Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy.
OBJECTIVE
Pimagedine inhibits the formation of advanced glycation end products and slows the progression of diabetic complications in experimental models. This study was undertaken to determine if pimagedine ameliorates nephropathy in type 1 (insulin-dependent) diabetes mellitus.


METHODS
This was a randomized, double-masked, placebo-controlled study performed in 690 patients with type 1 diabetes mellitus, nephropathy, and retinopathy. The patients received twice daily dosing with placebo, pimagedine 150 mg, or pimagedine 300 mg for 2-4 years. The primary end point was the time to doubling of serum creatinine; the secondary end points included evaluations of proteinuria, kidney function, and retinopathy.


RESULTS
Serum creatinine doubled in 26% (61/236) of the placebo-treated patients and in 20% (91/454) of those who received pimagedine (p = 0.099). The estimated glomerular filtration rate decreased more slowly in the pimagedine-treated patients with a 36-month decrease from baseline of 6.26 ml/min/1.73 m(2) as compared with 9.80 ml/min/1.73 m(2) in the placebo-treated patients (p = 0.05), and pimagedine reduced the 24-hour total urinary proteinuria. (The mean reduction from baseline at month 36 was 732 mg/24 h at the low dose and 329 mg/24 h at the high dose as compared with 35 mg/24 h in the placebo group; p </= 0.001.) Fewer pimagedine-treated patients with baseline and end point evaluations (31/324; 10%) as compared with those receiving placebo (16%; 28/179) experienced a three-step or greater progression of the retinopathy (Early Treatment of Diabetic Retinopathy Study) score (p = 0.030). Three patients receiving high-dose pimagedine but none receiving low-dose treatment developed glomerulonephritis.


CONCLUSIONS
While this study did not demonstrate a statistically significant beneficial effect of pimagedine on the progression of overt nephropathy resulting from type 1 diabetes, it is noteworthy in providing the first clinical proof of the concept that inhibiting advanced glycation end product formation can result in a clinically important attenuation of the serious complications of type 1 diabetes mellitus.
Bolton
W Kline
WK
Department of Medicine, University of Virginia Health System, Charlottesville, Va. 2908-0133, USA. wkb5s@virginia.edu
Cattran
Daniel C
DC
Williams
Mark E
ME
Adler
Sharon G
SG
Appel
Gerald B
GB
Cartwright
Kenneth
K
Foiles
Peter G
PG
Freedman
Barry I
BI
Raskin
Philip
P
Ratner
Robert E
RE
Spinowitz
Bruce S
BS
Whittier
Frederick C
FC
Wuerth
Jean-Paul
JP
D000328:Adult; D000419:Albuminuria / Q000517:prevention & control; D001795:Blood Pressure Determination; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005919:Glomerular Filtration Rate; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D006146:Guanidines / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D011446:Prospective Studies; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; C004479:pimagedine