What are the recommended doses for SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors, such as canagliflozin, empagliflozin, and dapagliflozin, in patients with impaired renal function?

SGLT2 Inhibitor Dosing in Impaired Renal Function

For patients with impaired renal function, SGLT2 inhibitors should be dosed based on indication (glycemic control vs. cardiorenal protection) and eGFR thresholds: dapagliflozin and empagliflozin 10 mg daily can be initiated down to eGFR ≥20 mL/min/1.73 m² for cardiorenal protection, while canagliflozin 100 mg daily can be initiated down to eGFR ≥30 mL/min/1.73 m²; however, none should be initiated for glycemic control alone if eGFR <45 mL/min/1.73 m². 1, 2

Dapagliflozin Dosing by Indication and eGFR

For Cardiorenal Protection (CKD, Heart Failure, CV Risk Reduction)

• eGFR ≥20 mL/min/1.73 m²: Initiate dapagliflozin 10 mg once daily (fixed dose, no titration needed) 1, 2
• eGFR <20 mL/min/1.73 m²: Do not initiate; however, if already on therapy, may continue 10 mg daily until dialysis 2, 3
• This indication applies regardless of diabetes status and provides benefits for reducing CKD progression, cardiovascular death, and heart failure hospitalization 1, 2

For Glycemic Control in Type 2 Diabetes

• eGFR ≥45 mL/min/1.73 m²: Start 5 mg once daily; may increase to 10 mg once daily if additional glycemic control needed 2, 3
• eGFR <45 mL/min/1.73 m²: Do not initiate for glycemic control—likely ineffective due to mechanism of action 1, 2
• If already on dapagliflozin when eGFR falls below 45 mL/min/1.73 m², continue 10 mg daily for cardiorenal protection (not glycemic control) 3, 2

Empagliflozin Dosing by eGFR

For Cardiorenal Protection

• eGFR ≥20 mL/min/1.73 m²: Initiate empagliflozin 10 mg once daily 1
• The 2023 ADA guidelines lowered the threshold from ≥25 to ≥20 mL/min/1.73 m² based on EMPEROR heart failure trial subgroup analyses showing safety and efficacy at these lower eGFR levels 1

For Glycemic Control

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

Canagliflozin Dosing by eGFR

For Cardiorenal Protection

• eGFR ≥30 mL/min/1.73 m²: Initiate canagliflozin 100 mg once daily 1, 4
• Post-hoc analysis from CREDENCE trial showed benefits even in patients with eGFR <30 mL/min/1.73 m² at randomization (mean 26 mL/min/1.73 m²), with 66% slower eGFR decline versus placebo 4
• If already on canagliflozin when eGFR falls <30 mL/min/1.73 m²: Continue for cardiorenal benefits 1

For Glycemic Control

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

Critical Clinical Algorithm

Step 1: Determine Primary Indication

• If cardiorenal protection is the goal (CKD with albuminuria, heart failure, high CV risk): Use SGLT2i down to eGFR ≥20 mL/min/1.73 m² 1
• If glycemic control is the primary goal: Only initiate if eGFR ≥45 mL/min/1.73 m² 1, 2

Step 2: Select Agent Based on eGFR

• eGFR ≥45 mL/min/1.73 m²: Any SGLT2i appropriate (dapagliflozin, empagliflozin, canagliflozin) 1
• eGFR 30-44 mL/min/1.73 m²: Dapagliflozin 10 mg or empagliflozin 10 mg preferred for cardiorenal protection; canagliflozin 100 mg also acceptable 1
• eGFR 20-29 mL/min/1.73 m²: Dapagliflozin 10 mg or empagliflozin 10 mg only (not canagliflozin for initiation) 1
• eGFR <20 mL/min/1.73 m²: Prefer GLP-1 receptor agonists (dulaglutide, semaglutide, liraglutide); if already on canagliflozin or dapagliflozin, may continue 1, 2

Step 3: Monitoring After Initiation

• Expect initial eGFR dip of 3-5 mL/min/1.73 m² within first 1-4 weeks—this is hemodynamic, reversible, and does not indicate harm 1, 3
• Recheck eGFR within 1-2 weeks of initiation, then every 3-6 months if eGFR 45-59 mL/min/1.73 m², or annually if eGFR ≥60 mL/min/1.73 m² 1, 3
• Do not discontinue SGLT2i solely because of initial eGFR dip unless >30% decline with signs of hypovolemia 3

Key Safety Considerations and Dose Adjustments

Volume Depletion Risk

• Assess and correct volume depletion before initiating SGLT2i, especially in patients on diuretics, ACE inhibitors, or ARBs 1, 2
• Consider reducing concurrent diuretic doses when starting SGLT2i to prevent excessive volume depletion 3

Diabetic Ketoacidosis Prevention

• Withhold SGLT2i at least 3 days before major surgery or procedures with prolonged fasting 1, 2
• Discontinue during acute illness with reduced oral intake, fever, vomiting, or diarrhea 3
• Maintain at least low-dose insulin in insulin-requiring patients even when SGLT2i is held during illness 3
• Educate patients that euglycemic DKA can occur with normal blood glucose levels (<200 mg/dL) 1, 3

Concomitant Medication Adjustments

• Metformin: Reduce to 1000 mg daily if eGFR 30-44 mL/min/1.73 m²; discontinue if eGFR <30 mL/min/1.73 m² 1
• Sulfonylureas: Consider dose reduction when adding SGLT2i to prevent hypoglycemia 3
• Insulin: Monitor glucose closely and adjust doses as needed when adding SGLT2i 3

Common Pitfalls to Avoid

• Do not discontinue SGLT2i when eGFR falls below 45 mL/min/1.73 m² if patient is already on therapy—cardiorenal benefits persist even when glycemic efficacy is lost 1, 3
• Do not withhold SGLT2i initiation in patients with eGFR 20-44 mL/min/1.73 m² who need cardiorenal protection simply because glycemic efficacy is reduced 1
• Do not ignore the initial eGFR dip—this is expected and beneficial long-term, but verify it stabilizes within 2-4 weeks 1, 3
• Do not use SGLT2i as monotherapy for glycemic control in advanced CKD (eGFR <45 mL/min/1.73 m²)—use insulin or GLP-1 RA instead 1, 3

Evidence Strength and Guideline Evolution

The recommendation to initiate SGLT2i at eGFR ≥20 mL/min/1.73 m² represents a recent evolution from prior thresholds of ≥25 or ≥30 mL/min/1.73 m² 1. This change is based on:

• DAPA-CKD trial: Enrolled patients with eGFR ≥25 mL/min/1.73 m² and demonstrated 39% reduction in composite kidney outcome 1, 3
• CREDENCE trial: Enrolled patients with eGFR ≥30 mL/min/1.73 m², with post-hoc analysis showing benefits in subgroup with eGFR <30 mL/min/1.73 m² 1, 4
• EMPEROR trials: Showed efficacy and safety at eGFR >20 mL/min/1.73 m² in heart failure populations 1

The 2022 ADA/KDIGO consensus and 2023 ADA Standards of Care now uniformly recommend eGFR ≥20 mL/min/1.73 m² as the threshold for initiation 1.