W. Creutzfeldt (Ed.)

Acarbose for the Treatment of Diabetes Mellitus

With 61 Figures and 36 Tables

Springer-Verlag Berlin Heidelberg New York London Paris Tokyo

W. Creutzfeldt, Prof. Dr. med. Dr. h. c. Abteilung Gastroenterologie und Endokrinologie Zentrum Innere Medizin Georg-August-UniversWit G6ttingen Robert-Koch-Str. 40

3400 G6ttingen

Library of Congress Cataloging-in-Publication Data

Acarbose for the treatment of diabetes mellitus / W. Creutzfeldt (ed.). p. cm. Includes index.

ISBN-13: 978-3-540-19145-2 e-ISBN-13: 978-3-642-73583-7 DOl: 10.1007/978-3-642-73583-7 1. Acarbose--Therapeutic use--Testing--Congresses. 2. Diabetes­-Chemotherapy--Congresses. I. Creutzfeldt, W. (Werner), 1924-. [DNLM: 1. Diabetes Mellitus--drug therapy. 2. Hypoglycemic Agents--therapeutic use. 3. Trisaccharides--therapeutic use. WK 825 A168j RC661.A33A27 1988 616.4'62061--dc 19 DNLMlDLC for Library of Congress

88-30819 CIP

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustra­tions, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. Duplication of this publications or parts thereof is only permitted under the provisions of the German Copyright Law of September 9, 1965, in its version of June 24, 1985, and a copyright fee must always be paid. Violations fall under the prosecution act of the German Copyright Law.

© Springer-Verlag Berlin Heidelberg 1988

The use of general descriptive names, trade names, trade marks, etc. in this publication, even if the former are not especially identified, is not to be taken as a sign that such names, as understood by the Trade Marks and Merchandise Marks Act, may accordingly be used freely by anyone.

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Contents

Introduction

w. CREUTZFELDT

Experimental Data on Acarbose I

Toxicology of Acarbose, with Special Reference to Long-Term Carcinogenicity Studies

G.SCHLOTER

Discussion

The Disposition and Pharmacokinetics of Acarbose in Man

F. O. MOLLER, H. K. L. HUNDT, H. G. Luus, M. VAN DYK, G. GROENEWOUD, and!. HILLEBRAND ........... .

Discussion

Experimental Data on Acarbose II

The Pharmacological Rationale of Diabetes Mellitus Therapy with Acarbose

W. PULS, andH. BISCHOFF

Discussion

Pharmacodynamics of Acarbose: Clinical Investigations

B.LEMBCKE

Discussion

1

5

15

17

25

29

39

41

53

VI Contents

Posters

Comparative Effects of Acarbose on Glycemia, Weight Gain, and Serum Lipids in Adult Male and Female Diabetic Wistar Fatty Rats

O. L. TULP, C. STEVENS, O. BARBEE, M. L. APOSTOLOU, and O. E. MICHAELIS . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Effects of Low-Dose Acarbose on Glycemia, Adiposity, and Cholesterolemia in Obese and Obese Non-Insulin-Dependent Diabetic Corpulant Rats

O. E. TULP, S. P. DEBoLT, L. PIETRANGELO, R. SCHNITZER-POLOKOFF, A. ABDOLLAHI, M. E. HESS, and N. HAUGARD .............. 58

A Preclinical Study on the Effects of Acarbose on Mice Rendered Obese with Gold Thioglucose

I. MAROT, and Y. LEMARcHAND-BRUSTEL

Enhancement of Insulin Binding and Glucose Transport by Acarbose in Adipocytes of Zucker Rats

J. R. VASSELLI, T. FLORY, andS. K. FRIED ........ .

Treatment of Streptozotocin-Diabetic Rats with Acarbose: Influence on Metabolism and Heart Function

P.ROSEN ......... " ................ .

Effects of Acarbose on Cardiac and Hepatic Metabolism in Diabetic Rats

M. E. HESS, N. HAUGARD, A. TORBATI, A. RASTOGI, and O. L. TULP

Effects of Acarbose on Experimental Diabetic Nephropathy, Metabolic Control, and Intestinal Glycosidase Activity in Normal and Genetically Diabetic Mice

S.M.LEE ............................ .

The Effectiveness of Acarbose in the Reduction of Diabetic Symptoms and Neuropathic Complications in an NIDDM Animal Model

R. G. PETERSON, M. A. NEEL, L. A. LITTLE, J. C. KINCAID, andN. S. FINEBERG ..................... .

Effects of Acarbose on the Hormonal and Metabolic Response to the Simultaneous Ingestion of Sucrose and Ethanol

B.JANDRAIN,J. GERARD,E. VERDIN,andP.J.LEFEBVRE ...

59

60

61

62

63

64

66

Contents VII

Effects of Acarbose on Serum Lipids and Lipoproteins in Healthy Individuals During Prolonged Administration of a Fiber-Free Diet

I. WALTER-SACK, P. KRANz-RIBs, G. WOLFRAM, andN. ZOLLNER .

Lower Triglyceride Production with Carbohydrate-Rich Diets During Treatment with Acarbose

P.J.NESTEL

Long-Term Metabolic Effects of Acarbose in Healthy Young Men

C. COUET, M. ULMER, M.liAMDAOUI, and G. DERBY . . . . . . .

Mode of Action of the a-Glucosidase Inhibitor Acarbose in the Small Bowel: A Perfusion Study in Man

H.-J. HAGEL, H. RUPPIN, J. PICHL, W. FEUERBACH, S. BLOOM, and W. DOMSCHKE . . . . . . . . . . . . . . . . . . . . . . . .

Effect of Acarbose in Fecal Short-Chain Fatty Acid Excretion in Man

W. SCHEPPACH, C. FABIAN, M. SACHS, M. SPENGLER, andH. KASPER

Effect of Acarbose on Colonic Nitrogen Metabolism in Man

C. FABIAN, W. SCHEPPACH, M. SPENGLER, andH. KASPER

The Influence of Acarbose Dosage Scheme on Intestinal Symptoms and Intestinal Transit Time in Healthy Volunteers

H. J. WILDGRUBE, M. SPENGLER, and K. BOEHME . . . . . . . .

The Development of a Method for Measuring Starch Absorption and its Alteration by a-Glucosidase Inhibitors

S. PYE, andJ. RAoZIUK ..................... .

Acarbose in NIDDM

Acarbose in Non-Insulin-Dependent Diabetes Mellitus: Short-Term Studies in Combination with Oral Agents

B. WILLMS

Acarbose in Non-Insulin-Dependent Diabetes - Long-Term Studies in Combination with Oral Agents

G.SACHSE

Discussion

67

68

69

70

71

73

74

75

79

92

102

VIII Contents

Acarbose Monotherapy in the Treatment of Non-Insulin-Dependent Diabetes Mellitus

J. TUOMILEHTO

Discussion

Posters

Acarbose Treatment of NIDDM: Multiclinic Trial for Dose Finding

Y. GOTO, S. NAKAGAWA, N. HOSOYA, H. ORIMO, Y. IKEDA, N. SAKAMOTO,

104

117

I. FUKUI, S.TARUI, S. BABA, T. KANEKO, and G. MIMURA . . . . . . . . .. 121

Metabolic Effects of Acarbose in Normal and NIDDM Subjects

P.-H. GROOP, L. GROOP, K. J. TOTTERMANN, andF. FYHRQUIST

Efficacy and Tolerability of a 3-Month Treatment with Acarbose in Type II Diabetic Outpatients Treated with a High Dose of Sulfonylurea

122

B.MAY,andD.HOPPE . . . . . . . . . . . . . . . . . . . . . . . . . . .. 124

Metabolic Control in Type II Diabetes with Long-Term Acarbose Therapy: A Double-Blind Study

M. RODIER, J. L. RICHARD, L. MONNIER, and J. MIROUZE . . . . . . . . .. 125

Clinical Trial to Investigate the Efficacy and Tolerability of Acarbose in Type II Diabetic Patients Treated with Diet Alone

R. PORTEN, J. R. BAUER, and K. BOEHME .................. 126

Comparison of the Action of an a-Glucosidase Inhibitor (Acarbose) and a Sulfonylurea Preparation (Glisoexpide) in Non-Insulin-Dependent Diabetics

J. FABIAN-KRAUSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 127

Efficacy of the Glucosidase Inhibitor Acarbose Compared to the Sylfonylurea Glisoexpide on Metabolic Control in Diet-Treated Type II Diabetics

R. MIES, M. SPENGLER, U. HENKE, and K. BOEHME . . . . . . . . . . . 128

Multicenter Clinical Trial Up to 15 Months: Efficacy and Tolerability of Acarbose in Glibenclamide-Treated Type II Diabetics with Secondary Sulfonylurea Failure Versus Glibenclamide Therapy Alone

M. SPENGLER, K. BOEHME, and R. AUBELL ................ 129

Contents IX

Acarbose Does not Affect Glibenclamide Pharmacokinetics in Type II Diabetic Patients

J.GERARD,A.J.SCHEEN,andP.J.LEFEBVRE . . . . . . . . . . . . . 130

Effect of Acarbose in Type II Diabetics Treated with Diet Alone, with Diet, and with Sulfonylurea, Diet, and Insulin

V. PROFOZIC, M. KosEu, H. SCHULZ, M. GRANIC, I. HILLEBRAND, and Z. SKRABALO . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

The Long-Term Effects of Acarbose on Type II Diabetics on Diet or Oral Agents

S. RAPTIS, D. HAoJIDAKIS, A. RAPTIs, andE. DIAMANTOPOULOS . . 132

Long-Term Effects of Acarbose Treatment on Postprandial Glucose, Pancreatic and Gut Hormone Responses and Fasting Serum Lipids in Non-Insulin-Dependent Diabetics on Sulfonylureas

L. O. U'ITENTHAL, O. O. UKPONMWAN, M. GmGLIONE, S. M. WOOD, M. A. GHATEI, I. M. TRA YNER, and S. R. BLOOM ......... 133

Acarbose in the Treatment of NIDDM Patients with Hyperlipemia

H. BAR-ON, I. RAz, and M. KIDRON ............... .

Effectiveness and Tolerability of the a-Glucosidase Inhibitor Acarbose in NIDDM Patients with Elevated Liver Enzyme Activity

134

E. HAUPT, I. HILLEBRAND, andH. PFEFFER ................. 135

Effect of Acarbose on Blood Glucose and Insulin Response to a Sucrose Load in Subjects with Reactive Hypoglycemia

J. L. RICHARD, M. RODIER, L. MONNIER, and J. MIROUZE . . . . . . . . .. 136

Relapse-Reducing Effects of Acarbose After Weight Reduction in Severely Obese Subjects

L. SJOSTROM, and T. WILLIAM-OLSSON . . . . . . . . . . . . . . . . . . .. 137

Acarbose in IDDM

Acarbose Treatment in Insulin-Dependent (Type I) Diabetes Mellitus

S. RAPTIs, G. DIMITRIADIS, andD. HADJlDAKIS 141

Discussion 153

X Contents

Acarbose Treatment and Sulfonylurea Secondary Failure

C.ROSAK .

Discussion

Clinical Studies with Acarbose for the Control of Hyperglycemia which is the Major Pathogenetic Factor of the Complications of Diabetes Mellitus

H. E. ELIAHOU, P. SEGAL, I. HILLEBRAND, D. SACHS, B. HELLBERG,

156

162

A. BLAU, andE. TOPPER . . . . . . . . . . . . . . . . . . . . . . . . 163

Discussion

Posters

Inhibition of a-Glucosidase by Acarbose as an Additional tool for Glycemia Control in Insulin-Dependent Diabetics on Conventional Insulin Therapy

169

J. TAT6N .................................. 173

Acarbose in Insulin-Dependent Diabetes Mellitus: Efficacy and Tolerance

S. G. T.HuLST,P.F.J.M. SPOOREN,P.A. SMITH,andT.HuLK

Nonrandomized Follow-up Study with Acarbose Treatment and Pre- and Post-treatment with Placebo in Type I Diabetic Children

M. DAMJANOVA

Effects of Acarbose on Glycemic Control in IDDM under Feedback Control with Artificial Endocrine Pancreas

174

175

K. ITOH, and Y. IKEDA ............................ 176

Effects of Sucrose Meal on Insulin Requirement in IDDM and its Modulation by Acarbose

J.-L. CHIASSON . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 177

Effect of Acarbose on Insulin Sensitivity and Liver Uptake in Patients with Type I Diabetes

P. POZZILLI, V. FIGHI, V. FIORE, M. CASANICA, A. GIACCARI, P. SBRACCIA, andG. TAMBURRANO . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 178

Contents XI

Comparative Metabolic Availability of Glucose and Sucrose and the Effect of Acarbose on Sucrose Utilization During Exercise in Type I Diabetic Patients

P. JANDRAIN, F. PIRNAY, A. SCREEN, M. LACROIX, F. MOSORA,

and P. J. LEFEBVRE . . . . . . . . . . . . . . . . . . . . . . . . .

Acarbose Treatment in Insulin-Dependent Diabetics

G. VIVIANI, L. CAMOGLIANO, M. G. BORGOGLIO, P. SALVINI, H. OHNMEISS,

180

andL. AoEZATI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 182

Panel Discussion: FutureAspects of a-Glucosidase Inhibition 183

SubjectIndex 195

Author Index 197

Presenting Authors

BAR-ON,H.

Hadassah Hospital, Jerusalem, Israel

CHIASSON, J.-L. IRCM, Montreal, Quebec, Canada

COUET, C.

Centre de Nutrition Humaine, Universite de Nancy I, 54000 Nancy, France

CREUTZFELDT, W. Abteilung Gastroenterologie und Endokrinologie, Medizinische Klinik und Poliklinik, Georg-August-Universitat Gottingen, Robert-Koch-StraBe 40, 3400 Gottingen, Federal Republic of Germany

DAMJANOVA, M. Research Institute of Pediatrics, G. Sofiiski str. I, Sofia 1431, Bulgaria

ELIAHOU, H. E.

Department of Nephrology, The Chaim Sheba Medical Center, Tel Aviv University, Sackler School of Medicine, Tel-Hashomer 52621, Israel

FABIAN, C.

Medizinische Klinik der Universitat Wiirzburg, Josef-Schneider-StraBe 2, 8700 Wiirzburg, Federal Republic of Germany

FABIAN-KRAUSE, J. Medizinische Klinik Schwenningen, 7730 VS-Schwenningen, Federal Republic of Germany

GERARD,J.

Division of Diabetes, Institute of Medicine, Hopital de Baviere, 66, Boulevard de la Constitution, 4020 Liege, Belgium

GOTO, Y. Acarbose Study Group, 3rd Department of Internal Medicine, Tohoku University School of Medicine, Seirvo-machi, Sendai, Mivagi Pref., Japan

GROOP, P.-H.

Fourth Department of Medicine, Helsinki University Central Hospital, Unioninkatu 38, 00170 Helsinki, Finland

XIV Presenting Authors

HAGEL, H.-J. WeiBenburger StraBe 4, 8540 Schwabach, Federal Republic of Germany

HAUPT, E. Klinikum Bad Kissingen der BfA, Saale-Klinik, KurhausstraBe 20, 8730 Bad Kissingen, Federal Republic of Germany

HEss, M. E. Department of Pharmacology, University of Pennsylvania, Philadelphia, P A, USA

HULST, S. G. T. Department of Internal Medicine, Biochemistry and Dietectics, Ziekenhuis "Ziekenzorg", Haaksbergerstraat 55, 7513 ER Enschede, The Netherlands

ITOH, K. Third Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, Japan

JANDRAIN, B. Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, University of Liege, 4020 Liege, Belgium

LEE, S. M.

Renal Section, Department of Medicine, University Medical Center, Tucson, AZ 85724, USA

LEMBCKE, B. Abteilung fUr Gastroenterologie, Zentrum der Inneren Medizin, Johann-Wolfgang-Goethe-Universitat, Theodor-Stern-Kai 7,6000 Frankfurt 70, Federal Republic of Germany

MAROT,1.

INSERM U 145, Faculte de Medecine, Avenue de Valombrose, 06034 Nice Cedex, France

MAY,B. Abteilung fUr Gastroenterologie und Hepatologie der Universitatsklinik, Bergmannsheil, HundscheidtstraBe 1,4630 Bochum 1, Federal Republic of Germany

MIEs, R. Abteilung fUr Innere Medizin, St. Antonius Hospital, 5000 Koln 51, Federal Republic of Germany

MULLER, F. O. Department of Pharmacology, University of the Orange Free State, P. O. B. 339, ZA-Bloemfontein 9300, Republic of South Africa

NESTEL, P. J. CSIRO Division of Human Nutrition, Adelaide, Australia

PETERSON, R. G. Department of Anatomy, Indiana University School of Medicine, Indianapolis, Indiana 46223, USA

Presenting Authors XV

PYE,S. Division of Gastroenterology, Department of Medicine, Royal Victoria Hospital, Montreal, Canada

PORTEN,R.

Pforzheimer StraBe 318, 7000 Stuttgart 31, Federal Republic of Germany

POZZILLI, P.

Endocrinologia (I), II Clinica Medica, University of Rome, "La Sapienza", 00100 Rome, Italy

PROFOZIC, V. Vuk Yrhovac Institute of Diabetes, Endocrinology and Metabolic Disease, School of Medicine, University of Zagreb, Yugoslavia

PULS, W. Bayer AG, Pharma Forschungszentrum, Institut fiir Pharmakologie, Aprather Weg 18, 5600 Wuppertal1, Federal Republic of Germany

RAPTIs, S. II. Medizinische Universitatsklinik, Propadeutik, "Evangelismos" Hospital, P. O. Box 14127,11510 Athen, Griechenland

RICHARD, J. L. Service de Diabetologie, Centre Medico-Chirurgical, 30240 Le Grau du Roi, France

RODIER, M. Services des Maladies Metaboliques et Endocriniennes, Hopital Lapeyronie, 34059 Montpellier, France

ROSAK, C. Krankenhaus Sachsenhausen, Diabetologie, SchulstraBe 31, 6000 Frankfurt 70, Federal Republic of Germany

ROSEN, P. Diabetesforschungsinstitut an der Universitat Dusseldorf, Auf'm Hennekamp 65, 4000 Dusseldorf 1, Federal Republic of Germany

SACHSE, G. Deutsche Klinik fiir Diagnostik, Fachbereich Diabetologie, Aukammallee 33, 6200 Wiesbaden, Federal Republic of Germany

SCHEPPACH, W. Medizinische Klinik der UniversiHit Wurzburg, Josef-Schneider-StraBe 2, 8700 Wurzburg, Federal Republic of Germany

SCHLOTER,G. Bayer AG, Pharma Forschungszentrum, Institut fiir Toxikologie, Friedrich-Ebert-StraBe 217,5600 Wuppertal1, Federal Republic of Germany

XVI Presenting Authors

SJOSTROM, L. Department of Medicine I, Sahlgren's Hospital, University of Goteborg, Goteborg, Sweden

SPENGLER, M. Bayer AG, Pharma Forschungszentrum, Aprather Weg 18, 5600 Wuppertal1, Federal Republic of Germany

TAT6N,J.

Chair and Department of Internal Medicine and Diabetology, Warsaw Medical School, Warsaw, Poland

TULP, O. L. IV. Department of Nutrition and Food Sciences, Drexel University, Philadelphia, PA,USA

TUOMILEHTO, J.

National Public Health Institute, Department of Epidemiology, Mannerheimintie 166, 00280 Helsinki, Finland

UTTENTHAL, L. O. Department of Medicine, Royal Postgraduate Medical School, London W12 OHS, United Kingdom

V ASSELU, J. R. Obesity Research Center, St. Luke's-Roosevelt Hospital Center, New York, NY 10025, USA

VIVIANI, G. Istituto Scientifico Medicina Interna, Cattedra di Patologia Medica B, Universita di Genova, Genova, Italy

WALTER-SACK, I. Abteilung fiir Klinische Pharmakologie, Medizinische Universitatsklinik Heidel­berg, Bergheimer StraBe 58, 6900 Heidelberg, Federal Republic of Germany

WILDGRUBE, H. J.

Institut fiir angewandte Diagnostik, 6450 Hanau, Federal Republic of Germany

WILLMS, B. Fachklinik fiir Diabetes und Stoffwechselkrankheiten, Kirchberg 21, 3422 Bad Lauterberg, Federal Republic of Germany