Does the Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitor affect kidney function in terms of Estimated Glomerular Filtration Rate (EGFR)?

From the Guidelines

SGLT2 inhibitors do not damage kidney function in terms of eGFR; in fact, they provide renal protection, and can be used in individuals with eGFR as low as 20 mL/min/1.73 m2, as recommended by the latest guidelines 1. The initial decline in eGFR caused by SGLT2 inhibitors is hemodynamic in nature, resulting from increased sodium delivery to the macula densa, which activates tubuloglomerular feedback and reduces intraglomerular pressure. After this initial dip, eGFR stabilizes and the long-term trajectory shows significantly slower decline in kidney function compared to patients not taking these medications. Some key points to consider when using SGLT2 inhibitors include:

• They can cause a small, reversible decrease in eGFR (about 3-5 ml/min/1.73m²) within the first few weeks of treatment 1.
• The renoprotective effects of SGLT2 inhibitors occur through multiple mechanisms including reduced hyperfiltration, decreased albuminuria, improved tubular oxygenation, and reduced inflammation.
• Multiple large clinical trials have demonstrated that SGLT2 inhibitors reduce the risk of kidney disease progression, major adverse kidney events, and cardiovascular events in patients with diabetes, chronic kidney disease, or heart failure 1.
• SGLT2 inhibitors are now recommended for kidney protection independent of their glucose-lowering effects, and can be used in combination with other medications such as metformin and GLP-1 RAs. It is essential to monitor eGFR and adjust the dose of metformin accordingly, as it may accumulate with reduced kidney function and increase the risk for lactic acidosis 1. Overall, the benefits of SGLT2 inhibitors in reducing the risk of kidney disease progression and cardiovascular events make them a valuable treatment option for patients with diabetes and chronic kidney disease.

From the FDA Drug Label

Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m^2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. There have been post-marketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA.

The use of SGLT2 inhibitors, such as canagliflozin, may be associated with an increased risk of kidney damage in terms of eGFR, particularly in patients with impaired renal function or those at risk for volume depletion.

• Key factors that may increase the risk of kidney damage include:
  • Impaired renal function (eGFR less than 60 mL/min/1.73 m^2)
  • Elderly patients
  • Patients on loop diuretics
• Monitoring for signs and symptoms of volume depletion and kidney injury is recommended after initiating therapy with canagliflozin 2.

From the Research

SGLT2 Inhibitors and Kidney Function

• The effects of SGLT2 inhibitors on renal outcomes in patients with chronic kidney disease (CKD) have been demonstrated in recent trials 3.
• SGLT2 inhibitors reduce the risk of worsening kidney function, end-stage kidney disease (ESKD), or renal death by 30% in patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 3.
• These inhibitors also reduce the risk of major renal outcomes by 46% in patients with atherosclerotic cardiovascular disease and macroalbuminuria (defined as UACR > 300 mg/g) 3.

Mechanisms of Renal Protection

• SGLT2 inhibitors reduce intraglomerular pressure and decrease albuminuria, resulting in a slower decline in glomerular filtration rate (GFR) in patients with kidney disease 4, 5.
• They also have anti-inflammatory and antifibrotic effects, which contribute to their nephroprotective effects 4, 6.
• The mechanisms of renal protection extend beyond glucose-lowering, weight-lowering, and blood pressure-lowering effects, and include tubuloglomerular feedback, improved tubular oxygenation and metabolism, and reduced renal inflammation and fibrosis 6.

Effects on eGFR

• SGLT2 inhibitors have been shown to slow the decline in eGFR in patients with type 2 diabetes and renal disease 7, 5.
• They also reduce the risk of adverse kidney outcomes, including eGFR decline >50%, end-stage kidney disease (ESKD), or all-cause mortality, in patients with type 2 diabetes 7.
• The renal benefits of SGLT2 inhibitors are maintained across different levels of eGFR, including eGFR <45 mL/min/1.73 m2 3, 7.

Safety and Efficacy

• SGLT2 inhibitors have not increased the risk of urinary tract infections or the risk of acute kidney injury 6.
• However, introduction of an SGLT2 inhibitor in patients with a very low GFR is not encouraged due to an initial dip in GFR, and it is prudent to discontinue therapy if there is an acute renal event, hypovolaemia, or hypotension 6.