Sulodexide fails to prevent renal function decline in Type 2 diabetes
MedWire News: Sulodexide is no more effective than placebo for preventing progression to kidney failure in patients with Type 2 diabetes and nephropathy, research shows.
"Diabetic nephropathy is now the most common cause of ESRD [end-stage renal disease] in developed nations. Type 2 diabetic nephropathy accounts for the majority of patients with diabetes and ESRD," explain David Packham (Melbourne Renal Research Group, Australia) and colleagues.
Angiotensin receptor blockers are commonly used in the treatment of Type 2 diabetic nephropathy, but they do not abolish progression to ESRD.
Preliminary studies have shown that sulodexide, a mixture of naturally occurring glycosaminoglycan polysaccharide components, reduces albuminuria in patients with diabetes, but it is unknown whether it is renoprotective.
Packham and team therefore conducted the randomized, double-blind, placebo-controlled, sulodexide macroalbuminuria (Sun-MACRO) trial, which evaluated the renoprotective effects of sulodexide in patients with Type 2 diabetes, renal impairment, and significant proteinuria (>900 mg/day). All participants were already receiving maximal therapy with angiotensin II receptor blockers.
The primary endpoint of the study was a composite of a doubling of baseline serum creatinine level, development of ESRD, or a serum creatinine level at or above 6.0 mg/dL.
The researchers planned to enrol 2240 patients over approximately 24 months, but terminated the study early, after enrolling 1248 patients (1029 person-years of follow-up), because they did not detect any significant differences between sulodexide and placebo.
More specifically, the primary composite endpoint occurred in 26 (4.2%) of 619 patients in the sulodexide group, and in 30 (4.8%) of 629 patients in the placebo groups.
There were also no significant differences between the groups for the secondary endpoints of all cause mortality (16 vs 20 deaths in sulodexide vs placebo groups), mean serum creatinine change from baseline to 18 months (+0.38 vs +0.35 mg/dL per year), mean proteinuria/creatinine ratio (PCR) change from baseline to 18 months (-0.02 vs +0.01 mg/g), or mean albumin/creatinine ratio from baseline to 3 months (-0.03 vs -0.07 mg/g).
Furthermore, the side effect profiles were similar for both groups, with 218 serious adverse events in the sulodexide group and 203 in the placebo group.
The researchers note in the Journal of the American Society of Nephrology that their decision to discontinue (which followed the negative findings of a similar study among patients with microalbuminuria) the trial was based on analysis of change in serum creatinine - a surrogate marker for the primary outcomes of doubling of baseline creatinine or ESRD - and the mean change in quarterly urine PCR.
"Although discontinuing a trial on this basis may be open to criticism, the statistical validity of the data analysis on serum creatinine and urinary PCR up to trial termination is sufficient to exclude a significant difference in serum creatinine and PCR change between treatment and placebo groups by virtue of the narrow confidence intervals," they write.
Packham and co-authors conclude that although the early termination of the trial precludes a definitive answer as to whether sulodexide is an effective therapeutic agent in Type 2 diabetic nephropathy, they found no evidence of an effect on change in serum creatinine or urinary PCR with sulodexide treatment.
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By Laura Dean