What are the uses and dosing of Sodium Glucose Co-Transporter 2 (SGLT2) inhibitors, such as canagliflozin (canagliflozin), in patients with type 2 diabetes?

SGLT2 Inhibitors for Type 2 Diabetes: Uses and Dosing

SGLT2 inhibitors are recommended for patients with type 2 diabetes who have established atherosclerotic cardiovascular disease (ASCVD), heart failure, diabetic kidney disease (DKD), or are at high risk for ASCVD, due to their proven cardiovascular and renal benefits beyond glucose control. 1

Mechanism of Action

• SGLT2 inhibitors work by selectively inhibiting sodium-glucose co-transporter 2 proteins in the proximal convoluted tubule of the kidneys, blocking glucose reabsorption and increasing urinary glucose excretion 1
• They function independently of beta-cell function and insulin secretion, making them suitable for use regardless of diabetes duration, provided renal function is acceptable 1, 2
• By reducing renal glucose threshold, these medications increase glucosuria, thereby reducing hyperglycemia and improving both insulin secretion by β-cells and peripheral insulin sensitivity 1

Available SGLT2 Inhibitors and Dosing

FDA-Approved SGLT2 Inhibitors:

• Canagliflozin: 100 mg PO daily (may increase to 300 mg daily if needed and eGFR ≥60 mL/min/1.73 m²) 1, 3
• Dapagliflozin: 10 mg PO daily 1
• Empagliflozin: 10 mg PO daily (can be increased to 25 mg PO daily) 1
• Ertugliflozin: FDA-approved for T2DM 1

Renal Dosing Adjustments:

• Canagliflozin:

  • eGFR ≥60 mL/min/1.73 m²: No dose adjustment required
  • eGFR 45-59 mL/min/1.73 m²: Do not exceed 100 mg/day
  • eGFR 30-45 mL/min/1.73 m²: Use is allowed specifically for patients with DKD 1
  • eGFR <30 mL/min/1.73 m²: Use is not recommended 1

• Dapagliflozin:

  • eGFR <45 mL/min/1.73 m²: Not recommended for glycemic control
  • eGFR <30 mL/min/1.73 m²: Contraindicated 1

• Empagliflozin:

  • eGFR ≥45 mL/min/1.73 m²: No dose adjustment required
  • eGFR <45 mL/min/1.73 m²: Not recommended for glycemic control 1

Clinical Benefits

Glycemic Control:

• SGLT2 inhibitors reduce HbA1c by 0.5-1% and fasting plasma glucose by approximately 15-35 mg/dL 4
• They demonstrate greater reduction of HbA1c maintained up to 1 year compared to other oral antihyperglycemic agents 1
• The glycemic effect is diminished in patients with reduced renal function 4

Cardiovascular Benefits:

• Significant reduction in major adverse cardiovascular events (MACE) in patients with high cardiovascular risk 1
• Reduced risk of hospitalization for heart failure 1
• Cardiovascular benefits appear to be present down to eGFR of 30 mL/min/1.73 m² 1

Renal Benefits:

• Reduced risk of kidney failure, sustained decline in eGFR, and death from renal causes 5
• Particularly beneficial in patients with diabetic kidney disease 1, 5
• The CREDENCE trial showed a 30% lower risk of composite renal and cardiovascular outcomes with canagliflozin in patients with T2DM and kidney disease 5

Additional Benefits:

• Modest weight reduction (1.5-3.5 kg) 4
• Reduction in systolic blood pressure (3-5 mmHg) 4
• Reduction in visceral fat area 6

Considerations for Initiation and Monitoring

Before Starting Therapy:

• Assess renal function (eGFR) to determine appropriate dosing 1
• Consider reducing doses of insulin (by ~20%) or sulfonylureas if patient is well-controlled or at risk for hypoglycemia 1
• Evaluate for conditions that may increase risk of adverse effects (e.g., history of genital mycotic infections, volume depletion) 1

Monitoring:

• Educate patients about potential genital mycotic infections and importance of genital hygiene 1
• Monitor for volume depletion, especially if used with diuretics; consider reducing diuretic dose if symptoms of dehydration occur 1
• Instruct patients to monitor glucose more closely for the first 4 weeks of therapy, especially if on insulin or sulfonylureas 1
• Educate patients about symptoms of diabetic ketoacidosis (nausea, vomiting, abdominal pain, weakness) and that it can occur even with modestly elevated blood glucose levels (150-250 mg/dL) 1
• Emphasize proper foot care, especially in patients with diabetic neuropathy 1

Contraindications and Cautions

Contraindications:

• Pregnancy or breastfeeding 1
• Severe renal impairment (see specific eGFR cutoffs for each agent) 1
• History of serious hypersensitivity reaction to the drug 1

Cautions:

• Discontinue at least 3 days before planned surgery to prevent postoperative ketoacidosis 1
• Use with caution in patients with prior amputation, severe peripheral arterial disease, or active diabetic foot ulcers (particularly with canagliflozin) 1
• May contribute to intravascular volume contraction; consider stopping or reducing diuretic dose if applicable 1
• History of recurrent genital candidiasis 1

Adverse Effects

• Genital mycotic infections (most common adverse effect) 1, 4
• Urinary tract infections (less common and generally benign) 7
• Volume depletion symptoms (lightheadedness, orthostasis, weakness) 1
• Diabetic ketoacidosis (rare but serious) 1
• Increased risk of bone fractures (caution with canagliflozin) 1

SGLT2 inhibitors represent an important addition to the treatment arsenal for type 2 diabetes, particularly for patients with or at high risk for cardiovascular and renal complications. Their insulin-independent mechanism of action, favorable effects on weight and blood pressure, and proven cardiovascular and renal benefits make them valuable options for many patients with type 2 diabetes.