Diabetic kidney disease (DKD) develops in approximately 40% of patients who are diabetic and is the leading cause of chronic kidney disease (CKD) worldwide. The natural history of diabetic kidney disease includes glomerular hyperfiltration, progressive albuminuria, declining GFR, and ultimately end-stage renal disease. Despite current therapies, there is large residual risk of diabetic kidney disease onset and progression, and despite decades of research on various mechanism including fibrosis and inflammation, hemodynamic effects through simultaneous reduction in blood pressure and renal filtration/hyperfiltration is currently the only mechanism that show efficacy in DKD, as evident by ACEi/ARB and SGLT-2 inhibition.
O304, DKD and CKD
In kidney of DIO mice, O304 increases p-T172 AMPK and the expression of PGC1α, which both show renoprotective effects. Moreover, like SGLT-2 inhibitors, and in part also ACEi/ARB inhibition, O304 lowers blood pressure and reduces eGFR by a rapid, stable and reversible hemodynamic effect in T2D patients and in obese non-diabetic subjects. Moreover, O304 also reduces eGFR in T2D patients treated with ACEi/ARB inhibitors (SoC), indicating different mechanisms of action. Reduction in filtration / hyperfiltration is also observed in obese T2D patients after caloric restriction and after bariatric surgery, conditions under which AMPK is activated. In a 6 month tox study in rat, compared to vehicle, O304 at high daily doses has no effect on plasma creatinine.
O304 and SGLT-2 inhibition
SGLT-2 inhibitors are currently contra-indicated in T2D patients with impaired renal function because of lack of efficacy on HbA1c. Accordingly, Dapagliflozin did not decrease HbA1c in obese (BMI 35) patients with T2D and Stages 3b–4 CKD, but decreased UACR and blood pressure. However, O304 and the SGLT-2 inhibitor Canagliflozin (and Empagliflozin) potently and synergistically reduces hyperglycemia, hyperinsulinemia and insulin resistance in DIO mice, and one may expect a combinatorial beneficial renal hemodynamic effect of these two classes of compounds. Moreover, the recent identification of 5 subgroups of T2D patients has now opened up the possibility and the requirement for more individualized treatment of groups of T2D patients. In particular, subgroup 3 of T2D patients that are obese (BMI ~35), insulin resistant, hyperinsulinemic, have a 5 fold higher risk of developing DKD, and resemble the patients in the Dapagliflozin cohort with DKD, is currently lacking efficient anti-hyperglycemic treatment.