Above what creatinine level should Dapagliflozin (SGLT2 inhibitor) and Eplerenone (mineralocorticoid receptor antagonist) not be given to patients with impaired renal function?

Renal Function Thresholds for Dapagliflozin and Eplerenone

Dapagliflozin should not be initiated below eGFR 20 mL/min/1.73 m², and eplerenone is contraindicated below eGFR 30 mL/min/1.73 m² (or serum creatinine >2.5 mg/dL in men or >2.0 mg/dL in women). 1, 2

Dapagliflozin (SGLT2 Inhibitor) Thresholds

Current Evidence-Based Recommendations

• The 2023 American Diabetes Association guidelines recommend using SGLT2 inhibitors in patients with eGFR ≥20 mL/min/1.73 m² and UACR >200 mg/g creatinine to reduce CKD progression and cardiovascular events. 1

• This represents an evolution from the 2022 guidelines, which recommended eGFR ≥25 mL/min/1.73 m² as the threshold. 1

• The lowering of the threshold to eGFR 20 mL/min/1.73 m² is based on subgroup analyses from DAPA-CKD and EMPEROR heart failure trials demonstrating safety and efficacy at these lower eGFR levels. 1

Specific Dapagliflozin Dosing by eGFR

• eGFR ≥25 mL/min/1.73 m²: Dapagliflozin 10 mg daily can be initiated. 1

• eGFR 20-24 mL/min/1.73 m²: Initiation is not recommended per FDA labeling, but may be continued if already established for kidney and cardiovascular benefit until dialysis. 1

• eGFR <20 mL/min/1.73 m²: Initiation not recommended; may continue if tolerated for kidney and cardiovascular benefit until dialysis. 1

Key Clinical Trial Evidence

• The DAPA-CKD trial enrolled patients with eGFR 25-75 mL/min/1.73 m² and demonstrated a 39% relative risk reduction in the primary composite outcome (sustained ≥50% eGFR decline, ESKD, or renal/cardiovascular death). 3

• The trial included 4,304 participants with mean baseline eGFR of 43.1 mL/min/1.73 m² and median UACR of 949 mg/g, with 67.5% having type 2 diabetes. 1, 3

Eplerenone (Mineralocorticoid Receptor Antagonist) Thresholds

Absolute Contraindications

• eGFR <30 mL/min/1.73 m² (or GFR <30 mL/min) 2

• Serum creatinine >2.5 mg/dL in men or >2.0 mg/dL in women 1, 4

• Serum potassium >5.0 mEq/L at baseline 2, 4

Rationale for Strict Contraindications

• Eplerenone carries a high risk of life-threatening hyperkalemia in patients with severely impaired renal function. 2

• The 2008 European Society of Cardiology guidelines explicitly state that MRAs should only be used in patients with adequate renal function and normal serum potassium. 1

• Real-world hyperkalemia rates with MRAs range from 24-36% compared to 2-5% in clinical trials, particularly in patients with renal dysfunction. 4

Monitoring Requirements When Using Eplerenone

• Initial monitoring: Check potassium and renal function within 2-3 days of initiation, then at 1 week, 4 weeks, and monthly for the first 3 months. 1, 2, 4

• Dose adjustment thresholds:

  • If potassium rises to 5.5-6.0 mmol/L: Halve the dose (e.g., 25 mg on alternate days) and monitor closely. 1
  • If potassium rises to ≥6.0 mmol/L: Stop eplerenone immediately. 1, 2
  • If creatinine rises to >220 mmol/L (2.5 mg/dL): Halve the dose and monitor closely. 1
  • If creatinine rises to >310 mmol/L (3.5 mg/dL): Stop eplerenone immediately. 1

Combined Use of Dapagliflozin and Eplerenone

Safety and Efficacy Data

• A 2022 randomized crossover trial demonstrated that combining dapagliflozin with eplerenone resulted in a robust additive UACR-lowering effect (-53% reduction) compared to either agent alone (dapagliflozin -19.6%, eplerenone -33.7%). 5

• Hyperkalemia occurred less frequently with combination therapy (4.3%) compared to eplerenone alone (17.4%), suggesting dapagliflozin may mitigate hyperkalemia risk. 5

• Post-hoc analysis of DAPA-CKD showed consistent efficacy and safety of dapagliflozin in the 5.3% of participants receiving conventional MRAs at baseline. 6

Practical Algorithm for Combined Therapy

Step 1: Assess baseline renal function and potassium

• Measure eGFR, serum creatinine, and potassium levels. 2, 4

Step 2: Apply contraindication criteria

• Do not use eplerenone if eGFR <30 mL/min/1.73 m², creatinine >2.5 mg/dL (men) or >2.0 mg/dL (women), or potassium >5.0 mEq/L. 2, 4
• Do not initiate dapagliflozin if eGFR <20 mL/min/1.73 m² (though may continue if already established). 1

Step 3: Initiate therapy sequentially if both agents are indicated

• Start with dapagliflozin 10 mg daily first, as it may reduce hyperkalemia risk. 5
• After 2-4 weeks of stable dapagliflozin therapy, add eplerenone 25 mg daily if potassium remains <5.0 mEq/L. 1, 4

Step 4: Implement intensive monitoring

• Check potassium and renal function 2-3 days after adding eplerenone, then weekly for 4 weeks, then monthly. 2, 4

Common Pitfalls and How to Avoid Them

• Pitfall: Using eplerenone in patients with borderline renal function (eGFR 30-35 mL/min/1.73 m²) without adequate monitoring.

  • Solution: Even at eGFR just above 30 mL/min/1.73 m², check potassium within 2-3 days and weekly for the first month. 2, 4

• Pitfall: Continuing eplerenone during acute illness, dehydration, or diarrhea.

  • Solution: Instruct patients to temporarily stop eplerenone during these episodes. 2, 4

• Pitfall: Failing to adjust diuretic doses when initiating dapagliflozin.

  • Solution: Assess volume status and consider reducing loop diuretic dose to prevent intravascular volume contraction. 7

• Pitfall: Using concomitant NSAIDs, potassium supplements, or high-potassium diet with eplerenone.

  • Solution: Avoid these combinations entirely in patients on eplerenone. 2