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Recent developments in insulin preparation in clinical use Symposium 2: Prospective antidiabetic drugs The 56the Annual Meeting of the Japan Diabetes Society.

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Presentation on theme: "Recent developments in insulin preparation in clinical use Symposium 2: Prospective antidiabetic drugs The 56the Annual Meeting of the Japan Diabetes Society."— Presentation transcript:

1 Recent developments in insulin preparation in clinical use Symposium 2: Prospective antidiabetic drugs The 56the Annual Meeting of the Japan Diabetes Society Chairs: Prof. Yasuhiko Iwamoto, and Prof. Kohei Kaku May 16, : 30 ~ 11 : 30 (25min) Mielparque Kumamoto, 3F Nekodake, Venue , Suido-cho, Kumamoto-shi, Kumamoto , Suido-cho, Kumamoto-shi, Kumamoto Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University Matsuda, Masafumi

2 The Japan Diabetes Society COIDisclosure Masafumi Matsuda, MD, PhD The author have no financial conflicts of interest to disclose concerning the presentation.

3 Progress Animal Insulin Human Insulin (Gene technology) Ultra-rapid-acting Insulin analogue Ultra-long-acting Insulin analogue Discovery of Insulin (Banting & Best) time Biphasic Insulin analogue History of Insulin Preparation To achieve better control of plasma glucose concentration, Insulin preparation has been improved.. Neutral Protamine Hagedorn ( NPH ) Insulin 1946 Medical preparations of insulin are never just 'insulin in water‘. 34G 1993 DCCT publication

4 (n=730) (n=711) conventional intensive For Type 1 Diabetes mellitus Duration of diabetes was 1 to 5 years

5 76% 54% Diabetic retinopathy cumulative incidence Primary prevention Secondary prevention conventional intensive conventional intensive conventional intensive conventional intensive years Incidence For Type 1 Diabetes mellitus

6 For Type 2 Diabetes mellitus Kumamoto Study 76% 54%

7 Physiological replacement of insulin + + Fasting intervention Prandial intervention Morning Lunch Evening Morning Basal Prandial

8 Artificial pancreas → Real time CGM & CSII

9 the International Diabetes Center at Park Nicollet, Minneapolis (R.M.B.); Yale University, New Haven, CT (W.V.T.); Oregon Health and Science University, Portland (A.A.); University of North Carolina School of Medicine, Chapel Hill ( J.B.B.); Scripps Institute, La Jolla (G.D.), and Medtronic, Northridge (T.P., J.B.W.) — both in California; University of Maryland School of Medicine, Baltimore (S.N.D.); Memorial University of Newfoundland, Health Science Centre, St. John’s, NL, Canada (C.J.); Toronto General Hospital, Toronto (B.A.P.); Children’s Hospital of Philadelphia, Philadelphia (S.M.W.); and Helen DeVos Children’s Hospital, Grand Rapids, MI (M.A.W.). The MiniMed Paradigm REAL-Time System is comprised of six components: 1) the Paradigm® 722 insulin pump (MMT-722), 2) the MiniLink™ REAL-Time transmitter (MMT- 7703) with charger (MMT-7705), 3) the glucose sensor (MMT-7002/7003), 4) the Paradigm® Link glucose meter, 5) the ComLink (MMT-7304), and 6) a Personal Computer (PC). The rate of severe hypoglycemia in the pump-therapy group (13.31 cases per 100 person-years) did not differ significantly from that in the injection- therapy group (13.48 per 100 person-years, P = 0.58). N Engl J Med Jul 22;363(4):

10 N Engl J Med 2013;368: the 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 (M.P., E.A., S.M., I.M., R.N.), and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (M.P.) — both in Israel; the Department of Pediatric Endocrinology, Diabetes and Metabolism, University Medical Center-University Children’s Hospital, and Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (T. Battelino, N.B., M.A.S.); and the Diabetes Center for Children and Adolescents, Auf der Bult, Kinder- und Jugendkrankenhaus, Hannover, Germany (O.K., T. Biester, T.D.).

11 Figure 1. Glycemic Control in the Two Study Treatments. The upper graphs show the sensor glucose profiles during the nights when the artificial pancreas was used (Panel A) and during the nights when the sensor- augmented insulin pump (control) was used (Panel B), and the middle and lower graphs show the respective profiles for basal and bolus insulin infusions. In the upper graphs, the solid black lines indicate the median glucose levels, and the two dashed lines indicate the interquartile range. The circles indicate the median capillary glucose measurements taken every 3 hours during the overnight sessions (11 p.m. to 7 a.m.), and the vertical lines indicate the interquartile ranges. The horizontal dashed lines indicate glucose measurements of 63 mg per deciliter, 140 mg per deciliter, and 180 mg per deciliter. In the middle graphs, the mean basal rates of insulin infusion are indicated by solid black lines, with dashed lines indicating the ranges. In the bottom panels, the total amounts of insulin delivered over time as bolus doses are indicated by the vertical black lines with circles. To convert the values for glucose to millimoles per liter, multiply by N Engl J Med 2013;368:

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13 Progress Animal Insulin Human Insulin (Gene technology) Ultra-rapid-acting Insulin analogue Ultra-long-acting Insulin analogue Discovery of Insulin (Banting & Best) time Biphasic Insulin analogue History of Insulin Preparation To achieve better control of plasma glucose concentration, Insulin preparation has been improved.. Neutral Protamine Hagedorn ( NPH ) Insulin 1946 Medical preparations of insulin are never just 'insulin in water‘. 2 nd generation Ultra-long-acting Insulin analogue

14 For Ideal Basal Replacement (Basal)

15 Curr Diab Rep Dec;12(6): Fig. 1 (a) Ribbon model of wild-type insulin (b) Structure of insulin hexamer. Two axial zinc ions are coordinated by 6 histidine side chains. (c) Structure of insulin degludec showing the dicarboxylic acid attached to the ε-amino group of Lys B29. (d) Structure of LY showing PEG attached to the ε- amino group of Lys B28. (e) Exploiting the TR transition in supramolecular protein engineering: schematic representation of the mechanism of insulin degludec.

16 Insulin degludechttp://www.novonordisk.com/press/photo_library Insulin degludec is a ultralong-acting basal insulin analogue being developed by Novo Nordisk. It is injected subcutaneously three-times a week to help control the blood sugar level of those with diabetes. It has a duration of action that lasts up to 40 hours, unlike the 18 to 26 hours provided by current marketed long-acting insulin such as insulin glargine and insulin detemir. palmitic acid Insulin degludec is a modified insulin that has one single amino acid deleted in comparison to human insulin, and is conjugated to palmitic acid: CH 3 (CH 2 ) 14 CO 2 H at the amino acid lysine at position B29. IDeg(A) (600 μmol/L, 1 unit = 6 nmol); IDeg(B) (900 μmol/L; 1 unit = 9 nmol). 一般のインスリン human:Mol.mass 5807 g/mol 21A-30B 1 microU/mL = 7.18 pmol/L (100U/ml= 3.53 mg/ml=0.609mmol/l) Detemir Mol. Mass 5913 myristic acid A fatty acid (myristic acid: CH 3 (CH 2 ) 12 COOH ) is bound to the lysine amino acid at position B29. Insulin detemir is formulated with a greater molar ratio than human NPH and glargine (4:1:1, respectively)

17 insulin degludec (Novo Nordisk, Bagsvaerd, Denmark) three times a week (900 nmol/mL formulation, dosed in the evening on Monday, Wednesday, and Friday), insulin degludec group A (600 nmol/mL formulation) once a day, insulin degludec group B (900 nmol/mL formulation) once a day, or insulin glargine (600 nmol/mL formulation; Sanofi - Aventis, Paris, France) once a day, all in combination with metformin. 100U/mL Lancet 2011; 377: 924–31

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21 Figure 2: Mean HbA 1C and plasma glucose concentrations by trial intervention (A) Mean HbA 1C. (B) Mean fasting plasma glucose. (C) Mean nine-point self monitored blood glucose profiles. Data are reported mean values from all randomised participants. Last observation carried forward is used for each time point in A and B. Plasma-calibrated values are shown in C. IDeg 3TW=insulin degludec three times a week. IDeg OD(A)=insulin degludec (group A) once a day. IDeg OD(B)=insulin degludec (group B) once a day. IGlar=insulin glargine once a day. Lancet 2011; 377: 924–31

22 Figure 2: Mean HbA1C and plasma glucose concentrations by trial intervention (A) Mean HbA1C. (B) Mean fasting plasma glucose. (C) Mean nine-point self monitored blood glucose profiles. Data are reported mean values from all randomised participants. Last observation carried forward is used for each time point in A and B. Plasma-calibrated values are shown in C. IDeg 3TW=insulin degludec three times a week. IDeg OD(A)=insulin degludec (group A) once a day. IDeg OD(B)=insulin degludec (group B) once a day. IGlar=insulin glargine once a day. 126 mg/dl 180 mg/dl Lancet 2011; 377: 924–31

23 BMI, body mass index; IAsp, insulin aspart; IDeg, insulin degludec; IGlar, insulin glargine; OD, once daily Heller et al. Lancet 2012;379: Study design

24 HbA 1c over time Heller et al. Lancet 2012;379: Mean±SEM; FAS, full analysis set; LOCF, last observation carried forward Comparisons: estimates adjusted for multiple covariates

25 Nocturnal confirmed hypoglycaemia SAS Comparisons: estimates adjusted for multiple covariates Heller et al. Lancet 2012;379:

26 Study design BMI, body mass index; IAsp, insulin aspart; IDeg, insulin degludec; IGlar, insulin glargine; OAD, oral antidiabetic drug; OD, once daily Garber et al. Lancet 2012;379:

27 HbA 1c over time Garber et al. Lancet 2012;379: Mean±SEM; FAS, full analysis set; LOCF, last observation carried forward Comparisons: estimates adjusted for multiple covariates

28 Nocturnal confirmed hypoglycaemia SAS Comparisons: estimates adjusted for multiple covariates Garber et al. Lancet 2012;379:

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31 LY is a novel, long-acting basal insulin consisting of insulin lispro covalently modified with a 20-kDa polyethylene glycol moiety. It is a solution based basal insulin with a time-action profile that is believed to be modulated indirectly through slowed depot absorption and reduced clearance due to increased molecular size. LY has a duration of action of more than 36 h with low variability, acting considerably longer than insulin glargine. 1 unit = 10 nmol

32 In this randomized, Phase 2, open-label, 232 crossover study, 137 patients received once-daily basal insulin (LY or glargine) plus mealtime insulin for 8 weeks, followed by crossover treatment for 8 weeks. Daily mean blood glucose was obtained from 8-point self-monitored blood glucose profiles. Diabetes Care 36:522–528, 2013 Type 1 Diabetes: A randomized, crossover study.

33 Diabetes Care 36:522–528, 2013 Baseline LY Glargine LY Baseline

34 Figure 2 Mean A1C and weight during treatment with LY and insulin GL. Patients received treatment with one basal insulin for the first 8-week treatment period and were switched to the other basal insulin for the second treatment period. Insulin GL, ○; LY , ■. A: Mean (± SE) A1C throughout the two treatment periods. B: Mean (± SE) weight throughout the two treatment periods. Diabetes Care 36:522–528, 2013

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36 Diabetes Care 35:2140–2147, 2012 The 12-week, randomized, open-label, Phase 2 study with type 2 diabetes (hemoglobin A1c [A1C] < 10.5%), taking metformin and/or sulfonylurea with GL or NPH insulin once daily.

37 The LY1 algorithm, adapted from Yki-Järvinen et al., was based on the mean FBG of three consecutive mornings before the visit: for a mean FBG 101 to 180 mg/dL (5.5 to 10.0 mmol/L), the LY dose was increased by 10 nmol (10 mL or 1 volumetric unit) and for a mean FBG.180 mg/dL (10.0 mmol/L), the LY dose was increased by 20 nmol (20 mL or 2 volumetric units). The GL dosing algorithm was similar to the Yki- Järvinen et al. algorithm using the same two and four IU increments, respectively. Yki-Järvinen H, Kauppinen-Mäkelin R, Tiikkainen M, et al. Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study. Diabetologia 2006;49:442–451 The LY2 algorithm was adapted from Riddle et al. and likewise was based on the mean of three consecutive mornings before the visit: for a mean FBG of 101 to 120 mg/dL (5.5 to 6.7 mmol/L), the LY dose increased by 10 nmol (10 mL or 1 volumetric unit); for 121 to 140 mg/dL (6.8 to 7.8 mmol/L), the LY dose increased by 20 nmol (20 mL or 2 volumetric units); for 141 to 180mg/dL (7.9 to 10.0mmol/L), the LY dose increased by 30 nmol (30 mL or 3 volumetric units); and for.180 mg/dL (10.0 mmol/L), the LY dose increased by 40 nmol (40 mL or 4 volumetric units). Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investigators. The treat- to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003;26:3080–3086

38 Diabetes Care 35:2140–2147, 2012

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42 Stable, and it may be possible to used orally or pulmonary

43 For Ideal Prandial Replacement (Bolus)

44 Diabetes Care Apr;36(4):780-5.

45 Figure 2 A: Mean insulin curve for 9 × 2 IU (C) and 1 × 18 IU (○) injections of insulin aspart. Values represent mean 6 SD (only one direction shown for clarity). B: Mean glucose infusion rate curve for 9 × 2 IU (solid line) and 1 × 18 IU (dashed line) injections of insulin aspart. Diabetes Care Apr;36(4):780-5.

46 Microneedle-based insulin Delivery

47 (a) Solid microneedles (150 µm tall) etched from a silicon wafer (b) Solid microneedles (1000 µm tall) laser-cut from a stainless steel sheet (for rat) (c) Solid microneedles vaccine delivery in vivo; (d) Solid microneedles (200 µm tall) chemically etched from a silicon wafer (e) Hollow microneedles (500 µm tall) Advanced Drug Delivery Reviews 56 (2004) 581– 587

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53 specificity to the receptor

54 Study NCT : This study is being conducted to assess efficacy and safety of insulin glargine/lixisenatide fixed combination versus insulin glargine alone on top of metformin in T2DM patients. This is a phase II, randomized, 24-week, open-label, 2-arm parallel-group, multicentric study including 310 subjects and is expected to be completed by December 2012 Drug: Insulin glargine /lixisenatide fixed combination (HOE901/AVE0010) Pharmaceutical form:Solution for injection using a re-usable pen-type self-injector device (Tactipen®). Route of administration: subcutaneous Drug: Insulin glargine (HOE901) Pharmaceutical form:Solution for injection using a disposable self injector device (Lantus® SoloSTAR®). Route of administration: subcutaneous Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2012, 6, Insulin + GLP-1 analogue premixed (http://clinicaltrials.gov/ct2/show/record/NCT )

55 Intensive insulin regime using an ultra-rapid-acting insulin analogue and an ultra-long-acting insulin analogue is the solid way for the treatment of both type 1 and type 2 diabetic subjects without adequate endogenous insulin. Recent developments in insulin preparation further facilitate intensive insulin treatment without hypoglycemia. Since the medical costs used after the development of severe complication are significantly high, the new types of insulin replacement therapy are quite important issues that may worthwhile to invest resources for development. Implication

56 2009 年 11 月 14 日

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58 Insulin preparation and its delivery system have been developed remarkably. Use of insulin to human body helped to prevent miserable consequences from diabetes mellitus. We usually need two different types of insulin, one for basal replacement to suppress hepatic glucose production and another for bolus replacement to facilitate disappearance of glucose after a meal. Combination use of these two kinds of insulin needs frequent injection. Application of ultra-fine needles up to 34G in diameter and pen-type syringes is now available. Self-monitoring of blood glucose (SMBG) machines are quite easier to use compared from those used previously. Real time continuous glucose monitoring (CGM) is a realistic option in foreign countries. Just recently insulin degludec, ultra long-acting insulin has been approved in Japan. This makes stable basal replacement of insulin possible. However, prolongation of insulin action may be dangerous in some cases in which acute changes of glucose metabolism develops in the body like emergency situation and operation. Analogue rapid and short-acting insulin preparations like insulin aspart, insulin lispro, and insulin glulisine are not rapid or short enough to determine insulin doses after meals or after glucose measurements. There still have a room for further development. Combination regime of long acting insulin and GLP-1 analogue may be quite useful to treat type 2 diabetic subjects, while continuous subcutaneous ultra-short acting insulin infusion with feel back of glucose monitoring may be a good option for the future treatment of type 1 diabetes mellitus. Other developments may include oral insulin regime, a sheet with micro-needles containing insulin, and transplantation of islets prepared by iPS cells. Access to insulin treatment in economically poor patients, in busy young generations, and in mentally disturbed subjects may be other targets or goals for the future development of insulin regimes. Since the medical costs used after the development of severe complication are significant, the new types of insulin replacement therapy are quite important issues that may worthwhile to invest resources for development. ABSTRACT


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