Heart failure (HF) is one of the most pressing global health challenges, affecting more than 64 million people worldwide. Despite advances in pharmacotherapy—including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs), and beta-blockers—mortality and hospitalization rates remain unacceptably high.
In the past decade, sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as a groundbreaking addition to the heart failure armamentarium. Initially developed as oral antihyperglycemic agents for type 2 diabetes mellitus (T2DM), these drugs have demonstrated remarkable cardiovascular benefits independent of glycemic control. Clinical trials have shown that SGLT2 inhibitors reduce hospitalizations for HF, improve symptoms, and prolong survival, even in patients without diabetes.
This article explores their role in HFrEF (heart failure with reduced ejection fraction) and HFpEF (heart failure with preserved ejection fraction), reviews evidence from pivotal trials, and highlights benefits beyond glucose lowering.
1. Mechanism of Action of SGLT2 Inhibitors
SGLT2 inhibitors (dapagliflozin, empagliflozin, canagliflozin, ertugliflozin) act on the proximal renal tubules, blocking glucose and sodium reabsorption. This results in glucosuria and natriuresis, with downstream metabolic and hemodynamic effects beneficial in heart failure.
Key mechanisms include:
- Osmotic diuresis and natriuresis → reduce preload and pulmonary congestion.
- Afterload reduction → via decreased arterial stiffness and blood pressure.
- Improved cardiac metabolism → shift toward ketone utilization, enhancing myocardial efficiency.
- Reduction in interstitial fibrosis and inflammation → protecting cardiac structure.
- Weight loss and reduced visceral adiposity → improving vascular health.
- Renal protection → lowering intraglomerular pressure and slowing progression of CKD.
These mechanisms explain why benefits are seen across both diabetic and non-diabetic HF patients.
2. Emerging Role in HFrEF (Heart Failure with Reduced Ejection Fraction)
Traditionally, HFrEF management has relied on quadruple therapy:
- ACE inhibitors/ARNI
- Beta-blockers
- MRAs
- SGLT2 inhibitors (now considered a core pillar).
A. Evidence from DAPA-HF Trial
- DAPA-HF (2019):
- Enrolled > 4,700 patients with symptomatic HFrEF (EF ≤ 40%), with or without diabetes.
- Compared dapagliflozin 10 mg daily vs placebo, on top of guideline-directed medical therapy.
- Results:
- Reduced primary endpoint (CV death or worsening HF hospitalization) by 26%.
- Benefits were consistent regardless of diabetes status.
- Improved quality of life scores (Kansas City Cardiomyopathy Questionnaire).
This trial was pivotal in establishing dapagliflozin as a first-line HF drug, independent of glycemic status.
B. Evidence from EMPEROR-Reduced Trial
- EMPEROR-Reduced (2020):
- Enrolled ~3,700 HFrEF patients.
- Tested empagliflozin 10 mg daily vs placebo.
- Results:
- Reduced combined endpoint of CV death or HF hospitalization by 25%.
- Slowed decline in estimated GFR, highlighting renal protective effects.
- Benefit again extended to non-diabetic patients.
Taken together, DAPA-HF and EMPEROR-Reduced firmly established SGLT2 inhibitors as standard therapy for HFrEF.
3. Emerging Role in HFpEF (Heart Failure with Preserved Ejection Fraction)
HFpEF has long been a therapeutic challenge, as most trials with traditional HF therapies failed to show mortality benefit. SGLT2 inhibitors, however, have changed this paradigm.
A. EMPEROR-Preserved Trial
- EMPEROR-Preserved (2021):
- Included > 5,900 patients with symptomatic HF and EF > 40%.
- Empagliflozin 10 mg vs placebo.
- Results:
- Reduced composite endpoint of CV death or HF hospitalization by 21%.
- Major driver: reduced hospitalizations.
- Benefit observed across the spectrum of EF, though slightly attenuated at higher EF levels.
This was the first major trial to demonstrate a positive outcome in HFpEF, marking a landmark moment.
B. DELIVER Trial (with dapagliflozin)
- DELIVER (2022):
- Evaluated dapagliflozin in > 6,200 patients with HF and EF > 40%.
- Showed significant reduction in worsening HF or CV death, mirroring EMPEROR-Preserved.
- Benefits extended even to patients with mid-range EF (HFmrEF, EF 41–49%).
Together, EMPEROR-Preserved and DELIVER provide strong evidence that SGLT2 inhibitors are disease-modifying agents across the full EF spectrum.
4. Benefits Beyond Glucose Control
One of the most fascinating aspects of SGLT2 inhibitors is their ability to provide benefits independent of glycemic control.
A. Hemodynamic Benefits
- Mild diuretic and natriuretic effects → reduce preload and congestion without significant electrolyte disturbances (unlike loop diuretics).
- Lower blood pressure modestly, reducing afterload.
B. Metabolic Benefits
- Promote a shift toward ketone utilization, which is a more efficient myocardial fuel.
- Improve cardiac energetics and reduce oxidative stress.
C. Renal Protection
- Reduce intraglomerular hypertension, albuminuria, and progression of CKD.
- Trials like CREDENCE and DAPA-CKD showed robust renal benefits in both diabetic and non-diabetic populations.
D. Weight and Volume Control
- Promote modest weight loss (~2–3 kg).
- Lower visceral fat, which is metabolically harmful.
E. Quality of Life
- Improved exercise tolerance, NYHA functional class, and patient-reported outcomes.
Thus, SGLT2 inhibitors represent a multisystem therapy—benefiting the heart, kidneys, and metabolism.
5. Safety Profile and Considerations
SGLT2 inhibitors are generally well-tolerated, but some considerations include:
- Genitourinary infections: Due to glucosuria, increased risk of mycotic infections.
- Volume depletion: Caution in patients with hypotension or on high-dose diuretics.
- Diabetic ketoacidosis (DKA): Rare, mainly in type 1 diabetes (hence contraindicated).
- Amputations and fractures: Initially seen with canagliflozin, though not consistently across the class.
Overall, the safety profile is favorable, particularly compared to their broad benefits.
6. Clinical Implementation
A. Guideline Recommendations
- ESC 2021 and AHA/ACC/HFSA 2022 guidelines recommend SGLT2 inhibitors (dapagliflozin or empagliflozin) as a Class I therapy in HFrEF, regardless of diabetes.
- Also recommended in HFpEF (Class IIa), making them the first proven treatment in this group.
B. Practical Use
- Dose: Dapagliflozin 10 mg daily, Empagliflozin 10 mg daily.
- No need for titration.
- Can be started in both outpatient and inpatient settings (except acute hemodynamic instability).
- Should be used alongside standard therapy (ARNI/ACEi, beta-blockers, MRAs).
7. Future Directions
Research is ongoing to explore:
- Combination therapy with other novel HF agents.
- Use in acute decompensated HF (early trials like EMPULSE show promise).
- Broader application in patients with advanced CKD.
- Potential anti-inflammatory and anti-fibrotic roles in myocardial remodeling.
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