Effects of sulodexide in patients with type 2 diabetes and persistent albuminuria

Abstract

Background. Urinary albumin excretion frequently persists in diabetic patients who are treated with angiotensinconverting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Sulodexide, a glycosaminoglycan mixture of 80% heparan sulfate and 20% dermatan sulfate, has been hypothesized to reduce persistent albuminuria. We have conducted a multi-center randomized double-blind pilot study in order to determine the effect of 6 months' therapy with sulodexide on urinary albumin excretion and to address logistical issues for a full-scale trial. Methods. A total of 149 patients with type 2 diabetes and an albumin:creatinine ratio (ACR) between 20 and 300 mg/g were randomized with equal allocation to either placebo, 200 mg of sulodexide or 400 mg of sulodexide. The primary endpoint was the achievement, at 6 months, of either 3(1) return to normoalbuminuria (ACR < 20 mg/g with a decrease of at least 25%) or (2) a decrease in ACR of at least 50% from the baseline value. All patients used a maximum tolerated recommended FDA approved dose of an ACEI or ARB for at least 60 days and had stable blood pressure prior to randomization. Results. The primary efficacy endpoint was achieved in 25.3% of the patients in the two sulodexide groups combined versus 15.4% of the placebo-treated patients (P = 0.26). The primary endpoint was achieved in 33.3% (P = 0.075 for the comparison to placebo) in the sulodexide 200 mg group and 18.4% (P = 0.781) in the sulodexide 400 mg group. (No consistent patterns of side effects were observed.Correspondence and offprint requests to: H. J. Lambers Heerspink, Department of Clinical Pharmacology University Medical Center Groningen, University of Groningen, A. Deusinglaan, 19713 AV Groningen, The Netherlands. Tel: +31-50-363-2809; Fax: +31-50-363-2812; E-mail: H.J.Lambers.Heerspink@med.umcg.nl Conclusion. Based on the experience gained in this pilot study, one full-scale trial is currently being conducted to evaluate the effects of sulodexide on change in ACR in patients with persistent microalbuminuria, and a longerterm trial is underway to evaluate the effects of sulodexide on long-term renal disease progression in patients with overt proteinuria.

Role of the Vascular Wall in Sodium Homeostasis and Salt Sensitivity

“…Not all trials investigating long-term sulodexide administration reported BP values or BP reduction, and none of the studies were designed to specifically examine the effect of sulodexide on BP. 59,[66][67][68] Moreover, BP was already on target when sulodexide was added in most of the studies, and antihypertensive drugs were not actively controlled. 58,[66][67][68] Because the largest BP-lowering effect (mean placebo-subtracted BP reduction=214.6/28.3 mmHg) was observed in a crossover study in patients with diabetes and uncontrolled hypertension, sulodexide may especially lower BP in patients with hypertension and expanded ECV.…”

“…59,[66][67][68] Moreover, BP was already on target when sulodexide was added in most of the studies, and antihypertensive drugs were not actively controlled. 58,[66][67][68] Because the largest BP-lowering effect (mean placebo-subtracted BP reduction=214.6/28.3 mmHg) was observed in a crossover study in patients with diabetes and uncontrolled hypertension, sulodexide may especially lower BP in patients with hypertension and expanded ECV. 60 In conclusion, new pathophysiologic concepts have arisen from the notion that sodium homeostasis and salt sensitivity seem to relate to not only the kidney, but also extrarenal factors-most intriguingly, the endothelium.…”

Sulodexide Fails to Demonstrate Renoprotection in Overt Type 2 Diabetic Nephropathy

“…30 Results from the Diabetic Nephropathy and Albuminuria Sulodexide Study 22 showed that, in 223 patients with either type 1 or type 2 diabetes and with either microalbuminuria or more advanced nephropathy, sulodexideassigned patients showed a significant decrease in albumin excretion rate, regardless of the stage of their independent diabetic nephropathy and effects of angiotensin-converting enzyme (ACE) inhibitors. Effects were maximal after 4 months and seemed to persist for at least another 4 months after cessation of sulodexide.…”

“…[15][16][17][18][19][20][21][22] A number of studies suggest different modes of action to explain this phenomenon. [23][24][25][26][27][28][29] After conducting a previously reported pilot study, 30 the Collaborative Study Group (CSG) undertook two multinational, randomized, double-blind, placebocontrolled trials using sulodexide in patients with type 2 diabetes, and the study designs were reported in detail previously. 31 The sulodexide microalbuminuria (Sun-MICRO) trial 32 was conducted in patients with preserved renal function and microalbuminuria.…”

New Treatments for Diabetic Chronic Kidney Disease

“…In experimental and small clinical studies, sulodexide, a compound containing a mixture of glycosaminoglycans, has been shown to reduce albuminuria, possibly through restoring glomerular glycoproteins or by restoring anionic heparin sulphate charge on the GBM. Furthermore, small, short-term clinical trials have suggested that sulodexide can reduce albuminuria [59,60]. However, in a large double blind, randomised control (SUN-Micro) trial involving 1000 patients with type 2 diabetes and microalbuminuria who were already receiving maximal doses of ACE inhibitors or ARBs, sulodexide failed to reduce albuminuria [61].…”