Diabetic Kidney Disease

Diabetic Kidney Disease

The overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world, and DKD is an area of high unmet medical need. The etiology of the disease progression is complex because of an interplay between systemic metabolic and vascular dysfunctions that involves both tubular and glomerular renal systems. Current therapies slow down but do not prevent the progression of the disease. Recently, SGLT2i/Dapagliflozin that elicits an initial reduction in eGFR, which over time translates to a diminished decline in eGFR compared to placebo, and a significantly reduced risk of ESRD and CV and renal death in both DKD and CKD. Mechanisms of action of SGLT2i in DKD and CKD remains poorly understood but appears to be independent of the hyperemic effect. As an off-target effect SGLT2i inhibits mitochondria and activates AMPK indirectly by lowering energy charge that may contribute to efficacy. Dapagliflozin shows a ~30% reduction in proteinuria in DKD but with no effect in CKD.

AMPK and DKD: A reduced phosphorylation state of T172 AMPK has been correlated with diminished kidney function in both humans and animal models of renal disease. Direct AMPK activators are profoundly reno-protective in a rat model of progressive diabetic nephropathy by reducing proteinuria, improving glomerular filtration rate and kidney fibrosis.

Clinical: In T2D patients, O304 both lowered systemic blood pressure and increased microvascular perfusion. Moreover, in both the phase I and IIa clinical studies O304 potently reduced eGFR by a rapid, stable and reversible haemodynamic effect both in obese non-diabetic subjects and in T2D patients on metformin. O304 also reduced eGFR both in T2D patients with no anti-hypertensive treatment or on top of ACEi/ARB drug treatment (standard of care for DKD). These effects on renal filtration/hyperfiltration are similar to what has been reported for SGLT2 inhibitors. Since O304 also reduces blood glucose and insulin resistance, lowers blood pressure and increases microvascular perfusion. The combination of O304 and SGLT2i as treatment for DKD and CKD is therefore of high interest.