Study description

Study synopsis

Background: Diabetes affects 9% of the European population and the cost of caring for patients with diabetes accounts for 15% of the European health care budget expenditure. Almost 90% of patients have type 2 diabetes, and absolute numbers are expected to rise in parallel to the current obesity and metabolic syndrome epidemic. Patients with diabetes are at risk of developing diabetic nephropathy, which will ultimately result in the requirement for renal replacement therapy and is also associated with high cardiovascular morbidity and mortality.

Transition between the stages of albuminuria (i.e. normo- to microalbuminuria and micro- to macroalbuminuria) is considered a hallmark of progression of renal disease in diabetes. However, once transitioned from normo to microalbuminuria or to macroalbuminuria, regression of disease is very difficult to achieve. In fact, recent trials in normo- and microalbuminuric diabetic subjects showed that early intervention (in normoalbuminuric stage) is more effective with the same drug (RAAS intervention) than late intervention. Early markers that detect those that have an increased chance for developing micro- or macroalbuminuria could thus help us reduce the number of patients at renal risk through selective preventive treatments of such patients. In two independent studies we have demonstrated that urinary proteomics offers the prospect of detecting nephropathy earlier in the preclinical phase, enabling targeted treatment at an earlier stage.

If individuals with high risk for initiation of diabetic nephropathy are identified it will be possible to target intervention to these patients. We have defined urinary biomarkers of type 1 and type 2 diabetes and a panel of biomarkers for diagnosis of chronic kidney disease that have in different blinded studies by now proven to identify with high accuracy patients who will develop microalbuminuria and ultimately diabetic nephropathy.  Additionally, we could in other randomised controlled trials demonstrate that spironolactone shows potential benefit over and in addition to standard care, by significantly reducing albuminuria in patients with micro or macroalbuminuria. The effect tended to be better the earlier treatment was started (microalbuminuria vs macroalbuminuria) so it is hypothesised that intervention with spironolacton in normoalbuminuric patients with positive urinary biomarker test (high risk) will delay or even prevent development of microalbuminuria and potentially macroalbuminuria and ultimately CKD.

Objectives: The aim is to assess the potential of proteomics targeted therapy with the aldosterone receptor antagonist (spironolactone) in the prevention of diabetic nephropathy, as add-on to recommended antihypertensive therapy including angiotensin converting enzyme (ACE) inhibition or angiotensin II receptor blockers (ARBs) according to national guidelines.

Hypotheses: Early initiation of preventive therapy with spironolacton reduces risk of progression of albuminuria in those identified by urinary proteomics to be at high risk, and thereby delays progression to overt nephropathy. Treatment can be spared for those with low risk according to urinary proteomics, paving the way of personalised medicine.

Design: Observational follow up study, with biomarker positive patients included in a randomized, double-blind, placebo-controlled, multicenter study
Patient Population: 2000 patients with type 2 diabetes and normoalbuminuria.
Intervention: The expected 260 patients that display a high risk urinary proteomic pattern will be randomized to spironolactone 25 mg once daily or placebo

Endpoints:  Development of confirmed microalbuminuria (>30 mg/g in 2 out of 3 consecutive first morning void urine samples)