SGLT2 Inhibitors: Types and Characteristics
The five main SGLT2 inhibitors currently available are dapagliflozin, empagliflozin, ertugliflozin, canagliflozin, and sotagliflozin, with the first three being highly selective for SGLT2 receptors, while canagliflozin has lower selectivity and sotagliflozin has dual SGLT1/SGLT2 action. 1
Mechanism of Action
SGLT2 inhibitors work by blocking the sodium-glucose co-transporter 2 (SGLT2), which is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. By inhibiting SGLT2:
- They reduce renal glucose reabsorption in the proximal convoluted tubule
- Lower the renal threshold for glucose
- Increase urinary glucose excretion
- Promote glycosuria in diabetic patients 1, 2
This mechanism is independent of insulin action, making these medications effective regardless of beta-cell function or insulin resistance.
Available SGLT2 Inhibitors
1. Empagliflozin
- Selectivity: High selectivity for SGLT2
- Brand name: Jardiance
- Dosage: 10 mg and 25 mg once daily 2
- Notable approvals: First SGLT2 inhibitor specifically approved by the FDA to reduce the risk of cardiovascular death in adults with T2D and established cardiovascular disease 3
2. Dapagliflozin
- Selectivity: High selectivity for SGLT2
- Indications: Type 2 diabetes, chronic kidney disease, cardiovascular risk reduction 1
- Additional approval: In Europe, also approved as an adjunct to insulin in patients with type 1 diabetes mellitus 4
3. Ertugliflozin
- Selectivity: High selectivity for SGLT2
- Brand name: Steglatro
- Dosage: 5 mg and 15 mg once daily 5
- Characteristics: Potent inhibitor with high selectivity over glucose transport via SGLT-1 and several other glucose transporters (GLUT-1-4) 6
4. Canagliflozin
- Selectivity: Lower selectivity for SGLT2 with some SGLT1 inhibition
- Unique cautions: Increased risk of lower limb amputations and bone fractures compared to other SGLT2 inhibitors 3, 1
5. Sotagliflozin
- Selectivity: Dual SGLT1/SGLT2 inhibitor
- Unique feature: The only dual-action inhibitor in this class 1, 7
Clinical Benefits Beyond Glucose Control
SGLT2 inhibitors provide significant benefits beyond glycemic control:
- Reduce risk of major adverse cardiovascular events
- Decrease hospitalization rates for heart failure
- Slow progression of chronic kidney disease
- Promote weight reduction of 1.5-3.5 kg
- Lower systolic blood pressure by 3-5 mmHg 1
These cardiovascular and renal benefits are present down to an estimated glomerular filtration rate (eGFR) of 30 mL/min/1.73 m² 1.
Safety Considerations
Common adverse effects include:
- Genitourinary tract infections
- Volume depletion (particularly in elderly patients)
- Rare but serious: euglycemic diabetic ketoacidosis
- Canagliflozin-specific: increased risk of lower limb amputation and bone fractures 3, 1
Dosage Adjustments for Renal Function
- For patients with eGFR ≥60 mL/min/1.73 m²: Standard dosing
- For patients with eGFR 45-59 mL/min/1.73 m²: Lower dosage recommended
- For patients with eGFR <45 mL/min/1.73 m²: Not recommended for glycemic control, though may still provide cardiovascular benefits down to eGFR of 30 mL/min/1.73 m² 1
SGLT2 inhibitors represent a significant advancement in diabetes management, offering benefits that extend well beyond glucose control to include substantial improvements in cardiovascular and renal outcomes, which directly impact mortality, morbidity, and quality of life for patients with type 2 diabetes.