SGLT2 Inhibitors in Heart Failure: Agent Selection and Comparative Efficacy

Primary Recommendation

Dapagliflozin and empagliflozin are the two SGLT2 inhibitors with robust evidence for heart failure treatment, and they should be considered interchangeable based on formulary availability and cost, as both demonstrate equivalent mortality and morbidity benefits across the heart failure spectrum. 1, 2

Evidence-Based SGLT2 Inhibitor Options

Agents with Strong Heart Failure Evidence

Dapagliflozin (10 mg once daily):

Reduces cardiovascular death or worsening heart failure by 26% in HFrEF (HR 0.74,95% CI 0.65-0.85) 3
Reduces worsening heart failure or cardiovascular death by 18% in HFpEF (HR 0.82,95% CI 0.73-0.92) 3
FDA-approved for heart failure regardless of ejection fraction or diabetes status 4
Can be initiated when eGFR ≥25 mL/min/1.73 m² 3, 5

Empagliflozin (10 mg once daily):

Reduces cardiovascular death or heart failure hospitalization by 25% in HFrEF (HR 0.75,95% CI 0.65-0.86) 3
Reduces cardiovascular death or heart failure hospitalization by 21% in HFpEF 1, 6
Shows benefits within 12 days of initiation (58% relative risk reduction at day 12) 3
Can be initiated when eGFR ≥20 mL/min/1.73 m² 5

Sotagliflozin (dual SGLT1/2 inhibitor):

Reduces cardiovascular death, heart failure hospitalization, or urgent heart failure visits by 33% 1
Limited to patients with diabetes and recent heart failure hospitalization 1
Not FDA-approved as of 2021 1

Agents WITHOUT Heart Failure Evidence

Ertugliflozin:

Has not been studied in any dedicated heart failure outcome trials 3
Lacks evidence comparable to DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, or DELIVER 3
Should not be used for heart failure indications 3

Canagliflozin:

Demonstrated 33-39% reduction in heart failure hospitalizations in diabetes trials (CANVAS, CREDENCE) 3
No dedicated heart failure outcome trials in non-diabetic populations 7
May be considered when dapagliflozin or empagliflozin are unavailable 5

Head-to-Head Comparison: Dapagliflozin vs. Empagliflozin

Efficacy Equivalence

Meta-analysis of DAPA-HF and EMPEROR-Reduced (8,474 patients combined):

All-cause death reduction: 13% (pooled HR 0.87,95% CI 0.77-0.98) 2
Cardiovascular death reduction: 14% (HR 0.86,95% CI 0.76-0.98) 2
Cardiovascular death or first heart failure hospitalization: 26% reduction (HR 0.74,95% CI 0.68-0.82) 2
Recurrent heart failure hospitalizations or cardiovascular death: 25% reduction (HR 0.75,95% CI 0.68-0.84) 2
No significant heterogeneity between trials (all tests for heterogeneity non-significant) 2

Key Differences

Renal function thresholds:

Dapagliflozin: initiation at eGFR ≥25 mL/min/1.73 m² 3, 5
Empagliflozin: initiation at eGFR ≥20 mL/min/1.73 m² (per updated 2025 guidelines) 5

Onset of benefit:

Empagliflozin shows measurable benefit within 12 days (58% relative risk reduction) 3
Dapagliflozin shows benefit within weeks 3

Regulatory approval:

Both have Class I, Level A recommendations from ACC/AHA/HFSA 1
Both approved for heart failure regardless of diabetes status 1

Clinical Decision Algorithm

Step 1: Confirm Heart Failure Indication

HFrEF (LVEF ≤40%): Use dapagliflozin 10 mg or empagliflozin 10 mg 1, 3
HFmrEF (LVEF 41-49%): Use dapagliflozin 10 mg or empagliflozin 10 mg 3
HFpEF (LVEF ≥50%): Use dapagliflozin 10 mg or empagliflozin 10 mg 3, 6

Step 2: Check Renal Function

eGFR ≥25 mL/min/1.73 m²: Either dapagliflozin or empagliflozin 3, 5
eGFR 20-24 mL/min/1.73 m²: Empagliflozin preferred (approved down to eGFR 20) 5
eGFR <20 mL/min/1.73 m²: Do not initiate either agent 5

Step 3: Consider Formulary and Cost

No generic SGLT2 inhibitors are available 5
Choose based on insurance coverage and patient assistance programs 5
Both agents have equivalent cardiovascular and renal benefits 2

Step 4: Initiate Early

Start during hospitalization in stabilized patients (no IV diuretics for 6 hours, no IV vasodilators/inotropes for 24 hours) 3
Do not wait for "optimal" background therapy 8
Benefits are independent of baseline medications 3, 8

Safety Profile Comparison

Shared Adverse Effects

Genital mycotic infections: ~6% vs. 1% placebo 5
Urinary tract infections: 2.3-2.7% 3
Volume depletion/hypotension: 5.7% (higher in elderly ≥75 years) 3, 5
Euglycemic diabetic ketoacidosis: rare but serious 5, 4

Safety Advantages

Minimal effects on blood pressure, heart rate, or potassium 3
No dose titration required 1, 3
Reduce risk of hyperkalemia (facilitates use of MRAs) 5, 8
Renal protective effects (composite renal endpoint reduced by 62%, HR 0.62,95% CI 0.43-0.90) 1, 2

Common Pitfalls to Avoid

Do not discontinue SGLT2 inhibitors when eGFR falls below 45 mL/min/1.73 m² – cardiovascular and renal benefits persist even when glucose-lowering efficacy is lost 3, 5
Do not stop for initial eGFR dip – a transient decline of 2-5 mL/min/1.73 m² within 2-4 weeks is expected and hemodynamic, not indicative of kidney injury 5
Do not reduce the dose below 10 mg – all outcome trials used the fixed 10 mg dose for cardiovascular/renal protection 3, 5
Do not use ertugliflozin for heart failure – it lacks dedicated heart failure outcome trial data 3
Withhold during acute illness – hold for at least 3 days before major surgery or during illness with reduced oral intake, fever, vomiting, or diarrhea 5, 4

Integration with Guideline-Directed Medical Therapy

SGLT2 inhibitors are foundational therapy alongside:

ACE inhibitors/ARBs/ARNI 1
Beta-blockers 1
Mineralocorticoid receptor antagonists 1

Key advantages:

No dose titration required 1, 3
Can be initiated simultaneously with other GDMT 8
Benefits occur within weeks 3, 8
Effective across entire LVEF spectrum 3
Independent of diabetes status 3, 2

Which sodium‑glucose cotransporter‑2 (SGLT‑2) inhibitors are commonly used for heart failure, and how do their efficacy and safety profiles compare?

Help us tailor your experience