Anti-Glycation and Anti-Albuminuric Effects of GLY-230 in Human Diabetes

Abstract

Background/Aims: Inhibiting nonenzymatic glycation with GLY-230 lowers glycated albumin without affecting hyperglycemia and ameliorates renal dysfunction in the db/db mouse, but the effects of this compound in man have not been assessed. We report results from the first clinical trial in patients with diabetes of this new glycation inhibitor. Methods: 21 diabetic men were randomly assigned to receive a total dose of 250, 500 or 750 mg of GLY-230 or placebo (1:1:1:1.2 ratio) daily for 14 days to evaluate safety and the effect of drug on plasma concentrations of glycated albumin and on urinary albumin. Results: GLY-230 dose-responsively decreased glycated albumin in all participants, in whom HbA1c did not change. Among participants exhibiting microalbuminuria at baseline, mean albumin excretion significantly decreased in patients receiving GLY-230 (µg albumin/mg creatinine = 61.4 ± 15.8 and 29.8 ± 10.4 at baseline and completion, respectively; p = 0.001), but not placebo. There were no serious adverse events or laboratory abnormalities, and all safety parameters remained within normal limits. Conclusions: This first-in-diabetic man study indicates that GLY-230 lowers glycated albumin and that this decrease is associated with a reduction in urine albumin excretion in patients with preexisting microalbuminuria. These data encourage further evaluation of GLY-230 in diabetic renal dysfunction.

Diabetic nephropathy – complications and treatment

“…GLY-230 reduced glycated albumin and albuminuria compared to baseline but not placebo. 191 AGE crosslink breakers, such as alegebrium, and inhibitors of the AGE receptor have shown benefit in DN models but have not been studied in humans.…”

Immunity and inflammation in diabetic kidney disease: translating mechanisms to biomarkers and treatment targets

“…GLY-230 [2-(3-chlorophenylamino)phenylacetic acid] is a new small molecule that inhibits modification of albumin by Amadori glucose adducts. In a small clinical trial of GLY-230 in patients with diabetes, GLY-230 significantly reduced albuminuria (92). Pyridoxamine has been shown to have an anti-AGE effect and is currently under investigation in a phase 2 clinical trial (https://clinicaltrials.gov/).…”

Early- and advanced non-enzymatic glycation in diabetic vascular complications: the search for therapeutics

“…In preclinical studies in diabetic animal models, GLY-230 significantly reduced Amadori-albumin, decreased urine albumin excretion, restored glomerular nephrin, downregulated TGF-β 1 and VEGF overexpression, ameliorated matrix accumulation, histomorphometric changes and the development of renal insufficiency as well as vitreous alterations (Cohen et al 2002, 2005, 2007, 2008). A recent study in diabetic man demonstrated that GLY-230 lowers glycated albumin and that this decrease is associated with a reduction in urine albumin excretion in patients with pre-existing microalbuminuria (Kennedy et al 2010). …”