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Oral Sulodexide Reduces Albuminuria in Microalbuminuric and Macroalbuminuric Type 1 and Type 2 Diabetic Patients: The Di.N.A.S. Randomized Trial

Giovanni Gambaro^*, Ida Kinalska, Adrian Oksa, Peter Pont’uch^||, Miluse Hertlová, Jindrich Olsovsky^¶, Jacek Manitius^**, Domenico Fedele, Stanislaw Czekalski^o, Jindriska Perusicová, Jan Skrha, Jan Taton, Wladyslaw Grzeszczak^¶¶ and Gaetano Crepaldi^o

*Department of Medical and Surgical Science, Division of Nephrology, University of Padua, Padua, Italy; Department of Endocrinology, Medical Academy, Bialystoc, Poland; Institute of Preventive and Clinical Medicine, Clinical Pharmacology Department, Bratislava, Slovak Republic; ^||First Internal Clinic of Medicine, Faculty Hospital, Bratislava, Slovak Republic; Internal Clinic, Faculty Hospital, Brno, Czech Republic; ^¶Second Internal Clinic of Medicine, Diabetology Day-Hospital, Brno, Czech Republic; ^**Department of Nephrology, The Ludwik Rydygier Medical University in Bydgoszcz, Bydgoszcz, Poland; Department of Medical and Surgical Science, Diabetic Center, Geriatric Hospital, University of Padua, Padua, Italy; ^oDepartment of Nephrology, Medical Academy, Poznan, Poland; Third Department of Internal Medicine, Faculty Policlinic, 1^st Faculty of Medicine, Charles University, Prague, Czech Republic; Chair and Department of Internal Diseases and Diabetology, Medical School, Warsaw, Poland; ^¶¶Department and Clinic of Internal Diseases and Diabetology, Silesian School of Medicine, Zabrze, Poland; Department of Medical and Surgical Science, 1^st Medical Clinic, University of Padua, Padua, Italy.

Correspondence to Dr. Giovanni Gambaro, Department of Medical and Surgical Sciences, Division of Nephrology, University Hospital, Via Giustiniani 2, 35128 Padova, Italy. Phone: +39-049-8218153; Fax: +39-049-8212151; E-mail: giga{at}unipd.it

ABSTRACT. Diabetic nephropathy may be effectively prevented and treated by controlling glycemia and administering angiotensin-converting 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 150 µmol/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 ± 0.18 at T0 to 3.98 ± 0.11 at T4 (P < 0.05), which was maintained till T8 (4.11 ± 0.13; P < 0.05 versus T0). Moreover, the sulodexide-induced 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 = 0.03; 49% [30 to 63%], P = 0.0001; and 74% [64 to 81%], P = 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 = 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.

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