Background/Aims: 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 m2 as compared with 9.80 ml/min/1.73 m2 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.

Keywords:
Pimagedine, Advanced glycation end product inhibition, Diabetic nephropathy, Diabetic retinopathy
1.
US Renal Data Systems: USRDS 1999 Annual Data Report. Bethesda, National Institutes of Health, 1999.
2.
Brownlee M: The pathological implications of protein glycation. Clin Invest Med 1995;18:275–281.
3.
Vlassara H: Protein glycation in the kidney: Role in diabetes and aging. Kidney Int 1996;49:1795–1804.
4.
Berg T, Clausen J, Torjesen P, Dahl-Jorgensen K, Bangstad H, Hanssen K: The advanced glycation end product Nepsilon-(carboxymethyl)lysine is increased in serum from children and adolescents with type 1 diabetes. Diabetes Care 1997;21:1997–2002.
5.
Berg T, Bangstad H, Torjesen P, Osterby R, Bucala R, Hanssen K: Advanced glycation end products in serum predict changes in the kidney morphology of patients with insulin-dependent diabetes mellitus. Metabolism 1997;46:661–665.
6.
Beisswenger P, Makita Z, Curphey T, et al: Formation of immunochemical advanced glycosylation end products precedes and correlates with early manifestations of renal and retinal disease in diabetes. Diabetes 1995;44:824–829.
7.
Li Y, Steffes MW, Donnelly T, et al: Prevention of cardiovascular and renal pathology of aging by the advanced glycation inhibitor aminoguanidine. Proc Natl Acad Sci USA 1996;93:3902–3907.
8.
Bucala R, Vlassara H: Advanced glycosylation end products in diabetic renal and vascular disease. Am J Kidney Dis 1995;26:875–888.
9.
Friedman EA, Distant DA, Fleishhacker JF, Boyd TA, Cartwright K: Aminoguanidine prolongs survival in azotemic-induced diabetic rats. Am J Kidney Dis 1997;30:253–259.
10.
Cockcroft DS, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41.
11.
American Diabetes Association: Clinical Practice Recommendations. Diabetes Care 1999;22(suppl):S1–S114.
12.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456–1462.
13.
Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Am J Kidney Dis 2002;39(suppl):S1–S266.
14.
Bolton WK, Kliger AS: Chronic renal insufficiency: Current understandings and their implications. Am J Kidney Dis 2000;36(6 Suppl 3):S4–S12.
15.
Makino H, Shikata K, Hironaka K, et al: Ultrastructure of nonenzymatically glycated mesangial matrix in diabetic nephropathy. Kidney Int 1995;48:517–526.
16.
Horie K, Miyata T, Maeda K, et al: Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions: Implications of glycoxidative stress in the pathogenesis of diabetic nephropathy. J Clin Invest 1997;100:2995–3004.
17.
Makino H, Shikata K, Kushiro M, et al: Role of advanced glycation end-products in the progression of diabetic nephropathy. Nephrol Dial Transplant 1996;11(Suppl 5):76–80.
18.
Vlassara H, Striker L, Teichberg S, Fuh H, Li Y, Steffes MW: Advanced glycation end products induce glomerular sclerosis and albuminuria in normal rats. Proc Natl Acad Sci USA 1994;91:11704–11708.
19.
Wright JT Jr, Bakris G, Greene T, et al for the African American Study of Kidney Disease and Hypertension Study Group: Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: Results from the AASK Trial. JAMA 2002;288:2421–2431.
20.
Agodoa LY, Appel L, Bakris GI, et al for the African American Study of Kidney Disease and Hypertension Study Group: Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: A randomized controlled trial. JAMA 2001;285:2719–2728.
21.
Lewis EJ, Hunsicker LG, Clarke WR, et al for the Collaborative Study Group: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851–860.
22.
Keane WF, Eknoyan G: Proteinuria, albuminuria, risk, assessment, detection, elimination (PARADE): A position paper of the National Kidney Foundation. Am J Kidney Dis 1999;33:1004–1010.
23.
Cerami C, Founds H, Nicholl I, et al: Tobacco smoke is a source of toxic reactive glycation products. Proc Natl Acad Sci USA 1997;94:13915–13920.
24.
Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986.
25.
Torffvit O, Thysell H, Nassberger L: Occurrence of autoantibodies directed against myeloperoxidase and elastase in patients treated with hydralazine and presenting with glomerulonephritis. Hum Exp Toxicol 1994;13:563–567.
26.
Mason P, Lockwood CM: Rapidly progressive nephritis in patients taking hydralazine. J Clin Lab Immunol 1986;20:151–153.
© 2004 S. Karger AG, Basel
2004
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.