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ARE INSULIN ANALOGUES ANY BETTER FOR THE MANAGEMENT OF TYPE 1 DIABETES ?

ARE INSULIN ANALOGUES ANY BETTER FOR THE MANAGEMENT OF TYPE 1 DIABETES ?. DR COLIN JOHNSTON WHHT. GOALS OF MANAGEMENT . IMPROVED LIFE-EXPECTANCY REDUCED MORBIDITY/COMPLICATIONS IMPROVED QUALITY OF LIFE. INFLUENCES ON QUALITY OF LIFE. FREEDOM FROM COMPLICATIONS FREEDOM FROM HYPOGLYCAEMIA

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ARE INSULIN ANALOGUES ANY BETTER FOR THE MANAGEMENT OF TYPE 1 DIABETES ?

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  1. ARE INSULIN ANALOGUES ANY BETTER FOR THE MANAGEMENT OF TYPE 1 DIABETES ? DR COLIN JOHNSTON WHHT

  2. GOALS OF MANAGEMENT • IMPROVED LIFE-EXPECTANCY • REDUCED MORBIDITY/COMPLICATIONS • IMPROVED QUALITY OF LIFE

  3. INFLUENCES ON QUALITY OF LIFE • FREEDOM FROM COMPLICATIONS • FREEDOM FROM HYPOGLYCAEMIA • KNOWLEDGE AND BEING ‘IN CONTROL’

  4. INSULIN • 1921 INSULIN INTRODUCED • ANIMAL DERIVED • 1947 NPH • 1970s MC PORCINE • 1980s HUMAN • 1990s-now ANALOGUES

  5. CLINICAL MANAGEMENT OF TYPE I DIABETES IN 1989 • LIFE EXPECTENCY IMPROVED • COMPLICATIONS STILL SEVERE • MOST PATIENTS POORLY CONTROLLED • MANY ON BD REGIMENS • HUMAN INSULIN SAGA

  6. NICE GUIDELINES/TARGETS HbA1C 6.5-7.5%

  7. 24-hour plasma glucose and insulin profiles in healthy individuals ©Elsevier Science. Reproduced with permission from Elsevier Science (The Lancet, 2001, Vol 358, pages 739–746). Owens DR et al. Lancet 2001;358:739–746

  8. NovoRapid®: more physiological insulin profile than soluble human insulin Insulin aspart, t = 0 min Human insulin, t = 0 min Human insulin, t = –30 min (insulin dose 0.15 U/kg) 600 500 400 Plasma insulin (pmol/l) n = 22 300 200 100 0 0 1 2 3 4 5 6 Time (hours) Lindholm et al. Diabetes Care 1999;22:801-5 024

  9. 24-hour plasma glucose and insulin profiles in healthy individuals ©Elsevier Science. Reproduced with permission from Elsevier Science (The Lancet, 2001, Vol 358, pages 739–746). Owens DR et al. Lancet 2001;358:739–746

  10. Pro Asp Phe Gly Arg Phe Tyr Glu Thr Gly Asp Cys B28 Lys B30 Thr A21 Asn Cys Val Tyr Leu Gly Asn Tyr Ile Glu Leu Val Leu Ala Glu Gln Glu Gln Tyr Val Cys Leu Ser Cys Thr Ser Ile Leu Cys His Ser Gly Cys Leu B1 Phe Val Asn Gln His Structure of insulin aspart

  11. NovoRapid®: more physiological insulin profile than soluble human insulin Insulin aspart, t = 0 min Human insulin, t = 0 min Human insulin, t = –30 min (insulin dose 0.15 U/kg) 600 500 400 Plasma insulin (pmol/l) n = 22 300 200 100 0 0 1 2 3 4 5 6 Time (hours) Lindholm et al. Diabetes Care 1999;22:801-5 024

  12. Self-monitored blood glucose profilesEuropean trial 12 Insulin aspart Human insulin 11 p < 0.001 10 p < 0.01 p < 0.001 p < 0.01 9 Blood glucose (mmol/l) p < 0.01 8 7 n = 1070 6 0 Before and90 min after breakfast Before and90 min after dinner 2 a.m. Before and90 min after lunch Bedtime Home et al. Diabetic Med 2000;17:762-70 035

  13. 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0 Postprandial blood glucose increment:mean over the three meals at 6 months p < 0.001 p < 0.001 Insulin aspart Human insulin Blood glucose increment (mmol/l) Prandial increment is the mean increase in blood glucose from pre-meal to 90 min post-meal European trial North American trial n = 884 n = 1070 Home et al. Diabetic Med 2000;17:762-70, Raskin et al. Diabetes Care 2000;23:583-8 035, 036

  14. 10 –2 –1 0 1 2 3 4 5 6 7 8 9 11 12 Basal-bolus dose optimisation study: protocol Insulin aspart + basal NPH insulin n = 213 Run-in Screening n = 213 Human insulin + basal NPH insulin Time (weeks) Nine-point blood glucose profile Blood sampling for HbA1c/dosing and adverse event assessment Tamas et al. Diabetes Res Clin Pract 2001;54:105-14 065

  15. Basal dose optimisation study: glycaemic control (2) **p < 0.01 n = 426 8.5 Baseline ** 8.3 12 weeks ** 8.1 HbA1c (%) 7.9 7.7 7.5 NB: Broken axis 0 Insulin aspart Human insulin Tamas et al. Diabetes Res Clin Pract 2001;54:105-14 065

  16. IAsp HI Insulin aspart significantly reduces the rate of severe nocturnal hypoglycaemia 72% risk reduction with IAsp 3 n = 155 2.5 2 Hypoglycaemia event rate (events per patient-year) 1.5 1 0.5 0 Totalevents Nocturnalevents Diurnalevents Heller et al. Diabetic Medicine 2004, in press 066

  17. 10 8 6 4 2 0 5 Differences between DTSQ scores for insulin aspart and HI groups from baseline to 3 and 6 months Favours insulin aspart Favours human insulin 3 months Preference-weighted treatment satisfaction Total DTSQ score 6 months Preference-weighted treatment satisfaction Total DTSQ score Data are mean differences in unadjusted changes in DTSQ scores and 95% CI Bott et al. Diabet Med. 2003 Aug;20(8):626-34. 035 QoL

  18. Conclusions • Patients considered insulin aspart treatment to be more flexible and convenient compared with HI • Overall treatment satisfaction improved with insulin aspart treatment • Insulin aspart improved QoL regarding diet restrictions compared with HI • Modest benefits in glycaemic control Bott et al. Diabetic Medicine 2003;20:626-634 035 QoL

  19. Limitations of protracted-acting insulin formulations – peak in insulin levels (1) Patients with Type 1 diabetes Study duration 4 weeks (+ 15-day run-in period) n=29 (subset shown) Porcellati F et al. Diabetologia 2001;44(Suppl 1):A208 (Abstract 799) (Adapted from poster)

  20. COOH A-chain A21[Gly] NH2 COOH S B31[Arg] B32[Arg] S B-chain S NH2 S S S Primary structure of insulin glargine (Lantus®) Rosskamp R, Park G. Diabetes Care 1999;22(Suppl 2):B109–B113

  21. Retardation principle of insulin glargine (Lantus®) Clear solution pH 4 Acidic solution injected (pH 4) Precipitation in tissue (pH 7.4) Slow dissolution of free hexamers from precipitated insulin glargine (Lantus®) Delayed absorption, protracted action pH 7.4 Precipitation Dissolution Hexamer Dimers Monomers 10-3 M 10-5 M 10-8 M Capillary membrane Insulin in blood Heinemann L et al. Diabetes Care 2000;23:644–649

  22. Pharmacokinetics of insulin glargine (Lantus®) – flat insulin profile with no pronounced peaks (1) Patients with Type 1 diabetes Study duration 4 weeks (+ 15-day run-in period) n=29 Porcellati F et al. Diabetologia 2001;44(Suppl 1):A208 (Abstract 799) (Adapted from poster)

  23. Pharmacodynamics of insulin glargine (Lantus®) – flat activity profile with no pronounced peaks (1) Patients with Type 1 diabetes Study duration 4 weeks (+ 15-day run-in period) n=29 Porcellati F et al. Diabetologia 2001;44(Suppl 1):A208 (Abstract 799) (Adapted from poster)

  24. Less intrasubject variability with insulin glargine (Lantus®) vs NPH insulin (1) Patients with Type 1 diabetes *p <0.05 vs CSII and insulin glargine Study duration 4 weeks (+ 15-day run-in period) n=29 Porcellati F et al. Diabetologia 2001;44(Suppl 1):A208 (Abstract 799) (Adapted from poster)

  25. Significantly lower FPG and HbA1c with insulin glargine (Lantus®) vs NPH insulin *p=0.0005 and **p=0.03 vs insulin glargine (Lantus®) treatment groups combined Study duration 4 weeks n=333 Only the insulin glargine [30] formulation is marketed Pieber TR et al. Diabetes Care 2000;23:157–162

  26. Significantly lower FPG with less hypoglycaemia, with insulin glargine (Lantus®) vs NPH insulin Hypoglycaemia *p <0.03; **p<0.02 Study duration 28 weeks; n=534 Ratner RE et al. Diabetes Care 2000;23:639–643

  27. Benefits of insulin glargine (Lantus®) in Type 1 diabetes • Lower FBG level achieved with insulin glargine (Lantus®) versus NPH insulin in combination with either regular human insulin or insulin lispro • Equivalent reduction in HbA1c compared with NPH insulin • Efficacy associated with a lower risk of hypoglycaemia, especially nocturnal and/or severeepisodes

  28. NICE GUIDANCE TECH APRAISAL 53 DEC 2002 A TREATMENT OPTION FOR THOSE WITH TYPE 1 DIABETES

  29. AUDIT OF GLARGINE AT HH/SACH • 56 SUBJECTS (8 NOT FOLLOWED, ) • 41/48 HBAIC FELL FROM 8.6% TO 8.1% AT 6 MONTHS • 40 CONTACTABLE , 29 REDUCED HYPOGLYCAEMIA, 11 NO CHANGE • 26 IMPROVED QUALITY OF LIFE 14 NO CHANGE

  30. WHY CONTINUED POOR CONTROL • CLINICAL EXPERIENCE • VARIATION IN INSULIN ACTION • SAFETY • PEN DEVICE • OTHERS

  31. Insulin detemir – amino acid structure LysB29(N-tetradecanoyl)des(B30)human insulin C14 fatty acid chain (Myristic acid) Phe Gly Phe Arg Tyr Glu Thr Gly Pro Cys Lys Val Thr Lys Asn Cys A21 B29 Leu Tyr Gly A1 Asn Tyr Ile Leu Glu Val Leu Ala Glu Glu Gln Gln Tyr Val Cys Leu Leu Cys Ser Ser Thr Ile Cys His Ser Gly Cys Leu Gln His Asn Val Phe B1

  32. Insulin detemir – albumin binding • the myristic acid attached to position B29 of the insulin detemir molecule binds to albumin • >5 distinct free fatty acid binding sites are available per albumin molecule5 5) Curry et al., Nature Structural Biology,1998; Vol. 5: 827-835

  33. 5.0 4.0 Insulin detemir, 0.4 U/kg 3.0 GIR (mg/kg/min) 2.0 1.0 0 14 16 18 20 22 24 0 2 4 6 8 10 12 Time since insulin injection (hours) Time-action profile of insulin detemir • Insulin detemir provides a smooth and protracted pharmacodynamic profile10 • The duration of action of insulin detemir is up to 24 hours depending on dose10 Adapted from 10) Pieber et al. Diabetes, 2002;51 (Suppl. 2): A53

  34. Detemir significantly reduces within patient variability vs. glargine and NPH -60% -44% GIR-AUC0-24h Co-efficient of variation (%) p < 0.001 • 24-hour clamp study • 54 subjects • 0.4 U/kg CV = Co-efficient of variation = (Standard deviation / Mean) x 100 expressed as percentage 1. Heise, T. et al., Diabetes, 2003; Vol. 52 (Suppl. 1): A121 Medinfo/Det/0147 April 2004

  35. Insulin detemir - long-term safety12 Adapted from: 12) Kurtzhals P. et al., Diabetes 2000; Vol. 49: 999-1005

  36. 1374 Study design 8.Hermansen et al Diabetes UK abstract 2004 type 1 64 sites in 15 countries Randomized 1:1 Insulin Detemiram+bed + meal aspart (n = 298) 2 weeks NPHam+bed + meal HSI (n = 297) Screening Randomization 18 weeks Titration target: European Diabetes Policy Group (5.7-7.3 mmol/L fasting and pre-prandial; 8.5-10.1 mmol/L post-prandial) Medinfo/Det/0147 April 2004

  37. 1374 Results of HbA1C 8.Hermansen et al Diabetes UK abstract 2004 9. Data on File 1374 Non-inferiority criterion: Upper confidence limit of difference <0.4% (absolute) Superiority criterion: Non-inferiority met and upper confidence limit of difference <0% (absolute) Medinfo/Det/0147 April 2004

  38. Hypoglycaemia • Detemir reduced the risk of allhypoglycaemic episodes by 22% vs. NPH • Detemir reduced the risk of nocturnal hypoglycaemic episodes by 34% vs. NPH 3. Vague, P. et al., Diabetes Care, 2003; Vol. 26, No. 3: 590-596 Medinfo/Det/0147 April 2004

  39. 6) Russell-Jones, D. et Al Diabetologia 2002;45(Suppl. 2):A147 3) Vague, P. et al., Diabetes Care, 2003; Vol. 26, No. 3: 590-596 4) Standl, E. et al., Diabetes, 2002; Vol. 51 (Suppl. 2): A115 5) De Leeuw, I. et al., Diabetologia 2002;45(Suppl. 2):A257 No weight gain (in type 1’s) 6 month studies 12 month studies p = 0.002 1.5 p < 0.001 1.4 Insulin detemir 1.2 1.0 NPH insulin p = 0.001 p = 0.003 0.7 0.5 Changes in body weight (Kg) 0.4 0 0.1 0.2 0.2 0.3 -0.5 Vague Russell-Jones Leeuw, de Standl Medinfo/Det/0147 April 2004

  40. IMPROVED CONTROL IN TYPE 1 DIABETES PROGRESS? • INSULIN TYPE • INSULIN DELIVERY • GLUCOSE MONITORING • DIET (DAFNE) • PSYCHOLOGY

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