SGLT2 inhibitors in CKD: are they really effective in all patients?

Area of Science:

• Nephrology
• Pharmacology
• Internal Medicine

Background:

• Sodium-glucose cotransporter-2 (SGLT2) inhibitors are established treatments for slowing chronic kidney disease (CKD) progression and reducing cardiovascular events, particularly in patients with diabetes and obesity.
• Current evidence primarily derives from trials in overweight or obese patients with advanced CKD, where mechanisms like sodium retention and glomerular hyperfiltration are prominent.

Purpose of the Study:

• To evaluate the uncertain efficacy of SGLT2 inhibitors across diverse CKD subgroups, especially in lean, non-diabetic individuals.
• To investigate whether SGLT2 inhibitor benefits are contingent on body mass index (BMI) and disease-specific progression mechanisms.

Main Methods:

• Review of existing clinical trial data and emerging evidence, including animal studies and molecular data on SGLT2 expression.
• Analysis of factors influencing SGLT2 inhibitor efficacy, such as BMI, underlying CKD etiology (e.g., genetic, immune-mediated), and disease drivers.

Main Results:

• Emerging evidence suggests SGLT2 inhibitors may be less effective in lean individuals (BMI < 25), whose CKD may stem from inflammation, autoimmunity, or genetic factors rather than hyperfiltration.
• Animal studies indicate limited renal protection from SGLT2 inhibitors in certain genetic and immune-mediated kidney diseases.
• SGLT2 expression is mainly in the proximal tubule, suggesting limited impact on CKD driven by non-hyperfiltration mechanisms.

Conclusions:

• The role of SGLT2 inhibitors in lean, non-diabetic CKD patients remains unclear, necessitating dedicated clinical trials.
• Personalized treatment strategies are required, considering CKD subgroups and individual patient characteristics for optimal therapeutic outcomes.