What are the Glomerular Filtration Rate (GFR) thresholds for initiating spironolactone, Jardiance (empagliflozin), and Entresto (sacubitril/valsartan)?

From the Guidelines

The recommended GFR thresholds for initiating spironolactone, empagliflozin (Jardiance), and sacubitril/valsartan (Entresto) are ≥30 mL/min/1.73m², ≥20 mL/min/1.73m², and ≥30 mL/min/1.73m², respectively. These thresholds are based on the most recent and highest quality studies, including the 2022 AHA/ACC/HFSA guideline for the management of heart failure 1 and the 2024 clinical practice guideline for the evaluation and management of CKD 1. Key considerations for each medication include:

• Spironolactone: should be used cautiously with close potassium monitoring as kidney function declines, due to the risk of hyperkalemia 1.
• Empagliflozin (Jardiance): its glycosuric effect diminishes with declining kidney function, but its cardiorenal benefits persist even at lower GFR levels 1.
• Sacubitril/valsartan (Entresto): can be started when GFR is ≥30 mL/min/1.73m², with dose adjustment recommended for moderate to severe kidney impairment 1. Regular monitoring of kidney function and electrolytes is essential when using these medications, especially in patients with borderline kidney function. Some studies suggest that SGLT-2 inhibitors, such as empagliflozin, should generally not be newly initiated with GFR <20 mL/min per 1.73 m2, though they may be continued even if GFR drops below this threshold for individuals already on therapy 1. However, the most recent guideline recommends that empagliflozin can be started with eGFR >30 mL/min/1.73 m2, though pivotal trials for each included participants with eGFR <30 mL/min/1.73 m2 and demonstrated benefit in subgroups with low eGFR 1. In clinical practice, the decision to initiate these medications should be individualized based on the patient's specific clinical context, including their kidney function, electrolyte levels, and overall health status.

From the FDA Drug Label

In patients with volume depletion, correcting this condition prior to initiation of JARDIANCE is recommended [see Warnings and Precautions (5. 1), Use in Specific Populations (8.5) and Patient Counseling Information (17)]. 2.2 Patients with Renal Impairment Assessment of renal function is recommended prior to initiation of JARDIANCE and periodically thereafter. JARDIANCE should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2.

1. 7 Dose Adjustment for Severe Renal Impairment In adults and pediatric patients with severe renal impairment estimated glomerular filtration rate (eGFR less than 30 mL/min/1.73 m2), start sacubitril and valsartan tablets at half the usually recommended starting dose.

The GFR thresholds for initiating the mentioned medications are:

• Jardiance (empagliflozin): should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2 2
• Entresto (sacubitril/valsartan): in adults and pediatric patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), start at half the usually recommended starting dose 3
• Spironolactone: The FDA drug label does not answer the question.

From the Research

GFR Thresholds for Initiating Medications

The following GFR thresholds are recommended for initiating spironolactone, Jardiance (empagliflozin), and Entresto (sacubitril/valsartan):

• Spironolactone:
  • eGFR > 30 mL/min/1.73 m2 prior to initiation, with potassium < 5.0 mEq/L 4
  • Can be safe to initiate in hospitalized patients with heart failure and chronic kidney disease, but requires careful monitoring 4
  • A study found that spironolactone was well-tolerated in patients with early stage chronic kidney disease (eGFR 30-89 mL/min/1.73 m2) 5
• Jardiance (empagliflozin):
  • eGFR of at least 20 but less than 45 mL/min/1.73 m2, or eGFR of at least 45 but less than 90 mL/min/1.73 m2 with a urinary albumin-to-creatinine ratio of at least 200 6
• Entresto (sacubitril/valsartan):
  • No specific GFR threshold mentioned in the provided studies, but it is recommended to use with caution in patients with renal impairment, as it can increase the risk of hyperkalemia 7

Key Considerations

• Patients with chronic kidney disease should be closely monitored for hyperkalemia and changes in renal function when initiating these medications 4, 5, 8
• The use of spironolactone in patients with chronic kidney disease may require dose adjustments and careful monitoring of potassium levels and renal function 7, 5
• Empagliflozin has been shown to reduce the risk of progression of kidney disease or death from cardiovascular causes in patients with chronic kidney disease 6