Oral Sulodexide Reduces Albuminuria in Microalbuminuric and Macroalbuminuric Type 1 and Type 2 Diabetic Patients

Abstract

Abstract. Diabetic nephropathy may be effectively prevented and treated by controlling glycemia and administering angiotensinconverting enzyme (ACE) inhibitors. However, strict metabolic control can be difficult, and ACE inhibitors may be poorly tolerated and only partially effective, particularly in diabetes mellitus type 2 (DM2), warranting the search for ancillary treatment. Sulodexide is a glycosaminoglycan, a new class of drug that has demonstrated nephroprotective activity in experimental investigations. The Di.N.A.S. study was a randomized, double-blind, placebo-controlled, multicenter, dose-range finding trial to evaluate the extent and duration of the hypoalbuminuric effect of oral sulodexide in diabetic patients. A total of 223 microalbuminuric and macroalbuminuric DM1 and DM2 patients with serum creatinine Յ150 mol/L and stable BP and metabolic control were recruited. They were randomly allocated to one of four groups: 50 mg/d, 100 mg/d, or 200 mg/d sulodexide daily or placebo for 4 mo (T0 to T4), with 4 mo of follow-up after drug suspension (T4 to T8). Treatment with 200 mg/d sulodexide for 4 mo significantly reduced log albumin excretion rate (logAER) from 5.25 Ϯ 0.18 at T0 to 3.98 Ϯ 0.11 at T4 (P Ͻ 0.05), which was maintained till T8 (4.11 Ϯ 0.13; P Ͻ 0.05 versus T0). Moreover, the sulodexideinduced percent reductions in AER at T4 were significantly different from the placebo value at T4 and approximately linear to dose increments (30% [confidence limits, 4 to 49%], P ϭ 0.03; 49% [30 to 63%], P ϭ 0.0001; and 74% [64 to 81%], P ϭ 0.0001 in the sulodexide 50, 100, and 200 mg/d groups, respectively. At T8, the sulodexide 200 mg/d group maintained a 62% (45 to 73%) AER significant reduction versus placebo (P ϭ 0.0001). Subanalysis by type of diabetes (DM1 versus DM2, microalbuminuric versus macroalbuminuric, or on concomitant ACE inhibitors versus not on ACE inhibitors) demonstrated similar findings. These effects were obtained without any significant variation in metabolic control and BP or serum creatinine. Very few adverse events were reported; none were serious. In conclusion, a 4-mo course of high doses of sulodexide significantly and dose-dependently improves albuminuria in DM1 and DM2 patients and micro-or macroalbuminuric patients with or without concomitant ACE inhibition. The effect on albuminuria is long-lasting and seemingly additive to the ACE inhibitory effect.Diabetes is the most common cause of end-stage renal disease (ESRD) in Western countries. In the United States, diabetes currently accounts for 44% of all new cases of ESRD (1). Despite advances in clinical care, the incidence of diabetes mellitus type 2 (DM2)-related cases of ESRD is rapidly increasing (2), and survival of DM-related ESRD patients on dialysis is markedly low (3,4).The anatomic hallmarks of diabetic nephropathy (DN) include thickening of the glomerular basement membrane (GBM) and mesangial expansion with hyalinosis both in the mesangium and capillary lumen. These lesions lead to glomerular fibrosis, which progressiv...

Heparanase induces a differential loss of heparan sulphate domains in overt diabetic nephropathy

“…The supposition that loss of heparan sulphate in the GBM contributes to proteinuria in overt diabetic nephropathy is indirectly supported by the observation of an antiproteinuric effect in diabetic patients treated with several glycosaminoglycan-based drugs, including heparin (highly sulphated heparan sulphate) [39], sulodexide (80% fast-moving heparin and 20% dermatan sulphate) [40][41][42][43], enoxaparin (low molecular weight heparin) [44] and danaparoid (mixture of glycosaminoglycans consisting predominantly of heparan sulphate) [45]. Since these drugs can also inhibit heparanase activity [46,47], it is possible that their ameliorating effect on proteinuria is due to inhibition of heparanase.…”

Mechanisms and Treatment of CKD

“…117 However, results of a randomized, controlled trial in 1056 diabetic patients with overt nephropathy that has been recently stopped because of futility, definitely signaled the end of this line of research.…”

Diabetic Nephropathy in Type 2 Diabetes Prevention and Patient Management

“…Although the renal risk in diabetic nephropathy can be reduced by 20 to 40% (IDNT and RENAAL), the fact remains that 70% still progress, justifying attempts to develop novel (113). Albuminuria was reduced, seemingly additive to ACE inhibition.…”