What is the role of Jardiance (empagliflozin) in treating Grade 3 diastolic dysfunction?

Treatment of Grade 3 Diastolic Dysfunction with Jardiance (Empagliflozin)

Empagliflozin is strongly recommended for patients with Grade 3 diastolic dysfunction, as it significantly improves left ventricular filling pressures, diastolic function, and reduces cardiovascular mortality and heart failure hospitalizations regardless of ejection fraction or diabetes status. 1, 2

Understanding Grade 3 Diastolic Dysfunction

Grade 3 diastolic dysfunction represents severe disease characterized by a restrictive filling pattern with abnormally reduced mitral annular e′ velocity (septal <7 cm/sec, lateral <10 cm/sec) and markedly elevated left ventricular filling pressures. 3 This advanced stage is associated with poor outcomes and typically occurs when LV relaxation is severely impaired alongside markedly elevated filling pressures. 3

Evidence for Empagliflozin in Diastolic Dysfunction

Guideline-Based Recommendations

• The American College of Cardiology and American Heart Association strongly recommend empagliflozin for all patients with symptomatic chronic heart failure regardless of ejection fraction or diabetes status. 3, 1, 2

• The American Diabetes Association designates SGLT2 inhibitors, including empagliflozin, as first-line agents for patients with diabetes who have heart failure or are at high risk for heart failure. 3

• Benefits are consistent across the entire spectrum of heart failure, including both HFrEF (ejection fraction ≤40%) and HFpEF (ejection fraction >40%), which commonly presents with diastolic dysfunction. 1, 2

Cardiovascular Outcomes

• Empagliflozin reduces cardiovascular death or hospitalization for heart failure by 21% (HR 0.79 [95% CI 0.69-0.90]; P < 0.001) in patients with heart failure across all ejection fractions. 3, 1, 2

• In the EMPA-REG OUTCOME trial, empagliflozin reduced hospitalization for heart failure by 35% compared to placebo in patients with type 2 diabetes and high cardiovascular risk. 3, 4

• The number needed to treat to prevent one heart failure hospitalization or cardiovascular death is 35 over 3 years. 4

Direct Effects on Diastolic Function

The most compelling evidence for Grade 3 diastolic dysfunction comes from studies demonstrating rapid and sustained improvement in left ventricular filling pressures:

• Empagliflozin significantly reduces the E/e' ratio (a key marker of LV filling pressure) within 24 hours of initiation, with sustained improvement throughout treatment. 5 This rapid effect explains the early separation of heart failure hospitalization curves seen in clinical trials. 5

• In diabetic patients with HFpEF, empagliflozin treatment for 6 months significantly decreased the E/e' ratio both at rest and during exercise, improved LA volume index, and enhanced LV diastolic reserve. 6

• Empagliflozin improves diastolic function by increasing phospholamban phosphorylation and SERCA2a/PLN ratio, which enhances calcium handling and cardiac relaxation. 7

• The reduction in early mitral inflow velocity (E velocity) occurs rapidly (within 1 day) and is primarily responsible for the improved E/e' ratio. 5

Clinical Implementation Algorithm

Patient Selection

• Initiate empagliflozin 10 mg daily in all patients with Grade 3 diastolic dysfunction who have symptomatic heart failure (NYHA class II-IV). 1, 2
• Benefits occur regardless of diabetes status, so do not limit use to diabetic patients only. 1, 2
• The medication can be used with eGFR as low as 20 mL/min/1.73m², though it is contraindicated below this threshold. 2, 8

Dosing

• Standard dose is empagliflozin 10 mg once daily. 3, 6, 5
• No dose titration is required, unlike many other heart failure medications. 2
• Benefits appear within days to weeks of initiation. 2, 5

Monitoring Requirements

Critical safety monitoring includes:

• Monitor for symptomatic hypotension, particularly in elderly patients, those with low baseline systolic blood pressure, renal impairment, or patients on diuretics. 1

• Watch for signs of diabetic ketoacidosis (including euglycemic ketoacidosis), especially during illness, fasting, or in susceptible patients. 1

• Expect a mild, transient decrease in eGFR after initiation—this does not indicate kidney injury and should not prompt discontinuation. 8

• Monitor for genital mycotic infections (1.5-1.7% incidence) and urinary tract infections (2.3-2.7% incidence), which are generally manageable. 8

Expected Hemodynamic Effects

• Empagliflozin does not significantly alter cardiac index, stroke volume index, systemic vascular resistance, or heart rate. 5 This distinguishes it from traditional diuretics and makes it safer in patients with borderline hemodynamics.

• The primary mechanism involves improved LV filling pressure through enhanced diastolic relaxation rather than changes in preload or afterload. 5

• Urinary volume increases by approximately 300-400 mL/24 hours within the first day, with significant glucosuria in diabetic patients. 5

Important Clinical Considerations

Contraindications

• eGFR <20 mL/min/1.73m² 2, 8
• History of serious hypersensitivity to empagliflozin 8
• Polycystic kidney disease or recent immunosuppressive therapy for kidney disease 8

Advantages Over Other Medications

Empagliflozin offers distinct advantages in Grade 3 diastolic dysfunction:

• Unlike thiazolidinediones, which worsen heart failure, empagliflozin reduces heart failure risk. 3, 2
• Unlike DPP-4 inhibitors (which have mixed or neutral effects on heart failure), empagliflozin provides robust heart failure benefits. 3, 2
• The benefits appear independent of glucose-lowering effects, representing direct cardiovascular protection. 3, 2

Combination Therapy

• Empagliflozin can be safely combined with other guideline-directed medical therapy for heart failure, including ACE inhibitors, ARBs, beta-blockers, and mineralocorticoid receptor antagonists. 4
• Effects are consistent across categories of background heart failure medications. 4

Mechanism of Benefit

The cardiovascular benefits in diastolic dysfunction are multifactorial and not fully explained by diuresis alone:

• Enhanced myocardial calcium handling through improved SERCA2a function 7
• Improved myocardial insulin sensitivity and glucose utilization 7
• Reconciliation of diabetes-associated MAPK dysregulation 7
• Improved LA reservoir and contractile function 6
• Enhanced chronotropic reserve 6
• Reduction in profibrotic biomarkers (sST2) and NT-proBNP 6

Quality of Life and Functional Capacity

• Empagliflozin significantly improves 6-minute walk test distance in patients with HFpEF and diastolic dysfunction. 6
• Treatment improves symptoms, physical limitations, and overall quality of life. 2
• Functional improvements correlate with enhanced cardiac reserves (LV diastolic, LA reservoir and contractile, and chronotropic). 6