What is the comparison of SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors for reducing Major Adverse Cardiovascular and Kidney Disease outcomes?

SGLT2 Inhibitors for Reducing Major Adverse Cardiovascular and Kidney Disease Outcomes

SGLT2 inhibitors are strongly recommended for patients with type 2 diabetes who have established cardiovascular disease, multiple cardiovascular risk factors, or chronic kidney disease, as they significantly reduce major adverse cardiovascular events, heart failure hospitalizations, and kidney disease progression. 1

Cardiovascular Benefits of SGLT2 Inhibitors

Established Evidence

• Multiple large randomized controlled trials have demonstrated statistically significant reductions in cardiovascular events for three FDA-approved SGLT2 inhibitors: empagliflozin, canagliflozin, and dapagliflozin (with lesser benefits seen with ertugliflozin) 2
• SGLT2 inhibitors reduce risk of atherosclerotic major adverse cardiovascular events (MACE) in patients with type 2 diabetes and established ASCVD 2
• Key cardiovascular benefits include:
  • Reduction in hospitalization for heart failure (HR 0.70,95% CI 0.62-0.79) 3
  • Reduction in all-cause mortality (HR 0.85,95% CI 0.78-0.94) 3
  • Reduction in cardiovascular death (HR 0.83,95% CI 0.74-0.93) 3

Comparison Between Agents

• Empagliflozin (EMPA-REG OUTCOME): Showed 14% reduction in primary composite outcome (HR 0.86,95% CI 0.74-0.99), with 38% reduction in cardiovascular death (HR 0.62,95% CI 0.49-0.77) and 35% reduction in heart failure hospitalization (HR 0.65,95% CI 0.50-0.85) 2
• Canagliflozin (CANVAS/CANVAS-R): Demonstrated 14% reduction in primary composite outcome (HR 0.86,95% CI 0.75-0.97), with 13% reduction in cardiovascular death (HR 0.87,95% CI 0.72-1.06) and 33% reduction in heart failure hospitalization (HR 0.67,95% CI 0.52-0.87) 2
• Dapagliflozin: Showed significant reduction in heart failure hospitalization (HR 0.70,95% CI 0.54-0.90) 2

Renal Benefits of SGLT2 Inhibitors

Kidney Protection Mechanisms

• SGLT2 inhibitors provide renoprotection through multiple mechanisms 1:
  • Reducing intraglomerular pressure
  • Decreasing renal tubular glucose reabsorption
  • Lowering systemic blood pressure
  • Reducing albuminuria
  • Decreasing oxidative stress in the kidney

Kidney Outcomes

• SGLT2 inhibitors decrease the risk of kidney failure (HR 0.70,95% CI 0.62-0.79) 3
• They reduce composite kidney outcomes (kidney failure, kidney death with or without ≥40% decrease in eGFR) (HR 0.68,95% CI 0.59-0.78) 3
• Specific trials showing renal benefits:
  • Canagliflozin (CREDENCE): 32% risk reduction for development of ESKD 2
  • Dapagliflozin (DAPA-CKD): 39% reduction in the kidney composite endpoint (HR 0.61,95% CI 0.51-0.72) 2
  • Empagliflozin (EMPA-KIDNEY): 24% lower HR for major kidney disease events 2

Patient Selection and Clinical Application

Recommended Patient Populations

• Patients with type 2 diabetes and established ASCVD, multiple ASCVD risk factors, or CKD 2
• Patients with CKD and eGFR ≥20 mL/min/1.73 m², with highest priority for those with albuminuria (ACR ≥200 mg/g) 1
• Both diabetic and non-diabetic CKD patients can benefit 4

FDA-Approved Indications

• Dapagliflozin: Approved to reduce risk of sustained eGFR decline, ESKD, CV death, and HF hospitalization in adults with CKD at risk of progression 5
• Canagliflozin: Approved to reduce risk of ESKD, doubling of serum creatinine, CV death, and HF hospitalization in adults with T2DM and diabetic nephropathy with albuminuria 6

Dosing Considerations

• Empagliflozin: 10 mg or 25 mg PO daily; do not initiate if eGFR <45 mL/min/1.73 m² 2
• Canagliflozin: 100 mg PO daily (may increase to 300 mg if eGFR ≥60 mL/min/1.73 m²); do not exceed 100 mg/day if eGFR 45-59 mL/min/1.73 m² 2
• Dapagliflozin: 10 mg PO daily 1

Monitoring and Safety Considerations

Potential Adverse Effects

• Genital mycotic infections (higher risk in women than men: 6% vs 1%) 1
• Volume depletion (especially in patients on diuretics) 1
• Diabetic ketoacidosis 1
• Urinary tract infections 1
• Hypoglycemia (when used with insulin or sulfonylureas) 1

Monitoring Recommendations

• Assess renal function prior to initiation and periodically thereafter 1
• Anticipate initial, reversible decline in eGFR (hemodynamic effect) 1
• Monitor volume status, especially in patients on diuretics 1
• Consider reducing diuretic doses before starting therapy 1

Contraindications

• eGFR <20 mL/min/1.73 m² 1
• Kidney transplant recipients 1
• Patients requiring or with recent immunosuppressive therapy for kidney disease 1
• Not recommended for CKD in polycystic kidney disease 1

Clinical Decision Algorithm

1. Assess patient eligibility:

   • Type 2 diabetes with established ASCVD, multiple CV risk factors, or CKD
   • eGFR ≥20 mL/min/1.73 m²
   • Presence of albuminuria (prioritize if ACR ≥200 mg/g)

2. Select appropriate SGLT2 inhibitor:

   • For patients with predominant CV disease: Consider empagliflozin (strongest CV death reduction)
   • For patients with diabetic kidney disease with albuminuria: Consider canagliflozin or dapagliflozin
   • For patients with heart failure: Consider dapagliflozin or empagliflozin

3. Dose based on renal function:

   • eGFR ≥60 mL/min/1.73 m²: Full dose of any SGLT2 inhibitor
   • eGFR 45-59 mL/min/1.73 m²: Empagliflozin 10-25 mg, canagliflozin 100 mg, or dapagliflozin 10 mg
   • eGFR 20-44 mL/min/1.73 m²: Dapagliflozin 10 mg or consider other agents based on specific indications

4. Continue therapy even if eGFR falls below the initiation threshold, unless patient is not tolerating treatment or kidney replacement therapy is initiated 1

SGLT2 inhibitors represent a breakthrough in cardiovascular and kidney protection for patients with type 2 diabetes and CKD, with benefits extending beyond glycemic control to include significant reductions in mortality, cardiovascular events, and kidney disease progression.