Handbook of Experimental Pharmacology Volume 119 Editorial Board G.V.R.Born,London P. Cuatrecasas, Ann Arbor, MI D. Ganten, Berlin H. Herken, Berlin K.L. Melmon, Stanford, CA Springer-Verlag Berlin Heidelberg GmbH Oral Antidiabetics Contributors H.J. Ahr, S.L. Ali, J.M. Amatruda, E.M. Bardolph, H. Bischoff, H.H. Blume, E.-M. Bomhard, E. Brendel, L. Groop, F. Hartig, A. Hasselblatt, L.S. Hermann, B. Junge, J. Köbberling, H.P. Krause, J. Kuhlmann, K.H. Langer, H.E. Lebovitz, P.J. Lefebvre, M. Matzke, M.L. McCaleb, G. Neugebauer, M. Noel, P. Ochlich, U. Panten, H.J. Ploschke, H. Plümpe, E. Prugnard, W. Puls, W. Rebel, A.J. Scheen, H. Schlecker, F.H. Schmidt, B.S. Schug, E. Schütz, C. Schwanstecher, M. Schwanstecher, S. Seip, J. Stoltefuss, R.H. Taylor, N.F. Wiernsperger, W. Wingender, C. Wünsche Editors Jochen Kuhlmann and Walter Puls Springer Professor Dr.med. JOCHEN KUHLMANN Bayer AG Institut für Klinische Pharmakologie Aprather Weg 42096 Wuppertal Germany Professor Dr.med. WALTER PULS Krummacher Straße 200 42115 Wuppertal Germany With 140 Figures and 85 Tables ISBN 978-3-540-62456-1 ISBN 978-3-662-09127-2 (eBook) DOI 10.1007/978-3-662-09127-2 Library of Congress Cataloging·in-Publieation Data. Oral antidiabetics/contrihutors. H.J. Ahr ... /et aLl: editors, Jochen Kuhlmann and W. Puls. p. em. - (Handbook 01' experimental pharmacology: v. 119) ISBN 3·540·58990·2 (hardcover: alk. paper) 1. Hypoglycemic agents. 2. Non·insulin·dependent diabetes - Chemotherapy. I. Ahr. H.J. 11. Kuhlmann, J. (Jochen) III. Puls, Walter. IV. Series. [DNLM: 1. Hypoglycemic Agents - pharmacology. 2. Hypoglycemic Agents - therapeutie usc. 3. Diahctes Mellitus. Non·Insulin-Dependent - drug therapy. Wl HA51L v. 119 199h/WK 825 063 1996/ QP905.1I3 vol. 119 [RC661.Al] 615'.ls - dc20 [616.4'62061] DNLMIDLC for Library 01' Congress 96-23697 This work is subject to copyright. All rights are reserved. whether the whole or part 01' the material is concerned, specifically the rights of translation, rcprinting, reuse 01' illustrations. reeitation. broadeasting, reproduction on microfilm or in any othcr ways, and storage in data banks. Duplieation 01' this puhlieation or parts thereof is permitted only under the provisions of the German Copyright Law of Septemher 9, 1965, in its eurrent version, and permission for use mus! always he obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. © Springer-Verlag Berlin Heidelherg 1996 Originally published by Springer-Verlag Berlin Heidelberg New York in 1996. Softcover reprint ofthe hardcover 1st edition 1996 Thc use of general deseriptive names, registered names, trademarks, etc. in this puhlication does not imply. even in the absence of a spccific statement, that such names are excmpt from thc relevant protcctivc laws and regulations and thercfore free for general usc. Product liability: The publisher eannot guarantee the aeeuraey of any information ahout dosagc ami appli calion contained in this hook. In every individual case the user must check such information hy eonsulting the relevant literature. Cover design: Springer-Verlag. Design & Production Typesetting: Best-set Typesetter Ltd .. Hong Kong SPIN: 10126523 27/3136/SPS - 5 432 1 0 - Printed on acid-free paper Preface The prevalence of diabetes continues to increase worldwide. Traditionally, diabetes in its adult form has not been considered a serious life-threatening disease. This attitude needs to be changed because the complications asso ciated with the adult form of diabetes affect almost every organ system. The high morbidity and mortality of non-insulin-dependent diabetes mellitus (NIDDM) suggest that current treatment strategies are unsatisfactory. We therefore face an urgent need for new therapeutic approaches. When the first Handbook 0/ Oral Antidiabetics was edited by H. Maske in 1971, the risks and benefits associated with the use of oral antidiabetics were still under discussion. Nowadays, oral antidiabetics hold a strong posi tion in the long-term treatment of diabetes. Roughly 30% -50% of the patients with diabetes in Europe and the United States are treated with oral antidiabetics, chiefly sulfonylureas. While acknowledging the value of the ß cytotropic sulfonylureas, we also need to recognize important limitations of their use, e.g., in the treatment of obese diabetic patients. A re-assessment of the association of biguanides, especially of metformin treatment, with lactic acidosis by investigators in Sweden has brought a revival in the use of biguanides. Today, metformin is the only biguanide recommended for the treatment of NIDDM, and it is included in the large United Kingdom Prospective Diabetes Study (UKPDS) concerning long term benefits. Metformin has recently undergone extensive investigations in the United States and received marketing approval from the Food and Drug Administration (FDA) at the end of 1994. There is also an increasing interest in the effect of metformin on insulin resistance, hyperinsulinemia and other components of the recently recognized "metabolie syndrome" or "syndrome X." A brand-new approach to managing IDDM and NIDDM was offered in the early 1990s by the introduction of a pseudo tetrasaccharide of microbial origin, which reduces diet-induced hyperglycemia and endogenous insulin secretion by inhibiting intestinal a-glucosidases. It may be of particular interest that repeated administration of a glucosidase inhibitor ameliorated or prevented diabetes-related neuropathy and microvascular complications in preclinical studies. We are most grateful to the authors for the high quality of their contri butions and (in most cases) for their prompt submission of manuscripts. We VI Preface believe that the weaIth of knowledge of oral antidiabetics presented he re offers the clinician the widest possible selection for the optimal treatment of this widespread disease. We hope this information will stimulate scientists to improve therapeutic standards by developing agents that may prevent dangerous late complications or the manifestation of NIDDM. We would like to thank Mrs. Doris Walker from Springer-Verlag for her efficient management and editorial ass ist an ce through the entire project. We would also like to thank Mrs. G. Lion for secretarial and administrative help of exceptional quality. JOCHEN KUHLMANN WALTER PULS List of Contributors AHR, H.J., Bayer AG, PH-PD Toxicology, Geb. 514, 42096 Wuppertal, Germany ALl, S.L., Zentrallaboratorium Deutscher Apotheker, Ginnheimerstr. 20 65760 Eschborn, Germany AMATRuDA, J .M., Miles Inc., Pharmaceutical Division, Institute for Metabolic Disorders, 400 Morgan Lane, West Haven, CT 06516-4175, USA BARDoLPH, E.M., Department of Medicine, Royal Naval Hospital, Haslar, Gosport, Hampshire P012 2AA, United Kingdom BISCHOFF, H., Bayer AG, Institut für Herz/Kreislauf- und Arteriosklero seforschung, Geb. 500, 42096 Wuppertal, Germany BLUME, H.H., Zentrallaboratorium Deutscher Apotheker, Ginnheimerstr. 20, 65760 Eschborn, Germany BOMHARD, E.M., Bayer AG, Fachbereich Toxikologie, Aprather Weg, 42096 Wuppertal, Germany BRENDEL, E., Bayer AG, Institut für Klinische Pharmakologie, Geb. 405, 42096 Wuppertal, Germany GROOP, L., Malmö General Hospital, Department of Endocrinology, Södra Förstadsg 101,21401 Malmö, Sweden HARTIG, F., Boehringer Mannheim GmbH, Sandhofer Str. 116, 68305 Mannheim, Germany HASSELBLATr, A., Institut für Pharmakologie und Toxikologie der Univer sität, Robert-Koch-Str. 40, 37075 Göttingen, Germany HERMANN, L.S., Meda Sverige AB, P.O. Box 138, 40122 Göteborg, Sweden JUNGE, B., Bayer AG, Central Research, Geb. Q 18, 51368 Leverkusen, Germany KÖBBERLlNG, J., Ferdinand-Sauerbruch-Klinikum Wuppertal, Akademisches Lehrkrankenhaus der Heinrich-Heine-Universität Düsseldorf, Arrenberger Str. 20, 42117 Wuppertal, Germany VIII List of Contributors KRAUSE, H.P., Bayer AG, PH-PD Predinical Development, Geb. 402, 42096 Wuppertal, Germany KUHLMANN, l., Bayer AG, Institut für Klinische Pharmakologie, Geschäfts bereich Pharma, Aprather Weg, 42096 Wuppertal, Germany LANGER, K.H., Hoechst AG, Pharma Entwicklung Pathologie H 811,65926 Frankfurt, Germany LEBOVITZ, H.E., Endocrinology and Metabolism/Diabetes, State University of New York, 450 Clarkson Avenue, Box 1205, Brooklyn, NY 11203, USA LEFEBVRE, P.l., Centre Hospitalier de Liege, Departement de Medecine, Service de Diabetologie, Nutrition et Maladies metaboliques, CH. U. - Domaine Universitaire du Sart Tilman, B. 35, 4000 Liege 1, Belgium MATZKE, M., Bayer AG, Central Research, Geb. Q 18,51368 Leverkusen, Germany MCCALEB, M.L., Miles Inc., Pharmaceutical Division, Institute for Metabolie Disorders, 400 Morgan Lane, West Haven, CT 06516-4175, USA NEUGEBAUER, G., Boehringer Mannheim Gmbh, Abt. Klinische Phar makologie, Sandhofer Str. 116, 68305 Mannheim, Germany NOEL, M., Groupe LIPHA, Centre de Recherche Chilly-Mazarin, 4, rue de la Division Ledere, 91380 Chilly Mazarin, France OCHLICH, P., Boehringer Mannheim GmbH, Sandhofer Str. 116, 68305 Mannheim, Germany PANTEN, U., Institut für Pharmakologie und Toxikologie der Technischen Universität, Mendelssohnstr. 1, 38106 Braunschweig, Germany PLOSCHKE, H.l., Bayer AG, PH-R Structural Research, 42096 Wuppertal, Germany PLÜMPE, H., Kirschbaum Str. 9,42115 Wuppertal, Germany PRUGNARD, E., Groupe LIPHA, Centre de Recherche Chilly-Mazarin, 4, rue de la Division Ledere, 91384 Chilly-Mazarin, France PULS, W., Krummacher Str. 200, 42115 Wuppertal, Germany REBEL, W., Boehringer Mannheim GmbH, Sandhofer Str. 116, 68305 Mannheim, Germany SCHEEN, A.l., Centre Hospitalier de Liege, Departement de Medecine, Service de Diabetologie, Nutrition et Maladies metaboliques, CH.U. - Domaine Universitaire du Sart Tilman, B. 35, 4000 Liege 1, Belgium SCHLECKER, H., Bayer AG, PH-R Structural Research, 42096 Wuppertal, Germany List of Contributors IX SCHMIDT, F.H., Stockacher Str. 1,68239 Mannheim, Germany SCHUG, B.S., Zentrallaboratorium Deutscher Apotheker, Ginnheimerstr. 20, 65760 Eschborn, Germany SCHÜTZ, E., Am Bräunling 12,65719 Hofheim-Diedenbergen, Germany SCHWANSTECHER, c., Institut für Pharmakologie und Toxikologie der Technischen Universität, Mendelssohnstr. 1, 38106 Braunschweig, Germany SCHWANSTECHER, M., Institut für Pharmakologie und Toxikologie der Technischen Universität, Mendelssohnstr. 1, 38106 Braunschweig, Germany SEIP, S., Bayer AG, PH-R Structural Research, 42096 Wuppertal, Germany STOLTEFUSS, J., Bayer AG, PH-R-CR Medical Chemistry III, Geb. 460, 42096 Wuppertal, Germany TAYLOR, R.H., Department of Medicine, Royal Naval Hospital, Haslar, Gosport, Hampshire P012 2AA, United Kingdom WIERNSPERGER, N.F., Groupe LIPHA, Strategie Development Division, International Pharmacological Development Department, 34, rue Saint Romain, 69379 Lyon, Cedex 08, France WINGENDER, W., Bayer AG, Institut für Klinische Pharmakologie, Geb. 429, 42096 Wuppertal, Germany WÜNSCHE, C., Bayer AG, PH-R Structural Research, 42096 Wuppertal, Germany