10ª EDIZIONE Giornate Diabetologiche Salernitane

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2 10ª EDIZIONE Giornate Diabetologiche Salernitane

3 10ª EDIZIONE Giornate Diabetologiche Salernitane Il presente Insuline umane Analoghi rapidi Analoghi lenti Miscele precostituite

4 10ª EDIZIONE Giornate Diabetologiche Salernitane Insuline umane Lilly Humulin R Humulin I Humulin 30/70 Novo Actrapid Protaphane Actraphane 30 Sanofi Insuman Rapid Insuman Basal Insuman Combo flaconcino flaconcino flaconcino flaconcino flaconcino flaconcino flaconcino/penna preriempita(solostar) registrata, non commercializzata registrata, non commercializzata

5 10ª EDIZIONE Giornate Diabetologiche Salernitane Analoghi rapidi Lilly Humalog Novo Novorapid Sanofi Apidra lispro aspart glulisina

6 10ª EDIZIONE Giornate Diabetologiche Salernitane Analoghi lenti Lilly Humalog basal Novo Levemir Sanofi Lantus lispro protamina detemir glargina

7 10ª EDIZIONE Giornate Diabetologiche Salernitane Gli analoghi dell insulina

8 10ª EDIZIONE Giornate Diabetologiche Salernitane Miscele di analoghi precostituite Lilly Humalog mix 25 Humalog mix 50 Novo NovoMix 30 NovoMix 50 NovoMix 70

9 10ª EDIZIONE Giornate Diabetologiche Salernitane Confronto di efficacia Short actinginsulinanaloguesvs regular humaninsulinin patients with diabetes mellitus(cochrane Database Syst Rev 2006): onlya minor benefit ofshort actinginsulinanaloguesin the majority of T1DM/T2DM patients Long-acting insulinanalogues(glargine, detemir) vs humannph insulin in T2DM (Cochrane Database Syst Rev 2007): metabolic control did not differ in a clinical relevant way between treatment groups Systematic review: Comparative effectiveness and safety of premixedinsulinanaloguesin T2DM (AnnInternMed2008): premixed insulin analogues were similar to premixed human insulin in decreasing fasting glucose levels and HbA1c levels

10 The role of different insulins: hypoglycemia Severe hypoglycemias (episodes per 100 person-years): 0 to 30.3 (median 0.6) with short acting analogues 0 to 50.4 (median 2.8) with regular insulin Cochrane Database Syst Rev 2004, Oct 18;(4):CD and Apr 19;(2):CD003287

11 The role of different insulins: hypoglycemia Cochrane Database Syst Rev 2007, Apr 18;(2):CD005613

12 The role of different insulins: hypoglycemia Cochrane Database Syst Rev 2007, Apr 18;(2):CD005613

13 The role of different insulins: hypoglycemia Ann Intern Med 2008;149:

14 10ª EDIZIONE Giornate Diabetologiche Salernitane Controlloglicemico vs ipoglicemia Little S etal, DiabetesTechnol Ther2011

15 10ª EDIZIONE Giornate Diabetologiche Salernitane Il presente, quindi Propone numerosi tipi di insulina, che, se usati congruamente, consentono di ottenere risultati, in termini efficacia, relativamente poco diversi tra di loro (anche se gli analoghi presentano, rispetto alle insuline umane, alcuni vantaggi di farmacocinetica). Più importanti sono le differenze per quanto riguarda gli eventi ipoglicemici, relativamente meno frequenti con gli analoghi rapidi rispetto all insulina pronta umana (?) e meno probabili (soprattutto quelli notturni) con gli analoghi lenti.

16 10ª EDIZIONE Giornate Diabetologiche Salernitane Limitazioni della terapia insulinca attuale Rischio di ipoglicemie Insulinizzazionebasale non sempre soddisfacente Insulina glarginae detemirnon miscibili con insuline ad azione rapida

17 10ª EDIZIONE Giornate Diabetologiche Salernitane Il futuro Analoghi rapidi Analoghi lenti

18 10ª EDIZIONE Giornate Diabetologiche Salernitane Gli analoghi dell insulina Evans M etal, DiabetesObesMetab2011

19 Lilly s two basal insulin analogue candidates are expected to enter Phase III clinical testing in Lilly s two basal insulin analogue candidates are: LY , a structurally novel basal insulin analogue, and LY , a new insulin glargineproduct.

20 LY phase-1 trial: pharmacokinetics, pharmacodynamics, safety, and tolerability of LY in 18 patients with type 2 diabetes mellitus after multiple, daily subcutaneous doses. This study has been completed, but results have not yet been published or presented. 2 phase-2 trials: clinical efficacy and safety of LY OD compared with IGlarOD. One is a 16-week crossover trial in type 1 diabetes patients. The other, a parallel trial with a duration of 12 weeks, is performed in type 2 diabetes patients. In the latter trial two dosing algorithms of LY will be tested. Both phase 2 trials have been completed at the beginning of phase-3 trial: IMAGINE 2: double-blind, randomized study comparing LY to glargineas basal insulin in combination with OAD in insulin-naive Type 2 diabetic patients Airin C.R. Simon and J. Hans DeVries. Diabetes Technology & Therapeutics. June 2011, 13(S1): S-103- S-108. doi: /dia

21 LY phase-1 trial: pharmacokinetics and pharmacodynamicsof LY compared to those of basal insulin. Safety and tolerability of LY in healthy subjects. The study is approximately 12 weeks. This study has been completed, but results have not yet been published or presented. 2 phase-3 trials: -The ELEMENT 2 Study: prospective, randomized, double-blind trial comparing LY to glargine in adult patients with type 2 diabetes -prospective, randomized, open-label trial comparing LY to glarginein combination with Lispro in adult patients with Type 1 diabetes Both trials are ongoing

22 Insulin degludec structure LysB29(Nε-hexadecandioyl-γ-Glu) des(b30) human insulin s s G I V E Q C C T S I C S L Y Q L E N Y C N A chain s s 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 B chain desb30 Insulin K O NH L-γ-Glu HO O Hexadecandioyl O N H O OH Glutamic acid spacer Fatty diacid side chain I Jonassen et al. Diabetes 59 (Suppl. 1): A11, 2010 I Jonassen et al. Diabetologia 2010;53(Suppl.1):S P

23 Insulin degludec association From injection to absorption Multi-hexamer formation key to protraction mechanism Insulin degludec di-hexamers Injected formulation -Phenol Insulin degludec multi-hexamers S.c. depot formation -Zn 2+ [ Phenol; Zn 2+ ] I Jonassen et al. Diabetes 59 (Suppl. 1): A11, 2010 I Jonassen et al. Diabetologia 2010;53(Suppl.1):S P Insulin degludec monomers Absorption

24 Insulin degludec pharmacokinetic profile Single dose and steady state People with type 1 diabetes (n=12) 0.4 U/kg once daily for 6 days Insulin deglude ec (pmol/l) 1000 Day 6 (steady state) Day Time since last injection (h) Jonassen I et al. Diabetes 2010; 59 (Suppl. 1): 0039-OR

25 Linear kinetics Available at beginning (injected + remaining) Remaining after 24 hours half-life ~ 10 Steady state (10 in : 10 out)

26 Birkeland KI et al, Diabetes Care 2011 Degludecin T1D

27 HeiseT etal, DiabetesCare 2011 Degludecin T2D

28 Sanofi Diabetes HOE901: New basal insulin (new formulation of glargine)

29 New glargineformulation with unique pharmacokinetics New glargine formulation provides New Insulin Glargine Formulation Depot formation after subcutaneous injection Unique flat PK/PD profile Lower injection volume Phase III trials recently initiated Lantus New Glargine Formulation Schematic illustration PK/PD: Pharmacokinetic/pharmacodynamic T2D: Type 2 Diabetes 29

30 10ª EDIZIONE Giornate Diabetologiche Salernitane Il futuro, quindi, proporrà 1) Soprattutto nuove insuline basali, delle quali sapremo ovviamente di più nei prossimi mesi 2) Ma anche eventi in grado di modificare i livelli glicemici a prescindere dal tipo e dalla dose di insulina, di cui sapremo ovviamente di più tra pochi giorni.

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