Which medication reduces mortality in adults with heart failure with preserved ejection fraction (ejection fraction ≥ 50%)?

SGLT2 Inhibitors Reduce Mortality in Heart Failure with Preserved Ejection Fraction

Dapagliflozin and empagliflozin both reduce the composite outcome of cardiovascular death or heart failure hospitalization in adults with HFpEF (EF ≥50%), and you should prescribe one of these agents at 10 mg once daily to all symptomatic patients with HFpEF. 1, 2

Evidence for Mortality and Morbidity Reduction

Dapagliflozin in HFpEF

• **Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death by 18% (HR 0.82,95% CI 0.73-0.92; P<0.001) in the DELIVER trial**, which enrolled 6,263 patients with heart failure and ejection fraction >40%. 3
• The benefit was driven primarily by a 21% reduction in worsening heart failure events (HR 0.79,95% CI 0.69-0.91), with cardiovascular death reduced by 12% (HR 0.88,95% CI 0.74-1.05). 3
• Results were consistent in patients with EF ≥60% and those with EF 50-59%, demonstrating efficacy across the entire preserved ejection fraction spectrum. 3
• The benefit occurred regardless of diabetes status—approximately 44% of patients had type 2 diabetes, and outcomes were equivalent in both diabetic and non-diabetic patients. 1, 3

Empagliflozin in HFpEF

• **Empagliflozin reduced the composite of cardiovascular death or heart failure hospitalization by 21% (HR 0.79,95% CI 0.69-0.90; P<0.001) in the EMPEROR-Preserved trial**, which enrolled 5,988 patients with heart failure and EF >40%. 4
• This benefit was primarily driven by a 27% reduction in heart failure hospitalizations (HR 0.73,95% CI 0.61-0.88; P<0.001). 4
• Approximately 50% of patients had type 2 diabetes at baseline, and the treatment effect was consistent regardless of diabetes status. 1, 4
• The benefit extended to patients with EF ≥50%, though some attenuation of effect has been observed at the highest EF ranges (>60%). 5

Guideline Recommendations

• The American College of Cardiology and American Diabetes Association provide Class I recommendations for SGLT2 inhibitors in all patients with symptomatic HFpEF to reduce cardiovascular death and heart failure hospitalizations. 1, 2
• Both dapagliflozin and empagliflozin are FDA-approved for heart failure treatment regardless of diabetes status. 2, 6
• These agents should be initiated at 10 mg once daily with no dose titration required, making them simpler to implement than other guideline-directed medical therapies. 2, 7

Choosing Between Dapagliflozin and Empagliflozin

• Dapagliflozin and empagliflozin are considered interchangeable with equivalent efficacy for mortality and morbidity reduction in HFpEF. 2, 6
• Base your choice on formulary availability and cost—dapagliflozin may be more cost-effective with an ICER of $36,902/QALY compared to empagliflozin. 8
• Both agents provide additional renal protection, reducing composite renal endpoints by 39-62%. 2, 6

Practical Implementation

• Initiate SGLT2 inhibitors during heart failure hospitalization once patients are stabilized (no increase in IV diuretics for 6 hours, no IV vasodilators or inotropes for 24 hours). 1, 2
• These medications can be started with eGFR as low as 20-25 mL/min/1.73m² and should be continued even if eGFR declines during treatment. 2, 7
• Do not discontinue for mild transient eGFR decline after initiation—this is expected and provides long-term kidney protection. 2, 6
• Benefits occur within weeks of initiation, with empagliflozin showing a 58% relative risk reduction at just 12 days. 2, 6

Safety Considerations and Monitoring

• Monitor for volume depletion and hypotension, though symptomatic hypotension occurs in only 0.3-5.7% of patients. 2, 6
• Watch for genital mycotic infections (1.5-1.7%) and urinary tract infections (2.3-2.7%), which are generally manageable. 6
• Euglycemic ketoacidosis is rare but requires prompt recognition, particularly in patients with diabetes who are fasting or have reduced insulin doses. 1, 6
• Check renal function and electrolytes at 1-2 weeks, then at 4 weeks after initiation. 7

Common Pitfalls to Avoid

• Do not withhold SGLT2 inhibitors based on lack of diabetes—the cardiovascular benefits are independent of glucose-lowering effects and occur equally in non-diabetic patients. 1, 2, 3, 4
• Do not delay initiation until after hospital discharge—deferring treatment results in many eligible patients never receiving the medication within 1 year. 2, 6
• Do not use ertugliflozin or other SGLT2 inhibitors without dedicated HFpEF outcome trial data—only dapagliflozin and empagliflozin have proven benefit in this population. 2, 6
• Recognize that SGLT2 inhibitors have minimal effects on blood pressure, heart rate, or potassium levels, making them safe to combine with other heart failure medications. 2, 6