What is the role of Dapagliflozin (SGLT2 inhibitor) in treating type 2 diabetes and heart failure?

Dapagliflozin: Role in Type 2 Diabetes and Heart Failure

Direct Recommendation

Dapagliflozin 10 mg once daily should be prescribed to all patients with heart failure (regardless of ejection fraction or diabetes status) and to patients with type 2 diabetes who have established cardiovascular disease or chronic kidney disease, as it significantly reduces cardiovascular death, heart failure hospitalizations, and kidney disease progression. 1, 2

FDA-Approved Indications

Dapagliflozin is FDA-approved for multiple cardiovascular and metabolic indications 2:

• Chronic kidney disease: Reduces sustained eGFR decline, end-stage kidney disease, cardiovascular death, and heart failure hospitalization in adults with CKD at risk of progression 2
• Heart failure: Reduces cardiovascular death, heart failure hospitalization, and urgent heart failure visits in adults with heart failure (any ejection fraction) 2
• Type 2 diabetes with cardiovascular disease: Reduces heart failure hospitalization in adults with established CVD or multiple CV risk factors 2
• Glycemic control: Adjunct to diet and exercise in adults and children ≥10 years with type 2 diabetes 2

Heart Failure Benefits: The Evidence

Heart Failure with Reduced Ejection Fraction (HFrEF)

The DAPA-HF trial established dapagliflozin as foundational therapy for HFrEF, demonstrating a 26% reduction in the composite outcome of worsening heart failure or cardiovascular death (HR 0.74,95% CI 0.65-0.85). 1, 3 This benefit was consistent whether patients had diabetes or not 1:

• 30% reduction in first worsening heart failure events (HR 0.70,95% CI 0.59-0.83) 1
• 18% reduction in cardiovascular death (HR 0.82,95% CI 0.69-0.98) 1
• 17% reduction in all-cause mortality (HR 0.83,95% CI 0.71-0.97) 3

The trial enrolled 4,744 patients with NYHA class II-IV heart failure and ejection fraction ≤40%, with 45% having type 2 diabetes at baseline 1, 3

Heart Failure with Preserved Ejection Fraction (HFpEF)

The DELIVER trial extended dapagliflozin's benefits to HFpEF, showing an 18% reduction in worsening heart failure or cardiovascular death (HR 0.82,95% CI 0.73-0.92) in patients with ejection fraction >40%. 1 This represents a major therapeutic advance, as few medications have proven effective in HFpEF 1:

• Benefits were consistent across the entire glycemic spectrum, from normoglycemia through prediabetes to type 2 diabetes 4
• The incidence of primary outcomes increased with worsening glycemic status (6.9 per 100 patient-years in normoglycemia vs 10.1 in diabetes), but dapagliflozin's relative benefit remained consistent 4

Mechanism: Beyond Glucose Lowering

The cardiovascular benefits of dapagliflozin are independent of glucose-lowering effects, representing a direct cardiovascular benefit through mechanisms that remain incompletely understood. 1, 5 This is evidenced by:

• Equivalent benefits in patients with and without diabetes 1
• Consistent effects across the entire HbA1c spectrum 4
• Benefits occurring within weeks of initiation 6

Type 2 Diabetes Management

Cardiovascular Risk Reduction

For patients with type 2 diabetes and established cardiovascular disease or multiple CV risk factors, dapagliflozin reduces heart failure hospitalization by 27-39% across multiple trials. 1 The American Diabetes Association recommends SGLT2 inhibitors with proven cardiovascular benefit in this population 1:

• DECLARE-TIMI 58 showed 27% reduction in heart failure hospitalization 1
• CREDENCE trial demonstrated 39% reduction in heart failure hospitalization in diabetic kidney disease 1

Renal Protection

Dapagliflozin provides robust kidney protection, reducing composite renal outcomes by 44% (HR 0.56,95% CI 0.45-0.68) in patients with chronic kidney disease. 5, 6 This renoprotective effect is independent of diabetes status 5:

• Reduces sustained eGFR decline ≥50%, end-stage kidney disease, and renal/cardiovascular death 6, 2
• Effective in patients with eGFR as low as 25 mL/min/1.73m² 6
• A mild, transient eGFR decrease after initiation does not indicate kidney injury and should not prompt discontinuation 6

Clinical Implementation Algorithm

Patient Selection

Initiate dapagliflozin 10 mg once daily in the following populations 1, 6, 2:

1. All patients with symptomatic heart failure (NYHA class II-IV), regardless of ejection fraction or diabetes status 1, 6
2. Patients with type 2 diabetes and established cardiovascular disease or multiple CV risk factors 1, 2
3. Patients with CKD (eGFR 25-75 mL/min/1.73m²) and albuminuria (UACR ≥200 mg/g), with or without diabetes 6, 2

Contraindications

Do not prescribe dapagliflozin in 6, 2:

• History of serious hypersensitivity to dapagliflozin 2
• Polycystic kidney disease 6, 2
• Recent immunosuppressive therapy for kidney disease 6, 2
• Type 1 diabetes (not FDA-approved for glycemic control, high ketoacidosis risk) 2

Dosing Considerations

Standard dose is 10 mg once daily, with no titration required 5, 6:

• No dose adjustment needed based on renal function (effective down to eGFR 25 mL/min/1.73m²) 6
• For glycemic control in type 2 diabetes, not recommended if eGFR <45 mL/min/1.73m² (ineffective for glucose lowering) 2
• For heart failure and CKD indications, continue even if eGFR declines to 20-30 mL/min/1.73m² 6

Safety Monitoring and Common Pitfalls

Critical Safety Concerns

Monitor for ketoacidosis, even with normal blood glucose (<250 mg/dL), particularly in patients with type 2 diabetes, pancreatic problems, or during acute illness. 2 Risk factors include 2:

• Reduced food/fluid intake, missed meals, or ketogenic diet
• Reduced insulin dose or missed insulin doses
• Acute illness, surgery, or excessive alcohol consumption
• Volume depletion

Stop dapagliflozin immediately if ketoacidosis symptoms develop: nausea, vomiting, abdominal pain, fatigue, or difficulty breathing 2

Volume Depletion and Hypotension

Dehydration occurs in approximately 5.7% of patients, with higher risk in those taking diuretics, on low-salt diets, with kidney problems, or age ≥65 years. 6, 2 Management strategies 2:

• Counsel patients on adequate daily fluid intake
• Monitor for orthostatic hypotension, dizziness, or lightheadedness
• Temporarily discontinue if acute illness causes reduced oral intake or fluid losses (vomiting, diarrhea)
• Reports of acute kidney injury exist in type 2 diabetes patients, often related to volume depletion 2

Genitourinary Infections

Genital mycotic infections occur in 1.5-1.7% of patients and urinary tract infections in 2.3-2.7%. 6 These are generally manageable with over-the-counter antifungal therapy 2:

• Women: vaginal yeast infections with odor, discharge, and itching 2
• Men: balanitis with penile redness, itching, swelling, and discharge 2
• Refer to provider if symptoms persist despite antifungal treatment 2

Common Pitfall: Discontinuing Due to Mild eGFR Decline

Do not discontinue dapagliflozin for mild, transient eGFR decreases after initiation—this is hemodynamic, not kidney injury, and long-term renal outcomes are improved. 6 Continue therapy unless eGFR falls below 20 mL/min/1.73m² 6

Pregnancy and Breastfeeding

Dapagliflozin may harm the fetus and should be discontinued if pregnancy occurs; do not breastfeed while taking dapagliflozin. 2 Switch to alternative glucose-lowering therapy during pregnancy 2

Class Effect Considerations

The cardiovascular and renal benefits of SGLT2 inhibitors represent a class effect, with empagliflozin showing similar results in EMPEROR-Reduced (21% reduction in CV death or HF hospitalization, HR 0.79). 1, 5 A large meta-analysis of 21,947 patients across five trials confirmed consistent benefits across the SGLT2 inhibitor class 1