Will increasing the dose of empagliflozin (Empagliflozin) improve kidney function in patients with impaired renal function?

From the Guidelines

Increasing the dose of empagliflozin is not recommended to improve kidney function in patients with impaired renal function. Empagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, is typically prescribed at doses of 10 mg or 25 mg once daily, but higher doses have not been shown to provide additional renal benefits in patients with kidney impairment, as supported by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) consensus report 1. In fact, the medication's efficacy decreases as kidney function worsens because it works by blocking glucose reabsorption in the proximal tubule of the kidney. For patients with an eGFR below 30 mL/min/1.73m², empagliflozin is not recommended at all due to reduced efficacy, and for those with eGFR between 30-45 mL/min/1.73m², the standard dose is appropriate without need for increase, as indicated in the Mayo Clinic Proceedings 1.

Some key points to consider when managing patients with impaired renal function on empagliflozin include:

• Monitoring renal function regularly while on empagliflozin
• Dose adjustments should be based on overall clinical response rather than attempting to improve kidney function through dose escalation
• The kidney-protective effects of empagliflozin come from its mechanism of reducing glomerular pressure, decreasing albuminuria, and improving other metabolic parameters—not from higher dosing, as noted in the studies 1
• Empagliflozin is not recommended for initiation in patients with eGFR <30 ml/min/1.73 m2 for glycemic control or <20 ml/min/1.73 m2 for heart failure, and higher doses are not effective for glucose lowering and do not offer further clinical benefit in this range of eGFR, as stated in the Kidney International study 1.

Overall, the current evidence suggests that increasing the dose of empagliflozin does not provide additional kidney benefits in patients with impaired renal function, and therefore, it is not recommended to increase the dose of empagliflozin in these patients 1.

From the FDA Drug Label

In patients with mild (eGFR: 60 to less than 90 mL/min/1.73 m2), moderate (eGFR: 30 to less than 60 mL/min/1. 73 m2), and severe (eGFR: less than 30 mL/min/1. 73 m2) renal impairment and subjects with kidney failure/end stage renal disease (ESRD) patients, AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal renal function. However, the fraction of empagliflozin that was excreted unchanged in urine, and urinary glucose excretion, declined with decrease in eGFR

The FDA drug label does not answer the question.

From the Research

Kidney Benefits of Empagliflozin

• The studies 2, 3, 4, 5, 6 suggest that empagliflozin has a beneficial effect on kidney outcomes in patients with type 2 diabetes mellitus and chronic kidney disease.
• Empagliflozin has been shown to reduce the risk of kidney outcome events, such as incident or worsening nephropathy, and slow the progression of chronic kidney disease 2, 3, 4.
• The effects of empagliflozin on kidney outcomes are consistent across different subgroups of patients, including those with and without heart failure, and across different ranges of estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio 2, 3, 4, 5, 6.

Dose-Response Relationship

• The studies do not provide clear evidence of a dose-response relationship between empagliflozin and kidney benefits 2, 4.
• The EMPA-REG OUTCOME trial found that both 10 mg and 25 mg doses of empagliflozin reduced the risk of kidney outcome events, but the study did not compare the effects of different doses directly 2.
• The EMPEROR-Reduced trial found that empagliflozin 10 mg reduced the risk of cardiovascular death or heart failure hospitalization and slowed the decline in eGFR, but the study did not investigate the effects of higher doses 5.

Increasing Empagliflozin Dose

• There is limited evidence to suggest that increasing the dose of empagliflozin beyond 10 mg would provide additional kidney benefits 2, 4.
• The studies suggest that the effects of empagliflozin on kidney outcomes are consistent across different subgroups of patients, but they do not provide clear evidence of a dose-response relationship 2, 3, 4, 5, 6.
• Further studies are needed to investigate the effects of higher doses of empagliflozin on kidney outcomes and to determine the optimal dose for patients with chronic kidney disease.