The combine effect of renin angiotensin aldosterone system blockage and Sodium-glucose co-transporter-2 receptor inhibition on renal outcomes in type 2 diabetes

Date of ISAC Approval: 
Lay Summary: 
Diabetes is a leading cause of severe kidney disease requiring the very expensive process of removing waste products and excess fluid from the body which also compromises patients' quality of life. Certain blood pressure medications called the Renin Angiotensin Aldosterone System inhibitors have been noted to prevent the deterioration of kidney disease in people with diabetes. Despite this finding and the increased use of these medications over the past 2 decades, kidney disease remains one of the major complications in people with diabetes. In recent years, another class of diabetes medications called the Sodium Glucose Transferase2 receptor (SGLT2-R) inhibitors have been noted to also show some signs suggesting a reduction in the speed of deterioration of kidney disease in people with diabetes. It is possible that combining these two classes of medications could potentially lead to even more drastic improvement of kidney disease in people with diabetes, hence the need for this current piece of research.
Technical Summary: 
The objective of this research is to assess the relative impact of RAAS blockage alone, SGLT2-R inhibitors alone or the combination of both SGLT2-I and RAAS blockage on renal outcomes in people with type 2 diabetes (T2DM). Both SGLT2-RIs, (acting on the afferent arteriole to decrease the hyper-filtration) and RAAS blockade, (acting on the efferent arterioles to decrease the hyper-filtration) lead to reductions in urinary albumin secretion. Using CPRD, we aim to assess whether the combined effect of an SGLT2-RI and RAAS blockade will be additive to decrease renal outcomes. A retrospective cohort study design will be used to estimate the risk of incident or worsening nephropathy using the Cox regression comparing people on dual therapies vs. single therapy or no therapy. Nephropathy outcomes are defined as new onset macro albuminuria, doubling of serum creatinine, initiation of renal replacement therapy or kidney related death. Unadjusted and adjusted analyses for all relevant confounding factors available in CPRD will be performed.
Health Outcomes to be Measured: 
1. End stage renal disease (<15 GFR) 2. Kidney related death using ONS cause of death 3. Renal replacement therapy (Dialysis/transplantation) 4. Doubling of creatinine from baseline

Dr Samuel Seidu - Chief Investigator - Leicester Diabetes Centre
Dr Francesco Zaccardi - Collaborator - University Of Leicester
Hajra Okhai - Collaborator - University Of Leicester
Professor Kamlesh Khunti - Collaborator - University Of Leicester
Professor Melanie Davies - Collaborator - University Of Leicester
Dr Samuel Seidu - Corresponding Applicant - Leicester Diabetes Centre

HES Admitted;HES Outpatient;ONS