In the second reporting period, the project has achieved its key objectives:
No serious adverse events have been reported. The study report has been provided as deliverable. O304 reduced fasting plasma glucose levels and insulin resistance, lowered systemic blood pressure, and increased microvascular perfusion, all beneficial effects in T2D patients. These results have been published "PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients" View the article here:
https://insight.jci.org/articles/view/99114(opens in new window).
In addition, the results provide evidence that O304 may be beneficial in diabetic kidney disease (DKD). Globally, approximately 40% of Type 2 diabetes (T2D) patients develop DKD, and diabetes is the leading cause of kidney failure, requiring dialysis or a kidney transplant. The increasing prevalence of DKD parallels the dramatic worldwide rise in prevalence of diabetes caused by the global pandemic of obesity.
Unfortunately, however, the current standard of care with anti-hypertensive ACEi/ARB drugs which reduce glomerular hypertension shows very limited efficacy, and despite decades of research on the various mechanisms such as fibrosis and inflammation, no new drugs have been approved in the last 15 years for the treatment of DKD or chronic kidney disease (CKD). Thus, there is a great need for novel, more efficient drugs to prevent and treat DKD and CKD.
Glomerular filtration is an essential process whereby fluid in the blood is filtered by the kidneys. Glomerular ‘hyperfiltration’ mediated by intraglomerular hypertension is common in the early stages of T2D and believed to provoke a later decline in globular filtration rate (GFR), ultimately potentially leading to kidney failure. The balance shifts to glomerular hyperfiltration as a result of high intraglomerular pressure caused by increased blood flow into and decreased blood flow out from the glomerulus.
SGLT2 inhibitors are recently introduced anti-hyperglycaemic agents that show improved renal outcome in T2D patients with established cardiovascular disease by reducing estimated globular filtration/hyperfiltration (eGFR) via activation of tubuloglomerular feedback that reduces blood flow into the glomerulus. However, SGLT2 inhibitors are contra-indicated in T2D patients with impaired renal function due to lack of anti-glycaemic effect in this group of patients.
