Yes, both dapagliflozin and empagliflozin are strongly recommended for HFrEF patients without diabetes mellitus.
Both SGLT2 inhibitors should be prescribed to all patients with HFrEF regardless of diabetes status, as they reduce cardiovascular death and heart failure hospitalizations with equal efficacy in diabetic and non-diabetic patients 1.
Evidence Base
The landmark trials DAPA-HF and EMPEROR-Reduced definitively established that SGLT2 inhibitors work independently of diabetes status:
DAPA-HF Trial (Dapagliflozin)
- 55% of patients did not have diabetes at baseline 1
- In non-diabetic patients: 26% reduction in the composite endpoint of cardiovascular death or worsening heart failure (HR 0.73,95% CI 0.60-0.88) 2
- In diabetic patients: 25% reduction (HR 0.75,95% CI 0.63-0.90) 2
- No statistical difference between groups (P-interaction = 0.80) 2
EMPEROR-Reduced Trial (Empagliflozin)
- 50% of patients had diabetes, 50% did not 3
- Non-diabetic patients: 22% reduction in primary outcome (HR 0.78,95% CI 0.64-0.97) 3
- Diabetic patients: 28% reduction (HR 0.72,95% CI 0.60-0.87) 3
- Benefits consistent regardless of diabetes status (P-interaction = 0.57) 3
Guideline Recommendations
The 2021 Canadian Cardiovascular Society/Canadian Heart Failure Society guidelines provide a Strong Recommendation with High-Quality Evidence: "We recommend an SGLT2 inhibitor, such as dapagliflozin or empagliflozin, be used in patients with HFrEF, with or without concomitant type 2 diabetes, to improve symptoms and quality of life and to reduce the risk of HF hospitalization and/or CV mortality" 1.
The 2022 AHA/ACC/HFSA guidelines similarly recommend SGLT2 inhibitors for HFmrEF (LVEF 41-49%) with Class 2a recommendation, noting benefits are independent of diabetes status 4.
Mechanism of Benefit
The cardiovascular benefits occur through glucose-independent mechanisms 5, including:
- Anti-inflammatory and antifibrotic effects
- Reduced oxidative stress
- Improved endothelial function
- Reverse cardiac remodeling
- Osmotic diuresis reducing preload
Importantly, empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia 3.
Practical Implementation
Dosing:
When to start: Initiate early in the disease course, even before full optimization of other guideline-directed medical therapy, given the significant residual risk in HFrEF patients 1.
Renal considerations:
- DAPA-HF excluded patients with eGFR <30 mL/min/1.73 m² 1
- EMPEROR-Reduced excluded patients with eGFR <20 mL/min/1.73 m² 1
- Dapagliflozin use is contraindicated when eGFR <30 mL/min/1.73 m² for glycemic control but can be used for heart failure indication 6
Safety Profile
No excess adverse events compared to placebo in non-diabetic patients 1:
- Volume depletion: 7.3% vs 6.1% (placebo) 2
- Renal adverse events: 4.8% vs 6.0% (placebo) 2
- No increased hypoglycemia risk in non-diabetics 3
Common adverse effects:
- Genital mycotic infections (10-15% in women, higher in uncircumcised men) - typically managed with antifungals without discontinuation 1
- Temporary eGFR reduction up to 15% that generally resolves within 1-3 months 1
Critical Caveats
Contraindications:
"Sick Day" management: Hold SGLT2 inhibitors during dehydrating illness to prevent diabetic ketoacidosis (rare, 0.1% incidence) 1.
Monitor volume status carefully when combining with ARNIs and loop diuretics due to concomitant diuretic effects 1.
The evidence is unequivocal: diabetes status should not influence the decision to prescribe dapagliflozin or empagliflozin in HFrEF patients. These agents are now foundational therapy for all HFrEF patients regardless of glycemic status.