What are the treatment options and dosing for SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors?

SGLT2 Inhibitor Treatment Options and Dosing

Available SGLT2 Inhibitors and Standard Dosing

The three SGLT2 inhibitors with proven cardiovascular and renal benefits are empagliflozin (10-25 mg daily), canagliflozin (100-300 mg daily), and dapagliflozin (10 mg daily), all taken orally once daily in the morning with or without food. 1

Specific Agent Dosing

• Empagliflozin: Start at 10 mg once daily; may increase to 25 mg daily if additional glycemic control is needed 1, 2

• Canagliflozin: Start at 100 mg once daily; may increase to 300 mg daily in patients with eGFR ≥60 mL/min/1.73 m² who require additional glucose lowering 1

• Dapagliflozin: 10 mg once daily (no titration needed) 1, 3

• Ertugliflozin: 15 mg once daily (maximum dose) 1

Dosing Based on Renal Function

eGFR ≥60 mL/min/1.73 m² (CKD Stages 1-2)

• All SGLT2 inhibitors can be used at standard doses with no adjustment required 4, 5
• Canagliflozin may be increased to 300 mg daily if needed for glycemic control 1, 4

eGFR 45-59 mL/min/1.73 m² (CKD Stage 3a)

• Empagliflozin: No dose adjustment required; do not initiate if eGFR <45 mL/min/1.73 m² 1, 2
• Canagliflozin: Maximum 100 mg daily; do not exceed this dose 1
• Dapagliflozin: 10 mg daily; use is not recommended for glycemic control but can be used for cardiovascular/renal protection 1, 3

eGFR 30-44 mL/min/1.73 m² (CKD Stage 3b)

• Canagliflozin: 100 mg daily, particularly if albuminuria >300 mg/day 1, 5
• Dapagliflozin: 10 mg daily (can be used for heart failure/renal protection) 3, 5
• Empagliflozin: Do not initiate; discontinue if eGFR falls persistently below 45 mL/min/1.73 m² 1, 2

eGFR 20-29 mL/min/1.73 m² (CKD Stage 4)

• Empagliflozin: 10 mg daily can be initiated for heart failure (eGFR ≥20 mL/min/1.73 m²) 3, 5
• Dapagliflozin: 10 mg daily can be initiated (eGFR ≥25 mL/min/1.73 m²) and continued even if eGFR falls below 25 3, 5
• Canagliflozin: 100 mg daily if albuminuria present 5

eGFR <30 mL/min/1.73 m² or Dialysis

• Contraindicated for glycemic control per FDA labeling 1, 2
• However, continue therapy if already established for cardiovascular/renal protection, as benefits persist independent of glucose-lowering effects 1, 5

Clinical Indications for Use

Type 2 Diabetes with Established ASCVD

SGLT2 inhibitors should be added to metformin-based therapy in all patients with type 2 diabetes and established atherosclerotic cardiovascular disease, regardless of HbA1c level. 1

• Empagliflozin and canagliflozin are FDA-approved to reduce cardiovascular death in this population 1
• Most cardiovascular outcome trials required baseline HbA1c ≥7% and patients were already on metformin 1

Type 2 Diabetes with Heart Failure

• SGLT2 inhibitors are recommended for patients with type 2 diabetes and heart failure, regardless of ejection fraction 1
• Dapagliflozin is FDA-approved to reduce hospitalization for heart failure in patients with type 2 diabetes and established cardiovascular disease 1
• Standard doses apply: dapagliflozin 10 mg, empagliflozin 10 mg, or canagliflozin 100 mg daily 3

Diabetic Kidney Disease

SGLT2 inhibitors are recommended for all patients with type 2 diabetes and eGFR <60 mL/min/1.73 m² without albuminuria, or for those with albuminuria ≥200 mg/g, independent of HbA1c level or target. 1

• The 2022 KDIGO guideline recommends SGLT2 inhibitors for all patients with eGFR >20 mL/min/1.73 m² independent of albuminuria 1
• Canagliflozin is FDA-approved to reduce risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in patients with diabetic nephropathy and albuminuria 1

First-Line Therapy Considerations

• In patients with or at high risk for ASCVD, heart failure, or kidney disease, SGLT2 inhibitors can be used as first-line therapy with or without metformin 1
• This represents a shift from traditional metformin-first approaches 1

Critical Management Principles

Continuation Despite eGFR Decline

Continue SGLT2 inhibitors even if eGFR falls below initiation thresholds, unless dialysis is started or the medication is not tolerated, as cardiovascular and kidney protective benefits persist at lower eGFR levels. 5

• A reversible decrease in eGFR of up to 30% within 4 weeks of initiation is expected and represents hemodynamic changes from reduced glomerular hyperfiltration, not kidney injury 5
• Do not discontinue therapy based on this expected eGFR dip 5

Pre-Initiation Assessment

Before starting SGLT2 inhibitors:

• Assess volume status and correct hypovolemia, particularly in elderly patients, those with low systolic blood pressure, or patients on diuretics 1, 5
• Consider reducing thiazide or loop diuretic doses to prevent volume depletion 5
• Verify normal serum potassium if planning combination with RAS inhibitors 5
• Assess renal function 4, 2

Hypoglycemia Prevention

• Reduce insulin doses by approximately 20% when initiating SGLT2 inhibitors 1
• Consider weaning or stopping sulfonylureas or glinides if HbA1c is well-controlled at baseline or if there is a history of frequent hypoglycemic events 1

Temporary Discontinuation Situations

Consider temporarily withholding SGLT2 inhibitors during:

• Acute illness or prolonged fasting 4
• Surgical procedures (discontinue at least 3 days before planned surgery to prevent postoperative ketoacidosis) 1
• Settings of reduced oral intake or significant fluid losses 2

Common Adverse Effects and Monitoring

Genital Mycotic Infections

• Occur in approximately 6% of patients on SGLT2 inhibitors 3
• More common in women (5-6% incidence) than men 1
• Counsel patients on genital hygiene 4
• Monitor and treat as appropriate 2

Urinary Tract Infections

• Frequency ranges from 7-9% across trials 1
• Higher risk in elderly patients (10.5-15.7% in those ≥75 years) 2
• Evaluate and treat promptly if signs/symptoms develop 2

Volume Depletion

• Risk increases in elderly patients (particularly ≥75 years: 2.1-4.4%), those with renal impairment, low systolic blood pressure, or on diuretics 1, 2
• Monitor for signs and symptoms during therapy 2

Euglycemic Diabetic Ketoacidosis

• Can occur even with normal blood glucose levels 3, 4
• Higher risk in insulin-dependent patients 3, 4
• Assess patients presenting with metabolic acidosis symptoms regardless of glucose level 2
• If suspected, discontinue SGLT2 inhibitor immediately, evaluate, and treat promptly 2

Canagliflozin-Specific Concerns

• Amputation risk: Use with caution in patients with prior amputation, severe peripheral neuropathy, peripheral vascular disease, or diabetic foot ulcers 1, 3
• Bone fractures: Increased risk observed in clinical trials 1

Laboratory Monitoring

• LDL-C increases: Monitor lipid levels and treat as appropriate 2
• Renal function: Monitor during therapy, particularly after initiation 4, 2

Cost Considerations

Monthly costs (based on maximum approved daily doses):

• Ertugliflozin 15 mg: AWP $354, NADAC $284 1
• Dapagliflozin 10 mg: AWP $621, NADAC $496 1
• Empagliflozin 25 mg: AWP $627, NADAC $501 1
• Canagliflozin 300 mg: AWP $622, NADAC $499 1

These prices do not account for discounts, rebates, or insurance coverage, which significantly affect actual patient costs 1

Contraindications

Absolute Contraindications

• History of serious hypersensitivity reaction to the specific SGLT2 inhibitor 1, 2
• Severe renal impairment, end-stage renal disease, or dialysis (for glycemic control indication) 1, 2
• Pregnancy or breastfeeding (dapagliflozin) 1

Relative Contraindications

• Type 1 diabetes mellitus (not FDA-approved for this indication) 2
• Diabetic ketoacidosis 2