What are the benefits and risks of using SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors, such as canagliflozin (Canagliflozin), dapagliflozin (Dapagliflozin), and empagliflozin (Empagliflozin), in patients with type 2 diabetes?

Benefits and Risks of SGLT2 Inhibitors in Type 2 Diabetes

SGLT2 inhibitors are strongly recommended 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 mortality, heart failure hospitalizations, and progression of kidney disease beyond glycemic control. 1, 2

Cardiovascular and Renal Benefits

Cardiovascular Protection

• Reduce major adverse cardiovascular events (MACE) by 14% in patients with established cardiovascular disease 2
• Decrease hospitalization for heart failure by 27-35% 2
• Empagliflozin specifically reduces cardiovascular death by 38% (HR: 0.62; 95% CI: 0.49 to 0.77) 1
• Dapagliflozin reduces the composite of CV death or hospitalization for heart failure with HR 0.83 (95% CI 0.73,0.95) 1

Renal Protection

• Significantly reduce risk of sustained eGFR decline, end-stage kidney disease, and death from renal causes 2
• Particularly beneficial in patients with albuminuria (UACR >300 mg/g) and eGFR 30-90 mL/min/1.73m² 1
• May have protective effects against acute kidney injury 3

Heart Failure Benefits

• Effective in both heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) 4
• Benefits observed regardless of diabetes status in heart failure patients 1

Metabolic Benefits

• Reduce HbA1c by 0.6-0.8% (6-8 mmol/mol) 5
• Promote weight loss through caloric loss (glucosuria) 1, 2
• Lower systolic blood pressure 1, 5
• Improve lipid profile and reduce hyperuricemia 5
• Minimal risk of hypoglycemia when used as monotherapy 1, 6

Risks and Adverse Effects

Common Side Effects

• Genital mycotic infections (most common adverse effect) 2, 6
• Urinary tract infections (though serious infections like urosepsis and pyelonephritis are rare) 7
• Increased urination due to osmotic diuresis 2

Serious Adverse Effects

• Diabetic ketoacidosis (DKA), including euglycemic DKA (blood glucose may be <250 mg/dL) 7, 5
• Volume depletion and hypotension, especially in elderly patients or those on diuretics 7
• Possible increased risk of lower-extremity amputation (primarily reported with canagliflozin) 5

Patient Selection and Contraindications

Ideal Candidates

• Patients with established cardiovascular disease or multiple cardiovascular risk factors 1
• Patients with heart failure, particularly HFrEF 1, 4
• Patients with chronic kidney disease with eGFR ≥25 mL/min/1.73m² 7
• Patients who would benefit from weight loss or blood pressure reduction 2

Contraindications and Cautions

• History of serious hypersensitivity to SGLT2 inhibitors 7
• Type 1 diabetes (significantly increases risk of ketoacidosis) 7
• Severe renal impairment (eGFR <25 mL/min/1.73m²) for initiating therapy 2, 7
• Caution in elderly patients at risk for volume depletion 7

Practical Considerations

Dosing and Administration

• Canagliflozin: 100 mg daily (maximum 100 mg daily for eGFR 30-59 mL/min/1.73m²) 2
• Dapagliflozin: 10 mg daily 2, 7
• Empagliflozin: 10 mg daily 2

Perioperative Management

• Withhold SGLT2 inhibitors at least 3 days before major surgery or procedures with prolonged fasting 2, 7
• Resume when the patient is clinically stable and has resumed oral intake 7

Monitoring

• Educate patients about signs/symptoms of ketoacidosis and when to seek medical attention 7
• Monitor renal function, especially in patients with baseline renal impairment 7
• Emphasize proper foot care to prevent complications 2

Clinical Pearls and Pitfalls

• SGLT2 inhibitors should be considered early in treatment algorithms for patients with established cardiovascular disease, heart failure, or kidney disease, regardless of baseline HbA1c 1
• The cardiovascular and renal benefits appear to be class effects, though empagliflozin has the strongest evidence for cardiovascular mortality reduction 1, 4
• Benefits on heart failure and kidney outcomes occur early (within weeks to months) and are independent of glucose-lowering effects 4, 5
• Ketoacidosis risk increases during periods of stress (surgery, acute illness) or reduced insulin dosing 7
• The mechanism of cardiovascular benefit appears to be primarily hemodynamic through osmotic diuresis and natriuresis rather than anti-atherosclerotic effects 5