What is the role of SGLT2 (sodium-glucose linked transporter 2) inhibitors in the management of type 2 diabetes mellitus with end-stage renal disease (ESRD)?

From the Guidelines

SGLT2 inhibitors can be used in Type 2 diabetes patients with end-stage renal disease (ESRD), but their benefits and dosing requirements change significantly with declining kidney function, and the most recent evidence suggests that they should be used cautiously in patients with eGFR ≥20 mL/min/1.73 m² to reduce CKD progression and cardiovascular events 1. For patients with ESRD on dialysis, only empagliflozin (Jardiance) is FDA-approved at a dose of 10 mg daily, based on the EMPA-KIDNEY trial showing cardiovascular benefits even in advanced kidney disease. Other SGLT2 inhibitors like dapagliflozin (Farxiga) and canagliflozin (Invokana) are not recommended for patients with eGFR below 15 ml/min/1.73m² or on dialysis. When using empagliflozin in ESRD patients, expect reduced glucose-lowering effects since these medications work by blocking glucose reabsorption in the kidneys, which is already compromised in ESRD. The primary benefits in ESRD shift toward cardiovascular protection and potential reduction in heart failure hospitalizations rather than glycemic control. Some key points to consider when using SGLT2 inhibitors in patients with ESRD include:

• Monitoring for volume depletion, hypotension (especially post-dialysis), and urinary tract infections
• Patients should be advised that while these medications may provide cardiovascular benefits, additional diabetes medications will likely be needed for adequate glucose control in the ESRD setting
• The selection of specific SGLT2 inhibitors may depend on comorbidity and CKD stage, with SGLT2 inhibitors being more useful for patients at high risk of CKD progression (i.e., with albuminuria or a history of documented eGFR loss) 1
• The evidence from the CREDENCE trial and secondary analyses of cardiovascular outcomes trials with SGLT2 inhibitors suggests that cardiovascular and renal events are reduced with SGLT2 inhibitor use in patients down to an eGFR of 30 mL/min/1.73 m², independent of glucose-lowering effects 1

From the FDA Drug Label

Patients with diabetes and renal impairment using dapagliflozin may be more likely to experience hypotension and may be at higher risk for acute kidney injury secondary to volume depletion. 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.

The usage of SGLT2 inhibitors like dapagliflozin in patients with diabetes type 2 and End-Stage Renal Disease (ESRD) is not recommended due to the increased risk of hypotension and acute kidney injury.

• The drug label does not provide direct evidence to support the use of dapagliflozin in patients with ESRD.
• Dapagliflozin is not recommended for glycemic control in patients without established CV disease or CV risk factors when eGFR is less than 45 mL/min/1.73 m2 2.
• Patients with eGFR less than 25 mL/min/1.73 m2 or on dialysis were not enrolled in efficacy and safety trials with dapagliflozin.

From the Research

Usage of SGLT2 Inhibitors in Diabetes Type 2 and ESRD

• SGLT2 inhibitors have been shown to be effective in reducing the risks of cardiovascular and renal outcomes in patients with type 2 diabetes mellitus (T2DM) and comorbid conditions, including end-stage renal disease (ESRD) 3, 4.
• These drugs can be used in patients with a wide range of comorbid conditions, including atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD), and in those with estimated glomerular filtration rates as low as 30 mL/min/1.73 m2 3.
• The use of SGLT2 inhibitors in patients with T2DM and renal disease has been associated with a reduced risk of development or worsening of albuminuria, a marker of renal damage 5.
• SGLT2 inhibitors have also been shown to have benefits in patients with heart failure (HF) and kidney disease, both in the presence and absence of T2DM, including improvements in fluid status, blood pressure, serum uric acid levels, and weight loss 6.
• The cardiovascular and renal benefits of SGLT2 inhibition appear to be maintained to estimated glomerular filtration levels as low as 30 mL/min/1.73 m2 5.
• However, the use of SGLT2 inhibitors can be associated with adverse events, including mild genitourinary infections and conditions related to volume depletion, as well as potentially serious adverse events such as hypoglycemia, lower limb ischemia, and diabetic ketoacidosis 4.

Mechanism of Action and Interactions

• The mechanism of action of SGLT2 inhibitors involves the inhibition of the sodium-glucose cotransporter 2, which leads to a reduction in glucose reabsorption in the kidney and an increase in glucose excretion in the urine 3.
• The use of SGLT2 inhibitors can be affected by the concomitant use of other medications, including antidiabetic and antihypertensive agents 7.
• Metformin has been shown to blunt the SGLT2 inhibitor-induced decrease in estimated glomerular filtration rate (eGFR), but coadministration of renin-angiotensin system inhibitors (RASis) can ameliorate this response 7.

Clinical Implications

• SGLT2 inhibitors should be considered as a treatment option for patients with T2DM and ESRD, as they have been shown to have benefits in reducing the risks of cardiovascular and renal outcomes 3, 4, 5, 6.
• The use of SGLT2 inhibitors in patients with T2DM and renal disease should be individualized, taking into account the patient's comorbid conditions, renal function, and concomitant medications 3, 4, 7, 5, 6.