title: Oral sulodexide reduces albuminuria in microalbuminuric and macroalbuminuric type 1 and type 2 diabetic patients: the Di.N.A.S. randomized trial.
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 < or =150 micromol/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.
authors.affiliation: Department of Medical and Surgical Science, Division of Nephrology, University of Padua, Padua, Italy. giga@unipd.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gambaro
authors.forename: Ida
authors.initials: I
authors.lastname: Kinalska
authors.forename: Adrian
authors.initials: A
authors.lastname: Oksa
authors.forename: Peter
authors.initials: P
authors.lastname: Pont'uch
authors.forename: Miluse
authors.initials: M
authors.lastname: Hertlová
authors.forename: Jindrich
authors.initials: J
authors.lastname: Olsovsky
authors.forename: Jacek
authors.initials: J
authors.lastname: Manitius
authors.forename: Domenico
authors.initials: D
authors.lastname: Fedele
authors.forename: Stanislaw
authors.initials: S
authors.lastname: Czekalski
authors.forename: Jindriska
authors.initials: J
authors.lastname: Perusicová
authors.forename: Jan
authors.initials: J
authors.lastname: Skrha
authors.forename: Jan
authors.initials: J
authors.lastname: Taton
authors.forename: Wladyslaw
authors.initials: W
authors.lastname: Grzeszczak
authors.forename: Gaetano
authors.initials: G
authors.lastname: Crepaldi
mesh_terms: D000284:Administration, Oral; D000419:Albuminuria / Q000188:drug therapy*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006025:Glycosaminoglycans / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D006025:Glycosaminoglycans; C007858:glucuronyl glucosamine glycan sulfate