Journey towardsCLOSING THE LOOP

paolo pozzilli

EDIZIONI MINERVA MEDICA

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ISBN: 978-88-7711-896-7

© 2017 – EDIZIONI MINERVA MEDICA S.p.A. – Corso Bramante 83/85 – 10126 Torinowww.minervamedica.it / e-mail: minervamedica@minervamedica.it

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Authors

Lia BaLLyWellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom; Department of Diabetes & Endocrinology, Cambridge University Hos-pitals NHS Foundation Trust, Cambridge, United Kingdom; Division of Diabetes, Endo-crinology, Clinical Nutrition & Metabolism, Inselspital, Bern University Hospital, Univer-sity of Bern, Bern, SwitzerlandTadej BaTTeLinoUniversity Children’s Hospital – UMC, Lju-bljana, Slovenia. Faculty of Medicine, Univer-sity of Ljubljana, SlovenianaTaša BraTinaUniversity Children’s Hospital – UMC, Lju-bljana, SloveniaraffaeLLa BuzzeTTiDepartment of Experimental Medicine, Uni-versity Sapienza, Rome, Italy aLessandro CappeLLiUnit of Endocrinology and Diabetes, Depart-ment of Medicine, University Campus Bio-Medico, Rome, ItalypraTik Choudhary MBBS MD FRCP, Senior Lecturer and consult-ant in diabetes, King’s College London, Lon-don, UK ohad CohenInstitute of Endocrinology, Chaim Sheba Med-ical Center, Tel Hashomer, IsraelThomas danneDiabetes Centre for Children and Adolescents, AUF DER BULT, Kinder- und Jugendkranken-haus, Hannover, Germany

anTonia de rosa Department of Internal Medicine, Diabetes Care Unit, Agostino Gemelli Hospital, Catho-lic University, Rome, Italyrosanna donviToDepartment of Emergency and Organ Trans-plantation, Section of Internal Medicine, Endo-crinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, ItalyfranCesCo GiorGinoDepartment of Emergency and Organ Trans-plantation, Section of Internal Medicine, Endo-crinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italyroman hovorkaWellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom; Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom przemysława jarosz-ChoBoTDepartment of Children’s Diabetology, Medical University of Silesia, Katowice, PolandTomasz kLupaDepartament of Metabolic Diseases, Unit on Advanced Technologies in Diabetes, Jagiellonian University Medical College, Kraków, PolandoLGa kordonouriDiabetes Centre for Children and Adolescents, AUF DER BULT, Kinder- und Jugendkranken-haus, Hannover, GermanyLuiGi LavioLaDepartment of Emergency and Organ Trans-plantation, Section of Internal Medicine, Endo-crinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy

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AuTHORSIV

anna riTa mauriziUnit of Endocrinology and Diabetes, Depart-ment of Medicine, University Campus Bio-Medico, Rome, ItalyChiara moreTTiDepartment of Experimental Medicine, Uni-versity Sapienza, Rome, Italy reviTaL nimriThe Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children’s Medical Center of Israel, Petah Tikva, Israelmoshe phiLLipThe Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children’s Medical Center of Israel, Petah Tikva, Israeljohn C. piCkupDiabetes Research Group, King’s College Lon-don, Faculty of Life Sciences and Medicine, Guy’s Hospital, London, UKdario piToCCoDepartment of Internal Medicine, Diabetes Care Unit, Agostino Gemelli Hospital, Catho-lic University, Rome, Italy

paoLo pozziLLi

Unit of Endocrinology and Diabetes, Depart-ment of Medicine, University Campus Bio-Medico, Rome, Italy

aLessandro rizzi

Department of Internal Medicine, Diabetes Care Unit, Agostino Gemelli Hospital, Catho-lic University, Rome, Italy

andreea soare

Unit of Endocrinology and Diabetes, Depart-ment of Medicine, University Campus Bio-Medico of Rome, Rome, Italy

jasna šupuT omLadič

University Children’s Hospital – UMC, Lju-bljana, Slovenia

hood ThaBiT

Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom; Department of Diabetes & Endocrinology, Cambridge University Hospi-tals NHS Foundation Trust, Cambridge, Unit-ed Kingdom

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AuTHORS

Contents

1. Preface ........................................................................................................................................ 1P. Pozzilli

2. A historical perspective on the use of insulin pump in diabetes management ....... 2O. Cohen, A. Cappelli, P. Pozzilli

3. Insulin pump therapy (CSII): overview, indications, clinical and economic outcomes and mortality reduction ........................................................................ 7John C. Pickup

4. Current guidelines on insulin pump therapy (CSII) and relevant regulatory aspects ........................................................................... 19T. Danne, O. Kordonouri, R. Nimri, M. Phillip

5. CSII in different special settings .......................................................................... 33A. Rizzi, A. De Rosa, D. Pitocco

6. Insulin pump therapy in type 2 diabetes ............................................................... 42A. R. Maurizi, P. Pozzilli

7. Real time CGM: current state of the art ............................................................... 49J. Šuput Omladič, N. Bratina, T. Battelino

8. Sensor Performance (MARD) ............................................................................... 57P. Choudhary

9. Sensor Augmented Pump therapy in pediatric and adult population ...................... 66T. Klupa, P. Jarosz-Chobot

10. Continuous glucose monitoring (CGM) in non-diabetic patients ............................ 79R. Buzzetti, C. Moretti, A. Soare

11. Data Management Solutions for Better Clinical Insights ....................................... 89L. Laviola, R. Donvito, F. Giorgino

12. Personalized insulin delivery with Automatic Suspension towards closing the loop ...................................................................................... 102O. Cohen

13. Closing the loop: another step forward ................................................................ 109L. Bally, H. Thabit, R. Hovorka

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1 PrefaceP. Pozzilli

Insulin pumps are medical devices used for the administration of insulin in the treatment of diabetes. This method, also known as continuous subcutaneous insulin infusion (CSII) therapy, has been used alongside traditional insulin infusion by syringe. With the passing of years, technology made these devices more and more sophisticated and available for everyone.

This book provides students with a highly authoritative overview on the use of insulin pumps. The contributions have been discussed by many eminent personalities from the USA and Europe, who can easily be defined real key opinion leaders in the field of diabetes.

The reader can travel through the history of pumps, starting from the first archaic devices to the smartest and automatic pumps of the new millennium. Students can also examine the role of insulin pumps in ameliorating the monitoring of diabetes during decades: how the continuous evolution of constructive strategies positively contributes to the lifestyle of people affected by diabetes, improving glucose monitoring and preventing complications induced by bad glycemic control. Many useful clinical cases have also been exhaustively illustrated, in which CSII was applied (diabetic patients, non-diabetic patients, use of CSII at home or dur-ing hospitalization, etc.), so as to give students an initial guideline for the use of this therapy. Moreover, to put some order in the field of rules, the book can provide a complete overview on regulatory procedures adopted in some countries, from Europe to the USA.

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journey towards closing the loop

2 A historical perspective on the use of insulin pump in diabetes managementO. Cohen, A. Cappelli, P. Pozzilli

The concept that it would be beneficial to provide insulin in a more physiological manner by continuous infusion began to receive serious attention in the mid 1970s. That was the time when the insulin pump therapy (CSII, continuous subcutaneous insulin infusion) started. Even before then, efforts at physiological insulin administration had already been made to achieve near-normal plasma glucose levels.

Dr. Arnold Kadish from Los Angeles, California, devised the first insulin pump in the early 1960s. It was worn on the back and was roughly the size of a rucksack.1 This prototype administered both insulin and glucagon and it was principally used for clinical tests (Fig. 2.1).

The best known (and certainly more comfortable to wear) insulin pump, developed by Dean Kamen, is dated 1972: this innovative device consisted in a programmable pump that automatically delivered accurate doses of insulin, over extended periods. This pump was small enough and represented not only an improvement in the glycemic control but also the begin-ning of focusing on the reach for a better lifestyle for people with diabetes which had often previously bedridden. Although the good diabetes control had been achieved, the risk of infec-tions was too high for everyday use because of the venous access, with the result that no last-

ing therapeutic option was derived from it. At the beginning of the 1970s, systematic tests in Germany (Munich) started with continuous intravenous insulin infusion in patients with poorly controlled type 1 diabetes.2

In 1976, John Pickup in the United King-dom and Gerard Slama and Jean-Louis Selam in France started to administer insulin con-tinuously via a catheter into the subcutane-ous fatty tissue using small battery-operated syringe pumps, which enabled the start of CSII.3-8 The subcutaneous route considerably decreased the risk of infections. A syringe pump meant a small motor-driven device in which a syringe was inserted. It provided patients with a constant amount of insulin throughout the day on a continuous basis.

Fig. 2.1. Insulin and glucagon pump from 1963 (A. Kadish).

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3journey towards closing the loop

The rate of administration, the basal rate, was first “calibrated” using saline solution, i.e. the dilution of insulin with saline solution determined the dose administered to the body. In order to administer a bolus, the units had to be administered by turning a screw and the replacement of the catheter always required medical interventions and had to be carried out under very sterile conditions. This treatment may seem complex today yet its success justified the further development of the therapy.

With the first systems being introduced on the market in the 1980s, such as the “Mill Hill infuser” or the Auto Syringe 6C (Fig. 2.2), designed by Dr. John Pickup, Prof. Harry Keen and Dr. John Parsons at the National Institute for Medical Research, Mill Hill and Guy’s Hospital in London, the insulin units also had to be calculated beforehand. The fairly large devices weighing approximately 250 g left a lot to be desired in terms of comfort for the wearer, but Mill Hill Infuser was the first portable insulin pump for treating diabetics and battery driven to supply insulin under the skin at a variety of controlled rates. Therefore, in the early 1980s, pump therapy was reserved only for the most difficult-to-manage cases; however, some clinical trials started in this period to compare this new system with the conventional strategies previ-ously used.9

Over the following years, insulin pumps became smaller and lighter. The Nordisk infuser from Novo Nordisk™, in which a pre-filled insulin reservoir with 570 IU was used, or the Be-tatron from Lilly™, were only as big as a cigarette packet. The insulin pump Syrotron 40 was also developed in Germany (Fig. 2.3). In this period, Minimed™ launched the first Minimed™ 404SP and it would fit in the palm of a hand. This pump required 3-mL Minimed dedicated

syringe reservoirs and specific set of tubes and needle and guaranteed a continuous or inter-mittent delivery of intravenous or subcutane-ous infusions of very minute amounts. Min-imed™ 404SP had some innovative features such as automatic changes in delivery rate or dose size and interval up to six times per day and allowed patients to accurately control their bolus dosage of insulin.

In 1983, with Betatron II, programming of alternative basal rates became available and the Minimed™ 504, launched in 1985 (Fig. 2.4), already had 4 different basal rates (upcoming 506 up to six, and the 507 up to twelve basal

Fig. 2.2. Auto Syringe 6C. Fig. 2.3. Syrotron 40.

Fig. 2.4. MiniMed 504 with four programmable basal rates.

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2 A hIStorICAl perSpeCtIve on the uSe of InSulIn puMp In dIAbeteS MAnAgeMent4 journey towards closing the loop

rates). Furthermore, Minimed™ 506 and 507 had an in-creased LCD screen and simplified pushbutton controls for easier use as well. This device also offered an optional short-syringe method which recessed the syringe con-nector inside the pump and improved patient comfort. Unstoppable advances in technology made these new so-phisticated devices suitable for everyone: in 1985 a study published on Diabetes revealed that 85% of people who tested new CSII devices were satisfied with the use of these systems and would like to continue using this thera-peutic strategy.10

The breakthrough to a 24-stage basal rate programma-ble on an hourly basis over a day finally came with the Hoechst Infuser MRS1, developed and manufactured by the Swiss company Disetronic™. In this device, program-ming of the basal rate was still done via an external pro-gramming tool in the medical practice; it was not until the successor model, the H-TRON Hoechst (Fig. 2.5), that the insulin pump could be programmed directly by the patient. What was especially important here was that this allowed the basal insulin supply to be subtly adjusted according to patients’ individual requirements, offering

important advantages in relation to near-normoglycemic blood glucose control.11

In the 1990s, Disetronic and MiniMed subsequently determined not just the development of the pump models but also the development of user-friendly infusion sets (disconnectable needles with different angles of insertion, teflon cannula, self-adhesive patch, injection aids, use of insulin-friendly tubes), pouches and other consumer materials.

From the end of the 1990s, innovations increasingly stemmed from the American com-pany Mini-Med (since 2001 it has belonged to Medtronic™). In the early 2000s the insulin pump (at the time the 507C model from Medtronic™) was applied for the first time in pa-tients with newly diagnosed type 1 diabetes to protect residual b-cell function and to induce clinical remission.12 This approach, which was tested again 10 years later, showed that inten-sive insulin therapy with the pump at diagnosis of type 1 diabetes goes beyond the simple concept of improving metabolic control.13, 14 The innovations concerned the implementation of various bolus options, a bolus calculator and direct communication with a blood glucose meter. In 2005, Medtronic launched the sensor-augmented pump therapy (SAP): the insulin pump could be linked to a continuous glucose monitoring, thus allowing to suspend insulin delivery when needed and so avoiding severe hypoglycemia events. The technology progress drove good clinical outcomes and a spread adoption of this therapy among Type1 diabetes patients. Later on, managing type 2 diabetes with insulin pump became an opportunity for diabetic patients who needed insulin therapy, too. The OpT2mise Trial showed that CSII was able not only to improve metabolic control (reduction of HbA1c) but also to protect residual ß-cell function.15, 16

In 2015 Medtronic launched the first hybrid closed-loop system, the MiniMed 640G (Fig. 2.6) that allows hypoglycemia prevention without a hyperglycemia rebound. This device is based on SmartGuard™ technology: by communicating with the sensor which sends periodical-ly blood glucose values, the device can predict when patients are approaching low glucose levels 30 minutes in advance and automatically stop insulin delivery.17 The continuous development

Fig. 2.5. the h-tron insulin pump - the first one programmable by patients.

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2 A hIStorICAl perSpeCtIve on the uSe of InSulIn puMp In dIAbeteS MAnAgeMent 5journey towards closing the loop

of new strategies to accurately manage blood glucose levels, like artificial pancreas, aims not only to reduce complications 18 caused by glu-cose level swing but also to improve patient lifestyle linked with less fear of hypoglycemia and more treatment satisfaction.19

There were also innovations from other companies, e.g. control of the insulin pump via remote control in the form of a hand-held com-puter (Insulet, Roche™), the development of a catheterless patch pump (OmniPod from In-sule™) that sticks to the skin or the introduction of meal tables into the pump menu (Animas). Innovations in controlling insulin pumps will make the whole CSII system “smarter”: in other words, people can control and manage their devices directly with a smartphone and parents will have the possibility to check blood glucose levels of their sons at school directly from home or from their work place. The realization of a smart system will supply the need of a perfect

managing of blood glucose levels from the early stage of diabetes especially in children, to prevent premature onset of complications caused by a bad compliance.20

references

1. Rahbar S, Blumenfeld O, Ranney HM. Studies of an unusual hemoglobin in patients with diabetes mellitus. Biochem Biophys Res Commun 1969;36:838-43.

2. Henrichs HR. HbA1c-Glycated Hemoglobin and Diabetes Mellitus. Bremen: UNI-MED Verlag; 2009.

3. 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. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-86.

4. The Diabetes Control and Complications Trial Research Group. The relationship of glycemic ex-posure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes 1995;44:968-83.

5. Kilpatrick ES, Rigby AS, Atkin SL. The effect of glucose variability on the risk of microvascular complications in type 1 diabetes. Diabetes Care 2009;32:1901-3.

6. Siegelaar SE, Kilpatrick ES, Rigby AS, Atkin SL, Hoekstra JBL, DeVries JH. Glucose variability does not contribute to the development of peripheral and autonomic neuropathy in type 1 diabe-tes: data from the DCCT. Diabetologia 2009;52:2229-32.

7. Kilpatrick ES, Rigby AS, Atkin SL. A1C variability and the risk of microvascular complica-tions in type 1 diabetes: data from the diabetes control and complications trial. Diabetes Care 2008;31:2198-202.

8. Piconi L, Quagliaro L, Da Ros R, Assaloni R, Giugliano D, Esposito K, et al. Intermittent high glucose enhances ICAM-1, VCAM-1, E-selectin and interleukin-6 expression in human um-

Fig. 2.6. Minimed 640g.

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2 A hIStorICAl perSpeCtIve on the uSe of InSulIn puMp In dIAbeteS MAnAgeMent6

bilical endothelial cells in culture: the role of poly(ADP-ribose) polymerase. J Thromb Haemost 2004;2:1453-9.

9. Mecklenburg RS, Benson JW Jr, Becker NM, Brazel PL, Fredlund PN, Metz RJ, et al. Clinical use of the insulin infusion pump in 100 patients with type I diabetes. N Engl J Med 1982;307:513-8.

10. Pickup JC, Sherwin RS, Tamborlane WV, Rizza RA, Service FJ. Conference on insulin pump therapy in diabetes. Multicenter study of effect on microvascular disease. The pump life. Patient responses and clinical and technological problems. Diabetes 1985;34 Suppl 3:37-41.

11. Risso A, Mercuri F, Quagliaro L, Damante G, Ceriello. Intermittent high glucose enhances apoptosis in human umbilical vein endothelial cells in culture. Am J Physiol Endocrinol Metab 2001;281:E924-30.

12. Pozzilli P, Crino A, Schiaffini R, Manfrini S, Fioriti E, Coppolino G, et al.; The IMDIAB Group. A 2-year pilot trial of continuous subcutaneous insulin infusion versus intensive insulin therapy in patients with newly diagnosed type 1 diabetes (IMDIAB 8). Diabetes Technol Ther 2003;35:965-74.

13. Ramchandani N, Ellis MK, Jain S, Bhandari S, Anhalt H, Maclaren NK, et al. Basal insulin re-quirements on continuous subcutaneous insulin infusion during the first 12 months after diagnosis of type 1 diabetes mellitus. J Diabetes Sci Technol 2010;4:610-4.

14. Kordonouri O, Hartmann R, Pankowska E, Rami B, Kapellen T, Coutant R, et al. Sensor aug-mented pump therapy from onset of type 1 diabetes: late follow-up results of the Pediatric Onset Study. Pediatr Diabetes 2012;13:515-8.

15. Conget I, Castaneda J, Petrovski G, Guerci B, Racault AS, Reznik Y, et al.; OpT2mise Study Group. The Impact of Insulin Pump Therapy on Glycemic Profiles in Patients with Type 2 Diabe-tes: Data from the OpT2mise Study. Diabetes Technol Ther 2016;18:22-8.

16. Reznik Y, Cohen O, Aronson R, Conget I, Runzis S, Castaneda J, Lee SW; OpT2mise Study Group. Insulin pump treatment compared with multiple daily injections for treatment of type 2 diabetes (OpT2mise): a randomised open-label controlled trial. Lancet 2014;384:1265-72.

17. Choudhary P, Olsen BS, Conget I, Welsh JB, Vorrink L5, Shin JJ. Hypoglycemia Prevention and User Acceptance of an Insulin Pump System with Predictive Low Glucose Management. Diabetes Technol Ther 2016;18:288-91.

18. Rosenlund S, Hansen TW, Andersen S, Rossing P. Effect of 4 years subcutaneous insulin infusion treatment on albuminuria, kidney function and HbA1c compared with multiple daily injections: a longitudinal follow-up study. Diabet Med 2015;32:1445-52.

19. EQuality1 Study Group--Evaluation of QUALITY of Life and Costs in Diabetes Type 1, Nicolucci A, Maione A, Franciosi M, Amoretti R, Busetto E, Capani F, et al. Quality of life and treatment satisfaction in adults with Type 1 diabetes: a comparison between continuous subcutaneous insulin infusion and multiple daily injections. Diabet Med 2008;25:213-20.

20. Zabeen B, Craig ME, Virk SA, Pryke A, Chan AK, Cho YH, et al. Insulin Pump Therapy Is Associated with Lower Rates of Retinopathy and Peripheral Nerve Abnormality. PLoS One 2016;11:e0153033.

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