What are the doses, indications, contraindications, and precautions for Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors, such as canagliflozin (Canagliflozin), dapagliflozin (Dapagliflozin), and empagliflozin (Empagliflozin), in patients with type 2 diabetes?

SGLT2 Inhibitors: Doses, Indications, Contraindications, and Precautions

SGLT2 inhibitors are recommended as first-line therapy for patients with type 2 diabetes who have established cardiovascular disease, heart failure, or chronic kidney disease due to their proven benefits in reducing cardiovascular and renal outcomes. 1

Recommended Doses

• Canagliflozin: 100 mg PO daily (can increase to 300 mg daily for glycemic control if eGFR ≥60 mL/min/1.73 m²) 1
• Dapagliflozin: Starting dose 5 mg PO daily for glycemic control (can increase to 10 mg daily); 10 mg PO daily for heart failure and kidney disease indications 1, 2
• Empagliflozin: 10 mg PO daily (can increase to 25 mg daily for additional glycemic control) 1

Indications

Canagliflozin

• Improve glycemic control in adults with T2DM as adjunct to diet and exercise 1
• Reduce risk of MI, stroke, or CV death in adults with T2DM and CV disease 1
• Reduce risk of end-stage kidney disease, doubling of serum creatinine, CV death, and hospitalization for heart failure in patients with T2DM and diabetic nephropathy with albuminuria 1

Dapagliflozin

• Improve glycemic control in adults and pediatric patients aged ≥10 years with T2DM 2
• Reduce risk of hospitalization for heart failure in adults with T2DM and established CV disease or multiple CV risk factors 1, 2
• Reduce risk of CV death and hospitalization for heart failure in adults with HFrEF 1, 2
• Reduce risk of sustained eGFR decline, end-stage kidney disease, CV death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression 2

Empagliflozin

• Improve glycemic control in adults with T2DM as adjunct to diet and exercise 1
• Reduce risk of CV death in adults with T2DM and established CV disease 1

Dose Modifications Based on Renal Function

Canagliflozin

• eGFR 30-59 mL/min/1.73 m²: Maximum dose 100 mg daily 1
• eGFR <30 mL/min/1.73 m²: Use not recommended for glycemic control; may continue 100 mg daily if tolerated for kidney and CV benefit until dialysis 1

Dapagliflozin

• eGFR <45 mL/min/1.73 m²: Not recommended for glycemic control 1, 2
• eGFR ≥25 mL/min/1.73 m²: Can be used for CV and renal indications 2
• eGFR <25 mL/min/1.73 m²: Initiation not recommended; may continue if already on treatment for CV and renal benefits 2

Empagliflozin

• eGFR <45 mL/min/1.73 m²: Not recommended for glycemic control 1

Contraindications

• History of serious hypersensitivity reaction to the specific SGLT2 inhibitor 1, 2
• Pregnancy or breastfeeding 1
• Patients on dialysis (for empagliflozin) 1
• Type 1 diabetes mellitus (risk of diabetic ketoacidosis) 2

Precautions and Monitoring

Before Initiating Therapy

• Assess renal function prior to initiation and periodically thereafter 2
• Assess volume status and correct volume depletion before starting therapy 2

Temporary Interruption

• Discontinue at least 3 days before planned surgery to prevent postoperative ketoacidosis 1, 2
• Consider pausing during periods of acute illness or stressors 1

Medication Adjustments

• If HbA1c is well-controlled at baseline or patient has history of hypoglycemic events, consider reducing doses of sulfonylureas, glinides, or insulin (by ~20%) when starting SGLT2 inhibitors 1
• May contribute to intravascular volume contraction; consider reducing diuretic dose if applicable 1

Adverse Effects to Monitor

Diabetic Ketoacidosis

• Risk of euglycemic ketoacidosis (minimal to no elevation in blood glucose) 1
• Higher risk in patients with T2DM requiring insulin 1
• Consider blood or urine ketone monitoring for detection 1
• Discontinue SGLT2 inhibitor and seek immediate medical attention if ketoacidosis is suspected 1

Genital Mycotic Infections

• Increased risk compared to placebo (6% vs. 1%), higher in women than men 1
• Daily hygienic measures may reduce risk 1
• Most infections are easily treated, but severe cases of Fournier gangrene have been reported 1

Other Adverse Effects

• Urinary tract infections 1
• Lower limb ulcerations and soft tissue infections 1
• Possible increased risk of bone fractures (particularly with canagliflozin) 1
• Use with caution in patients with prior amputation, severe peripheral neuropathy, severe peripheral vascular disease, or active diabetic foot ulcers 1

Special Considerations

• Glucose-lowering efficacy decreases as renal function declines, but cardiovascular and kidney benefits are preserved at lower eGFR levels 1
• SGLT2 inhibitors have demonstrated significant reductions in major adverse cardiovascular events, hospitalization for heart failure, and progression of kidney disease in multiple large randomized controlled trials 1
• For cardiovascular risk reduction, SGLT2 inhibitors can be used independent of A1C levels and independent of metformin use 1

By carefully considering these dosing recommendations, indications, contraindications, and precautions, clinicians can optimize the use of SGLT2 inhibitors to improve outcomes in patients with type 2 diabetes, particularly those with cardiovascular disease, heart failure, or chronic kidney disease.