Glomerular hyperfiltration is a major risk factor for accelerated glomerular filtration rate
(GFR) decline and renal and cardiovascular events despite optimized conservative therapy with
blood pressure and blood glucose (in diabetics) lowering medications and inhibitors of the
Renin Angiotensin System (RAS) such as Angiotensin Converting Enzyme (ACE) inhibitors and/or
Angiotensin Receptor Blockers (ARBs).
Progressive GFR decline initiated and sustained by glomerular hyperfiltration in subjects
with diabetes, unhealthy obesity, hypertension and other risk factors, is paralleled by
progressive glomerulosclerosis and loss of functioning nephrons.
The inhibition of the sodium-glucose cotransporter 2 (SGLT2) in the proximal tubular segments
of the nephrons appears to be an ideal, specific intervention to inhibit the
tubulo-glomerular feedback and ameliorate glomerular hyperfiltration in subjects with
absolute or relative hyperfiltration associated with unhealthy obesity or proteinuric chronic
kidney disease (CKD). Indeed, by reducing tubular sodium reabsorption, SGLT2 inhibitors may
enhance sodium chloride delivery to the macula densa, restore pre-glomerular resistances and
therefore limit glomerular hyperperfusion and consequent hyperfiltration. Moreover, because
of its natriuretic effects, SGLT2 inhibition therapy might reduce the sodium overload and
volume expansion which, along with secondary hypertension, may further contribute to kidney
hyperperfusion and glomerular hyperfiltration in obesity and CKD.
Phase:
Phase 2
Details
Lead Sponsor:
Mario Negri Institute for Pharmacological Research