What is the role of SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors in treating type 2 diabetes?

Role of SGLT2 Inhibitors in Type 2 Diabetes Management

SGLT2 inhibitors should be used as first-line therapy for patients with type 2 diabetes who have established cardiovascular disease, heart failure, or chronic kidney disease, regardless of baseline HbA1c levels. 1

Mechanism of Action

SGLT2 inhibitors work by:

• Inhibiting sodium-glucose cotransporter-2 in the proximal renal tubule, which is responsible for approximately 90% of urinary glucose reabsorption 2
• Inducing glucosuria by reducing renal glucose reabsorption and lowering the renal threshold for glucose 3
• Providing diuretic and natriuretic effects, weight loss, and lowering of systolic blood pressure 2
• Increasing delivery of sodium to the distal tubule, which increases tubuloglomerular feedback and reduces intraglomerular pressure 3

Cardiovascular and Renal Benefits

SGLT2 inhibitors offer significant benefits beyond glycemic control:

• Reduce major adverse cardiovascular events (MACE) by 14% in patients with established cardiovascular disease 2, 1
• Reduce heart failure hospitalizations by 27-35% 1
• Reduce progression of kidney disease by 32-47% in patients with type 2 diabetes 1
• Empagliflozin specifically reduces cardiovascular death by 38% and all-cause mortality by 32% 2

Indications Based on Comorbidities

For Patients with Heart Failure

• SGLT2 inhibitors are recommended for patients with type 2 diabetes who have heart failure (with either reduced or preserved ejection fraction) for glycemic management and prevention of heart failure hospitalizations 2

For Patients with Chronic Kidney Disease

• In adults with type 2 diabetes who have CKD (with confirmed eGFR of 20-60 mL/min/1.73 m² and/or albuminuria), an SGLT2 inhibitor should be used for minimizing progression of CKD, reduction in cardiovascular events, and reduction in hospitalizations for heart failure 2
• Note that glycemic benefits of SGLT2 inhibitors are reduced at eGFR <45 mL/min/1.73 m² 2

For Patients with Advanced CKD

• In adults with type 2 diabetes and advanced CKD (eGFR <30 mL/min/1.73 m²), a GLP-1 RA is preferred for glycemic management due to lower risk of hypoglycemia 2

Specific SGLT2 Inhibitors

• Empagliflozin (Jardiance): Reduces primary composite cardiovascular outcome by 14% and heart failure hospitalizations by 35% 1, 4
• Canagliflozin (Invokana): Reduces primary composite cardiovascular outcome by 14% and risk of end-stage kidney disease by 32% 1, 3
• Dapagliflozin (Farxiga): Reduces heart failure hospitalizations by 27% in patients with heart failure with reduced ejection fraction and chronic kidney disease 1

Dosing and Renal Considerations

• Canagliflozin: 100 mg PO daily; maximum dose of 100 mg daily for eGFR 30-59 mL/min/1.73 m², not recommended for eGFR <30 mL/min/1.73 m² 1, 3
• Dapagliflozin: 10 mg PO daily; not recommended for glycemic control if eGFR <45 mL/min/1.73 m², contraindicated if eGFR <30 mL/min/1.73 m² 1
• Empagliflozin: 10 mg PO daily; not recommended for glycemic control if eGFR <45 mL/min/1.73 m² 1, 4

Safety Considerations

• Risk of hypoglycemia is low unless SGLT2 inhibitors are used with insulin or insulin secretagogues 2
• When initiating SGLT2 inhibitors:
  • Consider weaning or stopping sulfonylurea or glinide
  • Reduce total daily insulin dose by approximately 20%, especially if HbA1c is well-controlled 1
  • Adjust diuretic doses to prevent volume depletion 1
• Discontinue at least 3 days before planned surgery to prevent postoperative ketoacidosis 1
• Monitor for:
  • Genital mycotic infections (most common side effect) 5, 6
  • Euglycemic diabetic ketoacidosis (rare but serious) 6
  • Volume depletion, especially in elderly patients or those on diuretics 1

Clinical Decision Algorithm

1. Assess patient comorbidities:

   • If patient has established cardiovascular disease, heart failure, or CKD → SGLT2 inhibitor recommended
   • If patient has advanced CKD (eGFR <30 mL/min/1.73 m²) → GLP-1 RA preferred

2. Check renal function:

   • eGFR ≥45 mL/min/1.73 m² → Any SGLT2 inhibitor appropriate
   • eGFR 30-45 mL/min/1.73 m² → Canagliflozin 100 mg (for cardiorenal protection, not glycemic control)
   • eGFR <30 mL/min/1.73 m² → Avoid SGLT2 inhibitors for glycemic control

3. Consider specific comorbidity profile:

   • Heart failure → Empagliflozin or dapagliflozin preferred
   • Established atherosclerotic cardiovascular disease → Empagliflozin preferred (mortality benefit)
   • CKD with albuminuria → Canagliflozin preferred (renal outcome data)

4. Adjust concomitant medications:

   • Reduce insulin dose by ~20% if well-controlled
   • Consider stopping or reducing sulfonylurea dose
   • Adjust diuretic dose if needed

By following this algorithm, clinicians can optimize the use of SGLT2 inhibitors to improve not only glycemic control but also reduce cardiovascular and renal outcomes in patients with type 2 diabetes.