What are the recommendations for using Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors, such as empagliflozin (Empagliflozin) or canagliflozin (Canagliflozin), in patients with diastolic dysfunction?

SGLT2 Inhibitors in Diastolic Dysfunction

SGLT2 inhibitors, specifically empagliflozin, canagliflozin, or dapagliflozin, are strongly recommended for patients with diastolic dysfunction, particularly when accompanied by type 2 diabetes, heart failure with preserved ejection fraction (HFpEF), or chronic kidney disease. 1, 2

Primary Recommendations by Clinical Context

For Patients with Type 2 Diabetes and Cardiovascular Disease

• Empagliflozin, canagliflozin, or dapagliflozin carry Class I recommendations to reduce cardiovascular events and mortality in patients with type 2 diabetes and established cardiovascular disease 1
• Empagliflozin specifically has a Class I recommendation to reduce cardiovascular death in this population 1, 2
• These agents reduce heart failure hospitalization risk by 30-35% across multiple cardiovascular outcome trials 1

For Heart Failure with Preserved Ejection Fraction (HFpEF/Diastolic Dysfunction)

• In patients with LVEF >40% (which includes most diastolic dysfunction), SGLT2 inhibitors receive a Class IIa recommendation to decrease heart failure hospitalizations and improve quality of life, regardless of diabetes status 1, 2
• This represents the highest level recommendation specifically addressing diastolic dysfunction in current guidelines 1
• The benefit occurs independent of glycemic control, making these agents appropriate even in non-diabetic patients with diastolic dysfunction 2, 3

For Heart Failure with Reduced Ejection Fraction (HFrEF)

• SGLT2 inhibitors carry Class I recommendations for patients with LVEF ≤40% to reduce cardiovascular death and heart failure hospitalization, irrespective of diabetes status 1, 2
• These agents should be added to standard heart failure therapy including ACE inhibitors/ARBs, beta-blockers, and mineralocorticoid receptor antagonists 2

Mechanisms Supporting Use in Diastolic Dysfunction

The cardioprotective effects in diastolic dysfunction occur through multiple pathways:

• Improved calcium handling and SERCA2a function, with increased phospholamban phosphorylation leading to enhanced cardiac relaxation 4
• Reduction in myocardial fibrosis in both atrial and ventricular tissues, a key pathologic feature of diastolic dysfunction 5, 6
• Decreased left ventricular filling pressures (improved E/E' ratio) and enhanced septal wall motion (improved E'/A' ratio) 6
• Attenuation of profibrotic signaling through SGK1/ENaC pathways 6
• Improved myocardial insulin sensitivity and glucose utilization through reconciliation of MAPK dysregulation and IRS1/Akt phosphorylation 4
• Plasma volume contraction and reduced preload through natriuresis and osmotic diuresis, improving subendocardial blood flow 7

Specific Agent Selection

All three agents have demonstrated cardiovascular benefits, but with nuanced differences:

• Empagliflozin: Strongest mortality reduction data (38% reduction in CV death), Class I recommendation for death reduction 1
• Canagliflozin: Demonstrated MACE reduction (HR 0.86) and renal protection in diabetic nephropathy 1, 8
• Dapagliflozin: Robust heart failure hospitalization reduction (26% reduction in DAPA-HF), approved for HFrEF regardless of diabetes 1

Practical Implementation

Dosing

• Empagliflozin: 10 mg daily 1
• Canagliflozin: 100 mg daily (can increase to 300 mg) 1, 8
• Dapagliflozin: 10 mg daily 1

Medication Adjustments When Initiating

• Reduce total daily insulin dose by approximately 20% if HbA1c is well-controlled at baseline 1, 2
• Consider weaning or stopping sulfonylureas or glinides to prevent hypoglycemia 1, 2
• Consider reducing diuretic doses if signs of volume contraction develop 1, 2

Renal Considerations

• Use is not recommended for glycemic control when eGFR <45 mL/min/1.73 m² for empagliflozin and dapagliflozin 1
• Canagliflozin maximum dose is 100 mg daily when eGFR 30-59 mL/min/1.73 m² 1
• Contraindicated when eGFR <30 mL/min/1.73 m² for all agents 1
• Despite these restrictions, SGLT2 inhibitors carry Class I recommendations to reduce progression of diabetic kidney disease 1, 2

Critical Safety Considerations

Perioperative Management

• Discontinue at least 3 days before planned surgery to prevent postoperative ketoacidosis 1, 2

Monitoring for Adverse Effects

• Genital mycotic infections are the most common adverse effect 2
• Volume depletion and hypotension risk, particularly when combined with loop diuretics 1
• Amputation risk observed with canagliflozin (though not with empagliflozin or dapagliflozin); exercise vigilance in patients with peripheral arterial disease, neuropathy, or history of amputation 1
• Bone fractures observed with canagliflozin in CANVAS (but not CANVAS-R) 1

Contraindications

• History of serious hypersensitivity reaction 1
• Pregnancy or breastfeeding (dapagliflozin) 1
• Dialysis or end-stage renal disease 1

Evidence Quality

The recommendations are based on Level A evidence from multiple large randomized controlled trials including EMPA-REG OUTCOME, CANVAS/CANVAS-R, DECLARE-TIMI 58, DAPA-HF, and EMPEROR-Reduced 1, 2. The consistency of heart failure benefits across all trials, regardless of baseline diabetes status or ejection fraction, provides robust support for use in diastolic dysfunction 1, 3.

The preclinical evidence demonstrates direct improvements in diastolic function parameters (E/E' ratio, E'/A' ratio) and reduction in myocardial fibrosis, the pathophysiologic hallmarks of diastolic dysfunction 5, 4, 6. These mechanistic benefits occur independent of blood pressure reduction, supporting a direct myocardial protective effect 6.