What is the indication and usage of Forziga (dapagliflozin) in patients with type 2 diabetes and heart failure?

Forxiga (Dapagliflozin): Indications and Usage

Forxiga (dapagliflozin) 10 mg daily is indicated for improving glycemic control in adults with type 2 diabetes, reducing hospitalization for heart failure in patients with type 2 diabetes and established cardiovascular disease or multiple risk factors, and reducing cardiovascular death and hospitalization for heart failure in all adults with heart failure with reduced ejection fraction (HFrEF) regardless of diabetes status. 1

FDA-Approved Indications

Dapagliflozin has three distinct FDA-approved indications 1:

• Type 2 Diabetes Management: Improve glycemic control in adults with type 2 diabetes as an adjunct to diet and exercise 1

• Heart Failure Risk Reduction in Diabetic Patients: Reduce the risk of hospitalization for heart failure in adults with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors 1

• Heart Failure with Reduced Ejection Fraction: Reduce the risk of cardiovascular death and hospitalization for heart failure in adults with HFrEF (NYHA class II-IV), with or without type 2 diabetes 1

Evidence Supporting Use in Type 2 Diabetes with Cardiovascular Disease

The American College of Cardiology recommends dapagliflozin for patients with type 2 diabetes and established cardiovascular disease to reduce major adverse cardiovascular events, with particular strength for preventing heart failure hospitalizations. 2

• In the DECLARE-TIMI 58 trial, dapagliflozin demonstrated cardiovascular safety with a 17% reduction in the composite outcome of cardiovascular death or hospitalization for heart failure (HR 0.83,95% CI 0.73-0.95) 2

• The trial enrolled 17,160 patients with type 2 diabetes, including 59.4% without prior established cardiovascular disease but with multiple risk factors, followed for a median of 4.2 years 2

• While dapagliflozin did not show superiority for major adverse cardiovascular events (MACE) in the overall population (HR 0.93,95% CI 0.84-1.03), it demonstrated strong benefits for heart failure outcomes and renal endpoints 2

Evidence Supporting Use in Heart Failure

The American Diabetes Association and American College of Cardiology strongly recommend dapagliflozin 10 mg once daily for all adults with heart failure to reduce cardiovascular death, hospitalization for heart failure, and urgent heart failure visits, regardless of diabetes status. 3

Heart Failure with Reduced Ejection Fraction (HFrEF)

• The DAPA-HF trial enrolled 4,744 patients with HFrEF (ejection fraction ≤40%), NYHA class II-IV, with 45% having type 2 diabetes 4

• Dapagliflozin 10 mg daily reduced the primary composite outcome of worsening heart failure or cardiovascular death by 26% (HR 0.74,95% CI 0.65-0.85) over 18 months 2, 3

• First worsening heart failure events were reduced by 30% (HR 0.70,95% CI 0.59-0.83) 3

• Cardiovascular death was reduced by 18% (HR 0.82,95% CI 0.69-0.98) 3

Heart Failure with Mildly Reduced or Preserved Ejection Fraction

• The DELIVER trial enrolled 6,263 patients with heart failure and ejection fraction >40% 4

• Dapagliflozin reduced the primary outcome of worsening heart failure (hospitalization or urgent visit) or cardiovascular death by 18% (HR 0.82,95% CI 0.73-0.92) 4, 3

• Benefits were consistent across the entire spectrum of glycemic status: normoglycemia, prediabetes, and type 2 diabetes (p for interaction = 0.82) 5

Clinical Implementation Algorithm

Dosing and Initiation

• Standard dose: Dapagliflozin 10 mg once daily 2, 1

• No dose titration required—full dose from initiation 3

• Can be initiated during hospitalization once the patient is stabilized, as deferring initiation is associated with high likelihood that eligible patients will never receive the medication within 1 year 4

Renal Considerations

• eGFR <45 mL/min/1.73 m²: Use is not recommended for glycemic control 2

• eGFR <30 mL/min/1.73 m²: Use is contraindicated 2, 1

• eGFR 25-30 mL/min/1.73 m²: Can be used for heart failure indication, as benefits were observed even at eGFR as low as 25 mL/min/1.73 m² 4

Combination with Other Heart Failure Therapies

• Continue existing guideline-directed medical therapy (ACE inhibitors, ARBs, beta-blockers, mineralocorticoid receptor antagonists), as dapagliflozin provides additive benefit 4

• Dapagliflozin provides incremental benefit regardless of whether patients are on optimal guideline-directed medical therapy, reducing the primary outcome by 26% (HR 0.74,95% CI 0.59-0.93) in patients already on ACE inhibitor/ARB, beta-blocker, and mineralocorticoid receptor antagonist 4

Benefits Independent of Glucose-Lowering Effects

The cardiovascular and heart failure benefits of dapagliflozin are consistent regardless of diabetes status, representing direct cardiovascular benefit through mechanisms beyond glycemic control. 4, 3

• Benefits are identical in patients with and without diabetes 3

• A meta-analysis of 21,947 patients confirmed benefits across the entire spectrum of glycemic status 3

• The mechanism involves shifting cardiac metabolism toward ketone utilization, which requires less oxygen than glucose or fatty acid metabolism, directly improving myocardial energetics 4

Safety Considerations and Contraindications

Absolute Contraindications

• History of serious hypersensitivity reaction to dapagliflozin 1

• End-stage renal disease or on dialysis 2, 4, 1

• Severe renal impairment (eGFR <30 mL/min/1.73 m² for diabetes indication; eGFR <25 mL/min/1.73 m² for heart failure indication) 2, 4

Important Warnings

• Diabetic ketoacidosis: Monitor for signs and symptoms, particularly in patients with type 1 diabetes (off-label use) 1

• Volume depletion: Assess volume status before initiating, particularly in elderly patients, those with renal impairment, or those on diuretics 1

• Genital mycotic infections: Occur in approximately 5-6% of patients; monitor and treat appropriately 1

• Urinary tract infections: Evaluate patients for signs and symptoms and treat promptly if indicated 1

• Fournier's gangrene: Rare but serious necrotizing infection requiring urgent surgical intervention; discontinue dapagliflozin if suspected 1

Hypoglycemia Risk

• When combined with insulin or insulin secretagogues (e.g., sulfonylureas), dapagliflozin may increase the risk of hypoglycemia 1

• A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with dapagliflozin 2, 1

Common Pitfalls to Avoid

• Do not discontinue existing heart failure medications when initiating dapagliflozin—the benefits are additive 4

• Do not delay initiation in hospitalized heart failure patients once stabilized, as this significantly reduces the likelihood of ever receiving the medication 4

• Minimal blood pressure effects occur with dapagliflozin; symptomatic hypotension occurred in only 0.3% of dapagliflozin patients vs 0.5% of placebo patients in DAPA-HF 4

• Use with caution when combined with high-dose loop diuretics due to enhanced natriuresis 4

• Dapagliflozin preserves kidney function rather than causing adverse renal effects, reducing the composite of ≥50% sustained eGFR decline, progression to end-stage kidney disease, or cardiovascular/renal death by 39% (HR 0.61,95% CI 0.51-0.72) 4