SGLT2 Inhibitors: Mechanism and Clinical Applications
SGLT2 inhibitors are oral medications that reduce plasma glucose by inhibiting sodium-glucose co-transporter 2 in the kidney, enhancing urinary glucose excretion while providing significant cardiovascular and renal benefits beyond glycemic control. 1, 2
Mechanism of Action
SGLT2 inhibitors work through an insulin-independent mechanism:
- Primary mechanism: Inhibit SGLT2, the predominant transporter responsible for glucose reabsorption from the glomerular filtrate back into circulation 2
- Physiological effect: Reduce renal reabsorption of filtered glucose and lower the renal threshold for glucose, thereby increasing urinary glucose excretion 2
- Daily glucose excretion: Approximately 64-78 grams per day with standard doses 2
- Additional effects: Increase urinary volume (osmotic diuresis) and promote natriuresis 3
Clinical Benefits
SGLT2 inhibitors provide multiple benefits beyond glycemic control:
Glycemic Control
- Lower HbA1c by 0.6-0.8% (6-8 mmol/mol) 4
- Minimal risk of hypoglycemia when used as monotherapy 1
- Efficacy dependent on renal function 1
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) 5
- Provide cardiovascular benefits regardless of diabetes status 5
- Particularly beneficial in patients with established cardiovascular disease or at high risk 1, 5
Renal Benefits
- Slow progression of chronic kidney disease 1
- Demonstrate renal benefits down to an eGFR of 30 mL/min/1.73 m² 1
- Reduce albuminuria 1
Metabolic Benefits
- Weight reduction 1, 4
- Blood pressure reduction, particularly systolic 1, 4
- Improved lipid profile 4
- Reduced hyperuricemia 4
Available SGLT2 Inhibitors
| 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 | Low | Type 2 diabetes, CKD, cardiovascular risk reduction |
| Sotagliflozin | Dual | Type 2 diabetes, CKD, cardiovascular risk reduction |
Clinical Considerations and Limitations
Renal Function
- Efficacy depends on renal function 1
- Generally not recommended for eGFR <45 mL/min/1.73 m² (varies by agent) 1
- Recent guidelines suggest benefits in CKD patients with eGFR ≥20 mL/min/1.73 m² 1
Adverse Effects
- Genital mycotic infections 1, 5
- Urinary tract infections 1, 5
- Volume depletion/hypotension (consider reducing diuretic doses) 5
- Euglycemic diabetic ketoacidosis (rare but serious) 5, 4
- Canagliflozin specifically: potential increased risk of lower limb amputations and bone fractures 4
Contraindications
- Severe renal impairment (eGFR thresholds vary by agent) 2
- End-stage renal disease or dialysis 2
- History of serious hypersensitivity reactions to the drug 2
Practical Prescribing Points
- Can be administered with or without food 2
- No dose titration required for most agents 5
- Consider reducing doses of diuretics when initiating to prevent volume depletion 5
- Monitor for symptoms of ketoacidosis, particularly in high-risk patients 5
- For patients on insulin or sulfonylureas, consider dose reductions of these agents when adding SGLT2 inhibitors to prevent hypoglycemia 5
SGLT2 inhibitors represent a significant advancement in diabetes management, with benefits extending beyond glycemic control to cardiovascular and renal protection, making them valuable agents in the treatment of type 2 diabetes, heart failure, and chronic kidney disease.