What is the latest on SGLT2 (sodium-glucose cotransporter 2) inhibitors, such as empagliflozin (Empagliflozin) and canagliflozin (Canagliflozin), for the treatment of heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF)?

SGLT2 Inhibitors for Heart Failure: HFrEF and HFpEF

SGLT2 inhibitors are now recommended for both HFrEF and HFpEF, representing a major breakthrough in heart failure management—empagliflozin and dapagliflozin reduce heart failure hospitalizations and cardiovascular mortality across the entire ejection fraction spectrum, regardless of diabetes status. 1

Evidence for HFrEF (LVEF ≤40%)

For HFrEF, SGLT2 inhibitors receive the strongest recommendations and should be initiated in all symptomatic patients (NYHA class II-IV) as foundational therapy alongside ACE inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. 1, 2, 3

Key Trial Data for HFrEF:

• DAPA-HF trial: Dapagliflozin reduced worsening heart failure or cardiovascular death by 26% (HR 0.74,95% CI 0.65-0.85), with benefits evident within weeks of initiation and sustained regardless of diabetes status 2

• EMPEROR-Reduced trial: Empagliflozin reduced cardiovascular death or heart failure hospitalization by 25% (HR 0.75,95% CI 0.65-0.86) 2

• Hospitalization reduction: SGLT2 inhibitors consistently reduce heart failure hospitalizations by 27-39% across multiple trials, with dapagliflozin specifically showing a 30% decrease in first episodes of worsening heart failure 2, 3

• Mortality benefit: Cardiovascular death reduced by 18% in HFrEF populations 2

Evidence for HFpEF (LVEF >40%)—The Recent Breakthrough

For HFpEF, SGLT2 inhibitors now carry a Class 2a recommendation (can be beneficial) for decreasing heart failure hospitalizations and cardiovascular mortality—this represents the first medication class to show consistent benefit in this historically difficult-to-treat population. 1

Key Trial Data for HFpEF:

• EMPEROR-Preserved trial (the landmark study you need to know): In 5,988 patients with LVEF >40% and NYHA class I-IV symptoms, empagliflozin reduced cardiovascular death or heart failure hospitalization by 21% over 26.2 months, with benefits consistent regardless of diabetes status 4, 5, 6

• Primary driver: The benefit was mainly from a 29% reduction in heart failure hospitalizations rather than cardiovascular death 5, 6

• DELIVER trial: Dapagliflozin reduced worsening heart failure or cardiovascular death by 18% in HFpEF patients 2

• Functional improvements: 6-minute walk distance improved by 25-30 meters, and Kansas City Cardiomyopathy Questionnaire scores increased by 5-10 points across studies 6

• NT-proBNP reduction: Biomarker levels decreased by 10-20% 6

HFmrEF (LVEF 41-49%)—The Middle Ground

SGLT2 inhibitors also receive a Class 2a recommendation for HFmrEF, with empagliflozin showing a 21% reduction in cardiovascular death or heart failure hospitalization in the EMPEROR-Preserved subgroup of 1,983 patients with LVEF 41-49%. 1, 4, 3

Practical Implementation Algorithm

Who Gets SGLT2 Inhibitors:

1. All symptomatic HF patients (NYHA class II-IV) with LVEF ≤40% → Start immediately as foundational therapy 1, 2

2. Symptomatic HF patients with LVEF 41-49% (HFmrEF) → Initiate SGLT2 inhibitor 1

3. Symptomatic HF patients with LVEF >40% (HFpEF) → Initiate SGLT2 inhibitor 1, 4

Dosing:

• Empagliflozin: 10 mg once daily 4
• Dapagliflozin: 10 mg once daily 2
• No titration required—unlike other HF medications, SGLT2 inhibitors do not need dose adjustment or up-titration 2

Contraindications and Precautions:

• eGFR <20 mL/min/1.73m² is the primary contraindication 2, 4
• Dialysis patients: Empagliflozin is contraindicated 4
• Type 1 diabetes: Avoid due to diabetic ketoacidosis risk 3
• Dapagliflozin can be used with eGFR as low as 20-30 mL/min/1.73m² 2

Monitoring:

• Renal function: Monitor periodically; expect a mild, transient eGFR decrease after initiation—this does not indicate kidney injury and should not prompt discontinuation 2, 4
• Volume status: Assess regularly due to diuretic effects 2, 3
• Genital mycotic infections: Occur in ~2.5% vs. 0.5% with placebo 6
• Symptomatic hypotension: Occurs in ~7% vs. 5% with placebo, especially with volume depletion 2, 6

Key Advantages Over Other HF Therapies

• Minimal hemodynamic effects: No significant impact on blood pressure, heart rate, or potassium levels 2
• Rapid onset: Benefits occur within weeks of initiation 2
• Diabetes-independent: Full benefits regardless of diabetes status 1, 2, 4
• Renal protection: Decreased slope of eGFR decline and 50% reduction in composite renal outcomes 4
• No up-titration needed: Unlike ACE inhibitors, ARBs, or beta-blockers 2

Common Pitfalls to Avoid

Do not discontinue SGLT2 inhibitors due to mild eGFR decline—this is expected hemodynamic effect, not kidney injury 2. Do not withhold in patients without diabetes—the cardiovascular benefits are independent of glucose-lowering effects 1, 2, 4. Do not delay initiation while titrating other medications—SGLT2 inhibitors can be started immediately alongside other guideline-directed medical therapy 2, 3.