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Insulin : Past, Present and Future

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Insulin : Past, Present and Future 2016.5.13. 29th Spring Congress of Korean Diabetes Association Insulin : Past, Present and Future Seung-Hwan Lee, MD, PhD Seoul St.Mary’s Hospital The Catholic Univ. of Korea 본 발표와 관련된 이해관계 • 강의 및 자문료: Sanofi Aventis, Eli Lilly History of glucose-lowering drugs Kahn SE et al. Lancet, 2014 Groundwork for the discovery of insulin Josef Von Mering Oskar Minkowski Paul Langerhans (1849-1908) (1858-1931) (1847-88) pancreatectomy in dog displayed polyuria, small clusters of cells in thirst, hyperphagia pancreas separated from exocrine & ductal tissue demonstrated blood glucose lowering properties of pancreas “islets of Langerhans” Insulin in medical history: 4 Nobel prizes Frederick Sanger Chemistry 1958 Aminoacid sequence of insulin Dorothy Hodgkin Frederick Banting & John Macleod Chemistry 1964 Medicine 1923 X-ray crystallography Discovery of insulin Rosalyn Yalow Medicine 1977 RIA Charles Best James Collip Developments in insulin therapy: a journey not a destination Isolation Hagedorn protamine of insulin -retarded insulin Recombinant human Basal (Banting & Macleod) NPH insulin insulin analogues 1922 1946 1977 2000s Time The beginning 1923 1950s 1990s Animal insulin p Lente® insulin Rapid-acting reparations series insulin analogues NPH, neutral protamine Hagedorn Isolation of insulin • 1921: Banting and Best filter pancreatic tissue to produce ‘isletin’ in Professor Macleod’s laboratory at the University of Toronto • Purification of insulin by Bertram Collip First use of insulin in human January 1922: At Toronto General Hospital, 14-year-old Leonard Thompson was the first human to receive insulin • Banting and Best injected a 14-year-old “charity” patient who weighed 29 kg with 7.5 ml of a “thick brown muck” in each buttock. • Abscesses developed and he became more acutely ill. • However, his blood glucose had dropped enough to continue refining what was called "iletin” insulin. • 6 weeks later, a refined extract caused his blood glucose to fall from 520 to 120 mg/dL in 24 hours. • Leonard lived a relatively healthy life for 13 years before dying of pneumonia (no Rx then) at 27. University of Toronto University of Toronto Flame of Hope 442 Adelaide Street, London, Ontario, Canada Pharmaceutical collaboration 1923: Macleod and Dr GHA Clowes (Eli Lilly and Company) agreed to collaborate on the mass production of insulin Hagedorn and Krogh obtained permission to produce insulin in Scandinavia. Krogh, Hagedorn and Kongsted founded Nordisk in 1923 Hans Christian Hagedorn August Krogh 1888–1971 1874–1949 Limitation of the first animal insulin preparations Animal insulin preparations had a number of limitations: • Poor long-term hyperglycaemic control • Insulin allergy/lipohypertrophy • Numerous injections with large volumes (40 U/mL formulation) • Peak effect 2–4 hours = raised nocturnal glucose levels Markus Michalczyk Arch Dis Child 2004;89:6240 King. Br J Nurs 2003;12:1137–41 NPH (Neutral Protamine Hagedorn) insulin • NPH insulin developed in 1946 by Nordisk • Intermediate duration of action (12–20 hours) • NPH insulin could be mixed with soluble insulin – Improved glycaemic control – Fewer injections: once or twice daily – Greater flexibility in treatment management, through mixing with soluble insulin Hagedorn et al. JAMA 1936;106:177–80 Ultralente insulin (1954) • Ultralente® had a longer duration of action than NPH • Presence of zinc and large crystal size gave 18–24 hour duration of action • Improved nocturnal blood glucose control • High day-to-day variability in absorption, inconsistent peak patterns and incompatibility with regular insulin limited its usefulness Schultz et al. Diabetologia 2005;48:1988–95; Riddle. Am J Med 2004;116(Suppl. 1):3–9 Lindström et al. Scand J Clin Lab Invest 2000;60:341–7 1980s: Recombinant human insulin • The 1980s saw the manufacture of recombinant human insulin using either E. coli or yeast • Allowing industrial scale production of insulin • Reduced incidence of immunogenic reactions FDA Drug Bull 1982;12:18–9; Skyler. Med J North Am 1988;72:1337–54 1990s-2000s: Development of insulin analogues 51개의 아미노산으로 구성 • 2개의 peptide chain • A 사슬 (21개 A.A.)과 B 사슬 (30개 A.A.) 2개의 disulfide bridges로 연결 • Recombinant technology provided the opportunity to modify insulin structure to improve properties and produce a more physiological action profile • Analogues were first designed to produce more rapid-action kinetics than human soluble insulin by minimising monomer–monomer interactions • Subsequent modifications aimed to extend action profile Trends in insulin usage Long acting insulin Short acting insulin Intermediate insulin (NPH) Regular insulin Currently used insulins in Korea KDA, 당뇨병진료지침, 2015 Rapid-acting and short-acting insulins KDA, DETM, 2015 Rapid-acting and short-acting insulins KDA, DETM, 2015 Rapid-acting and short-acting insulins KDA, DETM, 2015 Long-acting insulins KDA, DETM, 2015 Long-acting insulins KDA, DETM, 2015 Long-acting insulins (Insulin Glargine) Mechanism behind absorption of glargine Clear solution pH 4.0 pH 7.4 Precipitation Deprecipitation hexamers dimers monomers 10 – 3M 10 – 5M 10 – 8M Capillary membrane insulin glargine in blood Long-acting insulins (Insulin Detemir) Retardation principle of insulin detemir Clear solution Hexamer stability Dilution → disassociation Dihexamerisation Albumin binding hexamers dimers monomers 10 – 3M 10 – 5M 10 – 8M Capillary membrane insulin detemir in blood Plasma albumin binding Long-acting insulins KDA, DETM, 2015 Pre-mixed insulins KDA, DETM, 2015 Inhaled insulin Inhaled insulin New basal insulins Toujeo is a new long-acting basal insulin with a more constant and prolonged PK/PD profile vs Lantus 1 3 Reduction of volume by 2/3 More constant PK/PD profile Median insulin concentration, µU/mL 20 10 U300 Same amount of units U100 0 0 6 12 18 24 30 36 Glucose infusion rate, mg/kg/min U100 U300 3 2 U100 2 1 U300 Reduction of depot surface area by 1/2 0 0 6 12 18 24 30 36 Blood glucose, mg/dL 160 140 U100 120 100 U300 0 6 12 18 24 30 36 U100 U300 Time, h U300 has the same metabolism (M1 as main metabolite) as U100 Jax T et al. Poster presented at EASD 2013; Abstract 1029. Available at http://www.easdvirtualmeeting.org/resources/6226 Accessed May 2014 New basal insulins More stable and prolonged (beyond 24 hours) PK/PD profile with Toujeo vs Lantus Toujeo 0.4 U/kg, n=16 25 Lantus 0.4 U/kg, n=17 20 15 10 µU/mL 5 LLOQ 0 Insulin concentration, Insulin 0 6 12 18 24 30 36 3 2 1 mg/kg/min 0 Glucose infusionrate, Glucose 0 6 12 18 24 30 36 Time, hours • Double-blind, crossover euglycemic clamp study of Toujeo vs Lantus in 30 patients with T1DM LLOQ, lower limit of quantification; PD, pharmacodynamic; PK, pharmacokinetic; T1DM, type 1 diabetes mellitus Further details on study design can be found in the back-up slides Becker RH et al. Diabetes Care. 2015;38:637-43 New basal insulins Designing insulin degludec Des(B30) LysB29(γ-Glu Nε-hexadecandioyl) human insulin s s A1 A21 G I V E Q C C T S I C S L Y Q L E N Y C N s s DesB30 B1 s s F V N Q H L C G S H L V E A L Y L V C G E R G F F Y T P K T desB30 Insulin O NH L-γ-Glu Glutamic acid O ‘spacer’ HO OH N H O Hexadecandioyl O Fatty diacid side chain • 1U increment • Max 80 units per dose New basal insulins Half-life of degludec compared to glargine 100 IDeg 0.8 U/kg IGlar 0.8 U/kg 10 IGlar (% of maximum) (% Insulin concentration Insulin 1 0 24 48 72 96 120 Time since injection (hours) IDeg IGlar 0.4 U/kg 0.6 U/kg 0.8 U/kg 0.4 U/kg 0.6 U/kg 0.8 U/kg Half-life (hours) 25.9 27.0 23.9 11.8 14.0 11.9 Mean half-life 25.4 12.5 IDeg, insulin degludec; IGlar, insulin glargine; LLoQ, lower limit of quantification Heise et al. ADA 2011; 37-P LB; Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P) New basal insulins Insulin Degludec vs. Insulin Glargine (BEGIN Once Long) 1023 insulin-naïve patients with T2DM Cumulative hypoglycemic events confirmed <3.1 mmol/L Glargine 2.0 18% lower 1.6 with degludec Anytime 12 wk 26 wk p=0.11 events/pt 1.2 Degludec 0.8 0.4 IDeg od (n=766) IGlar od (n=257) 12 24 36 48 Weeks of treatment 0.40 Glargine 36% lower Nocturnal 0.32 with degludec events/pt 0.40 p=0.04 0.60 Degludec 0.80 Difference after 26 wk 12 24 36 48 Weeks of treatment Zinman B, et al. Diabetes Care 2012;35:2464-2471. Unmet medical needs in diabetes Reversal or halt of disease progression Specifically in type 2 diabetes Efficacious medications less likely to induce hypoglycaemia Improved weight loss medications Medications that target complementary disease pathways Improved methods of assessing disease-modification potential Improved screening for pre-diabetes Importance Improved long-term efficacy Medications that target complications Source: Metabolic Disorders Study – Type 2 Diabetes, Decision Resources, October 2010 Insulin development: Future • Premix insulin of ultra-long acting insulin (Degludec) and a mealtime insulin (Aspart) • Simple regimen with fewer injections than basal and bolus • Successful reductions in HbA1c • Lower risk of nocturnal and overall hypoglycaemia versus BIAsp30 delivered twice daily at main meals • Combination of basal insulin and GLP-1 analogue in one pen • Insulin biosimilars • Ultra fast-acting insulin analogue (Phase 3) • Oral insulin analogue (Phase 1~2) • Insulin patch Challenges with oral delivery of insulin Digestive System Absorption Variability . The type and size of the • Gastric-intestinal trans insulin molecule (peptide) it time (interdigestive .
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