Sulodexide is a low molecular weight heparin (LMWH) that has no measurable anticoagulant effect when taken orally. Preliminary studies have shown that sulodexide has a favorable effect on proteinuria in patients with diabetic nephropathy. This led to a large, multicenter, placebo-controlled, double-blinded study to determine the effect of this agent on urine albumin excretion in patients with Type 2 Diabetes and early diabetic nephropathy, defined by the presence of microalbuminuria in patients with serum creatinine less than 1.5 mg/dL. The results of this 6-month long intervention, studied in over 1000 individuals with early diabetic nephropathy, are reported this month in AJKD.
Dr. Kellie Calderon (eAJKD), eAJKD web advisory board member discusses this article with Dr. Edmund Lewis (EL) from Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL
eAJKD: Sulodexide is a novel therapy for proteinuria. Can you enlighten us about prior trials regarding this agent in decreasing proteinuria?
EL: Sulodexide is a term used for an oral preparation of LMWH and other heparinoid compounds. Several small European studies have shown that the use of heparin is associated with a decrease in proteinuria in patients with diabetic kidney disease. We performed a pilot trial to test this finding, and the results of this pilot seemed to show that one of the doses that we used was associated with a decrease in albuminuria in a well defined population of patients with early diabetic nephropathy. Accordingly, we then conducted a much larger trial.
eAJKD: Has a similar beneficial anti-albuminuric effect been seen with intravenous heparin?
EL: Yes. Physicians have observed for years that intravenous heparin reduces proteinuria in people with diabetes.
eAJKD: How was the oral preparation developed?
EL: The oral preparation has been around for many years. It’s approved for use in a number of European countries, where it is used to treat people with peripheral vascular disease and coronary artery disease.
eAJKD: In the current trial, you noted no significant difference in albuminuria among individuals treated with suledoxide versus those receiving placebo. Can you explain the differing results found in the pilot trial versus this trial?
EL: It’s challenging to perform an outcome based study on an oral medication if there is no way to study its pharmacokinetics or measure its absorption. Unlike what you expect with intravenous heparin, sulodexide does not seem to alter the clotting system. Therefore, you have to give the drug and just see whether it causes the effect you are looking for.
In our pilot trial, the amount of urine albumin excretion was lowered in patients given sulodexide, though the results were not significantly better. However, if this percentage difference was found in the follow up trial, then the results would have been statistically significant due to the higher number of enrolled patients.
eAJKD: What else would you like to highlight about the trial?
EL: There was a very big question that we faced: when working with an agent that you cannot study the pharmacokinetics of, there is no way to prove that the drug is absorbed or active. As you know, heparin has had serious production issues. We know that the chemical structure and content of sulodexide was accurate when tested, but we don’t know if the drug we used for the trial was absorbed at all.
The shame of it is that microalbuminuria is an important element in people with diabetes. It not only contributes to kidney disease, but also has been associated with cardiovascular disease. A drug like sulodexide, which lowers albuminuria, may be affecting a common mechanism for both kidney disease and cardiovascular disease, and this could be very positive for patients with diabetes. I think that a next step is to explore using low molecular weight heparin subcutaneously to study the effects of this agent on proteinuria. In that case, you could also study the pharmacokinetics of the intervention as well as its effects.
To view the entire article please visit AJKD.