What is the role of SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors, such as canagliflozin (Canagliflozin), dapagliflozin (Dapagliflozin), or empagliflozin (Empagliflozin), in the treatment of type 2 diabetes?

SGLT2 Inhibitors in Type 2 Diabetes Management

SGLT2 inhibitors should be prescribed for all patients with type 2 diabetes who have established ASCVD, multiple ASCVD risk factors, heart failure, or chronic kidney disease, regardless of A1C levels, as they significantly reduce cardiovascular mortality, heart failure hospitalizations, and progression of kidney disease. 1

Mechanism of Action and Efficacy

SGLT2 inhibitors work by:

• Inhibiting sodium-glucose cotransporter 2 in proximal renal tubules 2, 3
• Reducing reabsorption of filtered glucose, increasing urinary glucose excretion 3
• Lowering blood glucose levels independent of insulin action 1
• Reducing sodium reabsorption, which affects cardiac pre- and afterload 2

Glycemic efficacy:

• Reduce HbA1c by 0.7-1.0% 1
• Effective regardless of diabetes duration or β-cell function 1
• Can be used as monotherapy or add-on to other diabetes medications 1

Cardiovascular and Renal Benefits

Cardiovascular Outcomes

Multiple large randomized controlled trials have demonstrated that SGLT2 inhibitors:

• Reduce major adverse cardiovascular events (MACE) in patients with established ASCVD 1
• Significantly reduce heart failure hospitalizations across all ejection fraction types 4
• Reduce cardiovascular mortality 1

Key trials showing cardiovascular benefits:

• EMPA-REG OUTCOME (empagliflozin): 14% reduction in MACE, significant reduction in CV death 1, 4
• CANVAS (canagliflozin): Significant reduction in MACE 1
• DECLARE-TIMI 58 (dapagliflozin): Reduction in heart failure hospitalizations 1

Renal Protection

SGLT2 inhibitors demonstrate significant renal benefits:

• Slow decline in renal function 4
• Reduce risk of end-stage kidney disease 1
• Beneficial in patients with albuminuric kidney disease 1

Specific Agents and Dosing

Currently available SGLT2 inhibitors:

• Empagliflozin: 10-25 mg daily; FDA-approved for reducing CV death in adults with T2DM and established CV disease 1, 3
• Canagliflozin: 100-300 mg daily; FDA-approved for reducing risk of MACE and end-stage kidney disease 1
• Dapagliflozin: 10 mg daily; FDA-approved for reducing HF hospitalization risk in adults with T2DM and established CV disease or multiple risk factors 1, 2
• Ertugliflozin: 5-15 mg daily; Shows CV benefits in non-inferiority studies 1

Patient Selection and Contraindications

Ideal Candidates

• Patients with established ASCVD or high ASCVD risk 1
• Patients with heart failure (regardless of ejection fraction) 4
• Patients with chronic kidney disease 1
• Patients who would benefit from weight loss 1

Contraindications and Cautions

• eGFR <30 mL/min/1.73 m² for dapagliflozin 1, 2
• eGFR <20 mL/min/1.73 m² for all SGLT2 inhibitors 4
• History of serious hypersensitivity to the drug 1
• Pregnancy or breastfeeding 1
• Type 1 diabetes 4
• History of severe genital mycotic infections 4

Adverse Effects and Monitoring

Common adverse effects:

• Genital mycotic infections (most common) 1, 5
• Urinary tract infections (less common) 5, 6
• Volume depletion (especially in elderly or those on diuretics) 1, 2

Rare but serious adverse effects:

• Euglycemic diabetic ketoacidosis 1, 6
• Bone fractures (particularly with canagliflozin) 1
• Lower limb amputations (caution with canagliflozin in patients with peripheral vascular disease) 1

Monitoring recommendations:

• Renal function within 2-4 weeks after initiation 4
• Signs of genital mycotic infections 4
• Volume status, especially in elderly patients or those on diuretics 1
• Discontinue at least 3 days before planned surgery to prevent postoperative ketoacidosis 1

Practical Implementation

When to initiate:

• As early as possible in patients with established ASCVD, heart failure, or CKD 1, 4
• For patients hospitalized with heart failure, initiate before discharge when clinically stable 4
• Can be initiated regardless of baseline A1C or current diabetes medications 1

Dose adjustments:

• Canagliflozin: Maximum 100 mg daily if eGFR 30-59 mL/min/1.73 m² 1
• Dapagliflozin: Not recommended for glycemic control if eGFR <45 mL/min/1.73 m² 1, 2
• Empagliflozin: Not recommended for glycemic control if eGFR <45 mL/min/1.73 m² 1, 3

Cost Considerations

SGLT2 inhibitors are relatively expensive compared to older diabetes medications:

• Median monthly AWP (Average Wholesale Price) ranges from $354-$627 1
• Dapagliflozin: $621 (AWP), $496 (NADAC) for 10 mg 1
• Empagliflozin: $627 (AWP), $501 (NADAC) for 25 mg 1
• Canagliflozin: $622 (AWP), $499 (NADAC) for 300 mg 1
• Ertugliflozin: $354 (AWP), $284 (NADAC) for 15 mg 1

Cost may be a barrier to adherence for some patients, and cost-reducing strategies should be considered when appropriate.