Effect of Sulodexide in Overt Diabetic Nephropathy

Diabetes is now the most common cause of end-stage renal disease (ESRD) in the U.S. and in many other developed nations. Diabetic nephropathy now represents 44% of all new cases of ESRD in the U.S. Despite advances in clinical care, including improvements in glycemic and blood pressure control, the number of new cases of diabetes related ESRD continues to rise. In particular, the incidence of type 2 diabetes mellitus (DM2)-related cases of ESRD is rapidly increasing. From 1993 to 1997, 71% of all diabetes-related ESRD was attributable to DM2 (USRDS 1999). The earliest sign of diabetic kidney disease presents as microalbuminuria, the spilling of small of amounts of blood protein into the urine. Microalbuminuria correlates directly with the subsequent development of more advanced kidney disease. Improved glycemic control and blood pressure control with the use of inhibitors of the renin-angiotensin-aldosterone system can reduce the level of microalbuminuria and overt proteinuria. However, despite these measures, diabetic nephropathy continues to progress, albeit more slowly. Sulodexide belongs to a class of drugs called glycosaminoglycans (GAG). GAG therapy has been shown in animal models to prevent and or induce regression of albuminuria, and the morphologic changes associated with progressive diabetic nephropathy such as glomerular basement thickening, loss of the anionic charge density and mesangial collagen deposition. Sulodexide is approved in Europe to treat vascular indications. It has been utilized in several small phase II studies to treat early diabetic nephropathy, inducing an additional 40-70 % reduction in albuminuria in subjects whose albumin excretion was already reduced with tight glycemic control plus the use of inhibitors of the renin-angiotensin-aldosterone system for blood pressure control. The purpose of this study is to add to this body of evidence that Sulodexide may offer additional benefit in preventing or ameliorating more advanced diabetic nephropathy manifested as overt proteinuria and reduced GFR. Subjects with type 2 diabetes, moderately elevated serum creatinine and overt proteinuria will be treated with a standardized maximal recommended/tolerated dose of irbesartan 300 mg/day or losartan 100 mg/day plus additional concomitant non-ARB, non-ACEi antihypertensive drugs,for up to 2-3 months to establish adequate and stable blood pressure control and urine protein excretion. After establishing baseline serum creatinine and urine protein excretion they will be randomized to either Sulodexide 200 mg/d or matching placebo. Subjects will be seen every 3 months to monitor safety and efficacy parameters for up to 4 years. The primary outcome is a doubling of baseline serum creatinine (50% loss of kidney function) or end stage kidney disease (ESRD).