In the CREDENCE trial, canagliflozin in patients with diabetic nephropathy (eGFR 30–90, albuminuria ≥300 mg/g, on max RAAS blockade) reduced the primary composite renal outcome. The renoprotective mechanism of SGLT2 inhibitors independent of glycaemic control involves:

• A Direct podocyte protection via SGLT2 receptor on glomerulus
• B Reduction of intraglomerular pressure via afferent arteriole constriction from tubuloglomerular feedback restoration ✓
• C Anti-inflammatory effect via IL-6 inhibition
• D ACE inhibitor-like reduction in angiotensin II activity

Explanation

SGLT2 inhibitors inhibit glucose reabsorption at the proximal tubule, increasing luminal NaCl concentration reaching the macula densa. This restores tubuloglomerular feedback (TGF) by causing afferent arteriole constriction, reducing hyperfiltration and intraglomerular hypertension — the primary mechanism of diabetic nephropathy progression. This haemodynamic effect is immediate (within weeks) and precedes any metabolic benefit. CREDENCE was the landmark trial confirming significant renoprotection even with eGFR down to 30.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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Written and medically reviewed by the StethoPrep medical team.