Harnessing basic and clinic tools to evaluate SGLT2 inhibitor nephrotoxicity.

Area of Science:

• Nephrology
• Endocrinology
• Pharmacology

Background:

• Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of medications for Type 2 Diabetes Mellitus (T2DM).
• These drugs lower plasma glucose by inhibiting glucose reabsorption in the proximal convoluted tubule, leading to increased urinary glucose excretion.
• Beyond glycemic control, SGLT2 inhibitors offer benefits like weight loss, blood pressure reduction, and potential renoprotection, as seen with empagliflozin.

Purpose of the Study:

• To investigate the discrepancy between reported acute kidney injury (AKI) cases for SGLT2 inhibitors in the FDA Adverse Events Reporting System (FAERS) and the absence of AKI in controlled trials.
• To determine if FAERS-reported AKI represents true structural kidney injury or a functional decline in glomerular filtration rate.
• To address concerns that FDA warnings may deter the use of SGLT2 inhibitors in diabetic patients with chronic kidney disease (CKD).

Main Methods:

• Review of FAERS data for SGLT2 inhibitors (canagliflozin, dapagliflozin) reporting AKI.
• Comparison of FAERS reports with adverse event data from randomized controlled trials (RCTs) of SGLT2 inhibitors.
• Proposal to utilize clinical tools, experimental kidney injury biomarkers, and kidney-on-a-chip technology for further investigation.

Main Results:

• The FAERS database contains over 100 cases of AKI associated with canagliflozin and dapagliflozin, with a significant proportion requiring hospitalization, ICU admission, or hemodialysis.
• RCTs of SGLT2 inhibitors, even with co-prescription of renin-angiotensin-system antagonists and diuretics, do not consistently report AKI as an adverse event.
• A critical need exists to differentiate between functional and structural kidney injury in the context of SGLT2 inhibitor use.

Conclusions:

• The reported AKI associated with SGLT2 inhibitors requires further clarification to distinguish between functional and structural kidney injury.
• Accurate assessment of AKI risk is crucial for appropriate SGLT2 inhibitor prescription, especially in T2DM patients with CKD.
• Advanced research methodologies, including biomarker analysis and organ-on-a-chip technology, are proposed to resolve this clinical uncertainty.