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

Farxiga (Dapagliflozin): Indications and Usage

Farxiga is FDA-approved for three distinct indications: (1) improving glycemic control in adults with type 2 diabetes as an adjunct to diet and exercise, (2) reducing the risk of cardiovascular death and hospitalization for heart failure in adults with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors, and (3) reducing the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure with reduced ejection fraction (HFrEF), regardless of diabetes status. 1, 2

Primary Indications

Type 2 Diabetes Mellitus

• Dapagliflozin 10 mg daily is indicated to improve glycemic control in adults with type 2 diabetes as an adjunct to diet and exercise. 1, 2
• The medication works by inhibiting renal glucose reabsorption through SGLT2 inhibition, promoting urinary glucose excretion independent of insulin secretion or action. 2, 3
• Dapagliflozin provides glycemic control without intrinsic risk of hypoglycemia when used as monotherapy, though hypoglycemia risk increases when combined with insulin or insulin secretagogues (sulfonylureas). 2, 3

Cardiovascular Risk Reduction in Type 2 Diabetes

• In patients with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors, dapagliflozin reduces the risk of hospitalization for heart failure. 1
• The DECLARE-TIMI 58 trial demonstrated a 27% reduction in hospitalization for heart failure with dapagliflozin versus placebo in patients with type 2 diabetes. 1
• This cardiovascular benefit appears independent of glucose-lowering effects, representing a direct cardiovascular protective mechanism. 4

Heart Failure with Reduced Ejection Fraction (HFrEF)

• Dapagliflozin 10 mg daily is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with NYHA class II-IV heart failure and ejection fraction ≤40%, regardless of diabetes status. 1, 2
• The DAPA-HF trial enrolled 4,744 patients (45% with type 2 diabetes) and demonstrated a 26% reduction in the composite outcome of worsening heart failure or cardiovascular death (HR 0.74,95% CI 0.65-0.85). 1, 4
• Specific benefits included a 30% reduction in hospitalization for heart failure (HR 0.70,95% CI 0.59-0.83) and an 18% reduction in cardiovascular death (HR 0.82,95% CI 0.69-0.98). 1, 5
• The effect was consistent regardless of the presence or absence of type 2 diabetes, establishing dapagliflozin as a heart failure therapy independent of glycemic status. 1, 6

Dosing and Renal Considerations

Standard Dosing

• The recommended dose is dapagliflozin 10 mg orally once daily for all approved indications. 1, 4

Renal Function Limitations

• For glycemic control: dapagliflozin is not recommended when eGFR <45 mL/min/1.73 m² and is contraindicated when eGFR <30 mL/min/1.73 m². 1, 2
• The medication is contraindicated in patients on dialysis or with end-stage renal disease. 1, 7
• However, the heart failure indication may be used at lower eGFR thresholds based on clinical trial data, though specific FDA labeling should be consulted. 2

Critical Safety Considerations

Diabetic Ketoacidosis Risk

• SGLT2 inhibitors, including dapagliflozin, increase susceptibility to diabetic ketoacidosis, including atypical euglycemic presentations. 1, 2
• Risk factors include insulin pump malfunctions, significant insulin dose reductions, prolonged fasting, or carbohydrate restriction. 1
• This risk is particularly relevant in type 1 diabetes (where dapagliflozin is contraindicated) but can occur in type 2 diabetes under specific circumstances. 2, 7

Infection Risks

• Genital mycotic infections occur more frequently with dapagliflozin (approximately 5-6% in females, 2-3% in males) compared to placebo. 2
• Urinary tract infections, including serious complications like urosepsis and pyelonephritis, require prompt recognition and treatment. 2
• Fournier's gangrene (necrotizing fasciitis of the perineum) is a rare but life-threatening complication requiring immediate broad-spectrum antibiotics and surgical debridement. 2, 7

Volume Depletion

• Dapagliflozin can cause intravascular volume depletion, particularly in elderly patients, those with renal impairment, or those on diuretics. 2
• Monitor for signs of hypotension and volume depletion, especially when initiating therapy. 2

Hypoglycemia with Concomitant Therapy

• When dapagliflozin is combined with insulin or insulin secretagogues, dose reduction of these agents may be necessary to minimize hypoglycemia risk. 2

Clinical Trial Evidence Summary

Heart Failure Trials

• The DAPA-HF trial specifically enrolled patients with symptomatic HFrEF (NYHA class II-IV, ejection fraction ≤40%), demonstrating consistent benefit across diabetes status. 1, 4, 6
• Benefits extended to quality of life improvements, reduced urgent heart failure visits (57% reduction), and improved symptoms and physical limitations. 4, 5

Diabetes Cardiovascular Outcomes

• DECLARE-TIMI 58 enrolled patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, showing robust heart failure hospitalization reduction. 1, 8
• The cardiovascular benefits were consistent across multiple SGLT2 inhibitor trials (EMPA-REG OUTCOME, CANVAS, CREDENCE), with dapagliflozin showing 27-39% reductions in heart failure hospitalizations. 1

Renal Protection

• Dapagliflozin provides renal protection with a 44% reduction in composite renal outcomes (HR 0.56,95% CI 0.45-0.68), independent of diabetes status. 4
• This led to FDA approval for chronic kidney disease in 2021. 7

Contraindications

• History of serious hypersensitivity reaction to dapagliflozin. 1, 2
• eGFR <30 mL/min/1.73 m² or end-stage renal disease. 1, 2
• Patients on dialysis. 1, 2
• Type 1 diabetes mellitus (due to ketoacidosis risk). 7