

Critical Safety Considerations

Pre-Initiation Assessment:

• Assess renal function (eGFR) and volume status before starting dapagliflozin. 1, 3
• Correct volume depletion before initiation, especially in elderly patients, those on diuretics, or with low systolic blood pressure. 2, 3

Perioperative Management:

• Withhold dapagliflozin at least 3 days before major surgery or procedures requiring prolonged fasting to prevent postoperative ketoacidosis. 2, 3

Sick Day Rules:

• Temporarily discontinue during acute illness, particularly with fever, vomiting, diarrhea, or reduced oral intake. 2
• Monitor for euglycemic diabetic ketoacidosis (DKA)—can occur even with normal blood glucose levels. 2, 3
• Maintain at least low-dose insulin in insulin-requiring patients even when dapagliflozin is held. 2

Common Adverse Effects:

• Genital mycotic infections occur in approximately 6% of patients (vs. 1% with placebo). 2
• Urinary tract infections are more common with dapagliflozin. 2, 3
• Volume depletion risk, especially when combined with diuretics—consider reducing diuretic dose when initiating dapagliflozin. 2, 3

Key Clinical Pearls

• Cardiovascular and renal benefits persist even when eGFR falls below 45 mL/min/1.73 m²—do not discontinue solely because glycemic efficacy is lost. 2
• An initial eGFR dip of 3-5 mL/min/1.73 m² within 1-4 weeks is expected and reversible—this is hemodynamic, not nephrotoxic. 2
• Benefits are independent of glucose-lowering effects, explaining efficacy in non-diabetic patients with heart failure or CKD. 4, 3
• Dapagliflozin should be included in the regimen irrespective of metformin use or need for additional glucose lowering in patients with established cardiovascular or kidney disease. 4