Dapagliflozin Use in Non-Diabetic Patients with HFrEF or CKD

Indications and Benefits

The American Diabetes Association recommends dapagliflozin to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adults with heart failure, regardless of diabetes status, as supported by multiple large randomized controlled trials 1, 2
Dapagliflozin is indicated to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with CKD at risk of progression, with or without diabetes, as shown in the DAPA-CKD trial 2, 3

Efficacy in Non-Diabetic HFrEF Patients

In the DAPA-HF trial, dapagliflozin reduced the risk of worsening heart failure or cardiovascular death by 27% in non-diabetic patients with HFrEF (HR 0.73 [95% CI 0.60-0.88]) 1

Efficacy in Non-Diabetic CKD Patients

In the DAPA-CKD trial, dapagliflozin reduced the primary composite outcome (sustained decline in eGFR of ≥50%, end-stage kidney disease, or death from renal or cardiovascular causes) by 39% (HR 0.61 [95% CI 0.51-0.72]) 2, 3
The renal-specific composite outcome (excluding cardiovascular death) was reduced by 44% (HR 0.56 [95% CI 0.45-0.68]) 4

Safety Considerations

Hypotension may occur in approximately 5.7% of patients, especially those with volume depletion 5
While diabetic ketoacidosis is a concern in diabetic patients, this risk is significantly lower in non-diabetic populations 4
Genital mycotic infections (1.5-1.7%) and urinary tract infections (2.3-2.7%) can occur but are generally manageable 5

Clinical Implementation

Identify eligible non-diabetic patients, including HFrEF patients (LVEF ≤40%) with NYHA class II-IV symptoms, and CKD patients with eGFR 25-75 mL/min/1.73 m² and UACR ≥200 mg/g 1, 2, 3
Assess contraindications, including history of serious hypersensitivity to dapagliflozin, polycystic kidney disease, and recent immunosuppressive therapy for kidney disease 2
Monitor renal function periodically, signs of volume depletion (hypotension, dizziness), and symptoms of heart failure or kidney disease progression 1, 2, 5

Managing Heart Failure with SGLT2 Inhibitors

Benefits of SGLT2 Inhibitors in Heart Failure

The American College of Cardiology recommends dapagliflozin (10 mg daily) as a cornerstone therapy for heart failure with reduced ejection fraction (HFrEF), reducing cardiovascular death and heart failure hospitalizations regardless of diabetes status 6, 7
SGLT2 inhibitors demonstrate a beneficial class effect in patients with HFrEF, with dapagliflozin showing a 30% decrease in first episodes of worsening heart failure and 18% decrease in cardiovascular death 7
The European Society of Cardiology notes that SGLT2 inhibitors do not require dose adjustment or up-titration and have minimal impact on blood pressure, heart rate, or potassium levels 8
Benefits of dapagliflozin occur within weeks of initiation and are maintained regardless of age, sex, or background medical therapy 8

Considerations for SGLT2 Inhibitor Use

Dapagliflozin has been shown to be effective with an eGFR as low as 20-30 mL/min/1.73m² 7
A mild, transient decrease in eGFR may occur after initiating SGLT2 inhibitors but does not indicate kidney injury and should not prompt discontinuation 9, 8
The cardiovascular benefits of SGLT2 inhibitors are consistent across heart failure populations and should be prioritized over concerns about mild urinary symptoms 8

Role of SGLT2 Inhibitors in Heart Failure Patients

Benefits in Different Heart Failure Populations

SGLT2 inhibitors are strongly recommended for all heart failure patients with reduced ejection fraction (HFrEF) to reduce the risk of worsening heart failure, hospitalization, and cardiovascular death, regardless of diabetes status, as recommended by the American College of Cardiology and the American Diabetes Association 10, 11
SGLT2 inhibitors significantly reduce hospitalization for heart failure by 27-39% across multiple large clinical trials, demonstrating a consistent class effect, with high strength of evidence 12, 13
For patients with heart failure with reduced ejection fraction (HFrEF, LVEF ≤40%), SGLT2 inhibitors reduce cardiovascular death by 18%, as shown in clinical trials with moderate to high strength of evidence 14
In heart failure with preserved ejection fraction (HFpEF, LVEF >40%), empagliflozin reduced the composite of cardiovascular death or hospitalization for heart failure by 21% in the EMPEROR-Preserved trial, with moderate strength of evidence 15

Evidence from Major Clinical Trials

The DAPA-HF trial showed dapagliflozin reduced the primary outcome of worsening heart failure or cardiovascular death by 26% (HR 0.74 [95% CI 0.65-0.85]) in patients with HFrEF, with consistent benefits regardless of diabetes status, and high strength of evidence 13
The EMPEROR-Reduced trial demonstrated empagliflozin reduced the primary composite outcome of cardiovascular death or hospitalization for worsening heart failure by 25% (HR 0.75 [95% CI 0.65-0.86]) in HFrEF patients, with high strength of evidence 10
The DELIVER trial showed dapagliflozin reduced the composite of worsening heart failure or cardiovascular death by 18% in patients with HFpEF, with moderate strength of evidence 10

Clinical Implementation

The American College of Cardiology recommends SGLT2 inhibitors should be initiated in all eligible patients with HFrEF (LVEF ≤40%) with NYHA class II-IV symptoms, with high strength of evidence 11
For HFpEF (LVEF >40%), SGLT2 inhibitors are recommended for symptomatic patients (NYHA class II-IV), with moderate strength of evidence 11, 14

Important Considerations and Precautions

The American College of Cardiology states that main contraindications for SGLT2 inhibitors include eGFR <20 mL/min/1.73m², with high strength of evidence 11

Comparison with Other Heart Failure Medications

Unlike some other medications (e.g., thiazolidinediones), SGLT2 inhibitors reduce rather than increase heart failure risk, as shown in clinical trials with moderate to high strength of evidence 16, 15
DPP-4 inhibitors have mixed evidence regarding heart failure risk, while GLP-1 receptor agonists have not shown increased risk of heart failure hospitalization but do not have the robust heart failure benefits seen with SGLT2 inhibitors, with moderate strength of evidence 13, 15, 17

Dapagliflozin for Heart Failure Treatment

Evidence Supporting Dapagliflozin

The American Diabetes Association and American College of Cardiology strongly recommend dapagliflozin for all patients with symptomatic heart failure regardless of ejection fraction or diabetes status, based on high-quality evidence from the DAPA-HF trial and others 18, 19
Dapagliflozin reduced the composite outcome of worsening heart failure or cardiovascular death by 26% in the DAPA-HF trial, which enrolled 4,744 patients with NYHA class II-IV heart failure and ejection fraction ≤40% 18
First worsening heart failure events were reduced by 30%, and cardiovascular death was reduced by 18% in the DAPA-HF trial 18
The DELIVER trial demonstrated that dapagliflozin reduced the composite of worsening heart failure or cardiovascular death by 18% in 6,263 patients with ejection fraction >40%, providing evidence for its use in heart failure with mildly reduced or preserved ejection fraction 18, 19

Guideline Recommendations and Clinical Algorithm

The American College of Cardiology recommends choosing dapagliflozin 10 mg daily or empagliflozin 10 mg daily for patients with HFrEF, as both have Class I, high-quality evidence 19
Dapagliflozin should be initiated during heart failure hospitalization in stabilized patients, as deferring initiation results in many eligible patients never receiving the medication within 1 year 18, 19
The American Diabetes Association and American College of Cardiology emphasize using SGLT2 inhibitors "with proven benefit" for heart failure, which excludes ertugliflozin due to lack of dedicated outcome trials 18, 19

Ertugliflozin Limitations

Ertugliflozin has not been studied in any dedicated heart failure outcome trials comparable to DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, or DELIVER, and therefore lacks evidence for its use in heart failure 18, 19
The available evidence for SGLT2 inhibitors in heart failure comes exclusively from trials of empagliflozin, canagliflozin, dapagliflozin, and sotagliflozin, with ertugliflozin being conspicuously absent from all major cardiovascular outcome trials 18, 19

SGLT2 Inhibitors in Heart Failure

Introduction to SGLT2 Inhibitors

The European Society of Cardiology recommends SGLT2 inhibitors as a Class I, Level A treatment for patients with HFrEF to reduce cardiovascular death and heart failure hospitalizations 20
The American Heart Association recommends SGLT2 inhibitors as a Class 2a, Level B-R treatment for patients with HFpEF to decrease heart failure hospitalizations and cardiovascular mortality 21

Clinical Implementation

The American College of Cardiology suggests that SGLT2 inhibitors can be initiated during hospitalization in stabilized patients, with no increase in IV diuretics for 6 hours, no IV vasodilators or inotropes for 24 hours 22
Early initiation of SGLT2 inhibitors is critical, with empagliflozin showing a 58% relative risk reduction at just 12 days after initiation 22
The European Journal of Heart Failure recommends no dose titration for SGLT2 inhibitors, unlike other heart failure medications 23

Strength of Evidence

The evidence quality is highest for HFrEF (Class I, Level A) based on DAPA-HF and EMPEROR-Reduced trials 20
For HFpEF, the evidence is strong but slightly lower (Class 2a, Level B-R) based on EMPEROR-Preserved and DELIVER trials 21

SGLT2 Inhibitors in Heart Failure Treatment

Current Guideline Recommendations

The American College of Cardiology and the American Heart Association recommend SGLT2 inhibitors, such as dapagliflozin and empagliflozin, for heart failure treatment, regardless of diabetes status, due to their proven benefits in reducing cardiovascular death and heart failure hospitalizations 24, 25
For patients with heart failure with mildly reduced ejection fraction (HFmrEF, LVEF 41-49%), SGLT2 inhibitors receive a Class 2a, Level B-R recommendation to decrease heart failure hospitalizations and cardiovascular mortality, based on subgroup analysis from the EMPEROR-Preserved trial 24, 25
For patients with heart failure with preserved ejection fraction (HFpEF, LVEF >40%), SGLT2 inhibitors receive a Class 2a recommendation, with empagliflozin showing a 21% reduction in cardiovascular death or heart failure hospitalization in the EMPEROR-Preserved trial 24, 25

Unique Advantages of SGLT2 Inhibitors

SGLT2 inhibitors have the advantage of no dose titration required, unlike ACE inhibitors, ARBs, or beta-blockers, and no significant effect on blood pressure, heart rate, or potassium levels, making them safe to combine with other guideline-directed medical therapy 26
Benefits of SGLT2 inhibitors occur within weeks of initiation, with empagliflozin showing a 58% relative risk reduction at just 12 days, and are effective across the entire LVEF spectrum (reduced, mildly reduced, and preserved ejection fraction) 24, 25, 26
SGLT2 inhibitors can be used with eGFR as low as 20-30 mL/min/1.73m² for dapagliflozin and ≥30 mL/min/1.73m² for empagliflozin, and their benefits are independent of age, sex, background medical therapy, and diabetes status 26

Critical Clinical Considerations

The European Society of Cardiology and the American College of Cardiology recommend recognizing the evidence hierarchy, with empagliflozin and dapagliflozin having the strongest evidence for heart failure treatment from dedicated heart failure trials 24, 25
It is critical not to discontinue SGLT2 inhibitors for mild eGFR decline, as a transient eGFR drop after initiation is expected and provides long-term kidney protection 26

DAPA-HF Trial Summary: Efficacy and Safety of Dapagliflozin

Primary Outcome Results and Renal Function Considerations

Dapagliflozin was effective in patients with moderate renal impairment down to eGFR ≥25 mL/min/1.73 m², with a mild, transient eGFR decline that may occur after initiation but provides long-term kidney protection 27
The European Society of Cardiology recommends considering SGLT2 inhibitors like dapagliflozin for patients with HFrEF, given their favorable safety profile and effectiveness in reducing worsening heart failure and cardiovascular death 27

Unique Pharmacologic Advantages and Clinical Implementation

SGLT2 inhibitors like dapagliflozin have minimal effects on blood pressure, heart rate, or potassium levels, and require no dose titration, with benefits occurring within weeks of drug initiation 27
The American Heart Association suggests that dapagliflozin can be initiated at 10 mg once daily in all eligible HFrEF patients, with effectiveness maintained regardless of whether patients received ≥50% of target doses of background HF medications 27

Cardiovascular and Heart‑Failure Benefits of SGLT2 Inhibitors

Reduction in Hospitalizations and Cardiovascular Mortality

SGLT2 inhibitors lower heart‑failure hospitalizations by 27 %–39 % and cardiovascular death by 13 %–38 % across multiple large randomized controlled trials. (American Diabetes Association) 28
Empagliflozin reduced hospitalization for heart failure by 35 % and cardiovascular death by 38 % in the EMPA‑REG OUTCOME trial. (American College of Cardiology) 29, 30
Canagliflozin lowered heart‑failure hospitalizations by 33 % in the CANVAS program and by 39 % in the CREDENCE trial. (American Diabetes Association) 28
Dapagliflozin decreased heart‑failure hospitalizations by 27 % in DECLARE‑TIMI 58 and cut the composite of worsening heart failure or cardiovascular death by 26 % in DAPA‑HF. (American Diabetes Association) 28

Efficacy Independent of Diabetes Status and Across HF Phenotypes

The cardiovascular and heart‑failure benefits of SGLT2 inhibitors are observed in patients both with and without diabetes, extending to heart‑failure with reduced ejection fraction (HFrEF) and heart‑failure with preserved ejection fraction (HFpEF). (American Diabetes Association) 28

Guideline‑Based Clinical Indications

In patients with established atherosclerotic cardiovascular disease, SGLT2 inhibitors are recommended to reduce major adverse cardiovascular events and heart‑failure hospitalizations. (American College of Cardiology) 29, 30
For individuals with heart‑failure with reduced ejection fraction (LVEF ≤ 40 %), SGLT2 inhibitors should be used regardless of diabetes status to lower cardiovascular death and heart‑failure events. (American Diabetes Association) 28
Patients with chronic kidney disease and albuminuria (UACR > 300 mg/g) are advised to receive an SGLT2 inhibitor to slow CKD progression and diminish cardiovascular risk. (American Diabetes Association) 28

Safety Considerations

Clinicians must monitor for euglycemic diabetic ketoacidosis (DKA), an infrequent but serious adverse effect that can be precipitated by insulin‑pump malfunction, substantial insulin dose reductions, or prolonged fasting. (American Diabetes Association) 28
Although rare, DKA associated with SGLT2 inhibitors requires prompt recognition and management. (American Diabetes Association) 28

SGLT2 Inhibitors in Heart Failure – Evidence‑Based Recommendations

1. Agent Selection and Interchangeability

Dapagliflozin and empagliflozin provide equivalent reductions in mortality and morbidity across the full spectrum of heart failure and should be considered interchangeable, with the choice guided by formulary availability and cost. ACC/AHA/HFSA Class I, Level A recommendation. 31

2. Efficacy of Specific Agents

2.1 Empagliflozin

In patients with heart failure with preserved ejection fraction, empagliflozin reduces the composite of cardiovascular death or heart‑failure hospitalization by 21 %. ACC/AHA/HFSA Class I, Level A recommendation. 32

2.2 Sotagliflozin (dual SGLT1/2)

Sotagliflozin lowers the combined risk of cardiovascular death, heart‑failure hospitalization, or urgent heart‑failure visits by 33 % in the studied population. ACC/AHA/HFSA Class I, Level A recommendation. 31
Use of sotagliflozin is limited to patients who have diabetes and a recent heart‑failure hospitalization. 33
Sotagliflozin is not FDA‑approved for heart‑failure treatment as of 2021. 31

3. Regulatory and Guideline Endorsements

Both dapagliflozin and empagliflozin carry Class I, Level A recommendations from the American College of Cardiology (ACC), American Heart Association (AHA), and Heart Failure Society of America (HFSA) for heart‑failure therapy. 31
Both agents are approved for the treatment of heart failure regardless of diabetes status. 32 [31]

4. Renal Protective Effects

Treatment with an SGLT2 inhibitor reduces the composite renal endpoint by 62 % (hazard ratio 0.62; 95 % CI 0.43–0.90), indicating substantial renal protection in heart‑failure patients. ACC/AHA/HFSA Class I, Level A recommendation. 33

5. Practical Advantages for Clinical Use

No dose titration is required for dapagliflozin or empagliflozin, simplifying initiation alongside other guideline‑directed medical therapies. ACC/AHA/HFSA Class I, Level A recommendation. 32
SGLT2 inhibitors are positioned as foundational therapy together with ACE inhibitors/ARBs/ARNI, beta‑blockers, and mineralocorticoid receptor antagonists in heart‑failure management. ACC/AHA/HFSA Class I, Level A recommendation. 32 [31]