subcutaneous insulin infusion in type 1 diabetes

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diabetes verpleegkundigen, diëtisten, psychologen en maatschappelijk werkers (1-3). Zij leerden hun ... educatie, die begon met een klinische opname van een week, was men in staat om een dergelijke ...... Nederlandse Samenvatting ...

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SOURCE, OR PART OF THE FOLLOWING SOURCE: Type Dissertation Title Subcutaneous insulin infusion in type 1 diabetes mellitus Author R.P.L.M. Hoogma Faculty Faculty of Medicine Year 2006 Pages 156

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SUBCUTANEOUS INSULIN INFUSION IN TYPE 1 DIABETES MELLITUS

ROEL PLM HOOGMA

SUBCUTANEOUS INSULIN INFUSION IN TYPE 1 DIABETES MELLITUS

ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof.mr. P.F. van der Heijden ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Aula der Universiteit op vrijdag 6 oktober 2006, te 12.00 uur door Roeland Petrus Leonardus Maria Hoogma geboren te Kerkrade

Promotiecommissie: Promotores:

Prof. dr. M.M. Levi Prof. dr. J.B.L. Hoekstra

Co-promotor: dr. R.P.J. Michels Overige leden: Prof. dr. A. Sturk Prof. dr. W.M. Wiersinga Prof. dr. J.P. Kastelein Prof. dr. R. Heine Prof. dr. R.P. Stolk Prof. dr. F. Snoek Faculteit der Geneeskunde

If you are a brittle diabetic, change your doctor (George Alberti)

Voor mijn ouders

Voor Hendrien Voor Emile, Claire en Carlijn

Cover: insulin pump in europe, design by Nemma Koelewijn ISBN 90 855 9213 5 Printed by Optima Grafische Communicatie BV, Rotterdam Copyright © 2006 R.P.L.M. Hoogma, Amsterdam, the Netherlands,except for chapters 2, 3, 4, 5, 7. The copyright of these chapters is transferred as indicated. All rights reserved. No part of this book may be reproduced or transmitted an any form or by any means without the prior written permission of the holder of the copyright. The research described in this thesis was financially supported by an unrestricted research grant from Disetronic Medical Systems AG, Switserland. This grant is gratefully acknowledged. Financial support for the publication of this thesis was kindly provided by Groene Hart Ziekenhuis, Roche Medical Systems Nederland BV, Sanofi-Aventis Pharma BV, Novo Nordisk Farma BV, Eli Lilly Nederland BV, Diabetes Direct BV, Pfizer Nederland BV, MSD Nederland BV, Glaxo Smith Kline BV, Medtronics Nederland BV, Ypsomed Nederland BV.

Contents CHAPTER ONE, INTRODUCTION ................................................................................................................... 7 CHAPTER TWO, CONTINUE SUBCUTANE INSULINE INFUSIE (CSII) SOMS GOEDE OPTIE BIJ SLECHT GEREGULEERDE DIABETES MELLITUS TYPE 1 ........................................................................ 14 CHAPTER THREE, QUALITY OF LIFE AND METABOLIC CONTROL IN PATIENTS WITH DIABETES MELLITUS TYPE 1 TREATED BY CONTINUOUS SUBCUTANEOUS INSULIN INFUSION OR MULTIPLE DAILY INSULIN INJECTIONS ..................................................................................................... 23 CHAPTER FOUR, COMPARISON OF CONTINUOUS SUBCUTANEOUS INSULIN INFUSION (CSII) VS. MULTIPLE DAILY INSULIN INJECTIONS (MDI) IN REGARD TO METABOLIC CONTROL, A RANDOMIZED, CONTROLLED, CROSSOVER TRIAL ................................................................................. 37 CHAPTER FIVE, COMPARISON OF CONTINUOUS SUBCUTANEOUS INSULIN INFUSION (CSII) VS. MULTIPLE DAILY INSULIN INJECTIONS (MDI): IMPACT ON QUALITY OF LIFE................................ 58 CHAPTER SIX, A COST-COMPARISON OF CONTINUOUS SUBCUTANEOUS INSULIN INFUSION (CSII) VERSUS MULTIPLE DAILY INSULIN INJECTIONS (MDI) BASED ON A RANDOMIZED CONTROLLED CROSSOVER TRIAL............................................................................................................... 75 CHAPTER SEVEN, SAFETY OF INSULIN GLULISINE WHEN GIVEN BY CONTINUOUS SUBCUTANEOUS INFUSION USING AN EXTERNAL PUMP IN PATIENTS WITH TYPE 1 DIABETES …………………………………………………………………………………………………………………….92 CHAPTER EIGHT, REDUCTION OF SEVERE HYPOGLYCEMIA WITH CONTINUOUS INTRAPERITONEAL INSULIN INFUSION IN TYPE 1 DIABETIC PATIENTS UNSUCCESSFULLY TREATED BY CONTINUOUS SUBCUTANEOUS INSULIN INFUSION.................................................... 107 CHAPTER NINE, SUMMARY………………. ………………………………………………………………126 CHAPTER TEN, GENERAL DISCUSSION………….………………………………………………………132 CHAPTER ELEVEN, NEDERLANDSE SAMENVATTING…...…………………………………………..138 CHAPTER TWELVE, ACKNOWLEDGEMENTS…...……………………………………………………...147 CHAPTER THIRTEEN, LIST OF PUBLICATIONS AND CURRICULUM VITAE,……...………………152

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CHAPTER ONE

INTRODUCTION

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The number of diabetic patients treated with insulin has increased over recent decades for two reasons. First, there has been a marked increase in the incidence of diabetes mellitus type 1 (1,2) Second, more people with diabetes mellitus type 2 have to be treated with insulin to achieve better control of blood glucose levels (3). Both randomised trials and large cohort studies have shown that good control of blood glucose levels is associated with reduced risk of microvascular complications in type 1 and type 2 diabetics, such as retinopathy, nephropathy and neuropathy (4,5,6,7), and also an improvement in macrovascular outcome in type 1 diabetes, as was recently demonstrated (8). To obtain a good control of blood glucose levels in type 1 and type 2 diabetic patients a intensive insulin regimen like multiple daily insulin injection (MDI) or continuous subcutaneous insulin infusion (CSII) is required, as demonstrated in the DCCT (5). The advantages of a more flexible insulin regime and lifestyle are, however, balanced by an increased number of hypoglycaemias and –-in particular during CSII treatment- by a higher incidence of hyperglycaemia or ketoacidosis, as also shown in the DCCT (5). The aim of CSII is to approximate the insulin delivery profile more closely to the pattern of normal physiology. In the past short-acting regular insulin was used but nowadays more short-acting analogues are being utilized. A meta-analysis examined the risk of ketoacidosis during intensified treatment compared with conventional treatment (9). For trials in which patients could choose between multiple injections or continuous subcutaneous insulin infusion (CSII), there was some evidence of an increased risk of ketoacidosis with intensified treatment in type 1 diabetes, although this did not reach statistical significance. In trials that randomised patients to pumps however, there was a substantial increase in the risk of ketoacidosis in type 1 diabetes. It should be mentioned that the most recent study in this meta-analysis was conducted in 1992, so these results could be explained by the technical problems related to the insulin pumps at that time used, and may no longer apply to newer pumps. Several reviews on CSII demonstrated an overall decrease in HbA1c of approximately 0,5 %, and in some studies also less hypoglycaemic events (10,11,12). In the studies it appeared that the need of insulin decreased by approximately 25%, whereas no consistent difference in weight between CSII and MDI treatment was shown. However one of the missing items in all these studies is the lack of quality of life aspects. Some studies show patients preferences in favour of CSII, whereas other studies show that the majority of patients preferred MDI. A formal quality of life analysis, however, is missing.

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A comprehensive literature search did not identify studies containing data on the costs and cost-effectiveness of CSII versus MDI. Only a limited number of model-based approaches have been published assessing economic outcomes for type 1 diabetes mellitus (13,14,15). CSII has been reported by some patients to offer lifestyle benefits and opportunities to manage their diabetes in a more flexible way. However because of their set-up, from current trials it is impossible to quantify such benefits in respect to the purpose of an economic analysis. It is impossible to make a calculation of the cost estimates, because one is unable to identify health outcomes that can be quantified for analysis. Recent trials comparing longacting analogues versus NPH based MDI regimens, did not demonstrate a benefit in HbA1c levels, although there were less hypoglycaemic events, particular during night time (17). Certainly with regard to the timing and the number of injections there are still a lot of unanswered questions. Trials comparing CSII and MDI using a longacting insulin analogue are still not conclusive, but most studies suggest still a benefit for CSII therapy (18,19,20). Most of the studies comparing rapid acting insulin analogues in CSII and regular human insulin have been done with Lyspro and insulin Aspart (21,22,23). No real differences in metabolic control seems to exist between insulin lispro and insulin aspart, although no head to head comparisons have been made. In this thesis we will try to give some answers to these questions regarding CSII treatment in type 1 diabetes mellitus which have not been resolved by the trials and meta-analyses published so far. Therefore, we performed a retrospective study concerning the Quality of Life in type 1 diabetic patients who were treated by CSII and MDI (chapter two). Hereafter we describe three patients who were treated by CSII after a long period with different insulin regimens, which demonstrate the benefits and caveats of CSII therapy (chapter three). Most of the trials comparing CSII vs. MDI have included selected patients. We performed a multicenter randomized crossover trial comparing CSII and MDI in a non-selected patient population of diabetes mellitus type 1. In this study aspects of metabolic control (chapter four), quality of life (chapter five) and costs (chapter six) could be compared. Recently a new short-acting insulin analogue was introduced. We performed a comparative study between this new insulin analogue glulisine and the well known insulin aspart (chapter seven).

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CSII will not give an optimal diabetes control for everyone. Some caveats still exist, like serious hypoglycaemias in some patients and even hypoglycaemia unawareness in others. Furthermore, some patients will have insulin absorption problems, which could cause erratic fluctuations in blood glucose values. Continuous intraperitoneal insulin infusion (CIPII) could be a possible alternative for treating those patients. We performed a study comparing CIPII and CSII in patients with diabetes mellitus type 1 in which we used a novel designed Diaport catheter, instead of the commonly used implantable insulin pump, which is a promising but relatively expensive option (24,25) (chapter eight). Finally, we discuss the present and future place of CSII and CIPII in the treatment of diabetes mellitus type 1 (chapter nine and ten).

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References 1. Burden AC, Hearnshaw JR, Swift PG. Childhood diabetes mellitus: an increasing incidence. Diabet Med 1989;6:334-6 2. Green A, Gale EA, Patterson CC. Incidence of chilhood-onset insulin dependent diabetes mellitus: the EURODIAB ACE Study. Lancet 1992;339:905-9 3.

UKPDS Study Group. Intensive blood glucose control with sylphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53

4. Wang PH, Lau J, Chalmers TC. Meta-analysis of effects of intensive blood-glucose control on late complications of type 1 diabetes. Lancet 1993;341:1306-09 5. The 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;329:977-86 6. Reichard P, Nilsson B-Y, Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med 1993;329:304-9 7. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383-93. 8. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes. N Engl J Med 2005;353:2643-2653 9. Egger M, Davey-Smith G, Stettler C, Diem P. Risk of adverse effects of intensified treatment in insulin-dependent diabetes mellitus: a meta-analysis. Diabet Med 1997;14:919-28 10. Lenhard MJ, Reeves GD. Continuous subcutaneous insulin infusion: a comprehensive review of insulin pump therapy. Arch Intern Med 2001; 161: 2293-300 11. Pickup J, Mattock M, Kerry S. Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials. BMJ 2002:324: 1-6 12. Weissberg-Benchell J, Antisdel-Lomaglio J, Seshadri R. Insulin Pump Therapy: A meta-analysis. Diabetes Care 2003;26:1079-87 11

13. The Diabetes Control and Complications Trial Research Group. Lifetime benefits and costs of intensive therapy as practiced in the diabetes control and complications trial. JAMA 1996;276:1409-15 14. Palmer AJ, Weiss C, Sendi PP, Neeser K, Brandt A, Singh G, et al. The costeffectiveness of different management strategies for type 1 diabetes: a Swiss perspective. Diabetologia 2000;43:13-26 15. Tomar R, Lee S, Wu S, Klein R, Moss SE, Fryback DG, et al. Disease progression and cost of insulin dependent diabetes mellitus: development and application of simulation model. J Soc Health Syst 1998;5:24-37 16. Colquitt JL, Green C, Sidhu MK, Hartwell D, Waugh N. Clinical and costeffectiveness of continuous subcutaneous insulin infusion for diabetes. Health Technology Assessment 2004;8:no 43 17. Vries JH de. Will long acting insulin analogs influence the use of insulin pump therapy in type 1 diabetes? Curr Diab Rev 2005;1: 23-26 18. Hirsch IB, Bode BW, Garg S, Lane WS, Sussman A, Hu P,. Santiago OM, Kolaczynski JW for the Insulin Aspart CSII/MDI Comparison Study Group. Continuous Subcutaneous Insulin Infusion (CSII) of Insulin Aspart Versus Multiple Daily Injection of Insulin Aspart/Insulin Glargine in Type 1 Diabetic Patients Previously Treated With CSII. Diabetes Care 2005;28: 533-538 19. Doyle EA, Weinzimer SA, Steffen AT, Ahern J A, Vincent M, Tamborlane WV. A randomised, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion with multiple daily injections using insulin glargine. Diabetes Care 2004; 27:1554-1558 20. Bolli GB, Capani F, Home PD, Kerr D, Thomas R, Torlone E et al. Comparison of a multiple daily injection regimen with once-daily insulin glargine basal insulin and mealtime lispro, to continuous subcutaneous insulin infusion: a randomised, open, parallel study. Diabetes 2004; 53: Suppl 2: A107-A108 21. Renner R, A Pfutzner, M Trautmann, O Harzer, K Sauter, R Landgraf. Use of insulin lispro in continuous subcutaneous insulin infusion treatment. Results of a multicenter trial. German Humalog-CSII Study Group. Diabetes Care 1999; 22: 784-788

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22. Bode B, R Weinstein, D Bell. Comparison of insulin aspart with buffered regular insulin and insulin lispro for continuous subcutaneous insulin infusion. Diabetes Care 2002; 25: 439-444 23. Zinman B, H Tildeslex, J-L Chaisson. Insulin lispro in CSII: results of a double-blind crossover study. Diabetes 1997; 46: 440-443 24. Dunn FL, Nathan DM, Scavini M, Selam JL, Wingrove TG. Long-term therapy of IDDM with an implantable insulin pump. The Implantable Insulin Pump Trial Study Group. Diabetes Care 1997;20:59-63 25. Hanaire-Broutin H, Brousolle C, Jeandidier N, Renard E, Guerci B, Haardt M, Lassman-Vague V. Feasability of intraperitoneal insulin therapy with programmable implantable pumps in IDDM. A multicenter study. The EVADIAC Study Group. Diabetes Care 1995;18:388-92

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CHAPTER TWO KLINISCHE LES

Continue Subcutane Insuline Infusie (CSII) soms goede optie bij slecht gereguleerde diabetes mellitus type 1

RPLM Hoogma; JH de Vries; RPJ Michels; JBL Hoekstra; M Levi

NTVG 2005; 149: 2261-2264 14

Dames en heren, De behandeling van mensen met diabetes mellitus type 1 dient erop gericht te zijn een optimale glycemische regulatie te bereiken, waarbij zo min mogelijk in het dagelijkse leven wordt ingegrepen. Optimale regulatie kan gedefinieerd worden als zo laag mogelijke glucosespiegels, gemeten aan het HbA1c gehalte, in combinatie met zo min mogelijk hypoglycemieën. De standaard insulinebehandeling van mensen met diabetes mellitus type 1 bestaat sinds 1993 uit 3 maal daags kortwerkende insuline voor de maaltijden en 1 of 2 maal daags basale isofane insuline, ook wel aangeduid als “neutrale protamine insuline volgens Hagedorn”. In de Diabetes Control and Complications Trial (DCCT) heeft men bevestigd dat hiermee een veel lager HbA1c bereikt kan worden - met een geringere kans op chronische complicaties - dan met het schema dat tot dan toe gebruikelijk was, te weten tweemaal daags een insuline mengsel van kort- en middellangwerkende insuline (1-3). De genoemde trial bestond niet alleen maar uit een vergelijking van insulineschema’s, de patiënten in de intensief behandelde groep werden tevens uitgebreid begeleid door artsen, diabetes verpleegkundigen, diëtisten, psychologen en maatschappelijk werkers (1-3). Zij leerden hun maaltijd insulinedosis te variëren aan de hand van gemeten glucosewaarden en de te verwachten hoeveelheid voedselinname en lichamelijke inspanning. Mede door deze educatie, die begon met een klinische opname van een week, was men in staat om een dergelijke glycemische controle gedurende een aantal jaren te handhaven. In en ook na deze studie bleek een aanzienlijk deel van de mensen ondanks alle begeleiding niet in staat hun diabetes optimaal gereguleerd te krijgen of te houden (4). Eén van de mogelijke oorzaken hiervoor is gelegen in de wisselende opname en werkingsduur van NPHinsuline. Tot voor kort was insulinepomptherapie het enige alternatief voor basale insulinetoediening (5). Hier is met de komst van de langwerkende insuline analogen wel enige verandering in opgetreden, in die zin dat men allereerst een schema bestaande uit driemaal daags (ultra)kortwerkend insuline analoog en een- of tweemaal daags langwerkend analoog zal toepassen, alvorens over te gaan tot insulinepomptherapie. In deze les willen wij u aan de hand van enkele patiënten de plaats van insulinepomptherapie in het bestaande therapeutisch arsenaal toelichten. Patiënt A is een 26 jarige huisvrouw die sinds 1983 bekend is met diabetes mellitus type 1, in eerste instantie gereguleerd middels tweemaal daags een mengsel van isofane en gewone, kortwerkende insuline, in de verhouding van 30/70 en later 50/50. Op haar 13e werd dit 15

schema gewijzigd in driemaal daags een kortwerkende insuline en eenmaal daags isofane insuline. Vanwege een slechte regulatie volgden nog vele insulineschema’s, alle zonder een bevredigend resultaat. Toen zij 21 jaar was, zagen wij patiënte voor de eerste maal en wij besloten om de diabeteseducatie weer vanaf de basis aan te pakken. Tijdens de verschillende bezoeken blijkt er vooral een gebrek aan kennis te bestaan met betrekking tot het schatten van de aantallen koolhydraten in een maaltijd en het daarop aanpassen van de insuline dosering. Patiënte kreeg extra educatie naar aanleiding van het gemaakte huiswerk, om haar te leren rekenen met koolhydraten en de juiste koolhydraatinsulineratio vast te stellen, en hoe zij moest omgaan met de insulinedoseringen in verschillende situaties. In de 10 maanden daarna daalde het HbA1c van 9,5 naar 8,2 % . De nuchtere glucosewaarde bleef echter onvoorspelbaar, variërend van 2,1 tot 25 mmol/l, niet gerelateerd aan de waarden op de voorafgaande avond. Op grond hiervan wordt besloten om over te gaan op continue subcutane insuline infusie (CSII) met insuline lispro. Hiermee werd in de jaren daarop volgend een HbA1c van gemiddeld 7,2 % bereikt, zonder dat het aantal hypoglycemieën toenam. De nuchtere waarden waren nu ook veel stabieler , variërend tussen 3,2 en 9,8 mmol/l. Het insulinegebruik nam hierbij met 35% af. Patiënt B is een 56 jarige man, van beroep kantoormedewerker, die sinds zijn 13e bekend is wegens diabetes mellitus type 1 en destijds ingesteld werd op tweemaal daags menginsuline, namelijk isofane en gewone, kortwerkende insuline, in de verhouding 30/70. Toen hij 37 jaar was, werd proliferatieve diabetische retinopathie vastgesteld, waarvoor gedurende 10 jaar meerdere lasercoagulaties plaats vonden. Vanaf zijn 47e wordt hij behandeld met een flexibel, meermaal daags insuline schema, bestaande uit driemaal daags een kortwerkend insuline en eenmaal daags isofane insuline . Een jaar later maakte hij een myocardinfarct door. Op zijn 51e werd de kortwerkende insuline vervangen door een kortwerkend insuline analoog in verband met de ontwikkeling van een gestoorde gewaarwording van hypoglycemieën. Deze verminderde gewaarwording lijkt daarna eerder toe dan af te nemen, waarbij het gemiddelde HbA1c in die periode 7,5 % bedroeg. Ruim 2 jaar later zagen wij patiënt voor de eerste maal op de polikliniek, met de vraag of hij in aanmerking komt voor CSII therapie. Er bleken bij zorgvuldige controles van zijn bloedglucose waarden, ook ’s nachts, regelmatig glucose waarden ≤ 2,5 mmol/l voor te komen, vooral aan het begin van de nacht, hypoglycemieën die meestal niet worden opgemerkt. De dosering isofane insuline wordt hierop verlaagd, waarna deze lage waarden niet meer voorkomen en hypoglycemieën overdag 16

weer werden herkend. Het percentage HbA1c bedraagt voorafgaande aan deze verandering 7,3, maar steeg hierna naar 8,2. Ondanks gerichte educatie bestaande uit het opnieuw leren van rekenen met koolhydraten en het aanpassen van de insulinedoseringen aan de bloedglucosewaarden, laten de nuchtere bloedglucosewaarden sterke schommelingen zien, die variëren tussen 2,5 en 25,8 mmol/l. Er wordt na een periode van zes maanden besloten om de patiënt over te zetten op CSII therapie. Het resultaat na een jaar is een daling van het percentage HbA1c naar 7,4 en een weer kunnen herkennen van hypoglycemieën. De nuchtere bloedglucose waarden varieerden na een 6-tal maanden tussen 3,9 en 9,2 mmol/l. Patiënt C is een 41 jarige timmerman die sinds zijn 19e bekend is wegens diabetes mellitus type 1. Hij werd in eerste instantie behandeld met kristallijne zinkinsuline 1 maal daags, maar vanwege regelmatig optredende hypoglycemieën werd de insulinebehandeling na 2 jaar veranderd in tweemaal daags insuline, namelijk isofane en gewone, kortwerkende insuline, in de verhouding 30/70. De HbA1c waarden variëren in die periode tussen de 8,9 en 10,5 %, het aantal hypoglycemieën neemt toe, zodat men na een jaar besloot over te gaan naar kortwerkende insuline driemaal daags en isofane insuline eenmaal daags. De jaren daarop was zijn diabetes redelijk gereguleerd met een gemiddeld HbA1c van 7,2 %, maar er ontstonden steeds meer hypoglycemieën die zelfs met epileptische insulten gepaard gingen. In deze periode kwam hij zelden of nooit voor poliklinische controle, naar eigen zeggen vanwege zijn drukke werk. Op 38 jarige leeftijd blijkt het HbA1c 7,2 % te bedragen, wat echter wel gepaard ging met een verminderde gewaarwording van hypoglycemieën. Vanwege het drukke werk en de daarbij frequent optredende hypoglycemieën wordt besloten om over te gaan naar CSII therapie. Daarna traden er in eerste instantie nauwelijks meer hypoglycemieën op en bedraagt het HbA1c gemiddeld 7,1 %. Echter, na 2 jaar doen zich opnieuw ernstige, onvoorspelbare hypoglycemieën voor die hij nauwelijks meer aan voelde komen, die niet duidelijk gerelateerd waren aan werkzaamheden en die ook vaak direct na de maaltijden optraden. Hierop werd besloten om het glucosebeloop middels een continue glucose sensor meting te volgen en het geheugen van de insuline pomp uit te lezen. Hieruit bleek dat patiënt zijn bloedglucose ongeveer 9 maal per dag controleert en zichzelf andere insuline doseringen toediende dan door hem werden genoteerd. Ook werd regelmatig door hem met de insulinepomp gemanipuleerd in de zin van stopzetten, het tijdelijk verlagen en verhogen van de basale insuline toediening daar waar dit niet logisch of nodig is. Zo zouden er, zelfs zonder 17

dat de pomp aangesloten was hypoglycemieën ontstaan. De handelingen waren op zich niet moeilijk, maar er leek een duidelijk psychologisch probleem aanwezig te zijn, waardoor de patiënt ging manipuleren met de insuline en de bloedglucosewaarden. Nadat deze bevindingen met patiënt waren besproken, gaf hij er de voorkeur aan om weer terug te gaan naar een regime van injecties bestaande uit driemaal daags een kortwerkend insuline analoog en eenmaal daags insuline glargine. Hierna traden er volgens patiënt geen hypoglycemieën meer op. De nuchtere glucosewaarde varieerden na drie maanden tussen de 2,8 en 15,4 mmol/l bij een HbA1c waarde van 7,1 %. Wat kunnen de bovenstaande ziektegeschiedenissen ons leren ten aanzien van de plaats van CSII in de behandeling van mensen met diabetes mellitus type 1? In 1979 werd door de groep van Keen en Pickup melding gemaakt van een nieuwe vorm van insuline toediening bij mensen die slecht gereguleerd waren (6). Het betrof hier een aantal mensen met diabetes mellitus type 1, die op de gebruikelijke wijze niet goed te reguleren waren en kortwerkende insuline via een pomp subcutaan kregen toegediend. De resultaten waren bemoedigend en naar aanleiding hiervan werden dan ook meerdere onderzoeken gepubliceerd die eenzelfde gunstig resultaat lieten zien (7) De technische problemen die zich echter met deze pompen voordeden leidden nogal eens tot acute complicaties, met name ketoacidotische ontregelingen door pompdysfunctie (8). Na bekend worden van deze problemen nam de populariteit van pompbehandeling af. Gedurende de laatste decennia is de techniek van de insulinepompen geperfectioneerd en komt technisch falen vrijwel nooit meer voor. Ook het gebruiksgemak van de catheter waardoor de insuline subcutaan wordt toegediend is sterk toegenomen. Insulinepompbehandeling won hiermee weer aan populariteit. De moderne pomp heeft de grootte van een semafoon en maakt veelal gebruik van voorgevulde ampullen insuline. De snelheid waarmee de basale insuline toegediend wordt, wordt tevoren ingesteld en bij iedere maaltijd geeft de drager de pomp opdracht een aantal eenheden maaltijd insuline te injecteren. Effectiviteit. Recent hebben twee grote cross-over trials plaats gevonden bij mensen met een diabetes mellitus type 1 (9,10). In deze trials werden CSII en injectietherapie bestaande uit meermaal daagse insuline injecties met elkaar vergeleken, waarbij in beide gevallen gebruikgemaakt werd van een kortwerkend insuline-analoog, als respectievelijk pomp- en als maaltijdinsuline. De trials waren qua opzet enigszins verschillend, maar beide lieten een 18

duidelijke verbetering van de HbA1c-waarde zien, te weten 0,3 en 0,86%, met in één studie een duidelijke afname in de frequentie van hypoglycemieën. Uit beide onderzoeken bleek ook een duidelijke verbetering in de kwaliteit van leven na aanvang van CSII therapie. Een bezwaar is dat men in deze onderzoeken geen gebruik heeft kunnen maken van de thans beschikbare langwerkende insuline analogen. Men kan daar tegenin brengen dat het gebruik van insuline-analogen niet heeft geleid tot substantieel lagere HbA1c waarden (11,12). Recent werd een studie gepubliceerd waarin een directe vergelijking heeft plaats gevonden tussen CSII met een kortwerkend analoog en een injectieschema met een zowel een kort- als langwerkende insuline analoog. Uit deze studie bij adolescenten kwam naar voren dat er een betere regulatie optrad met CSII therapie: er werd een afname van het HbA1c van 0,3 % geobserveerd, terwijl zich minder hypoglycemiëen voordeden (13). Echter, twee hierop volgende studies lieten geen verschil zien tussen CSII en injecties met kort- en langwerkende analogen (14,15). Deze voorlopige, jongste studieresultaten zullen de terughoudendheid die bij sommigen bestaat ten aanzien van het gebruik van CSII therapie mede verklaren. Andere mogelijke oorzaken zijn gelegen in de tijd en moeite die nodig is voor ondersteuning van de patiënt en de onbekendheid met een vorm van behandeling die vaak gezien wordt als een ultimum refugium. Gebleken is uit recent onderzoek en een hierop volgende meta-analyse dat juist bij mensen met hoge HbA1c waarden CSII een additionele waarde heeft, mits uitgevoerd in een omgeving waar begeleiding door diabetesverpleegkundige en psycholoog voorhanden is (10,16). Ook kan de te verwachten winst in kwaliteit van leven bij een intensieve levensstijl een goede reden zijn om de patiënt een behandeling met CSII voor te stellen. Indicaties. Bij de huidige stand van zaken lijken de vanouds bekende indicaties voor CSII therapie nog onverminderd geldig: heeft men te maken met een slechte diabetesregulatie bij goed gemotiveerde patiënten, of met mensen met een redelijke diabetesregulatie die een zo flexibel mogelijke therapievorm wensen dan kan CSII overwogen worden. Hierbij dient overigens opgemerkt te worden dat een slechte regulatie zich niet alleen in een hoog HbA1c kan uiten, maar ook in sterk wisselende bloedglucose waarden. Dames en Heren, uit de ziektegeschiedenissen van patiënt A en B moge blijken dat problemen kunnen worden veroorzaakt door de onvoorspelbare werking van de isofane insuline en/of een zogenaamd dageraadfenomeen. Dit fenomeen wordt gekenmerkt door een stijging van het glucosegehalte aan het eind van de nacht onder invloed van een toegenomen 19

groeihormoon secretie. Mede door het gebruik van een kortwerkend insulineanaloog in een pomp en de zo nodig per uur te variëren insulinetoedieningsnelheid is het bij hen beiden mogelijk geworden om de nacht stabiel door te komen. De ziektegeschiedenis van patiënt C illustreert dat insulinepomptherapie geen oplossing is voor iedereen met een slechte glycemische instelling. Het afwegen van de voor- en nadelen van behandeling met CSII is een bijzondere uitdaging voor internist, diabetesverpleegkundige en patiënt.

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Literatuur: 1

Diabetes Control and Complications Trial Research Group DCCT. Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group. Ophthalmology 1995; 102: 647-661

2

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

3

Diabetes Control and Complications Trial Research Group. Implementation of treatment protocols in the Diabetes Control and Complications Trial. Diabetes Care 1995; 18: 361376

4

Writing Team for the Diabetes Control and Complications Trial/Epidemiolog of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nefropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 2003;290: 2159-67

5

Lenhard MJ, Reeves GD. Continuous subcutaneous insulin infusion: a comprehensive review of insulin pump therapy. Arch Intern Med 2001; 161: 2293-2300

6

Pickup JC, White MC, Keen H, Parsons JA, Alberti KG. Longterm continuous subcutaneous insulin infusion in diabetics at home. Lancet 1979; 2 (8148): 870-873

7

Pickup J, Mattock M, Kerry S. Glycaemic control with continuous subcutaneous insulin infusion compared with with intensive insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials. BMJ 2002:324: 1-6

8

Knight G. Risks with continuous subcutaneous insulin infusion can be serious. BMJ 1999; 319: 104-106

9

Hoogma RPLM, Hammond PJ, Gomis R, Kerr D, Bruttomesso D, Bouter KP, Wiefels KJ, de la Calle H, Schweitzer DH, Pfohl M, Torlone E, Krinelke LG, Bolli GB, on behalf of the 5-Nations Study Group. Comparison of Continuous Subcutaneous Insulin Infusion (CSII) vs. NPH-based Multiple Daily Insulin Injections (MDI) in Regard to Metabolic Control and Quality of Life Results of the 5-Nations trial. Diabetic Medicine, in press 21

10 Vries JH de, Snoek FJ, Kostense PJ, Masurel N, Heine RJ. A randomized trial of continuous subcutaneous insulin infusion and intensive injection therapy in type 1 diabetes for patients with long-standing poor glycemic control. Diabetes Care 2002; 25: 2074-2080 11 National Institute for Clinical Excellence. Final appraisal determination. Long-acting insulin analogues for the treatment of diabetes – insulin glargine. October 2002, www.nice.org.uk/glargine 12 Vries JH de. Will long acting insulin analogs influence the use of insulin pump therapy in type 1 diabetes? Curr Diab Rev 2005;1: 23-26 13 Doyle EA, Weinzimer SA, Steffen AT, Ahern J A, Vincent M, Tamborlane WV. A randomised, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion with multiple daily injections using insulin glargine. Diabetes Care 2004; 27:1554-1558 14 Bolli GB, Capani F, Home PD, Kerr D, Thomas R, Torlone E et al. Comparison of a multiple daily injection regimen with once-daily insulin glargine basal insulin and mealtime lispro, to continuous subcutaneous insulin infusion: a randomised, open, parallel study. Diabetes 2004; 53: Suppl 2: A107-A108 15 Hirsch IB, Bode BW, Garg S, Lane WS, Sussman A, Hu P,. Santiago OM, Kolaczynski JW for the Insulin Aspart CSII/MDI Comparison Study Group. Continuous Subcutaneous Insulin Infusion (CSII) of Insulin Aspart Versus Multiple Daily Injection of Insulin Aspart/Insulin Glargine in Type 1 Diabetic Patients Previously Treated With CSII. Diabetes Care 2005;28: 533-538 16 Retnakaran R, Hochman J, DeVries JH, Hanaire-Broutin H, Heine RJ, Melki V, Zinman B: Continuous subcutaneous insulin infusion versus multiple daily injections: the impact of baseline A1c. Diabetes Care 2004;27:2590–2596

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CHAPTER THREE Quality of life and Metabolic control in patients with diabetes mellitus type 1 treated by continuous subcutaneous insulin infusion or multiple daily insulin injections

Roel PLM Hoogma,Anton JM Spijker Margit van Doorn-Scheele,Talitha T van Doorn Robert PJ Michels,Rudi G van Doorn Marcel Levi, Joost BL Hoekstra

Neth J Med 2004:62;383-387

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Objective To assess the quality of life and metabolic control in patients with diabetes mellitus type 1 on continuous subcutaneous insulin infusion (CSII) in comparison to patients on multiple daily insulin injections (MDI) Research design and methods The study comprised of 49 patients, > 1 year on CSII (13 males, 36 females), age 41.4 ± 11.3 years (mean ± S.D.) and 79 patients, > 1 year on MDI (43 males, 36 females), age 43.1 ± 14.8 years, from 3 Dutch diabetic clinics. There were no statistically significant differences in duration of diabetes, social class, level of education, marital status, smoking or recent admissions to hospital. The questionnaires used were a Diabetes Quality of Life scale adapted from the DCCT, the Diabetes Satisfaction Questionnaire (DTSQ), and the WHO Well-being questionnaire. HbA1c was measured with an HPLC method (reference range 4.3 – 6.1 %) Results Using two-sided t-tests no statiscally significant differences were found between the patients on CSII and MDI with respect to quality of life (version A 4.32 ± .22 vs. 4.20 ± .30; version B 4.18 ± .25 vs. 4.29 ± .28), well-being (48.59 ± 9.23 vs. 50.99 ± 8.70), satisfaction with treatment (5.10 ± .69 vs. 5.15 ± .71) and HbA1c (8.14 ± 1.51 vs. 8.47 ± 1.40). Frequency of daily blood glucose monitoring was slightly higher in CSII patients than in MDI (4.52 ± 1.19 vs. 3.60 ± 1.47; p < 0.0001). Conclusions The present data indicate that patients on CSII have similar QoL based on questionnaires when compared to patients on MDI. These data suggest that in patients with less optimal control on MDI conversion of treatment strategy to CSII is not associated with decreased quality of life.

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Over the last ten year treatment with continuous subcutaneous insulin infusion (CSII) has become more popular, probably for a large part due to a more flexible lifestyle and a better quality of life. The strong improvement in the insulin pumps (such as better technology, less weight and smaller size) as well as the material (needles, catheters and strips, etc.) has strongly facilitated continuous subcutaneous insulin administration. Although multiple daily insulin injections (MDI) has proven its benefits regarding diabetes control and complications, one of the remaining and important concerns is the frequency of hypoglycaemias probably caused by the unpredictable absorption of subcutaneously injected insulin (1, 2). CSII therapy has probably solved this problem. CSII has been shown to improve glycemic control as compared to MDI in reasonably well-controlled diabetes patients (0.35% HbA1c) (3, 4, 5). In addition, in patients with poor metabolic control a 0,8% HbA1c improvement in metabolic control was recently shown (6). Moreover, several studies have shown an advantage in glycemic control in CSII treated patients with the use of a rapid acting insulin analogue instead of unmodified human insulin (7,8). However, even with these improvements, many diabetologists regard CSII therapy still as the last resort in insulin treatment for patients with diabetes mellitus. One of the reasons for this could be the idea that CSII therapy is a psychological burden for the patient. This, however, is not supported by systematic studies. Some initial and small studies suggest a better quality of life with insulin pump treatment, especially when compared with conventional insulin treatment (for example therapies consisting of twice daily insulin mixtures) but show less or equal benefit when compared with MDI. These studies were performed with the older, currently outdated equipment and measured different aspects of quality of life, like depression and anxiety separately (3, 9, 10, 11, 12, 13, 14). The aim of the present study was to compare the quality of life (QoL) in patients with diabetes mellitus type 1 on CSII to that in patients on MDI. To do so, we performed a cross-

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sectional study on items of QoL in two groups of patients with diabetes mellitus type 1 either treated with CSII or with MDI and who had a stable control for a long time. Research design and methods Patients with diabetes mellitus type 1 and who were stable at least for one year on insulin pump therapy were recruited from three different hospitals. In the three hospitals all patients with diabetes mellitus type 1 were treated by MDI (in total 945), and 95 patients were treated by CSII. At the time of the original cross-sectional study no patients with diabetes mellitus type 2 were treated by CSII and since at that time insulin analogues were only available for clinical trial purpose, no patients were treated with these new insulins. In total 55 patients using CSII were invited, for an information evening on new developments in insulin pump treatment. 49 patients responded and were asked to fill in a number of questionnaires. In each hospital twice as much patients with MDI were randomly selected and asked to fill in the questionnaires before the regular out-patient visit. In this group a total of 79 patients were recruited. Included patients had to be treated with MDI or CSII at least for one year. Patients with a documented mental disorder were excluded from the study. The questionnaires were provided to the patients by their own physician. All questionnaires were returned for analysis together with the most recent HbA1c value of the patient. Patients spent about 30 minutes for filling out the questionnaire. The questionnaires had a general section, consisting of socio-demographic data, like age, sex, marital status, education, smoking behaviour and more specific questions concerning the duration of diabetes, the number of hypoglycaemic events, and the number of blood sugar controls daily. In addition the following quality of life measurements were done; The quality of life for diabetic patients (DQOL) measures the current situation, the influence of having diabetes for daily functioning and the worries arising from it. The questionnaire

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consists of four subscales. These are satisfaction, impact, worries associated with diabetes and worries in general. The last subscale consists in two versions: version A is for persons younger than 30 years old and version B for 30 years and older. The subscale satisfaction consists of 23 items, the subscale "impact" of 20 items, the subscale "worries" associated with diabetes of 16 items and the subscale "worries in general" version A of 10 and version B of 9 items. In total the questionnaire consist of 69 (version A) or 68 items (version B), respectively. The scale in the DQOL is a five-point scale, ranging from 1 (very unsatisfied) to 5 (very satisfied) or from 1 (never) to 5 (always). A high score DQOL will mean that someone is very satisfied, the influence of diabetes at the daily functioning is not experienced as heavily en that someone has little general and diabetes-related worries. The internal consistency of the questionnaire version A was 0,9 and for version B 0,89, which is relatively high (15). Satisfaction with the therapy (DTSQ), this questionnaire was developed for measuring the satisfaction with the current therapy and is suitable for people with diabetes type 1 and 2. The questionnaire was developed by Bradly in collaboration with the Diabetes Research Group in 1993 (16, 17). The questionnaire consists of 8 items and covers 3 subscales. The scale for this score ranges from 0 (very unsatisfied) to 6 (very satisfied). Two items will give an indication of the frequency of hyperglycaemia and hypoglycaemia, the scale for this score ranges from 0 (never) to 6 (often). Hyperglycaemia was defined as a blood glucose value of more than 15.0 mmol/l. A severe hypoglycaemic event was defined as a blood glucose value for which third party assistance was necessary. The internal consistency of this questionnaire was 0.89, which is relatively high (16, 17).

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The questionnaire concerning well-being was originally developed in 1982 to have an instrument to measure depression, anxiety and the various aspects of well-being. This questionnaire was used by the WHO for measuring new treatment modalities in control of diabetes.The current questionnaire consists of 22 items and 4 subscales. The subscales concern depression, anxiety, energy and positive well-being. A total score of general wellbeing will be obtained by counting the scores after inverting the subscales of depression and anxiety. The scale is a four-point scale, from 0 (never) to 3 (always). A higher score is consistent with the mental state described by the different subscales. The internal consistency of the subscales was shown to be sufficient (0,46 till 0,89) (15).

To analyse the difference in quality of life in patients with diabetes mellitus who received a different type of intensive insulin treatment, patients on CSII treatment were compared with patients on MDI. Both groups received the same questionnaires. Because of the cross sectional design of the study, statistical analysis was performed by X2 for socio demographic and medical results. All other results were tested by Student’s t-test using the SPSS program. A p-value below 0.05 was considered to be statistically significant. Results The patient population consisted of 55 patients on CSII who fulfilled the inclusion criteria. Of this group, 49 patients filled out the questionnaire and 6 patients were not willing to participate in the trial. A randomly assigned group of 79 patients with MDI coming from the same outpatient clinics formed the control group. Social and demographic data are given in table 1.

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Table 1: Social and demographic data. Number of patients Sex (m/f) (n) Age Marital Status Married or living together (n) Unmarried (n) Divorced/widow (n) Education (%) ¾ None ¾ Low professional ¾ Low ¾ Middle ¾ Middle professional ¾ High ¾ Unknown Duration of diabetes (%) ¾ > 10 years ¾ 5-10 years ¾ 2-5 years ¾ < 2 years Retinopathy (%) Nephropathy Smoking (%)

CSII 49 13/36 41,4 ± 11,3

MDI 79 43/36 43,1 ± 14,8

40 7 2

55 18 6

8 25 8 37 12 10 0

5 20 16 11 18 27 3

65 29 6 0 2 0.5 25

73 14 10 3 3 1 22

The frequency of self measurement of blood glucose in the group treated with CSII was once daily in 81%, 5-6 times a week in 2%, 3-4 times a week in 2%, 1-2 times a week in 10% and never or seldom in 2%. In the MDI group these results were 63%, 8%, 6%, 19% and 4%, respectively. The frequency of performing a full daily glucose profile in patients treated with CSII was 18%, consisting in 63% of the measurement of blood glucose 4 times or more, 6% three times, 12% two times, and 6% once each day. In the MDI group the patients performed in 8% a daily glucose profile, of which 43% four times or more, 11% three times, 25% twice and 8% once each day. In general, patients on CSII performed significantly more self control than the patients on MDI.

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The number of hypoglycaemic episodes, which could be managed by the patient him/herself, in the week and in two months before the questionnaire was filled in, are shown in Table 2. No statistical differences were found between the group treated with CSII or MDI. The HbA1c for the CSII group was 8,1 ± 1,5% and for the MDI treated group 8,5 ± 1,4%. Only the frequency of blood glucose control was statistically different between the two groups (p Four 14 Hypoglycaemia during the night (%) None 63 One 21 Two 16 Three 0 Not available 0 Severe hypoglycemia/2months (%) Never 80 Once 16 Twice 2 Three times 2 Four times 0 HbA1c 8,1 ± 1,5 p < 0,05 (regarding to the number of daily controls)

MDI(%) 63 8 6 19 4 35 25 27 9 60 30 6 2 2 90 6 3 0 1 8,5 ± 1,4

No difference was found regarding to the outcome of the DQOL measurement between the groups treated with CSII or MDI (Table 3). Also the satisfaction of treatment measurement, in particular related to hyperglycemias and hypoglycemias, did not show any difference (Table 4).

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With regard to the general well being, only for the subscale "energy", the group treated with MDI showed somewhat better results compared to the group treated with CSII. Regarding the other items there were no statistical differences between the two groups (Table 5). Table 3: results regarding to the subscales satisfaction, impact, diabetes and general related worry and the total score DQOL Quality of life CSII MDI P Satisfaction NS 4.0 ± 0.6 4.0 ± 0.4 Impact NS 4.0 ± 0.3 4.1 ± 0.3 Diabetic Worry NS 4.2 ± 0.3 4.2 ± 0.4 Social Worry A NS 4.7 ± 0.3 4.6 ± 0.4 Social Worry B NS 4.5 ± 0.5 4.6 ± 0.3 DQOL A NS 4.3 ± 0.2 4.2 ± 0.3 DQOL B NS 4.2 ± 0.2 4.3 ± 0.3 (Values are expressed as mean ± SD) Table 4: Results satisfaction regarding to mentioned hyperglycemias (range 0-6) and hypoglycaemias (range 0-6) and DTSQ total (range 0-6) DTSQ CSII MDI P Hyperglycaemia NS 2.8 ± 1.6 2.7 ± 1.6 Hypoglycaemia NS 3.5 ± 1.7 3.1 ± 1.7 Satisfaction total NS 5.1 ± 0.7 5.2 ± 0.7 (Values are expressed as mean ± SD)

Table 5: results regarding to subscales depression (range 0-3), anxiety (range 0-9), energy (range 0-12) and positive well being (range 0-18) and total well being (range 0-66). Well being CSII MDI P Depression NS 3.7 ± 2.6 3.2 ± 2.2 Anxiousness NS 4.5 ± 3.7 4.0 ± 3.2 Energy 0.009 7.5 ± 2.4 8.7 ± 2.3 Pos well being NS 13.2 ± 3.0 13.5 ± 2.8 Well being total NS 48.6 ± 9.2 51.0 ± 8.7 (Values are expressed as mean ± SD) Conclusions This study shows that patients treated with CSII have similar scores on quality of life scales and respond similarly to questionnaires regarding satisfaction with the treatment and general well being in comparison with patients treated with MDI. Although we are oblivious of the 31

reasons patients have chosen for CSII, the CSII group did not differ from the MDI group on duration of diabetes, frequency of complications, marital status and level of education. No statistical difference between the CSII and MDI group regarding to their HBA1c values or the number of severe hypoglycaemias could be detected, although there was a tendency for a better HbA1c for the group treated by the insulin pump, as has also been shown by the two recent meta-analyses (3, 14). The similar quality of life of patients of CSII to those on MDI is in line with previous studies, one of which even showed that the quality of life in patients on CSII was improved (6). Even the fact that most of the patients who were on CSII therapy had a higher frequency of blood glucose control , this seems not to interfere with their quality of life. Based on these results, it may be concluded that the idea that seems to exist with some diabetologists about the impact of CSII therapy as an impairment in the quality of life, is actually a misconception. One of the main advantages of insulin pump treatment is caused by the provision of a better basal insulin administration instead of the problematic pharmacokinetics and pharmacodynamics of intermittent insulin in case of MDI (18, 19). It may, in fact, be considered as remarkable that patients are capable to regulate their diabetes with these schedules. Also the possibility to temporarily change the basal insulin requirement during different activities in patients with CSII might be considered as an at least theoretical benefit of this treatment strategy and should cause less hypoglycemias and hyperglycemias (18, 19). Our study may have been somewhat too small to detect such differences. Nevertheless, the results of the group treated with CSII therapy (and those on MDI) might have been better when the patients had been treated with insulin analogues, such as Lispro or Aspart. In different studies insulin Lispro and Aspart were shown to result in a slightly better HbA1c without causing an increased incidence of hypoglycaemias (7, 8, 20, 21, 22).

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This study, which is a cross sectional study, has some limitations. The groups were not randomly assigned; the reasons to choose for CSII therapy was for an important part caused by motivation of the patients, the Dawn phenomenon, badly controlled diabetes, and also problems related to the NPH-insulin. Because of these reasons the groups are strictly speaking not comparable, although one can argue to which extent these differences could have an effect on the parameters evaluated in this study. Despite these limitations of the present study, our data suggest, that patients who are in less than optimal control on MDI may be safely offered a trial of CSII therapy.

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References 1. The 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; 329:977986 2. Liebl A; Challenges in optimal metabolic control of diabetes. Diabetes Metab Res Rev.2002;18 Suppl 3:S36-41 3. Pickup J, Mattock M, and Kerry S: Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials. BMJ 2002; 324:3-6 4. Hanaire-Broutin H, Melki V, Bessieres-Lacombe S, Tauber JP. Comparison of continuous subcutaneous insulin infusion and multiple daily insulin injection regimens using insulin lispro in type 1 diabetic patients on intensified treatment: a randomized study. The Study Group for the Development of Pump Therapy in Diabetes. Diabetes Care 2000; 23: 1232 -1235 5. Tsui E, Barnie A, Ross S, Parkes R, Zimman B. Intensive Insulin Therapy With Insulin Lispro: A randomized trial of continuous subcutaneous insulin infusion versus multiple daily insulin injection. Diabetes Care 2001; 24: 1722-1727 6. De Vries JH, Snoek FJ, Kostense PJ, Masurel N, Heine RJ: Dutch Insulin Pump Study Group. A randomized trial of continuous insulin infusion and intensive injection therapy in type 1 diabetes for patients with long-standing poor glycemic control. Diabetes Care 2002; 25: 2074-2080 7. Melki V, Renard E, Lassmann-Vague V, Biovin S, Guerci B, Hanaire-Broutin H et al: Improvement of HbA1c and blood glucose stability in IDDM patients treated with lispro insulin analog in external pumps. Diabetes Care 1998; 21; 977-982

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8. Johansson UB, Adamson UC, Lins PE, Wredling RA. Improved blood glucose variability, HbA1c insuman infusat and less insulin requirement in IDDM patients using insulin lispro in CSII. The Swedish Multicenter Lispro Insulin Study. Diabetes Metab 2000;26:192-196 9. Schottenfeld-Naor Y, Galatzer A, Karp M, Jozefsberg Z, Laron Z: Comparison of metabolic and psychological parameters during continuous subcutaneous insulin infusion and intensified conventional insulin treatment in type 1 diabetic patients. Isr J Med Sci 1985;21: 822-828 10. Beck-Nielsen H, Richelsen B, Schwartz Sorensen N, Hother Nielsen O: Insulin pump treatment: effect on glucose homeostasis, metabolites, hormones, insulin antibodies and quality of life. Diabetes Res 1985;2:37-43 11. Bilbergeil H, Huttl I, Felsing U, Seidlein I, Herfurth S, Dabels J, Reichel G, Luder C, Albrecht G, et al: Thirty six months continuous insulin infusion (CSII) in insulin dependent diabetes (IDDM) – influence on early stages of retinopathy, nephropathy and neuropathy – psychological analysis. Exp Clin Endocrinol 1987;90:51-61 12. Boland EA, Grey M, Oesterle A, Fredrickson L, Tamborlane W: Continuous subcutaneous insulin infusion: a new way to lower risk of severe hypoglycaemia, improve metabolic control, and enhance coping in adolescents with type 1 diabetes. Diabetes Care 1999;22:1779-1784 13. Seigler DE, LaGreca A, Satin-Rappaport W, Reeves M, Skyler J: Psychological effects of intensification of diabetic control. Diabetes Care 5 (Suppl. 1):19-23, 1982 14. Weissberg-Benchell J, Antisdel-Lomaglio J, Seshadri R: Insulin pump therapy, a meta-analysis. Diabetes Care 2003;26:1079-1087 15. Doorn van TT: Thesis. KUB Tilburg,1995

35

16. Lewis KS, Bradley C, Knight G, Boulton AJ, Ward JD: A measure of treatment satisfaction designed specifically for people with insulin-dependent diabetes. Diabet Med 1988;5:235-42 17. Bradley C, Todd C, Gorton T, Symonds E, Martin A, Plowright R. : The development of an individualized questionnaire measure of perceived impact of diabetes on quality of life: the ADDQoL. Qual Life Res 1999;8:79-91 18. M Lepore, S Pampanelli, C Fanelli, F Porcellati, L Bartocci, A Di Vincenzo, C Cordoni, E Costa, P Brunetti, and GB Bolli: Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes Care 2000;49: 2142-2148 19. Bolli GB: Physiological insulin replacement in type 1 diabetes mellitus. Exp Clin Endocrinol Diabetes 2001;109 (suppl 2): S317-332 20. Zinman B.: Insulin pump therapy and rapid acting insulin: what have we learned? Int J Clin Pract Suppl.2001; 123:47-50 21. Bode BW, Tamborlane WV, Davidson PC. Insulin pump therapy in the 21st century. Strategies for successful use in adults, adolescents, and children with diabetes. Postgrad Med 2002; 111:69-77 22. Bode B, Weinstein R, Bell D, McGill J, Nadeau D, Raskin P, Davidson J, Henry R, Huang WC, Reinhardt RR.: Comparison of insulin aspart with buffered regular insulin and insulin lispro in continuous subcutaneous insulin infusion: a randomized study in type 1 diabetes. Diabetes Care 2002;25:439-44

36

CHAPTER FOUR Comparison of Continuous Subcutaneous Insulin Infusion (CSII) vs. Multiple Daily Insulin Injections (MDI) in regard to metabolic control, a randomized, controlled, crossover trial

Roel P.L.M. Hoogma, Peter J. Hammond, Ramon Gomis, David Kerr, Daniela Bruttomesso, K. Paul Bouter, Klaus J. Wiefels, Hermenegildo de la Calle, Dave H. Schweitzer, Martin Pfohl, Elisabetta Torlone, Lars G. Krinelke, Geremia B. Bolli, on behalf of the 5-Nations Study Group

In part: Diabetic Medicine 2006: 23; 141-147

37

Abstract Aims The goal of the study was to determine whether CSII differs from an NPH-based MDI regimen with respect to metabolic control in people with type 1 diabetes. Methods The 5-Nations trial was a randomised, controlled, crossover trial, running in 11 European centers. 272 patients have been treated with CSII or MDI during a 2-month run-in period followed by a 6-month treatment period, respectively. The quality of metabolic control has been assessed by HbA1c, blood glucose values, and the frequency of hypoglycaemic events. Results CSII treatment resulted in lower HbA1c (7.45% vs. 7.67%, p 15 mmol/L (270 mg/dL). Subjects recorded episodes of hypoglycemia (graded according to DCCT criteria) and blood glucose values in a diary.

41

Standardized eight point blood glucose profiles were performed the day before each study visit and contained measurements before meals, one hour after meals, before bed and between 02.00 and 03.00 hours.

Definition of primary and secondary endpoints, safety criteria

The first primary efficacy criterion was defined as mean glycosylated hemoglobin (HbA1c) values at the end of each treatment period (EOT). The second primary efficacy criterion was the daily blood glucose fluctuation. This was defined as the average standard deviation of the mean daily blood glucose, using measurements taken during the 14 days prior to the final visit in each treatment period. The significant secondary efficacy endpoints were: mean daily blood glucose values, determined from standardized 24-hour blood glucose profiles, and the frequency and severity of hypoglycemic episodes. Safety criteria included any signs of discomfort at the injection or infusion site and the occurrence of any serious adverse events, the significant ones being severe hypoglycemia and ketoacidosis.

Statistical analysis

Due to the lack of a carry-over effect the study was analyzed as a crossover one. The primary endpoint HbA1c was initially analyzed for non-inferiority of CSII with respect to MDI, using the method of Westlake (16, 17). Non-inferiority was shown if the upper limit of the onesided 97.5% confidence interval (CI) was ≤0.7% in favor of MDI. The test of inferiority was based on the per-protocol (PP) crossover cohort (212 patients). In case of non-inferiority, the

42

superiority of CSII to MDI was to be analyzed using a one-sided student’s t-test with a significance level of 2.5%. This analysis was based on the intention-to-treat (ITT) crossover cohort (229 patients). The second primary endpoint blood glucose fluctuation and the significant secondary endpoints were tested for treatment differences between CSII and MDI using a two-sided student’s t-test with a significance level of 5%. This analysis was based on the ITT cohort. Incident densities were calculated for episodes of hypoglycemia. Comparisons were made between treatment types (CSII vs. MDI). Run-in periods were excluded from the statistical analysis. Missing data was substituted by LOCF (last observation carried forward) for the statistical analyses. The analysis of adverse events was performed using data from the safety cohort (256 patients). The study was performed in accordance with the guidelines of Good Clinical Practice. Data were monitored and analyzed by the Clinical Research Organization Kendle GmbH & Co. GMI KG, Munich, Germany.

Results

Demographic data

272 individuals were enrolled and randomized for the study. 31 subjects (15 in group MDICSII, 16 in group CSII-MDI) withdrew during the first treatment phase. 12 subjects completed phase one (2 in group MDI-CSII, 10 in group CSII-MDI) but did not cross over into the second treatment phase. 6 subjects withdrew during phase two (3 in group MDI-CSII, 3 in group CSII-MDI). 223 subjects completed the study. The total duration of both treatment

43

phases (including the run-in periods) was 145.7 patient years for MDI and 151.7 patient years for CSII. Principal baseline characteristics of the study population are shown in table 1. There were no significant differences in respect to patients' characteristics, concomitant diseases or medications.

Table 1.Baseline population characteristics (data expressed as mean ± SD). Group MDI-CSII

Group CSII-MDI

Number

129

127

Sex (F/M)

69/60

66/61

Age (years)

37 ± 10.6

35.3 ± 9.8

BMI (kg/m2)

24.8 ± 3.4

24.9 ± 3.3

Duration of diabetes (years)

15.4 ± 10.1

14.4 ± 8.9

Duration of MDI (years)

8.1 ± 6.2

7.6 ± 4.3

C-peptide (nmol/L)

0.10 ± 0.11

0.11 ± 0.10

Total daily insulin usage (I.U.)

50.8 ± 18.5

53.4 ± 21.4

Insulin requirement

The daily insulin requirement was significantly lower whilst using CSII than MDI (p 90%) with both types of treatment. Slightly more patients about to start with MDI would have recommended the therapy when compared with patients at the start of CSII treatment. The situation changed in the course of treatment. After 8 months of treatment recommendations for MDI decreased while CSII was more often recommended, leading to a marked difference (> 20%) in favour of CSII (figure 4). Item 9 of the same questionnaire examined symptoms during hypoglycaemia. The symptoms occurring during hypoglycaemic episodes were divided into two symptom classes, neuroglycopenic and neurogenic. More than 95 % of the patients in each treatment had hypoglycaemic episodes within two months before treatment and prior to the end of both treatment periods. None had hypoglycaemia unawareness. There were no differences between treatment modalities in terms of hypoglycaemic symptoms.

68

Figure 3: lifestyle and therapy manageability

90 80

ICT-CSII: ICT ICT-CSII: CSII CSII-ICT: CSII CSII-ICT: ICT

Cross-over

Recommendation (% of patients)

100

70

60 50 0

2

4

6

8

10

12

Study duration (months)

Figure 4: therapy recommendation

69

14

16

Discussion CSII has been developed to improve glycemic control of type 1 diabetic patients by means of more physiological insulinization than that with MDI. Some of the shortcomings of the current available studies comparing CSII and MDI are the lack of results regarding to the quality of life. In this study we compared 3 different questionnaires related to the quality of life. The overall score for DQoL questionnaire show a significant difference in favour of CSII, which is caused by more satisfaction, less impact and less diabetes related worry. Although some studies show already a better quality of life with regard to CSII therapy, it was recently shown in a meta-analysis that especially those kind of studies were comprised of a mix of adults and pediatric patients, not showing a real outcome. In the SF-12 health survey questionnaire it was shown that the mental health as well the physical health was improved by CSII. In this regard this study show less depression and anxiety as was suggested by the meta-analysis (3,18). Regarding to the lifestyle and therapy manageability the total score was in favour of the CSII therapy, which was caused by a higher flexibility for eating and sleeping, as is suggested by the two different scores. Although in retrospective studies it had been shown that the improved flexibility is the most common response for patients on CSII, as far as we know we are the first who could answer this question in a prospective manner. Remarkable is the difference in the recommendation of therapy, as at the start of the study most of the patients would recommend MDI, also for the patients who were on CSII, but the opinion changed after a period of two months. It will be certainly have to do with the time people do need before getting the results of their education and flexibility in life style. This means that studies who are dealing only for a short period of therapy don’t gave the answers you are looking for. In terms of quality of life, we conclude that CSII is superior to an intensified MDI regimen with 4 – 8 injections/day.

70

References

1. 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. NEJM 1993;329:977-86. 2. Diabetes Control and Complications Trial Research Group. Implementation of treatment protocols in the Diabetes Control and Complications Trial. Diabetes Care 1995;18:361-76. 3. Lenhard MJ, Reeves GD. Continuous subcutaneous insulin infusion: a comprehensive review of insulin pump therapy. Arch Intern Med 2001;161:2293-300. 4. Schiffrin A, Belmonte MM. Comparison between continuous subcutaneous insulin infusion and multiple injections of insulin. A one-year prospective study. Diabetes 1982;31:255-64. 5. Schiffrin AD, Desrosiers M, Aleyassine H, Belmonte MM. Intensified insulin therapy in the type I diabetic adolescent: a controlled trial. Diabetes Care 1984;7:107-13. 6. Dahl-Jorgensen K, Brinchmann-Hansen O, Hanssen KF, et al. Effect of near normoglycaemia for two years on progression of early diabetic retinopathy, nephropathy, and neuropathy: the Oslo study. BMJ 1986;293:1195-99. 7. Helve E, Koivisto VA, Lehtonen A, Pelkonen R, Huttunen JK, Nikkila EA. A crossover comparison of continuous insulin infusion and conventional injection treatment of type I diabetes. Acta Med Scand 1987;221:385-93. 8. Hanaire-Broutin H, Melki V, Bessieres-Lacombe S, Tauber JP. Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens using insulin lispro in type 1 diabetic patients on intensified treatment: a randomized study. The Study Group for the Development of Pump Therapy in Diabetes. Diabetes Care 2000;23:1232-5.

71

9. Pickup J, Mattock M, Kerry S. Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: metaanalysis of randomised controlled trials. BMJ 2002;324:1-6. 10. Boland EA, Grey M, Oesterle A, Fredrickson L, Tamborlane WV. Continuous subcutaneous insulin infusion. A new way to lower risk of severe hypoglycemia, improve metabolic control, and enhance coping in adolescents with type 1 diabetes. Diabetes Care 1999;22:1779-84. 11. Bode BW, Steed RD, Davidson PC. Reduction in severe hypoglycemia with long-term continuous subcutaneous insulin infusion in type I diabetes. Diabetes Care 1996;19:324-7. 12. DeVries JH, Snoek FJ, Kostense PJ, Masurel N, Heine RJ. A randomized trial of continuous subcutaneous insulin infusion and intensive injection therapy in type 1 diabetes for patients with long-standing poor glycemic control. Diabetes Care 2002;25:2074-80. 13. Johansson UB, Adamson UC, Lins PE, Wredling RA. Improved blood glucose variability, HbA1c Insuman Infusat(R) and less insulin requirement in IDDM patients using insulin lispro in CSII. The Swedish Multicenter lispro insulin study. Diabetes Metab 2000;26:192-196. 14. Roel PLM Hoogma, P.J. P. J. Hammond, R. Gomis, D. Kerr, D. Bruttomesso, P. Bouter, K. J. Wiefels, H. de la Calle, D. H. Schweitzer, M. Pfohl, E. Torlone, L. G. Krinelke; on behalf of the 5-Nations Study Group: Comparison of continuous subcutaneous insulin infusion (CSII) vs. NPH-based multiple daily insulin injections (MDI) in regard to metabolic control and quality of life. Results of the 5-Nations trial. Diabetes Medicin 2006; 23: 141-147 15. Bruttomesso D, Pianta A, Crazzolara D, et al. Continuous subcutaneous insulin infusion (CSII) in the Veneto region: efficacy, acceptability and quality of life. Diabet Med 2002;19:628-34.

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16. Linkeschova R, Raoul M, Bott U, Berger M, Spraul M. Less severe hypoglycaemia, better metabolic control, and improved quality of life in Type 1 diabetes mellitus with continuous subcutaneous insulin infusion (CSII) therapy; an observational study of 100 consecutive patients followed for a mean of 2 years. Diabet Med 2002;19:746-51. 17. Schiffers T. Quality of life with intensive insulin therapy: a prospective comparison of insulin pen and pump. Psychother Psychosom Med Psychol 1997;47:249-54. 18. Weissberg-Benchell J, Antisdel-Lomaglio J, Seshadri R. Insulin Pump Therapy: A metaanalysis. Diabetes Care 2003;26:1079-87. 19. The DCCT Research Group: Reliability and validity of a diabetes quality-of-life measure for the diabetes control and complications trial (DCCT). Diabetes Care 1988;11:725-32 20. Jenkinson C, Layte R: Development and testing of the UK SF-12 (short form health survey). J Health Serv Res Policy 1997;2:14-18 21. Nerenz DR, Repasky DP, Whitehouse FW, Kahkonen DM .Ongoing assessment of health status in patients with diabetes mellitus. Med Care. 1992 (5 Suppl):MS112-24 22. Ware JE, Snow KK, et.al. SF-36 Health Survey: Manual and Interpretation Guide 1993. Boston Masachusetts.

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Appendix The members of the 5-Nation Study Group are as follows: Germany – K. Wiefels, DiabetesForschungs-Institut, Düsseldorf; A. Behre, M. Pfohl, BG-Kliniken Bergmannsheil – Universitätsklinik, Bochum; Italy – D. Bruttomesso, A. Pianta, A. Tiengo, University of Padova, Padova; B. Bolli, E. Torlone, University of Perugia, Perugia; Spain – R. Gomis, Hospital Clinic I Provincial de Barcelona, Barcelona; H. de la Calle, Hospital Ramon y Caja, Madrid; the Netherlands - P. Bouter, Bosch Medicentrum, Den Bosch; R.P.L.M. Hoogma, Groene Hart Ziekenhuis, Gouda; D. Schweitzer, Diakonessen Ziekenhuis, Voorburg; United Kingdom – D. Kerr, The Royal Bournemouth Hospital, Bournemouth; P.J. Hammond, Harrogate District Hospital, Harrogate

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CHAPTER SIX A cost-comparison of Continuous Subcutaneous Insulin Infusion (CSII) versus Multiple Daily Insulin Injections (MDI) based on a randomized controlled crossover trial.

Roel PLM Hoogma, Karin M Vermeulen, Robert PJ Michels, Joost BL Hoekstra, Marcel Levi, Geremia B Bolli, on behalf of the 5-Nations Study Group

75

Abstract Aims The goal of this study was to determine the costs of CSII vs. a NPH-based MDI regimen with respect to metabolic control and quality of life in people with type 1 diabetes. Methods The 5-Nations trial was a randomised, controlled, crossover trial, running in 11 European centers. 272 patients were treated with CSII or MDI during a 2 month run-in period followed by a 6 month treatment period, respectively. The costs were assessed by calculating the costs for supplies, medical consultations, medications and absence from work or other social responsibilities. The cost effectiveness ratios were determined for metabolic control and quality of life. Results CSII resulted in a better metabolic control, less hypoglycemias and an improvement in quality of life scores. However, CSII treatment resulted in substantially more costs than MDI therapy. For the better metabolic control achieved by CSII an extra investment of € 1975 per 8 months will result in a decrease in the HbA1c by 0,36 % ( € 5486 per 8 months will lower the HbA1c with one extra percent). To prevent one non-severe hypoglycaemia an extra investment of € 463 per year has to be made and to prevent one severe hypoglycaemia an extra investment of € 9197 per year is required. To improve the quality of life score (DQol) with 1 extra point in patients using CSII, an extra investment of € 314,- Euros is required compared to MDI. Conclusions CSII offers significant benefits over an NPH-based MDI for individuals with type 1 diabetes but is associated with more costs. However, these additional costs may outweigh current national guidelines for cost-effectiveness.

76

Introduction In recent years the incidence of type 1 diabetes mellitus has increased in young people in most of the European countries, and in all age groups the prevalence of the disease is rising (1,2). The costs for type 1 diabetes has increased substantially (3) and are a burden to the national health services. In the Netherlands, for example, these costs comprised 1,2 % of the total national budget for curative health care in 2002 and these costs are estimated to have increased in 2004 to 2% (4). It is likely that this figure will further increase over the next decade. Hence it is important to select cost-effective treatment strategies for type 1 diabetes. The principle aim of treating diabetes is to regulate blood glucose levels and to achieve normoglycemia, thereby minimizing the risk of diabetic complications and improving quality of life. The Diabetes Control and Complications Trial (DCCT)(5) and later on the results coming from the Epidemiology of Diabetes Interventions and Complications study (EDIC) (6) have demonstrated the importance of maintaining strict glucose control for preventing diabetes related complications. The main disadvantage of intensive insulin therapy by multiple daily insulin injections (MDI), however, is the frequency of hypoglycaemias. In the DCCT almost 40% of the patients were treated with continuous subcutaneous insulin infusion (CSII), showing a better glycemic control and less hypoglycaemias (6). The percentage of patients that is treated with CSII is quite variable in the various countries in the world, ranging from 1 to 12 % of the total group of type 1 diabetes patients. One of the underlying reasons for this difference is that although several reviews and meta-analyses have provided evidence that CSII is providing a slightly better glycemic control with less hypoglycaemias than MDI, some questions have remained, in particular related to quality of life and cost aspects. We have recently performed a large multicenter randomized controlled trial showing the advantages of CSII over MDI (using NPH as basal insulin) concerning metabolic control, the incidence of hypoglycaemias as well as the quality of life. CSII treatment resulted in

77

lower HbA1c levels and mean blood glucose level as well as less fluctuation in blood glucose levels compared to MDI. Furthermore, there was a marked reduction in the frequency of severe hypoglycaemic events using CSII compared to MDI (7). Interestingly, the overall score of the diabetes quality of life questionnaire was higher for CSII compared to MDI, and CSII was associated with an improvement in pump users' perception of mental health using the SF-12 questionnaire. In view of the impact of diabetes on the restricted health care resources above mentioned, it seems important to evaluate the cost effectiveness of CSII versus a MDIbased regime. It is likely that CSII generates extra costs for infusion sets, cartridges, and related accessories. However, it is so far unknown whether the costs for visits to health care professionals and hospital admissions are different in patients on CSII in comparison to patients in a MDI regimen. To our knowledge, no trials have been published directly comparing the costs of CSII versus MDI in type 1 diabetes. Some publications are based on calculations or estimations from modelling analyses but no direct data is available so far (8,9). Hence, our recent randomised controlled study may provide a proper dataset in which both effects and costs of CSII versus MDI can be evaluated, which was the purpose of the present study. The cross-over design of this trial allowed for a fair comparison minimizing patient-related factors affecting costs, since each patient served as his/her own control.

Methods

Study design and population The study was a multicenter, randomized-controlled, crossover trial, conducted in 11 European centers (see appendix for details) (7). Individuals with type 1 diabetes for at least 2 years, aged 18 to 65 years, on MDI (multiple daily insulin injections) for at least 6 months, were invited to participate. The glycemic targets 78

for both treatments were identical, i.e. blood glucose at 4.0 – 7.0 mmol/L in the fasting state, blood glucose at 6.0 – 10,0 mmol/L before meals and at bedtime, blood glucose at 8.0 – 10.0 mmol/L after meals. Subjects were randomly allocated to two parallel study groups, to using CSII followed by MDI, or MDI followed by CSII. Each treatment phase started with a twomonth run-in period, during which patients received education to optimize intensive insulin therapy, followed by a 6 months treatment period. Study visits took place at baseline and every 2 months thereafter. The total study duration was 16 months. Subjects using MDI were treated with at least 3 injections of insulin lispro (Eli Lilly Inc., Indianapolis, USA) before meals and at least one injection of insulin NPH to achieve optimal control. The subjects using continuous subcutaneous insulin infusion (CSII) received insulin lispro via a multi-programmable insulin infusion pump (Disetronic H-TRON® V100 or Disetronic H-TRON® plus V100, Disetronic Medical Systems AG, Burgdorf, Switzerland). The local research ethics committee at each institution approved the study protocol. Written informed consent was obtained from all patients.

Measurements

HbA1c values were determined by HPLC in a central laboratory (normal range 4.4 to 6.1%). Blood glucose values were measured by the subjects using One-Touch Ultra meters (Lifescan Inc., Milpitas, USA). Subjects used Ketostix (Bayer AG, Leverkusen, Germany) to test urine for ketones when blood glucose levels were > 15 mmol/L (270 mg/dL). Subjects recorded episodes of hypoglycemia (graded according to DCCT criteria) and blood glucose values in a diary.

79

Standardized eight point blood glucose profiles were performed the day before each study visit and contained measurements before meals, one hour after meals, before bed and between 02.00 and 03.00 hours. Patients were to complete at every study visit: the diabetes QoL (DQoL) questionnaire. The DQoL questionnaire examines the influence of current diabetes treatment on quality of life (10). This questionnaire is validated tool, containing 46 core items which have to be rated by the respondent on a 5-point Likert scale ranging from 1 to 5 (1 = no impact or worries, always satisfied,…, 5 = always affected, worried, never satisfied). The core items are distributed on 5 score categories (satisfaction with treatment, impact of treatment, worries about social / vocational issues and worries about diabetes related issues).

Evaluation of costs

Data regarding absence of work, illness, medications and medical consultations were obtained from cost diaries filled in by the patients. The data regarding usage of insulin, catheters, cartridges and pen needles were obtained from the Case Report Form. The cost analysis was performed from a societal perspective. All relevant costs during the two treatment phases both inside and outside the healthcare system were taken into account. Costs were divided in costs of medical consultations, costs for absence from work for patient and/ or partner, and costs of insulin and equipment. Information concerning all resource use was collected during the study visits, which were scheduled every 2 months, and was registered on a Case Report Form by the physician that treated the patient. Unit prices of all included costs categories were determined using country specific prices, which were mostly based on tariff lists, standard prices and reference costs given by the

80

manufacturers. Costs for absence from work were based on average country specific salary costs. One exception to this method were unit prices of infusion sets, empty cartridges and batteries/adapters, in which case Dutch standard prices were derived from the Z-index. The use of Z-index prices enhances the comparability of study results (11). The visits before the initiation of the study were not taken into account in the cost analysis.

The price level used was that of the year 2002, and costs were assessed in Euros. Since the two treatment periods did not exceed one year, costs were not discounted. All costs were aggregated to the total treatment period of 8 months. When no information was available on a specific cost category, or when costs for one or more visits were unknown, with regard to used materials and accessories, it was assumed no costs were made in that period. Regarding the costs of visits to health care professionals, 87 patients (almost 40 %) were included in the cost analysis that had one or more report forms completed, no visits were included when it was not possible to obtain the right date and so the right period of treatment.

Results

Demographic data

272 individuals were enrolled and randomised for the study. 31 Subjects (15 in group MDICSII, 16 in group CSII-MDI) withdrew during the first treatment phase. 12 subjects completed phase one (2 in group MDI-CSII, 10 in group CSII-MDI) but did not cross over to the second treatment phase. 6 subjects withdrew during phase two (3 in group MDI-CSII, 3 in group CSII-MDI). 223 subjects completed the study. The total duration of both treatment 81

phases (including the run-in periods) was 145.7 patient years for MDI and 151.7 patient years for CSII. Principal baseline characteristics of the study population are shown in table 1. There were no significant differences in respect to patients' characteristics, concomitant diseases or medications.

Table 1. Baseline population characteristics (data expressed as mean ± SD). Group MDI-CSII

Group CSII-MDI

Number

129

127

Sex (F/M)

69/60

66/61

Age (years)

37 ± 10.6

35.3 ± 9.8

BMI (kg/m2)

24.8 ± 3.4

24.9 ± 3.3

Duration of diabetes (years)

15.4 ± 10.1

14.4 ± 8.9

Duration of MDI (years)

8.1 ± 6.2

7.6 ± 4.3

C-peptide (nmol/L)

0.10 ± 0.11

0.11 ± 0.10

Total daily insulin usage (I.U.)

50.8 ± 18.5

53.4 ± 21.4

The results on efficacy of CSII compared to MDI in the 5-nations trial have been published in detail (7). In summary, CSII treatment resulted in lower HbA1c (7.45% vs. 7.67%, p350 mg/dL), without an apparent medical, dietary, insulin dosing or pump failure cause were also noted. Symptomatic, nocturnal and severe symptomatic hypoglycaemia were all monitored in this study. Severe hypoglycaemia was defined as an event with clinical symptoms resulting from hypoglycaemia that required assistance from another person, confirmed by blood glucose 7.0% with CSII were randomized to CIPII or CSII. The aim was to obtain the best possible blood glucose while avoiding hypoglycemias. Results The frequency of all hypoglycemias was similar (CIPII 118.2 (SD 82.61) events / patient year, CSII 115.8 (SD 75.70) p = 0.910). The incidence of severe hypoglycemias with CSII was more than twice the one with CIPII (CIPII 34.83 events / 100 patient years, CSII 86.14, p = 0.013). HbA1c, mean blood glucose, and glucose fluctuations were not statistically different. Treatment-related severe complications occurred mainly during CIPII: port infections (0.47 events / patient year), abdominal pain (0.21 events / patient year), insulin underdelivery (0.14 events / patient year). Weight gain was greater with CSII (+1.5 kg vs. –0.1 kg, p = 0.013), quality of life better with CIPII. Conclusions In type 1 diabetes unsuccessfully treated by CSII, CIPII with DiaPort can improve severe hypoglycemias, quality of life, and body weight. Because of potential complications, indications for CIPII must be strictly controlled. So CIPII with DiaPort is an alternative therapy when CSII is unsuccessful, and is currently an easily accessible way for intraperitoneal insulin therapy. 108

Introduction To reach the goal of near-normal glycemia aiming at an effective prevention of micro- and macrovascular complications (1,2) without increasing the frequency of hypoglycemia is a key-challenge in the treatment of type 1 diabetes. Fulfillment of these combined objectives seems to be crucial for a true improvement of diabetes related quality of life (3). Current insulin therapy using multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) may approach this goal, but cannot reach it. In routine clinical practice, an average HbA1c level of 7.3 % has been reported at best with a rate of severe hypoglycemias of 16 per 100 patient years (4). Better results than with MDI have been demonstrated with CSII, the current gold standard for subcutaneous insulin therapies (5). But even with CSII the best average HbA1c in routine clinical practice has been reported as 7.2 % with 12 severe hypoglycemias per 100 patient years (6). Recent data obtained with fast-acting insulin analogues using MDI or CSII managed to show closer approach to normal HbA1c, improvements in hypoglycemic events and blood glucose stability (7,8,9), while experiences with long-acting insulin analogues reported improved stability and less frequent nocturnal hypoglycemias, but rarely significant and relevant improvement of HbA1c results (10, 11, 12).

Further reduction of hypoglycemias is desirable (13), therefore alternatives to the subcutaneous delivery of insulin have to be implemented. Continuous intraperitoneal insulin infusion (CIPII) allows a more physiological substitution of insulin. Peripheral hyperinsulinemia and long acting subcutaneous insulin depots can be avoided. Schade (14) could demonstrate near-physiological insulin kinetics with CIPII. Selam (15) elegantly showed advantages in hypoglycemia counter regulation. Long-term studies with CIPII using implantable pumps (16, 17, 18) reported low rates of severe hypoglycemias (2 – 4 per 100 patient years), good HbA1c results (6.8 – 7.5%) and reduced blood glucose fluctuations. However there are a number of eventual adverse events associated with implantable pumps: pump pocket complications (19), catheter obstructions or encapsulations in the peritoneal cavity (20), and underdelivery of insulin due to insulin aggregations in the pumps (21). These complications seemed to have decreased in the recent years, but there are still problems with the physical stability in pumps of highly concentrated insulins as required for implantable 109

pumps (22). Furthermore the filling procedure of an implanted pump is an invasive procedure which can be performed only by skilled personnel. Due to these problems the development of a percutaneous insulin port for CIPII which is connected to a common external insulin pump could be a solution. Simple repairs, exchange of batteries and refilling of insulin can easily be performed by the patients themselves. In case of catheter obstruction, the medication catheter can be exchanged through the guiding catheter in a simple procedure Recently an innovative percutaneous port system was developed, the DiaPort (Roche Diagnostics, Mannheim, Germany). A small titanium body is implanted into the subcutaneous tissue of the abdominal wall. An external handheld insulin pump is connected through a catheter with a ball canula. From the body of the port, insulin is infused into the abdominal cavity through a flexible medication catheter. The medication catheter runs within a guiding catheter and can easily be exchanged in case of catheter obstruction. The DiaPort is smaller than the ports used before, and both biocompatibility of material and design have been improved which results in easier handling. An optimized catheter design also facilitates the exchange of obstructed medication catheters. The intention of this study - the DiaPort Study - was to investigate the frequency of severe and non-severe hypoglycemias, blood glucose control, quality of life and safety of CIPII with DiaPort. In this open, randomized, controlled, cross-over, multinational long-term study in type 1 diabetic patients, CIPII using regular insulin was compared to CSII using the short acting insulin analogue Lispro.

Research Design and Methods The DiaPort Study was conducted in 11 European study centers in the Netherlands, France, Germany, Austria and Switzerland. A list of all participating investigators is given in the appendix. 62 patients were recruited, 61 randomized, and 60 actually took part in the study. The study protocol was approved by the respective local Ethics Committees. Written informed consent was obtained from each participating patient before recruitment.

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Objectives The primary endpoint of the study was the frequency of hypoglycemias (defined as blood glucose below 54 mg/dl (3 mmol/l)) per patient year with CIPII using DiaPort in comparison to CSII with insulin Lispro. Secondary endpoints were frequency of severe hypoglycemias (defined by hospitalization, unconsciousness, seizures or intravenous glucose administration), metabolic control (HbA1c, blood glucose, blood glucose fluctuations), quality of life (DQoL (23, 24)), and safety of CIPII with DiaPort in comparison to CSII.

Study Design An open, randomized, controlled, cross-over, multinational study design was used. Due to the high drop out rate in this study, efficacy results were analyzed as a comparison of two parallel groups (CIPII group 12 months, CSII group 6 months) based on the results of the first treatment periods before the cross-over. In order to secure complete assessment of all possible complications, safety results were analyzed by type of treatment including the periods after cross-over. Patients were randomized 1:1 into two groups: The CIPII Group was treated with continuous intraperitoneal insulin infusion through DiaPorts for 12 months, the CSII group with continuous subcutaneous insulin infusion using insulin Lispro for 6 months. A longer observation period for the CIPII group was chosen because the establishment of a stable therapy after the surgical implantation of the port takes time, whereas patients in the CSII group had already been on established long-term CSII before the study. A scheme of the study design is presented in figure 1.

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Patients enrolled N = 62 Not randomized N =1 Group CIPII/ Æ CSII

Group CSII Æ CIPII Not treated N=1

Period I: CIPII Group N = 30

Period I: CSII Group N = 30

Withdrawn N = 10

Withdrawn N=4 Period I completed N = 20

Period I completed N = 26

Cross over

No cross over N=5 Period II: CSII Group N = 15

No cross over N=4 Period II: CIPII Group N = 22

Withdrawn N=3

Withdrawn N=9 Period II completed N = 12

Period II completed N = 13

Figure 1 - Study Design of the DiaPort study. Inclusion Criteria Male or female patients at least 18 years of age with type 1 diabetes unsuccessfully treated with CSII (i.e. frequent hypoglycemias according to the assessment of the investigator and/or HbA1c above 7.0%). Exclusion Criteria Main exclusion criteria were: lack of cooperation or of mental capacity, pregnancy or wish for pregnancy, abuse of alcohol or drugs, lack of personal hygiene, frequent change of treating physicians, severe liver disease, current malignant disease, HIV infection, continuous ambulatory peritoneal dialysis, contraindications for anesthesia or surgical operations, severe eating disorders, severe psychological or psychiatric disorders, and lack of willingness to perform at least 4 blood glucose self measurements per day.

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Treatment Patients in the CSII group continued their CSII using insulin Lispro. Patients in the CIPII group had an implantation of a percutaneous DiaPort system under general anesthesia. The catheter was placed into the peritoneal cavity. The exact localization of the DiaPort was chosen individually according to the regular habits and clothing of the patients. Mostly the port was implanted into the lower right or left quadrant of the abdomen. CSII was terminated, and the insulin pump was connected to the DiaPort. The insulin dosage was optimized during the stay in hospital and at each visit. In both treatment groups, the target was to obtain fasting and preprandial blood glucose values between 80 – 120 mg/dl, and average blood glucose values below 150 mg/dl, while avoiding hypoglycemias at the same time. In both groups H-TRONplus insulin pumps from Roche Diagnostics were used. For intraperitoneal infusion only regular insulin for pumps (Insuman Infusat® or H-tronin®, Aventis®) was administered. In both groups, there were regular evaluations of diabetes complications, vital parameters, HbA1c, safety laboratory data (one central laboratory for all study sites), abdominal ultrasound examination, quality of life (using the “Diabetes Quality of Life Measure” DQoL (23)), port-related complications, and photographic documentation. The patients performed and documented at least 4 blood glucose self measurements daily (prior to each main meal and just before bedtime). Before visits, additional measurements (two hours after each meal and during night time between 2:00 and 3:00 a.m.) were performed. Statistical Analysis All data analyses and statistical testing were performed using SAS procedures (release 8.2). Continuous variables were tested using t-tests, or in case of non-normal distribution using Wilcoxon tests. Discrete variables were tested using Chi-square statistics or Fisher’s exact test. Statistical tests were two-sided and considered statistically significant if p ≤ 0.05. Tests were 113

based on mean values at the end of the first parallel study periods, i.e. after 12 months in the CIPII group and after 6 months in the CSII group. The primary analyses were carried out based on the intent-to-treat population (ITT analysis). In order to secure complete assessment of all possible complications, safety results were analyzed by type of treatment including the periods after cross-over. The mean frequency of hypoglycemias per year (rate) was calculated as the number of hypoglycemias in the relevant period, divided by the number of days in the relevant period, multiplied by 365 days. Due to the fact that most patients had no severe hypoglycemias and the resulting multitude of tied values, for severe hypoglycemic events an analysis employing incidences and the incidence ratio (IR) was performed. Incidence was defined as the sum of severe hypoglycemias in the relevant period, divided by patient years in the relevant period. IR is the incidence for CSII, divided by the incidence for CIPII. Blood glucose fluctuation was expressed by the standard deviation (SD) of the mean blood glucose of self measurements. The Diabetes Quality of Life Questionnaire DQoL (23) contained 46 core items rated by the respondent on a 5-point Likert scale. Five scores (satisfaction with treatment, impact of treatment, worry about social/vocational issues, worry about diabetes related issues, and overall diabetes quality of life) were calculated (24) and compared between the two treatments (t-test).

Results Baseline characteristics A total of 60 Caucasian patients were randomized to the CIPII group (n=30) and to the CSII group (n=30). The baseline data of the two groups were not significantly different: 43% in the CIPII group and 73% in the CSII group were male, mean age was 45.3 (SD 11.7) years and 50.5 (SD 10.8) years, with a duration of diabetes of 25.1 (SD 13.2) and 26.3 (SD 13.8) years 114

respectively. Mean BMI in the CIPII group was 25.0 (SD 3.6) and in the CSII group 25.0 (SD 4.0) kg/m², daily insulin requirement was 44.2 (SD 16.6) and 46.0 (SD 23.6) I.U. per day, mean HbA1c was 8.3% (SD 1.2) with 0.7 (SD 2.1) severe hypoglycemias in the previous year, and 8.2% (SD 1.3) with 1.6 (3.2) severe hypoglycemias in the previous year respectively. Hypoglycemias The frequency of all documented hypoglycemias in the CIPII group was 118.2 (SD 82.61) events per patient year, in the CSII group 115.8 (SD 75.70) events per patient year. The observed difference was not statistically significant (p = 0.910, t-test). A trend towards a reduction in hypoglycemias with CIPII after the initial titration phase was observed: mean frequency with CIPII in month 1-3: 138.1 (SD 86.33), in month 4-12: 108.9 (SD 92.17). The incidence of severe hypoglycemias in the CSII group was more than twice the one in the CIPII group (figure 2), with the difference being statistically significant (incidence ratio = 2.47, confidence interval 1.11-5.5, p=0.013). Similar to the analysis of all hypoglycemias, the frequency of severe hypoglycemia with CIPII was much higher during the initial healing and titration phase in month 1-3: 72.42 (SD 206.25) events per 100 patient years, than during the stable therapy months 4-12: 15.59 (SD

per 100 patient years

Incidence of severe hypoglycemias

58.69) events per 100 patient years.

10 9 8 7 6 5 4 3 2 1

0 0 0 0 0 0 0 0 0 0 0

8 6 ,1 4

3 4 ,8 3

C IP II

C S II

Figure 2– Incidence of severe hypoglycemias per 100 patient years in patients with type 1 diabetes treated by continuous intraperitoneal insulin infusion (CIPII) or continuous subcutaneous insulin infusion (CSII) during the study 115

Quality of Glycemic Control In both groups there were similar improvements in HbA1c levels at the end of the study periods (CIPII group -0.5%, CSII group -0.6%; p = 0.374, t-test for differences between absolute values at end of treatment (EOT)). Similarly there were no significant differences between the mean blood glucose of the two groups: relative to baseline, mean self measurement blood glucose increased in the CIPII group +0.1 mmol/l (SD 2.13), in the CSII group 0.0 mmol/l (SD 1.35); p = 0.723, t-test for differences between absolute values at EOT). Fluctuations of blood glucose (expressed by the SD of self measured glucose values) were similar in both groups (at end of treatment SD 4.0 in CIPII, SD 4.3 in CSII). Quality of Life The five DQol scores (treatment satisfaction, treatment impact, social/vocational worries, diabetes related worries, and overall score) at the beginning of the study were well balanced between the two groups. All scores in both groups showed slight non-significant improvements in the course of the study, only treatment impact worsened non-significantly with CSII. Substantial improvements in quality of life from baseline to the end of treatment were detected in the CIPII group for treatment impact (DQol score improved from 65.0 to 68.1, p=0.016), as well as for the overall diabetes quality of life score (DQol score improved from 68.9 to 71.4, p=0,033). In the CSII group only an improvement of social/vocational worries was seen (DQol score improved from 81.0 to 85.6, p=0.041).

Safety and Complications Treatment-related complications occurred mainly during CIPII. 81% of all complications in the CIPII group were classified as “mild” or “moderate” by the investigators. Most frequent severe complications were local infections or inflammations around the implanted ports (0.47 events per patient year). Severe abdominal pain was reported with a frequency of 0.21 events per patient year, and severe insulin underdelivery (catheter obstruction or encapsulation by intraperitoneal tissue overgrowth) with 0.14 events per patient year.

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Of note, patients with port-related complications presented with higher mean HbA1c at study start (HbA1c 8.6%) than patients without complications (HbA1c 7.7%). The drop-out rate was higher during CIPII than during CSII treatment. 10 patients discontinued the study during CIPII (8 because of adverse events), and 4 patients during CSII (1 because of an adverse event). However, it has to be taken into consideration that the observation period for CSII was only half of the CIPII period. [for safety issues, both periods before and after cross-over are to be considered] Within the first 12 months observation period in the CIPII group mean body weight stayed constant (- 0.1 kg), whereas there was a significant increase within the first 6 month period in the CSII group (+ 1.5 kg, p = 0.013, paired t-test). There was a slight increase in anti-insulin antibody-levels in the CIPII group without clinical effects. All other parameters of safety laboratory, vital signs and diabetes-related complications were comparable in the two groups.

Conclusions

This open, randomized, controlled, cross-over, multinational study - the DiaPort Study - was performed to investigate differences between CIPII using regular insulin via DiaPort and CSII using insulin Lispro in patients poorly controlled by CSII. The frequency of all hypoglycemic events, which was the first end-point of the study, was not significantly different during the time periods while patients use CSII or CIPII as first allocated treatment. Of note, after the initial postoperative period a tendency for reduction of hypoglycemias with CIPII was observed: the frequency in the months 4-12 being lower than with CSII. Possibly due to a high rate of hypoglycemias in the first 3 months after the implantation of the ports, there was no significant difference between the groups for the whole study period. The lack of defined post-meal blood glucose targets may also play a role in the incidence of hypoglycemia during the study (25): forced titration to strict postprandial targets could have been in favour of CIPII as to the incidence of hypoglycemias.

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In accordance with the results for implantable insulin pumps (16, 17, 18) there was a significant reduction of severe hypoglycemias with CIPII using DiaPort. The incidence of severe hypoglycemias with CIPII was less than half of the incidence with CSII. Still there was a relatively high absolute number of severe hypoglycemias in patients with CIPII. This may be explained by the fact that the inclusion criteria lead to select a study population which was prone to hypoglycemias. The quality of glycemic control assessed by HbA1c, blood glucose and glucose fluctuations was similar in both groups. Since hypoglycemias contribute to lower HbA1c, analysis of this lack of difference in HbA1c is in favor of CIPII: with same HbA1c there was a dramatic reduction in severe hypoglycemias with CIPII The most important port-related complications were infections and inflammations around the ports, more than abdominal pain, and insulin underdelivery because of catheter obstruction or encapsulation. However, there seems to be a potential for patient selection, education and prophylactic procedures as suggested by more favorable data currently obtained in post-study clinical practice (26), in order to prevent port-related infections. Patients with higher HbA1c values before implantation had a greater risk for the development of complications. So HbA1c may be a prognostic tool for the identification of patients at risk for port-related complications, and in need of special education and follow-up. There was a relevant advantage of CIPII with DiaPort concerning body weight. This is an important aspect which will not only affect quality of life. Patients with type 1 diabetes who gain weight may be more exposed to vascular complications (2, 27). The reason for the more favorable evolution of body weight with CIPII using DiaPort is unclear. Reduced number of severe hypoglycemias resulting in less calorie intake might be one possible reason. Another important issue may be the physiological distribution of insulin in the body with CIPII: peripheral insulinemia is lower which may have lead to less weight gain (25, 28). A similar phenomenon has been shown with implantable pumps in type 2 diabetic patients (29). In spite of port-related complications, quality of life for patients with DiaPort was at least equivalent to CSII. The impact of treatment and the overall diabetes quality of life score were even significantly better with CIPII than withCSII.

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The results of this study might help to define the patients who may gain benefit from CIPII: CIPII with DiaPort seems to be especially advantageous for patients treated by CSII with recurrent severe hypoglycemias, which is often seen in patients with impaired awareness of hypoglycemia. Patients with documented defects or unexplained variations in the absorption of insulin from the subcutaneous tissue while using CSII might likely be the best candidates. Patients with identified defects of subcutaneous insulin absorption could not be included in this study because it would have been unethical to randomize them into the CSII arm. There are no studies with a direct comparison of DiaPort and implantable pumps, and up to now there is also no randomized, controlled, long-term study on implantable pumps compared to CSII using short acting insulin analogues (30). The initial costs (port and external pump versus implantable pump) as well as the ever lasting problems with U400 insulin required for implantable pumps could at least argue in favor of port therapy.

In conclusion, it has been shown in this study that, in type 1 diabetes unsuccessfully treated by CSII, CIPII with DiaPort can improve results with regard to severe hypoglycemias and might have advantages over CSII regarding body weight and quality of life. Because of potential complications, mainly at implantation site, indications for CIPII must however be strictly controlled. So CIPII with DiaPort could be considered as a valuable alternative therapy when CSII cannot reach the metabolic goals in type 1 diabetes, and appears currently as an easily accessible way for intraperitoneal insulin therapy for selected and difficult-tomanage patients.

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Appendix Participating Members of the European DiaPort Study Group: Liebl Andreas, Diabetes-und Stoffwechselzentrum, Bad Heilbrunn, Germany; Irsigler Karl, Ludwig Boltzmann Institute for Metabolic Diseases and Nutrition, Wien-Lainz, Austria; Diglas Josef, Wiener Gebietskrankenkasse, Wien-Lainz, Austria; Pinget Michel, Hôpital Civil, Strasbourg, France; Bringer Jacques, Hôpital Lapeyronie, Montpellier, France; Brun JeanMarcel, Hôpital du Bocage, Dijon, France; Fontaine Pierre, Clinique Marc Linquette, U.S.N.A., Lille, France; Hanaire Hélène, Hôpital de Rangueil, Toulouse, France; LassmannVague Véronique, Hôpital d'Adultes de la Timone, Marseille, France; Renard Eric, Hôpital Lapeyronie, Montpellier, France; Apostol Dominique, Hôpital Lapeyronie, Montpellier, France; Fermon Catherine, Clinique Marc Linquette U.S.N.A., Lille, France; Kessler Laurence, Hôpital Civil, Strasbourg, France; Melki Vincent, Hôpital de Rangueil, Toulouse, France; Schaepelynck-Bélicar Pauline, Hôpital d'Adultes de la Timone, Marseille, France; Klein Eberhard, Herz- und Diabeteszentrum, Bad Oeynhausen, Germany; Helferich Thomas, Städt. Krankenh. München-Bogenh., Munich Germany; Volkery Carsten, Herz- und Diabeteszentrum, Minden, Germany; Hoogma Roel, Groene Hart Ziekenhuis, Gouda, The Netherlands; Geelhoed-Duijvestijn P.H.L.M., Medisch Centrum Haaglanden, Den Haag, The Netherlands; Diem Peter, Inselspital, Bern, Switzerland; Krinelke Lars, Disetronic Medical Systems AG, Burgdorf, Switzerland; Frei Thomas, Disetronic Medical Systems AG, Burgdorf Switzerland.

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Muller UA, Femerling M, Reinauer KM, Risse A, Voss M, Jorgens V, Berger M, Muhlhauser I: Intensified treatment and education of type 1 diabetes as clinical routine. A nationwide quality-circle experience in Germany. ASD. Diabetes Care 1999;22 suppl 2: B29-B34

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with the short-acting insulin analog lispro in variable combination with NPH insulin at mealtime. Diabetes Care 1999;22:468-477 8

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Melki V, Renard E, Lassmann-Vague V, Boivin S, Guerci B, Hanaire-Broutin H, Bringer J, Belicar P, Jeandidier N, Meyer L, Blin P, Augendre-Ferrante B, Tauber JP: Improvementof HbA1c and blood glucose stability in IDDM patients treated with lispro insulin analog in external pumps. Diabetes Care 1998;21: 977-982

10 Ratner RE, Hirsch IB, Neifing JL, Garg SK, Mecca TE, Wilson CA: Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. U.S. Study Group of Insulin Glargine in Type 1 Diabetes. Diabetes Care 2000;23:639-643 11 Vague P, Selam JL, Skeie S, De Leeuw I, Elte JW, Haahr H, Kristensen A, Draeger E: Insulin detemir is associated with more predictable glycemic control and reduced risk of hypoglycemia than NPH insulin in patients with type 1 diabetes on a basal-bolus regimen with premeal insulin aspart. Diabetes Care 2003;26:590-596 12 Porcellati F, Rossetti P, Pampanelli S, Fanelli CG, Torlone E, Scionti L, Perriello G, Bolli GB: Better long-term glycaemic control with the basal insulin glargine as compared with NPH in patients with Type 1 diabetes mellitus given meal-time lispro insulin. Diabet Med 2004;21:1213-1220 13 Bolli GB: How to ameliorate the problem of hypoglycemia in intensive as well as nonintensive treatment of type 1 diabetes. Diabetes Care 1999;22 (suppl. 2): B43-B52

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15 Selam JL, Medlej R, M’Bemba J, Chevalier A, Guyon F, Ashworth L, Slama G : Hypoglycemic counterregulation with Intraperitoneal vs. peripheral insulin administration. Diabetologia 1994;37 (suppl. 1): A66

16 Broussolle C, Jandidier N, Hanaire-Broutin H: French multicentre experience of implantable insulin pumps. Lancet 1994;343: 514-515

17 Dunn FL, Nathan DM, Scavini M, Selam JL, Wingrove TG: Long-term therapy of IDDM with an implantable insulin pump. The Implantable Insulin Pump Trial Study Group. Diabetes Care 1997;20: 59-63

18 Hanaire-Broutin H, Broussolle C, Jeandidier N, Renard E, Guerci B, Haardt M, Lassmann-Vague V : Feasibility of intraperitoneal insulin therapy with programmable implantable umps in IDDM. A multicenter study. The EVADIAC Study Group. Diabetes Care 1995;18: 388-392

19 Belicar P, Lassmann-Vague V: Local adverse events associated with long-term treatment by implantable insulin pumps. The French EVADIAC Study Group experience. Diabetes Care 1998;21: 325-326

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20 Renard E, Baldet P, Picot MC, Jacques-Apostol D, Lauton D, Costalat G, Bringer J, Jaffiol C: Catheter complications with implantable systems for peritoneal insulin delivery. An analysis of frequency, predisposing factors and obstructing materials. Diabetes Care 1995;18 : 300-306

21 Renard E, Bouteleau S, Jacques-Apostol D, Lauton D, Boulet-Gibert F, Costalat G, Bringer J, Jaffiol C. Insulin under delivery from implanted pumps using peritoneal route : determinant role of insulin-pump compatibility. Diabetes Care 1996;19: 812-817

22 Gin H, Renard E, Melki V, Boivin S, Schaepelynck-Belicar P, Guerci B, Selam JL, Brun JM, Riveline JP, Estour B, Catargi B; EVADIAC Study Group: Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience. Diabetes Metab.2003;29:602-607

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24 Ware, J. E., K. K. Snow: SF-36 Health Survey: Manual and Interpretation Guide. Boston Massachusetts, 1993

25 Nathan DM, Dunn FL, Bruch J, McKitrick C, Larkin M, Haggan C, Lavin-Tompkins J, Norman D, Simon D: Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive

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CHAPTER NINE Summary

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The beneficial effect of improved glycemic control in patients with diabetes mellitus was demonstrated already in the 1970’s by Pirart (1). These data were confirmed in type 1 diabetes mellitus in the DCCT and EDIC (2,3) and the study by Reichard (4). However one of the problems in the DCCT was the high frequency of hypoglycaemias, which were inversely related to the decrease in HbA1c. Continuous subcutaneous insulin infusion (CSII) is an alternative to a regimen consisting of multiple daily injections (MDI) with insulin for optimizing glycemic control in type 1 diabetes. However, as described in the introduction of this thesis (chapter one), a lot of questions remain regarding the benefits of CSII in comparison with multiple daily injections (MDI) treatment in type 1 diabetic patients. Recent meta-analyses (5,6,8) demonstrated that a reduction of the HbA1c with 0,5 %, near normal blood glucose levels with less fluctuations and less hypoglycaemias could be achieved with CSII, as well as a 20 – 25 % reduction in insulin requirement. However, data concerning the benefits in quality of life in these studies are lacking.

In Chapter 2 we describe the clinical benefits of CSII therapy in some patients, who were previously treated otherwise without a good quality of diabetes control. However, one patient did not show any benefit of CSII therapy, which demonstrates again that there are some problems in the treatment of diabetic patients which cannot be resolved by CSII therapy.

In Chapter 3 of this thesis we demonstrated, although by a retrospective analysis, that the patients who were treated by CSII have the same quality of life in comparison to patients treated by MDI. A remarkable finding in this study was the relatively low percentage of mental depression, being substantially lower than reported in recent studies.

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In the Five Nations study we compared in a randomised controlled fashion CSII using lispro with a NPH- and lispro based MDI regimen. In Chapter 4 the results of the various metabolic parameters are presented . A significantly lower HbA1c in the group treated by CSII was found, as well as a remarkable reduction in hypoglycaemias and less blood glucose fluctuations. In this trial CSII resulted in less insulin requirement and absence of increase in bodyweight, just as was shown in recent meta-analyses. No differences were found for other metabolic parameters, such as lipids, renal function and microalbuminuria. The trial did not show any benefit in diabetes-related complications, which is probably due to the limited duration of the study.

In Chapter 5 we present the results of the various aspects of QoL in diabetes type 1 patients in the Five Nations Study. The results demonstrated a significant better overall score for QoL in favour of CSII, in particular by increased treatment satisfaction, a reduced impact of diabetes on the QoL and less diabetes-related worry. Similar to the results in chapter 3, the score for depression and anxiety in this study was relatively low, which is in contrast with recent metaanalyses. The benefits of CSII treatment did not only result in a better QoL but also in an improved mental and physical health compared with MDI-treatment. In retrospective studies an improved flexibility in lifestyle in patients on CSII compared to MDI treatment was found. This is -as far as we know- the first study reporting an improved flexibility in lifestyle in a prospective fashion. Most of the reported benefits in QoL were related to an increased flexibility in eating and sleeping habits. Most of the patients at the start of this trial considered MDI as therapy of choice. At the end of the study however, the majority of the patients preferred CSII as their therapy of first choice.

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In Chapter 6 the results with respect to the costs of CSII vs. MDI treatment in type 1 diabetic patients are presented. As expected the costs of CSII are substantially higher than those of MDI. When we take into account the lower number of hypoglycaemias and the gain in QoL, these increments in costs may be considered acceptable. Compared with MDI treatment for CSII an extra investment to the amount of € 5486,- per 8 month is required to lower the HbA1c with one extra procent. Furthermore it was calculated that investments of € 463,- or € 9197,- per year have to be made to prevent one extra hypoglycaemia, or one extra severe hypoglycaemia respectively. An investment of € 313,50 will improve the DQol score with one extra point in patients on CSII compared to MDI. Taken together, we feel these costs may be worthwhile.

In Chapter 7 we present the results of a randomized trial comparing insulin glulisine and insulin aspart in CSII treated type 1 diabetic patients. No differences could be found between the two insulin analogues neither with respect to catheter related problems, nor metabolic adverse events.

In Chapter 8 we describe a multicenter multinational study, comparing CSII and continuous intraperitoneal insulin infusion (CIPII) in type 1 diabetic patients who were not well controlled by CSII. In this study no benefit could be obtained with respect to glycemic control as measured by HbA1c. However the number of hypoglycaemias was lower in the CIPII group and also a decrease in bodyweight was observed in this group. In this study CIPII was complicated by several catheter related adverse events, like tissue overgrowth and catheter obstructions, and frequent infections at the access site (port).

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References: 1. Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4400 patients observed between 1947 and 1973. Diabetes Care 1978; 1:168-88 2. The Diabetes Control and Complications Trial Research Group. The Effect of Intensive Treatment of Diabetes on the Development and Progression of LongTerm Complications in Insulin-Dependent Diabetes Mellitus. N Engl J Med 1993; 329:977-986 3. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes. N Engl J Med 2005;353:2643-2653 4. Reichard P, Nilsson BY, Rosenquist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med 1993; 329:304-09 5. Pickup J, Mattock M, Kerry S. Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials. BMJ 2002;324:1-6. 6. Weissberg-Benchell J, Antisdel-Lomaglio J, Seshadri R. Insulin Pump Therapy: A meta-analysis. Diabetes Care 2003;26:1079-87 7. The Diabetes Control and Complications Trial Research Group. Implementation of treatment protocols in the Diabetes Control and Complications Trial. Diab Care 1995; 18:361-76

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8. Retnakaran R, Hochman J, DeVries JH, Hanaire-Broutin H, Heine RJ, Melki V, Zinman B: Continuous subcutaneous insulin infusion versus multiple daily injections: the impact of baseline A1c. Diabetes Care 2004;27:2590–2596 9. Vries JH de. Will long acting insulin analogs influence the use of insulin pump therapy in type 1 diabetes? Curr Diab Rev 2005;1: 23-26

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CHAPTER TEN General discussion

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In this thesis various benefits of CSII therapy were confirmed and extended, but there remain some questions. A recent meta-analysis demonstrated that especially patients with a bad control of their diabetes would benefit of CSII therapy (8). Most of the studies included in this meta-analysis had a design different from the Five Nations trial and the question arises which other benefits could be found in our study in comparison with this meta-analysis. Previous studies have demonstrated a clear relation between QoL and HbA1c. But are the benefits in QoL only attributable to the lower HbA1c and can we predefine patients for whom CSII would be worthwhile? A pre-selection of patients is important considering the cost and the expected benefit of this therapy in individual subjects. With respect to the Five Nations trial we have to realize that diabetes care has progressed. Recently, new long-acting insulin analogues have been introduced, showing some benefit regarding the frequency of hypoglycaemias, although in general not leading to lower HbA1c values. Recently initiated trials comparing CSII and long-acting insulin analogue-based MDI regimens are not conclusive. We propose to perform a new randomized cross-over trial with a sufficient number of patients comparing CSII and MDI with a long-acting insulin analoguebased MDI therapy (9). As has been demonstrated in the choice of the short-acting insulin analogue is irrelevant. This thesis gives no answer on the question whether a possible reduction in costs for CSII is feasible in the long run, caused by a potential reduction in micro- and macrovascular complications. Long term follow up studies are needed to demonstrate potential benefits of CSII versus MDI, with respect to costs, metabolic control, complications, and QUALY’s. Apparently, a subgroup of patients that will not benefit from CSII therapy still remains. This non responsiveness may be caused by various reasons, most of which are unknown. Nevertheless, it is still desirable to obtain a better result of the metabolic control in these patients. CIPII treatment may be considered in this situation. This treatment strategy indeed

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resulted in a better outcome in some patients, who were not well controlled by MDI or CSII therapy. However one of the drawbacks of CIPII at present is the absence of randomized trials, for example comparing CSII versus CIPII or MDI versus CIPII. Another point of concern could be the costs of this therapy and the rather time-consuming nature of this treatment for the various healthcare providers, as well as the number of disturbing and threatening complications. Recently a new opportunity for CIPII, in which the implantable pump is replaced by a so called Diaport system has been introduced. Although in this thesis some benefits of this CIPII treatment were demonstrated, a number of questions remain, in particular related to the system itself. Therefore, it is necessary to perform more studies on CIPII and in particular using the Diaport system focusing on their efficacy and safety as well as quality of life aspects

In the early days of pump therapy, CSII was presumed to be indicated for all patients with a special need for tight glycemic control, including such conditions as prepregnancy, symptomatic neuropathy, microalbuminuria, progressive retinopathy, growth retardation (see table 1). Later some of the guidelines issued included also a wish for flexible life style and a high number of hypoglycaemias as well as hypoglycaemia unawareness. Considering the current guidelines, the studies which have been done and our own experience in this thesis, it is certainly worthwhile to offer every patient who has not achieved a optimal glycemic control a period of CSII therapy.

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Table 1: Patient selection criteria for insulin pump use __________________________________________________________________________ •

Medical/metabolic indications . suboptimal glycemic control . wide blood glucose excursions . dawn phenomenon with elevated fasting blood glucose levels . frequent severe hypoglycaemia . nocturnal hypoglycaemia . pregnant or planning conception . variable daily schedule not well managed with injections . complications



Technical/physical ability



Intellectual ability



Motivational ability



Financial resources

___________________________________________________________________________ A lot of patients will not achieve an optimal glycemic control, and those will need another treatment. Until recently CSII therapy was the treatment of choice, but due to the introduction of the new longacting insulin analogues, the patients will first try a MDI therapy consisting of the new longacting insulin analogues. However the studies which have been performed do not show any benefit for the longacting analogues regarding HbA1c levels. The only observed benefit in these studies were less hypoglycaemias during the night. Although some studies have been performed comparing CSII therapy to longacting analogue based MDI treatment, they are certainly not conclusive and show still a benefit for CSII therapy.

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So, in general, CSII therapy is indicated for those patients who lack a strict control of their diabetes despite a optimal mode of self management, who wish to become pregnant, for those with frequent or severe hypoglycaemias or hypoglycaemia unawareness, and finally for those who simply wish to try out CSII. In contrast to the current situation, a try out period of six months for any patient scheduled for CSII therapy would be preferable. After this six months both the patient and the diabetes team would be able to come to a conclusion regarding the benefits of CSII. By changing the reimbursement rules, for instance to allocate the scheduled CSII patients to special clinics and a try out period of six months, we may spare money from those patients who have no benefits after six months. One objection against special clinics could be a financial one, certainly when all patients having a suboptimal glycemic control would have the opportunity for getting CSII therapy. However, it would not be necessary that the patients would stay in this outpatient clinics. The patient could be screened, installed on an insulin pump and in case of optimal control, referred back to his own clinic. By doing so, the patient could have earlier the possibility of getting CSII therapy. Unfortunately we are not able to calculate the cost benefits for this kind of handling, but having a lot of experience in this field, I certainly believe that more patients should be offered CSII therapy. How to handle the patients who get no optimal glycemic control even by CSII therapy? In these cases it could be considered to refer the patient to specially qualified clinics. Problems related to education, selfmanagement and/or psychological should be ruled out these. Some patients might have insulin absorption related problems , however this certainly will be a minority. In case of insulin absorption problems, a try out with CIPII therapy could be

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considered for instance with a Diaport device. Would this therapy be successful, one could refer the patient to a special clinic for implantable pumps.

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CHAPTER ELEVEN Nederlandse Samenvatting

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Inleiding

Het aantal patiënten met een door middel van insuline gereguleerde diabetes neemt de laatste jaren om een aantal redenen toe. Allereerst is er een zekere toename in het voorkomen van diabetes mellitus type 1. Daarnaast is niet alleen het aantal mensen met diabetes type 2 sterk toegenomen, maar ook de groep die met insuline behandeld dient te worden om een optimale bloedglucose controle te krijgen neemt toe. Dit laatste berust op nieuwe inzichten over wat optimale regulatie inhoudt. Zowel gerandomiseerde onderzoeken als grote studies van groepen mensen met diabetes mellitus hebben aangetoond dat een goede controle van bloedglucose waarden gepaard gaat met een afname van het risico op microvasculaire en macrovasculaire complicaties, zoals retinopathie, neuropathie, nefropathie en macroangiopathie. Dit geldt zowel voor type 1 als type 2 diabetes. Om een zo goed mogelijke controle van de bloedglucose waarden te verkrijgen is een therapie bestaande uit meerdere insuline injecties per dag (MDI) of continue subcutane insuline infusie (CSII = insulinepomptherapie) zowel bij type 1 als type 2 diabetes veelal noodzakelijk, zoals onder andere is aangetoond in respectievelijk DCCT en UKPDS. Naast de meer flexibele levensstijl en insuline therapie die hiermee mogelijk is, kleeft er aan deze intensieve insuline therapie het nadeel van een toename in het aantal hypoglycemieën. In het geval van CSII behandeling zou er mogelijk een toename in het aantal hyperglycemieën en het voorkomen van ketoacidose optreden. Bij CSII wordt er naar gestreefd om het insulineafgifteprofiel zo fysiologisch mogelijk te maken. In het verleden werd hiervoor vooral gebruik gemaakt van kortwerkende insuline; tegenwoordig worden de meeste mensen behandeld met kortwerkende insuline analogen.

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In een meta-analyse is het risico op het ontwikkelen van een ketoacidose gedurende een behandeling bestaande uit intensieve versus conventionele therapie onderzocht. In de onderzoeken die hiervoor werden geselecteerd, waarbij mensen mochten kiezen uit MDI of CSII, leek er een toename van het aantal ketoacidotische gebeurtenissen te bestaan in de groep van mensen die met een intensieve therapie bestaande uit MDI of CSII werden behandeld, echter dit verschil was niet significant. In de gerandomiseerde onderzoeken met CSII werd wel echter een duidelijke toename in het risico op ketoacidotische ontregelingen tijdens CSII aangetoond. Hierbij dient wel aangetekend te worden dat het merendeel van deze onderzoeken voor 1992 plaatsvond, zodat deze resultaten voor een groot deel verklaard kunnen worden door technische problemen van toenmalige insuline pompen. Dit gaat vermoedelijk helemaal niet meer op voor de huidige pompen. Verschillende reviews aangaande CSII therapie laten over het algemeen een afname in het HbA1c van 0,5 % zien met in sommige studies ook minder hypoglycemieën. Verder komt uit deze studies naar voren dat er een afname van ongeveer 25 % in het gebruik van insuline optrad, waarbij het verschil in gewicht tussen de met MDI en CSII behandelde groepen geen duidelijk consistent beeld liet zien. Wat echter in een groot aantal studies ontbreekt zijn aspecten van kwaliteit van leven en de eventuele impact van dergelijke vormen van behandeling hierop. Sommige studies laten zien dat mensen aan het eind van het onderzoek de voorkeur geven aan CSII, terwijl andere onderzoeken dit juist tegenspreken. Er blijken geen studies te bestaan die kosten en kosteneffectiviteit van MDI en CSII hebben onderzocht. Daarentegen zijn er wel een aantal publicaties die op basis van economische modellen een berekening hebben gemaakt van de behandelingskosten voor diabetes type 1. CSII wordt door sommige patiënten aanbevolen vanwege de meer flexibele levensstijl die het hun oplevert en het meer flexibel kunnen managen van hun diabetes. Echter, vanwege de opzet van de tot op heden gepubliceerde onderzoeken is het onmogelijk om deze voordelen te

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vertalen in een economische analyse en uitkomst. Het is onmogelijk een berekening te maken van de kosten, omdat de uitkomsten aangaande de gezondheidsvoordelen ontbreken. Recent zijn er een aantal onderzoeken gepubliceerd die het effect van langwerkende insuline analogen vergeleken met NPH insuline tijdens MDI therapie; deze hebben tot op heden geen voordeel laten zien met betrekking tot het HbA1c. Echter, er kon bij gebruik van langwerkende analogen wel een afname van met name het aantal nachtelijke hypoglycemiëen aangetoond worden. Er blijven echter nog wel een aantal vragen onbeantwoord, zoals bijvoorbeeld het aantal injecties dat nodig is en het juiste tijdstip hiervan. De onderzoeken die tot op heden zijn uitgevoerd aangaande CSII versus een op langwerkende insuline analoog geschoeide MDI therapie zijn niet eenduidig. Echter, de meeste studies laten een voordeel voor CSII zien. De meeste studies die een vergelijking maken tussen kortwerkende insuline en kortwerkende insuline analogen en CSII therapie zijn uitgevoerd met lispro en aspart. Er lijken tussen de twee kortwerkende insuline analogen geen echte verschillen te bestaan, alhoewel er geen directe vergelijkingsstudies zijn gedaan. Ook voor deze kortwerkende insuline analogen lijkt er ten opzichte van de kortwerkende insulines aangaande de glycemische controle geen echte verschillen te bestaan; wel wordt er een daling in het aantal hypoglycemieën gezien bij gebruik van kortwerkende analogen.

Hoofdstuk 2 In dit hoofdstuk worden aan de hand van een klinische les een aantal patiënten besproken. Ondanks verschillende therapieën waren deze patiënten niet in staat een optimale diabetes regulatie te bereiken en zijn om die reden met CSII behandeld. Uit deze les wordt duidelijk dat niet bij iedere patiënt een optimale controle van de diabetes bewerkstelligd kan worden en dat sommige problemen niet zullen en kunnen worden opgelost door een behandeling met een

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insuline pomp. In de discussie wordt er een lans voor gebroken om in het geval van een niet goede diabetes regulatie de mogelijkheid open te houden om iemand op proef met een insuline pomp te behandelen.

Hoofdstuk 3 In dit hoofdstuk wordt een retrospectieve analyse beschreven aangaande de kwaliteit van leven van een groep patiënten die behandeld worden met CSII en MDI. Uit deze analyse blijkt geen verschil in de kwaliteit van leven bestaat tussen de twee patiënten groepen. Opmerkelijk is het lage percentage mensen met depressieve scores, iets wat geheel in tegenstrijd is met de huidige literatuur.

Hoofdstuk 4 In dit hoofdstuk wordt het resultaat behandeld van de Five Nations Study aangaande de verschillende metabole parameters. De Five Nations Study is een multicenter multinationale studie, waarbij type 1 diabetes patiënten werden behandeld in een gerandomiseerde crossover opzet of met MDI therapie bestaande uit lyspro en NPH-insuline, of met CSII therapie met lyspro. In de groep die behandeld werd met CSII trad een significante daling van het HbA1c met 0,23 % op. Dit ging gepaard met een daling van de gemiddelde bloedglucose waarde van 0,8 mmol/l en een afname van de fluctuaties in de bloedglucose waarden van 0,4 mmol/l. Eveneens trad er een significante daling van het aantal hypoglycemieën op, niet alleen van het totale aantal, maar ook van het aantal ernstige hypoglycemieën. Daarentegen werd er geen toename in het aantal ketoacidotische gebeurtenissen gevonden. Er werd een afname van 20% gezien in het gebruik van insuline gedurende CSII therapie en er was geen verschil in gewicht tussen de twee groepen. Andere metabole parameters, zoals lipidenspectrum, nierfunctie en microalbuminurie waren niet verschillend.

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Hoofdstuk 5 In dit hoofdstuk worden de verschillende aspecten aangaande de kwaliteit van leven besproken van de mensen met diabetes mellitus type 1 die participeerden in de Five Nations Study. De resultaten laten een significante verbetering zien in de totale score van QoL in het voordeel van CSII therapie. Met name scoren de mensen die behandeld worden met CSII beter in het domein van tevredenheid met de behandeling, een duidelijke afname in de impact van hun diabetes mellitus op de kwaliteit van leven en een afname in de zorgen die zij hebben over hun diabetes. Opmerkelijk was ook in deze studie, zoals ook al is beschreven in hoofdstuk 3, de lage score voor depressie en angst, wat in schril contrast staat tot de verschillende meta-analyses. De voordelen van CSII werden niet alleen gezien voor de QoL, maar ook in de geestelijke en lichamelijke gezondheid in vergelijking met die van de mensen die behandeld werden met MDI. Deze resultaten zijn niet eerder gepubliceerd in een prospectief gerandomiseerd onderzoek. De voordelen van CSII die het meest worden genoemd door de mensen die behandeld worden met CSII zijn een grotere flexibiliteit van eet- en slaapgewoontes. Alhoewel het merendeel van de patiënten aan het begin van de studie aangaf dat zij andere mensen met name MDI therapie zouden aanraden, was dit aan het einde van de studie opmerkelijk veranderd in een uitgesproken voorkeur voor CSII als eerste keuze van behandeling.

Hoofdstuk 6 In dit hoofdstuk worden de verschillende kostenaspecten van de Five Nations Study beschreven. Zoals te verwachten liggen de kosten voor een behandeling met CSII substantieel hoger dan die van MDI therapie. Echter, nemen wij daarbij in acht het lager aantal hypoglycemieën en de winst in QoL, kan deze toename in de kosten als acceptabel gezien worden. Wanneer men CSII vergelijkt met MDI, is er een extra investering van € 5486,-- per

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8 maanden nodig om het HbA1c met 1 % te doen verlagen. Om een hypoglycemie of ernstige hypoglycemie te voorkomen dient respectievelijk € 463,-- en € 9197,-- per jaar extra uit gegeven te worden. Voor het verbeteren van de QoL met een punt dient € 313,50 extra betaald te worden. Bedragen die natuurlijk substantieel zijn, maar in onze optiek zeker de moeite waard, met name ook in het licht van welke bedragen wij in Nederland voor een aantal andere gezondheidszaken bereid zijn uit te geven.

Hoofdstuk 7 Recent werd er een nieuw kortwerkend insuline analoog, glulisine, op de markt gebracht. In dit hoofdstuk geven wij de resultaten weer van een studie die werd verricht in een groep van type 1 diabetes patiënten die behandeld werden met CSII therapie. De mensen werden gerandomiseerd naar of insuline aspart of insuline glulisine. Een duidelijk verschil tussen de twee behandelingen kon niet worden aangetoond, alhoewel er wel een tendens bestond naar minder katheter gelieerde problemen in de groep die werd behandeld met insuline glulisine.

Hoofdstuk 8 Daar lang niet alle patiënten optimaal behandeld kunnen worden met CSII therapie, zoals wij ook in hoofdstuk 2 hebben beschreven, wordt de mogelijkheid van continue intraperitoneale insuline infusie (CIPII) in dit soort situaties nog wel eens overwogen. De indicaties voor deze vorm van behandeling zijn vooralsnog zeer beperkt. De beperkte toepassing wordt mede veroorzaakt door de hoge kosten en tijdsinvestering van de medische professionals die deze vorm van behandeling vergen. In dit hoofdstuk beschrijven wij een studie naar een nieuwe methode van intraperitoneale insulinetoediening. Deze nieuwe techniek bestaat uit een intraperitoneaal te implanteren catheter, die vervolgens verbonden wordt aan een externe insuline pomp; dit in tegenstelling tot de implanteerbare pomp, welke bestaat uit een

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intraperitoneaal gelegen catheter en verbonden is aan een subcutaan gelokaliseerde pomp. De patiënten die in deze studie werden geincludeerd waren allen al voor een langere tijd ingesteld op CSII therapie, maar hadden desondanks geen optimale glycemische controle. Er kon geen voordeel aangetoond worden aangaande de glycemische controle; daarentegen was het aantal hypoglycemieën in de groep welke behandeld werd met CIPII lager. Een opmerkelijk gegeven in deze studie was het gewichtsverlies wat in de met CIPII behandelde groep optrad. Een belangrijk nadeel van CIPII therapie met behulp van deze nieuwe techniek was het aantal catheter- en poort- gerelateerde complicaties.

In dit proefschrift worden de reeds eerder gemelde voordelen van CSII therapie bevestigd en uitgebreid, maar desondanks blijven er nog steeds een aantal vraagstukken over. Recent werd middels een meta-analyse gesuggereerd dat vooral patiënten met een slechte metabole controle een voordeel van CSII ondervinden. Echter, een groot aantal van de studies die in deze meta-analyse waren geincludeerd hadden een andere opzet dan de Five Nations Study en het is dan ook maar de vraag of uit een nadere analyse van deze studie een zelfde resultaat gevonden kan worden. Verschillende studies hebben in het verleden aangetoond dat er een relatie bestaat tussen de QoL en het HbA1c. De vraag is dan ook of de voordelen in de QoL alleen toegedicht kunnen worden aan de verbetering in het HbA1c. Indien dit het geval is, zijn wij dan in staat van te voren vast te stellen welke patiënten een voordeel aan een dergelijke vorm van behandeling zullen ondervinden? Vanuit het oogpunt van kosten zou het te prefereren zijn als men inderdaad in staat zou zijn deze patiënten tevoren te identificeren. Met betrekking tot de Five Nations Trial moeten wij ons realiseren dat de algemene behandeling van diabetes gedurende de looptijd van deze studie wel veranderd is. Zo werden recent de langwerkende insulineanalogen geïntroduceerd, die niet geassocieerd blijken met een verbetering in de HbA1c waarden ten opzichte van NPH-insuline, maar wel met een

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duidelijke afname in het aantal hypoglycemieën. De onderzoeken die CSII therapie vergelijken met MDI therapie gebruik makend van een langwerkend insuline analoog laten vooralsnog een voordeel zien voor CSII therapie. Zoals in dit proefschrift beschreven, is er geen voordeel te verwachten van een van de beschikbare kortwerkende insulineanalogen. Het is dus zeer wel mogelijk dat de soort langwerkende insuline analoog bepalend is. Helaas geeft dit proefschrift geen antwoord op de vraag of CSII therapie op de lange termijn een kostenreductie geeft die veroorzaakt zou kunnen worden door een potentiële daling in micro- en mogelijk ook macrovasculaire complicaties. Er lijkt behoefte te bestaan aan een lange termijn studie, waarin niet alleen de kosten, maar ook complicaties en QUALY’s van CSII- en MDI therapie met elkaar worden vergeleken. Niet alle patiënten hebben een voordeel bij CSII therapie. Toch is ook voor hen betere regulatie noodzakelijk; CIPII therapie zou voor hen een optie kunnen zijn. Alhoewel in de literatuur aanwijzingen bestaan dat mensen die ondanks MDI- of CSII therapie niet goed gereguleerd zijn, wel een verbetering kunnen bereiken met CIPII therapie, komt dat uit onze studie niet duidelijk naar voren. Dit kan gelegen zijn in de opzet van het onderzoek of in de gebruikte techniek. Met name het aantal aan de catheter gerelateerde complicaties kan debet zijn aan het matige resultaat. Er bestaat dan ook behoefte aan onderzoek waarbij deze CIPII techniek nader bestudeerd wordt. Daarnaast is direct vergelijkend onderzoek tussen CIPII en CSII gewenst.

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CHAPTER TWELVE Acknowledgements

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Dit proefschrift is tot stand gekomen dankzij de hulp en inspanning van velen. Het belangrijkst zijn in dat opzicht de patiënten geweest, die aan de verschillende onderzoeken hebben deelgenomen. Deelnemen aan een klinisch onderzoek kan voordelen hebben, maar is tegelijkertijd arbeidsintensief en tijdrovend. Hoewel het enthousiasme van de patiënten voor een deel te maken kan hebben met een verbeterde instelling van hun diabetes kan er ook een verbetering ontstaan van de kwaliteit van leven. Desondanks heb ik veel bewondering voor hun gemotiveerdheid, die nodig is om te beginnen aan een studie die meer dan 16 maanden in beslag neemt. Ik heb bewondering voor hun doorzettings-vermogen, om ondanks de vele tegenslagen die zij hebben ervaren, de studie tot een goed einde te brengen.

Een groot aantal diëtisten en diabetes verpleegkundigen dat aan deze studie verbonden was, van wie Anita Dijkhuizen en Ineke van Felius ons helaas hebben verlaten, wil ik bedanken voor de inzet en het enthousiasme waarmee zij aan het geheel hebben bijgedragen. Zonder jullie hulp was dit proefschrift zeker niet tot stand gekomen.

Prof.dr. M.M. Levi, beste Marcel, een ding staat voor mij heel duidelijk vast: je enorme enthousiasme en werkijver zijn ongekend. Een onderwerp dat niet jouw dagelijkse materie is maak je je zeer snel tot eigen. Je inzicht en werklust uiten zich dan ook, niet alleen in een zeer snelle correctie van de manuscripten, maar ook nog in goede en nuttige aanvullingen. Ook al was er inhoudelijk misschien niets op te merken, je weet het gewoon toch net iets eleganter te formuleren.

Prof.dr. J.B.L. Hoekstra, beste Joost, je bent een voorbeeld voor iedere internist met belangstelling voor de behandeling van mensen met diabetes mellitus. De manier waarop jij zaken nuchter en tot de basis terugbrengt, opent mij steeds weer de ogen. Je spelde de

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manuscripten tot op de komma en voorzag ze van beter geformuleerde zinnen; ik heb jouw bijdrage enorm gewaardeerd. Jouw steun die je mij met name in het laatste gedeelte van het werk hebt gegeven, zal ik niet vergeten.

Dr. R.P.J. Michels, beste Bob, wij kennen elkaar jaren hebben menige nascholing en cursus samen mogen doen. De werklust, de altijd aanwezige aantekeningen, de kritische en prikkelende vragen kenmerken jou en roepen tegelijkertijd bij mij de vraag op: waar haalt hij de energie en tijd vandaan? Dankzij jou, die vond dat het toch zeker mogelijk zou moeten zijn op dit onderzoek te promoveren, kwam ik bij Marcel en later ook Joost terecht. Door jouw toedoen zijn wij dan ook tot het resultaat gekomen dat nu voor je ligt, en waarin je zelf ook een belangrijk aandeel hebt gehad. Ik zal je hiervoor steeds dankbaar blijven en hoop dat onze contacten zullen blijven bestaan.

Dear Professor Bolli, Alessandro Pianta, Elisabetta Torlone, Daniela Bruttomesso, David Kerr, Peter Harrogate, Andreas Liebl, Eric Renard, and all other diabetologists, a multicentre trial is a tremendous job. I would like to thank all of you for your contributions to this thesis. My special thanks to Geremia Bolli, who did a lot of work behind the scenes, especially for making it possible to publish our results. It has been a great pleasure and an honour to work with you. I hope we can work together for a few more years. I like to thank especially the persons from the UK, the time you gave my wife and me such a pleasant stay during our visits to your hospitals. I would like to thank all the diabetes nurses and dieticians from the participating centres in the different studies. You did a wonderful job in bringing the study to an end. Without your support it would have not been possible to finish this thesis. I hope that you will remember the

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study itself and especially the enthusiasm of the patients instead of the boring visits which I made to look at the different case reports etc.

Kristine Kipfer, Lars Krinelke, Bram van Bergen, Sander Bos, Jaap Stuut; all working for Disetronic at the time of the trial; many thanks for your help and support, not only at the difficult start but also at the end of the trial, when we had to convince the others of the necessity to do the economical analysis. Nowadays when cooperation between industry and clinicians meets with lots of criticism, I believe that our cooperation was an good example how it should be. Tenslotte, wil ik Karin Vermeulen bedanken voor alle hulp en steun die zij mij heeft gegeven bij het tot stand komen van de economische paragraaf van het onderzoek. Ook al was het een eind van huis, het was altijd gezellig en leerzaam in Groningen. De overige leden van de leescommissie dank ik voor de moeite en tijd die zij besteed hebben aan het lezen van mijn proefschrift. Ik was zeer vereerd van Marcel te horen dat u allen graag deel wilde nemen aan deze commissie.

Medewerkers van het Groene Hart Ziekenhuis, met name de mensen van de apotheek en het klinisch chemisch laboratorium en vooral Jose Stindt; ook jullie wil ik bedanken voor de wijze waarop jullie alles mogelijk hebben gemaakt. Met name het steeds weer op tijd leveren van de materialen en het niet verloren doen gaan van bloedmonsters heb ik zeer gewaardeerd.

Collega internisten, vaak werd gevraagd waar die Hoogma nu weer was, of werd schertsend de naam Prof. Elders genoemd. Ik ben jullie allen dankbaar dat jullie mij mijn vakanties zelf heb laten invullen, zodat ik al het werk kon doen dat voor een dergelijk project nodig is. De komende tijd zullen jullie op dezelfde vraag als antwoord krijgen dat hij nu echt op vakantie 150

is. Hiermee is zeker niet gezegd dat ik de komende jaren afzie van dergelijke grote onderzoeken, maar dan wellicht als coördinator van arts-assistenten.

Collega specialisten uit het Groene Hart Ziekenhuis; ook jullie en met name de altijd aanwezige, vakbekwame Ben Kothuis, wil ik bedanken voor datgene wat jullie voor mij en de patiënten hebben gedaan. Hoewel ik soms wel eens wat te kritisch of humeurig was, hoop ik dat jullie mij dit vergeven. In ieder geval zijn er twee mensen, Koos Favier en Michael Helfferich, die mij altijd het vertrouwen hebben gegeven dat dit proefschrift tot een goed einde zou komen. Ik wil jullie dan ook hiervoor bedanken, en ook al is Koos niet meer in ons midden, ik ben er zeker van dat hij trots op mij zou zijn.

Dit dankwoord eindigt met de mensen met wie het uiteindelijk allemaal begon. Allereerst mijn beide overleden ouders, die het mij mogelijk hebben gemaakt om een dergelijke carrière te maken. Het is jammer en spijtig dat zij geen van beiden bij deze gebeurtenis aanwezig kunnen zijn, maar ik ben er zeker van dat zij het geweldig hadden gevonden. Ik hoop dan ook dat zij toch op een bepaalde wijze hiervan getuige mogen zijn. Natuurlijk zou dit alles niet mogelijk zijn geweest zonder het onuitputtelijke geduld en steun van Hendrien, Emile, Claire en Carlijn. Jullie zullen natuurlijk niet verwachten dat ik het nu rustiger aan zal gaan doen, maar ik zal zeker meer tijd voor jullie en de vakanties gaan reserveren.

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CHAPTER THIRTEEN List of Publications and Curriculum Vitae

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List of Publications:

1. P.W. de Leeuw; R.P.L.M. Hoogma: Humoral and renal effects of MK-421 (Enalapril) in hypertensive subjects. J. Cardiovasc.Pharmacol. 1983; 5:731-6 2. P.W. de Leeuw; R.P.L.M. Hoogma: Physiological effects of short-term treatment with MK- 421 in hypertensive patients. J. Hypertension 1983; 1:87-91 3. P.W. de Leeuw; R.P.L.M. Hoogma: Neurohumoral response to hospitalization in hypertensive patients. Clin Sci 1981; 61 Suppl 7:385s-387s 4. R.P.L.M. Hoogma; D. van der Heide: Amiodarone and thyroid function. Neth J Med 1990; 36:209-16 5. A.P.G. van Gils; A.G.L. van der Meij; R.P.L.M. Hoogma: Iodine-123Metaiodobenzylguanidine scintigraphy in patients with chemodectomas of the head and neck region. J. Nucl. Med.1990; 31: 1147-55 9. A.P.G. van Gils; T.H.M. Falke; A.R. van Erkel; J.W. Arndt; M.P. Sandler; A.G.L. van der Meij and R.P.L.M. Hoogma: MR Imaging and MIBG scintigraphy of pheochromocytomas and extraadrenal functioning paragangliomas. Radiographics 1991; 11:37-57 7. P.D. Maaswinkel-Mooij; T.H.M. Falke; E.K.J. Pauwels; R.P.L.M. Hoogma: MRIscreening of kindred at risk of developing paragangliomas: Support for genomic imprinting in hereditary glomus tumours. Br.J. Cancer 1992; 65:903-7 8. D.J. Kwekkeboom; H. van Urk; B.K.H. Pauw; S.W.J. Lamberts; P.P.M. Kooij; R.P.L.M. Hoogma; E.P. Krenning: Octreotidescintigraphy for the detection of paragangliomas. J Nucl Med 1993:873-8

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9. K. Holwerda; R.P.L.M. Hoogma; C. Oldenbroek; R.C. Huige;A. Wester; J.M.M. Rijnierse: Efficacy and safety of Benazepril plus Hydrochlorothiazide versus Benazepril alone in hypertensive patients unresponsive to Benazepril monotherapy. Clinical Therapeutics 1994:16;942-51 10. B.J. Looij jr; A.C. Nieuwenhuizen Kruseman; F Roelfsema; D. van der Heide; R.P.L.M. Hoogma; J.P. Schröder-van der Elst: The effect of GHRH on TSH release in rats in vivo and vitro. Journal of Endocrinological Investigation 1995:18;214-9 11. M.L. Jacobs; J.W.F. Elte; B.M. van Ouwerkerk; E.N.W. Janssens; C. Schop; J.A. Knoop; R.P.L.M. Hoogma; R. Groenendijk; R.F.A. Weber and The Studygroup Diabetes Rijnmond (SDR): Effect of BMI, insulin dose and number of injections on glycaemic control in insulin-using diabetic patients. Neth J Med.1997:50;153-9 12. M.M.J. Janssen; F.J. Snoek; N. Masurel; RPLM Hoogma; WL Devillé; C. PoppSnijders; R.J. Heine: Optimized basal-bolus therapy using a fixed mixture of 75% liispro and 25% NPL insulin in type 1 diabetes patients: no favorable effects on glycemic control, physiological reponses to hypoglycemia, well-being, or treatment satisfaction. Diabetes Care 2000; 23: 629-33 13. G Mancia; S Omboni; G Parati; DL Clement; WE Haley; SN Rahman; RPLM Hoogma: Twenty-four hour ambulatory blood pressure in the Hypertension Optimal Treatment (HOT) Study. J Hypertension 2001;19:1755-63 14. Roel PLM Hoogma, Anton JM Spijker, Margit van Doorn – Scheele, Titia T van Doorn, Robert PJ Michels, Rudi G van Doorn, Marcel Levi, Joost BL Hoekstra: Quality of life and Metabolic control in patients with diabetes mellitus type 1 treated by continuous subcutaneous insulin infusion or multiple daily insulin injections. Neth J Med 2004;62: 383-7

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15. RPLM Hoogma; JH de Vries; RPJ Michels; JBL Hoekstra; M Levi: Continue Subcutane Insuline Infusie soms goede optie bij slecht gereguleerde diabetes mellitus. NTVG 2005;149:2261-4 16. Marian J Muis, Michiel L Bots, Henk JG Bilo, Roel PLM Hoogma, Joost BL Hoekstra, Diederick E Grobbee, Ronald P Stolk: High cumulative insulin exposure: a risk factor of atherosclerosis in type 1 diabetes? Atherosclerosis 2005;181:185-9 17. Roel PLM Hoogma, P.J. P. J. Hammond, R. Gomis, D. Kerr, D. Bruttomesso, P. Bouter, K. J. Wiefels, H. de la Calle, D. H. Schweitzer, M. Pfohl, E. Torlone, L. G. Krinelke; on behalf of the 5-Nations Study Group: Comparison of continuous subcutaneous insulin infusion (CSII) vs. NPH-based multiple daily insulin injections (MDI) in regard to metabolic control and quality of life. Results of the 5-Nations trial. Diab Med 2006; 23: 141-147 18. A Augustina M.A. Brands, Roy P.C. Kessels, Roel P.L.M. Hoogma, Johanna M. L. Henselmans, Johanna W. van der Beek Boter, L. Jaap Kappelle; Edward H.F. de Haan, Geert Jan Biessels; Cognitive performance, psychological well-being and brain MRI in older patients with type 1 diabetes. Diabetes 2006; 55:1800-6 19. RPLM Hoogma, D Schumicki; Safety of insulin glulisine when given by subcutaneous infusion using an external pump in patents with type 1 diabetes. Homone and Metabolic Research 2006; 38:429-33

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Curriculum Vitae

De auteur van dit proefschrift werd geboren op 2 juni 1953 te Kerkrade. Hij behaalde in 1971 het HBS-B diploma aan het Laurens College te Rotterdam. Datzelfde jaar begon hij de studie geneeskunde aan de Universiteit van Rotterdam. Tijdens zijn studie was hij met name zeer aktief in het onderwijs. In 1980 behaalde hij het artsexamen. Aansluitend begon hij als artsassistent interne geneeskunde in het Zuiderziekenhuis (Prof. W.H. Birkenhager). In augustus 1985 werd hij als internist geregistreerd. Vanaf 1986 volgde hij de opleiding endocrinologie in het LUMC (Prof. H.M.J. Krans) en werd als endocrinoloog geregistreerd in mei 1989. Tijdens de opleiding in het LUMC werd gestart met een onderzoek naar het effect van amiodarone op het schildklier metabolisme. Sinds 1 oktober 1989 is hij werkzaam in het Groene Hart Ziekenhuis in Gouda, alwaar hij zich met name heeft toegelegd op de endocrinologie, vasculaire geneeskunde en diabeteszorg. In 1999 startte hij het multicenter multinationale onderzoek in Europa op en reisde hij tot en met 2004 alle centra af, om dit zo optimaal mogelijk en gelijkwaardig in de verschillende klinieken te laten verlopen. Tijdens deze jaren waren er ook regelmatig mensen van verschillende diabetesteams in het Groene Hart Ziekenhuis op bezoek. Uiteindelijk werd onder invloed van Bob Michels het mogelijk om samen met Marcel Levi en Joost Hoekstra, al dit werk om te zetten in dit proefschrift. Roel Hoogma is sinds 1993 samenwonend met Hendrien van der Mark. Roel heeft drie kinderen, waarvoor hij samen met Hendrien verantwoordelijk is.

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