At what level of impaired renal function, as indicated by elevated creatinine (Creatinine) and decreased glomerular filtration rate (GFR), should Dapagliflozin (Dapagliflozin) be held?

From the Guidelines

Dapagliflozin should be held when the estimated glomerular filtration rate (eGFR) falls below 25 mL/min/1.73m² or if serum creatinine indicates severe renal impairment. For patients with type 2 diabetes, dapagliflozin is not recommended when eGFR is persistently below 45 mL/min/1.73m², though it may be continued until dialysis or transplantation for patients with heart failure or chronic kidney disease who have established benefits from the medication, as supported by the DAPA-CKD study 1.

Key Considerations

• Regular monitoring of renal function is essential when using dapagliflozin, with assessment recommended before initiation and periodically during treatment.
• The drug works by inhibiting sodium-glucose cotransporter-2 (SGLT2) in the proximal tubules of the kidneys, which reduces glucose reabsorption and increases urinary glucose excretion.
• This mechanism becomes less effective with declining kidney function, and the risk of adverse effects like volume depletion and acute kidney injury increases, as noted in the consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) 2.
• Patients with severely impaired renal function may not experience the intended glycemic benefits while still being exposed to potential risks.

Dosing Recommendations

• According to the package insert, dapagliflozin is approved for use at 10 mg once daily with an eGFR of 25 to <45 ml/min/1.73 m2, as mentioned in the ADA and KDIGO consensus report 2.
• Initiation is not recommended with eGFR <25 mL/min/1.73 m2; however, it may be continued if tolerated for kidney and CV benefit until dialysis, as seen in the DAPA-CKD study 1.

Clinical Evidence

• The DAPA-CKD study demonstrated a significant benefit of dapagliflozin for the primary end point of ≥50% sustained decline in eGFR, ESRD, or cardiovascular death, with a hazard ratio (HR) of 0.61 (95% CI 0.51–0.72; P < 0.001) 1.
• The study also showed a reduction in the risk of new or worsening nephropathy, with an HR of 0.56 (95% CI 0.45–0.68; P < 0.001) 1.

From the FDA Drug Label

Use of DAPAGLIFLOZIN TABLETS for glycemic control in patients without established CV disease or CV risk factors is not recommended when eGFR is less than 45 mL/min/1.73 m2 Efficacy and safety trials with dapagliflozin did not enroll patients with an eGFR less than 25 mL/min/1.73 m2 or on dialysis. Once enrolled in the DAPA-CKD and DELIVER trials, adult patients were not required to discontinue therapy if eGFR fell below 25 mL/min/1. 73 m2 or if dialysis was initiated. Once enrolled in the DAPA-HF trial, adult patients were not required to discontinue therapy if eGFR fell below 30 mL/min/1.73 m2 or if dialysis was initiated

Dapagliflozin should be held at an eGFR less than 25 mL/min/1.73 m2 in patients with no established CV disease or CV risk factors, as efficacy and safety trials did not enroll patients with an eGFR less than 25 mL/min/1.73 m2 or on dialysis 3. However, for patients already enrolled in trials, therapy was not required to be discontinued if eGFR fell below 25 mL/min/1.73 m2 or if dialysis was initiated.

• Key considerations: + eGFR threshold: less than 25 mL/min/1.73 m2 + Patient population: without established CV disease or CV risk factors + Clinical context: efficacy and safety trials did not enroll patients with an eGFR less than 25 mL/min/1.73 m2 or on dialysis 3

From the Research

Dapagliflozin and Renal Function

Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor used to treat type 2 diabetes. The following points summarize the relationship between dapagliflozin and renal function:

• Dapagliflozin may decrease glomerular filtration rate (GFR), especially in elderly patients and patients with impaired renal function 4.
• Renal function should be monitored before initiation of dapagliflozin, and it should not be used in patients with an estimated GFR <60 ml/min/1.73 m(2) 4.
• In patients with normal or mildly impaired renal function, dapagliflozin is not associated with increased risk of acute renal toxicity or deterioration of renal function 5.
• Dapagliflozin can be used in patients with an eGFR ≥45 mL/min/1.73 m2, but its use is limited in patients with more severe renal impairment 6.

Renal Safety of Dapagliflozin

The renal safety of dapagliflozin has been evaluated in several studies:

• A study of 4545 patients with type 2 diabetes found that dapagliflozin did not renal adverse events compared to placebo 5.
• A retrospective study of 111 patients who switched from dapagliflozin to empagliflozin found no significant changes in renal function after 6 months 6.
• A prespecified analysis of the DELIVER randomized clinical trial found that dapagliflozin slowed the rate of decline in eGFR compared to placebo in patients with heart failure and a mildly reduced or preserved ejection fraction 7.
• A prespecified secondary analysis of a randomized clinical trial found that the effect of dapagliflozin on cardiovascular outcomes was consistent across subgroups of baseline eGFR and urinary albumin to creatinine ratio 8.

Impaired Renal Function and Dapagliflozin

The following points summarize the use of dapagliflozin in patients with impaired renal function:

• Dapagliflozin should not be used in patients with an estimated GFR <60 ml/min/1.73 m2 4.
• In patients with an eGFR <60 mL/min/1.73 m2, the use of dapagliflozin may be limited, and alternative treatments such as empagliflozin may be considered 6.
• The renal safety of dapagliflozin has been evaluated in patients with impaired renal function, and the results suggest that it can be used safely in patients with an eGFR ≥45 mL/min/1.73 m2 6, 7, 8.