What are SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors and their mechanism of action?

SGLT2 Inhibitors: Mechanism of Action and Clinical Benefits

SGLT2 inhibitors work by blocking sodium-glucose cotransporter 2 proteins in the kidneys, reducing glucose reabsorption and increasing urinary glucose excretion, which lowers blood sugar levels while improving insulin secretion and sensitivity. 1, 2

Mechanism of Action

SGLT2 inhibitors target a specific mechanism of glucose regulation:

• Primary site of action: SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into circulation, primarily expressed in the S1 and S2 segments of the proximal convoluted tubule in the kidneys 3, 2

• Physiological effect: By inhibiting SGLT2, these medications:

  • Reduce renal glucose reabsorption
  • Lower the renal threshold for glucose
  • Increase urinary glucose excretion (approximately 64-78 grams per day) 2
  • Function independently of insulin action 1

• Pharmacodynamics: Following administration, SGLT2 inhibitors:

  • Rapidly increase urinary glucose excretion
  • Suppress renal threshold for glucose throughout the 24-hour period
  • May delay intestinal glucose absorption and reduce postprandial glucose 4

Available SGLT2 Inhibitors

The following SGLT2 inhibitors are currently available, with varying selectivity profiles:

SGLT2 Inhibitor	Selectivity	Indications
Dapagliflozin	High	Type 2 diabetes, CKD, cardiovascular risk reduction
Empagliflozin	High	Type 2 diabetes, CKD, cardiovascular risk reduction
Ertugliflozin	High	Type 2 diabetes, CKD, cardiovascular risk reduction
Canagliflozin	Lower	Type 2 diabetes, CKD, cardiovascular risk reduction
Sotagliflozin	Dual SGLT1/2	Type 2 diabetes, CKD, cardiovascular risk reduction

3, 1

Clinical Benefits Beyond Glycemic Control

SGLT2 inhibitors offer several important benefits beyond lowering blood glucose:

• Cardiovascular benefits:

  • Reduce risk of cardiovascular death and hospitalization for heart failure by 26% in heart failure with reduced ejection fraction (HFrEF) and 18% in heart failure with preserved ejection fraction (HFpEF) 1
  • Benefits seen regardless of diabetes status 1

• Renal benefits:

  • Slow progression of chronic kidney disease
  • Reduce albuminuria
  • Benefits seen down to an eGFR of 30 mL/min/1.73 m² 1

• Metabolic benefits:

  • Weight loss due to caloric loss through glucosuria 1, 5
  • Blood pressure reduction 1, 5
  • Improved lipid profile 5
  • Reduction in hyperuricemia 5

Safety Considerations

Important safety considerations when using SGLT2 inhibitors include:

• Common side effects:

  • Genital mycotic infections
  • Urinary tract infections
  • Volume depletion/hypotension
  • Euglycemic diabetic ketoacidosis (rare but serious) 1

• Medication adjustments:

  • When adding SGLT2 inhibitors to existing therapy, consider reducing:
    • Sulfonylurea dose by 50%
    • Basal insulin dose by 20% to prevent hypoglycemia 1

• Renal considerations:

  • Reduced glycemic efficacy at eGFR <45 mL/min/1.73m²
  • Cardiovascular and renal benefits persist down to eGFR of 30 mL/min/1.73m² 1

• Monitoring recommendations:

  • More frequent glucose monitoring during first 4 weeks of therapy
  • Regular kidney function assessment
  • Education about potential volume depletion 1

Clinical Positioning

SGLT2 inhibitors have evolved from purely glucose-lowering agents to medications with significant cardiorenal protective effects:

• They can be used regardless of baseline HbA1c to reduce major adverse cardiovascular events, heart failure hospitalization, cardiovascular death, or CKD progression 1

• They are particularly beneficial for patients with:

  • Type 2 diabetes with established cardiovascular disease
  • High cardiovascular risk
  • Heart failure
  • Chronic kidney disease 1, 5

• They offer the advantage of insulin-independent action, making them suitable for use regardless of diabetes duration (provided renal function is acceptable) 1, 5

SGLT2 inhibitors represent a significant advancement in diabetes management, offering multisystem benefits that extend well beyond their glucose-lowering effects.