What are the types of Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors available?

Types of SGLT2 Inhibitors

There are five main types of SGLT2 inhibitors currently available: dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, and sotagliflozin, with varying selectivity for SGLT2 receptors and approved indications. 1

Classification by Selectivity

SGLT2 inhibitors can be classified based on their selectivity for the SGLT2 receptor:

• High Selectivity SGLT2 Inhibitors:

  • Dapagliflozin
  • Empagliflozin
  • Ertugliflozin

• Lower Selectivity SGLT2 Inhibitor:

  • Canagliflozin (has some SGLT1 inhibition)

• Dual SGLT1/SGLT2 Inhibitor:

  • Sotagliflozin (intentionally targets both transporters)

Mechanism of Action

All SGLT2 inhibitors work through a similar mechanism:

• They inhibit sodium-glucose cotransporter 2 (SGLT2), which is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into circulation 2
• By inhibiting SGLT2, these medications reduce renal glucose reabsorption and lower the renal threshold for glucose, thereby increasing urinary glucose excretion 2, 3
• This mechanism is insulin-independent, making these medications effective regardless of beta-cell function or insulin resistance 1

Clinical Indications

SGLT2 inhibitors are approved for multiple indications:

• Type 2 diabetes mellitus - All five agents
• Cardiovascular risk reduction - Particularly empagliflozin, dapagliflozin, and canagliflozin
• Heart failure (both with reduced and preserved ejection fraction) - Dapagliflozin, empagliflozin, and sotagliflozin
• Chronic kidney disease - Dapagliflozin, empagliflozin, and canagliflozin 4, 1

Clinical Effects

SGLT2 inhibitors provide multiple benefits beyond glycemic control:

• Glycemic control: Reduce HbA1c by 0.5-1.0% 1, 5
• Cardiovascular benefits: Reduce major adverse cardiovascular events, particularly in patients with established cardiovascular disease 4, 1
• Heart failure benefits: Reduce hospitalization for heart failure by 27-35% 1
• Renal protection: Slow progression of kidney disease and reduce risk of end-stage kidney disease 1
• Weight loss: Promote modest weight reduction through caloric loss via glycosuria 5
• Blood pressure reduction: Lower systolic and diastolic blood pressure by 4-6 mmHg and 1-2 mmHg, respectively 6

Safety Considerations

Common adverse effects across all SGLT2 inhibitors include:

• Genitourinary infections: Particularly genital mycotic infections 1, 7
• Volume depletion: Risk of orthostatic hypotension, especially in elderly or those on diuretics 1
• Euglycemic diabetic ketoacidosis: Rare but serious adverse effect 7
• Renal function: Use is limited in patients with severe renal impairment 2, 3

Specific safety concerns:

• Canagliflozin: Has a unique caution regarding increased risk of lower limb amputations and bone fractures compared to other SGLT2 inhibitors 1

Dosing Considerations

• All SGLT2 inhibitors are administered orally once daily
• Dose adjustments are required based on renal function:
  • Empagliflozin: Not recommended when eGFR <30 mL/min/1.73 m² 2
  • Dapagliflozin: For glycemic control, not recommended when eGFR <45 mL/min/1.73 m² 3
• Can be taken with or without food 2, 3

Comparative Efficacy

In head-to-head trials of up to 2 years, SGLT2 inhibitors have demonstrated:

• Similar glucose-lowering activity compared to metformin, sulfonylureas, or sitagliptin 8
• Potentially better durability of glycemic effect compared to other oral antidiabetic agents 8
• Lower risk of hypoglycemia compared to sulfonylureas 8

Combination Therapy

SGLT2 inhibitors can be effectively combined with other antidiabetic medications:

• When adding to insulin or sulfonylureas, consider reducing sulfonylurea dose by 50% and total daily insulin dose by approximately 20% to prevent hypoglycemia 1
• Combination with GLP-1 receptor agonists provides complementary mechanisms with additive effects on weight loss and glycemic control 1