What are the indications and usage of Farxiga (dapagliflozin) in patients with type 2 diabetes and cardiovascular disease?

Farxiga (Dapagliflozin): Indications and Usage

Farxiga 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 cardiovascular risk factors, reducing cardiovascular death and hospitalization for heart failure in adults with heart failure with reduced ejection fraction (regardless of diabetes status), and reducing kidney disease progression in patients with chronic kidney disease. 1, 2, 3

FDA-Approved Indications

Type 2 Diabetes Mellitus

• Farxiga 10 mg once daily is approved to improve glycemic control in adults with type 2 diabetes as an adjunct to diet and exercise 1, 3

Cardiovascular Risk Reduction in Type 2 Diabetes

• Farxiga 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, 2, 3
• The American College of Cardiology specifically recommends dapagliflozin for this indication based on the DECLARE-TIMI 58 trial, which demonstrated a 27% reduction in hospitalization for heart failure (HR 0.73; 95% CI 0.61-0.88) 4

Heart Failure

• Farxiga 10 mg once daily reduces the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adults with heart failure with reduced ejection fraction (HFrEF), regardless of diabetes status 1, 2, 4
• The DAPA-HF trial showed a 26% reduction in the composite of worsening heart failure or cardiovascular death (HR 0.74; 95% CI 0.65-0.85) 1, 4
• The DELIVER trial extended this benefit to heart failure with preserved ejection fraction, showing an 18% reduction in worsening heart failure or cardiovascular death 4

Chronic Kidney Disease

• Farxiga 10 mg once daily is indicated to reduce kidney disease progression in patients with chronic kidney disease (eGFR 25-75 mL/min/1.73 m²), with or without diabetes 2, 5
• The DAPA-CKD trial demonstrated a 39% reduction in the composite outcome of sustained eGFR decline ≥50%, end-stage kidney disease, or renal/cardiovascular death (HR 0.61; 95% CI 0.51-0.72) 5
• The renal-specific outcome was reduced by 44% (HR 0.56; 95% CI 0.45-0.68) 5

Guideline-Based Recommendations for Cardiovascular Disease

Patients with Established Atherosclerotic Cardiovascular Disease

• SGLT2 inhibitors like dapagliflozin are recommended in patients with type 2 diabetes and established cardiovascular disease to reduce hospitalization for heart failure 1, 2
• The DECLARE-TIMI 58 trial showed cardiovascular safety with a significant benefit for cardiovascular death or hospitalization for heart failure (HR 0.83; 95% CI 0.73-0.95) 1, 5

Patients with Multiple Cardiovascular Risk Factors (Without Established CVD)

• Dapagliflozin can be considered in patients aged 55 years or older with indicators of high cardiovascular risk, including coronary, carotid, or lower extremity artery stenosis >50%, left ventricular hypertrophy, eGFR <60 mL/min/1.73 m², or albuminuria 1
• However, dapagliflozin did not demonstrate superiority for major adverse cardiovascular events (MACE) in the primary prevention population (HR 0.93; 95% CI 0.84-1.03), though it did reduce heart failure hospitalizations 1, 5

Heart Failure Specific Recommendations

• The American Diabetes Association and American College of Cardiology recommend SGLT2 inhibitors in patients with type 2 diabetes and heart failure, particularly those with HFrEF, to reduce hospitalization for heart failure, MACE, and cardiovascular death 1, 2, 4
• This recommendation extends to patients with heart failure regardless of diabetes status based on the DAPA-HF trial 4

Kidney Protection Recommendations

Chronic Kidney Disease with Type 2 Diabetes

• The American Diabetes Association recommends SGLT2 inhibitors for kidney protection in patients with type 2 diabetes and CKD, with the strongest evidence for those with UACR >300 mg/g and eGFR 30-90 mL/min/1.73 m² 1, 5
• Patients with eGFR 30 to ≤60 mL/min/1.73 m² or UACR >30 mg/g should be considered for SGLT2 inhibitor therapy 5
• The decision to use dapagliflozin for kidney protection should be made independently of baseline HbA1c or glycemic targets, as renal benefits are independent of glucose-lowering effects 5

Dosing for Renal Indications

• The American College of Cardiology recommends starting dapagliflozin 10 mg once daily in patients with type 2 diabetes with eGFR ≥25 mL/min/1.73 m² and evidence of kidney disease (albuminuria or reduced eGFR) 5
• Dapagliflozin should not be used in patients with eGFR <25 mL/min/1.73 m², as it is unlikely to be effective 5
• Use is not recommended for glycemic control when eGFR <45 mL/min/1.73 m² 1

Dosing and Administration

• The recommended dose is 10 mg orally once daily for all cardiovascular and renal indications 1, 2, 4
• Discontinue dapagliflozin at least 3 days before planned surgery or procedures with prolonged fasting to prevent postoperative ketoacidosis, and resume when the patient is clinically stable and has resumed oral intake 2, 4, 3

Concomitant Therapy Adjustments

With Insulin or Insulin Secretagogues

• When starting dapagliflozin in patients on insulin, consider reducing the insulin dose by approximately 20% to prevent hypoglycemia 2, 3
• A lower dose of sulfonylureas or other insulin secretagogues may be required to minimize hypoglycemia risk 1, 3

With Diuretics

• Assess volume status before initiation and consider reducing diuretic dose if the patient is at risk for volume depletion 4, 3

Safety Considerations and Adverse Effects

Common Adverse Effects

• Genital mycotic infections (particularly in women), urinary tract infections, and increased urination are the most common adverse effects 3
• Genital mycotic infections occurred in 5.7% of patients on dapagliflozin 10 mg versus 0.9% on placebo 3
• Urinary tract infections occurred in 4.3% on dapagliflozin 10 mg versus 3.7% on placebo 3

Serious Adverse Effects to Monitor

• Diabetic ketoacidosis (including euglycemic DKA): Monitor for signs even with normal blood glucose levels 4, 3
• Volume depletion: More common in patients on diuretics, elderly patients, or those with impaired renal function 3
• Urosepsis and pyelonephritis: Evaluate and treat urinary tract infections promptly 3
• Fournier's gangrene (necrotizing fasciitis of the perineum): Rare but life-threatening; assess patients with genital or perineal pain, tenderness, erythema, swelling, fever, or malaise 3

Contraindications

• History of serious hypersensitivity reaction to dapagliflozin 1
• Dialysis or end-stage renal disease (eGFR <15 mL/min/1.73 m²) 1

Special Populations Requiring Caution

• Patients with prior amputation, severe peripheral neuropathy, severe peripheral vascular disease, or active diabetic foot ulcers should only be treated after careful shared decision-making around risks and benefits with comprehensive education on foot care 1
• The American Diabetes Association notes that while amputation risk was elevated with canagliflozin in some trials, this has not been consistently observed with dapagliflozin 1

Clinical Evidence Summary

Cardiovascular Outcomes

• The DECLARE-TIMI 58 trial enrolled 17,160 patients with type 2 diabetes (59.4% without established CVD) with median follow-up of 4.2 years 1, 5
• Dapagliflozin demonstrated cardiovascular safety but not superiority for MACE (HR 0.93; 95% CI 0.84-1.03) 1, 5
• The cardiovascular benefit was driven primarily by a 27% reduction in hospitalization for heart failure (HR 0.73; 95% CI 0.61-0.88) 5, 4

Renal Outcomes

• Dapagliflozin showed a 47% reduction in composite renal events (HR 0.53; 95% CI 0.43-0.66) in DECLARE-TIMI 58 5
• In DAPA-CKD, all-cause mortality was reduced by 31% (HR 0.69; 95% CI 0.53-0.88) 5

Independence from Glycemic Effects

• The cardiovascular and renal benefits of dapagliflozin appear independent of glucose-lowering effects, with consistent benefits in patients with and without diabetes and across all HbA1c levels 5, 4