SGLT2 Inhibitor Agents: Available Drugs, Dosing, and Clinical Use
Available SGLT2 Inhibitors and Standard Dosing
Three SGLT2 inhibitors with proven cardiovascular and renal outcomes are available in the United States: empagliflozin, dapagliflozin, and canagliflozin. 1
Empagliflozin
- Starting dose: 10 mg orally once daily 1
- Maximum dose: 25 mg orally once daily 1
- Timing: Can be taken at any time of day 1
Dapagliflozin
- Starting dose: 5 mg orally once daily 1
- Titration: May increase to 10 mg once daily if additional glycemic control is needed 1
- Timing: Can be taken at any time of day 1
Canagliflozin
- Starting dose: 100 mg orally once daily before the first meal 1
- Titration: May increase to 300 mg once daily if needed in patients with eGFR ≥60 mL/min/1.73 m² 1
- Timing: Take before the first meal of the day 1
FDA-Approved Indications
Glucose Lowering
All three agents are approved to improve glycemic control in adults with type 2 diabetes. 1
Cardiovascular Protection
- Empagliflozin: Approved to reduce risk of cardiovascular death in patients with type 2 diabetes and established cardiovascular disease 1
- Canagliflozin: Approved to reduce risk of cardiovascular death in adults with type 2 diabetes and cardiovascular disease 1
- Dapagliflozin: Approved to reduce risk of cardiovascular death and hospitalization for heart failure in adults with heart failure with reduced ejection fraction (NYHA class II-IV) 1
Renal Protection
- Dapagliflozin: Approved for risk reduction of sustained eGFR decline, kidney failure, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease 1
- Canagliflozin: Approved to reduce risk of kidney failure, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes and diabetic kidney disease with albuminuria >300 mg/day 1
Heart Failure
- Dapagliflozin: Approved to reduce risk of hospitalization for heart failure in adults with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors 1
- Empagliflozin: Approved to reduce risk of cardiovascular death plus hospitalization for heart failure in adults with heart failure with reduced ejection fraction 1
Renal Dose Adjustments: Critical Algorithm
Empagliflozin 1
- eGFR ≥45 mL/min/1.73 m²: No dose adjustment required; use 10-25 mg daily
- eGFR <45 mL/min/1.73 m²: Do NOT initiate; discontinue if eGFR persistently falls below 45
- Dialysis: Contraindicated 1
Dapagliflozin 1
- eGFR ≥45 mL/min/1.73 m²: No dose adjustment for glucose lowering; use 5-10 mg daily
- eGFR 25 to <45 mL/min/1.73 m²: NOT recommended for glucose lowering, BUT use 10 mg daily for heart failure or chronic kidney disease indications
- eGFR <25 mL/min/1.73 m²: Do NOT initiate; may continue 10 mg in patients already on therapy for heart failure and chronic kidney disease
- Dialysis: Contraindicated 1
Canagliflozin 1
- eGFR ≥60 mL/min/1.73 m²: No dose adjustment; may use up to 300 mg daily
- eGFR 30 to <60 mL/min/1.73 m²: Maximum 100 mg daily
- eGFR <30 with albuminuria >300 mg/day: Use 100 mg daily (renal protection indication)
- eGFR <30 without albuminuria: Do NOT initiate
- Dialysis: Contraindicated 1
Key clinical point: The renal dose modifications exist because SGLT2 inhibitors are less effective at lowering glucose when kidney function declines, NOT because of specific safety concerns. Cardiovascular benefits persist down to eGFR 30 mL/min/1.73 m². 1
Primary Contraindications
Absolute Contraindications
- Dialysis: All SGLT2 inhibitors are contraindicated in patients on dialysis 1
- Severe renal impairment: Empagliflozin contraindicated when eGFR persistently <45; dapagliflozin and canagliflozin have more nuanced cutoffs as detailed above 1
Relative Contraindications and Cautions
- Type 1 diabetes: Not FDA-approved in the United States (though dapagliflozin is approved in Europe as adjunct to insulin) 2
- Recurrent genitourinary infections: Use with caution due to increased risk of genital mycotic infections 2, 3
- Volume depletion risk: Use caution in elderly patients, those on diuretics, or with low blood pressure 4
- History of lower limb amputation: Canagliflozin carries a warning for increased amputation risk 2, 5
- Bone fracture risk: Canagliflozin has been associated with increased fracture risk 5
Critical Safety Considerations
Diabetic Ketoacidosis Risk
Withhold SGLT2 inhibitors at least 3 days before major surgery or procedures with prolonged fasting to prevent euglycemic diabetic ketoacidosis. 4 This rare but serious adverse event can occur even with normal or near-normal glucose levels. 2, 5
Acute Illness Protocol
Stop SGLT2 inhibitors during acute illness to prevent diabetic ketoacidosis and volume depletion. 4
Insulin Dose Reduction
When adding an SGLT2 inhibitor to insulin therapy in well-controlled patients, reduce insulin dose by approximately 20% to prevent hypoglycemia. 4
Expected eGFR Changes
Expect a transient eGFR decline of 3-5 mL/min/1.73 m² in the first 1-4 weeks after initiation; this is reversible and associated with better long-term renal outcomes. 4 Monitor eGFR within 1-2 weeks after starting therapy. 4
Common Adverse Effects
- Genitourinary infections: Most common side effect, typically mild and treatable 2, 3
- Volume depletion: Monitor for orthostatic hypotension, especially in elderly patients 2
- Hypoglycemia: Only when combined with insulin or insulin secretagogues 2
Clinical Positioning in Treatment Algorithm
SGLT2 inhibitors are recommended as first-line therapy (with or without metformin) for patients with type 2 diabetes and eGFR <60 mL/min/1.73 m² or albuminuria ≥200 mg/g, independent of HbA1c level or glycemic target. 1 This represents a paradigm shift from glucose-lowering to cardiorenal protection as the primary indication. 1, 5
For patients with established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, SGLT2 inhibitors should be initiated alongside metformin rather than waiting for metformin failure. 1