1. Dr. Abdulmoein Al-Agha, MBBS,DCH, FRCP(UK) Assistant Professor & Pediatric Endocrinologist KAU & Erfan Hospitals aagha@kau.edu.sa Basal-bolus insulin therapy in children with type 1 DM

2. Basic points Most common endocrine disease in childhood Highest incidence in Finland and Sardinia Equal sex affection Highest incidence at 5-7 years and 10-12 years Increasing incidence in very young children (0–4 years) Seasonality ONLY 10-15% OF NEW PATIENTS HAVE A PARENT OR SIBLING WITH THE DISEASE

3. Insulin is a peptide hormone composed of 51 amino acids

4. Banting Best 1921 Insulin was the first discovered (late 1920's) which won the doctor and medical student who discovered it the Nobel Prize (Banting and Best)

5. Banting & Best

6. Patient J.L., December 15, 1922 February 15, 1923 The Miracle of Insulin

7. Insulin Therapy Two main Methods –Conventional therapy BD insulin injections –Intensive therapy Multiple daily injections (basal – bolus regimen) Insulin Pump Therapy

8. Everyone has different needs

9. 1)Maintain near-normal glycaemia 2)Avoid short-term crisis 3)Minimize long-term complications 4)Improve quality of life Goals of insulin therapy Treat The Target !...... Don’t go around it…… ?

10. A1C Goals for Children young age group < 6 yr < 8 – 8.5 % 6 – 12 yr <7.5% 12 – 20 yr <7.0% How to accomplish ????

11. Relative Risk of complications Level of Diabetes Control = HbA 1c Relative Risk of Progression of Diabetes Complications by Mean HbA1c: based on DCCT Data

12. Insulin regimens Most widely used insulin regimens –Twice-daily injections: mixture short & intermediate, before breakfast & evening meal –Three daily injections: mixture short & intermediate before breakfast & dinner, short-acting before lunch –Basal- bolus regimen: short-acting insulin before meals & long – acting basal insulin once daily

13. Typical insulin injection profiles 8101214 16 182022242468 Time BreakfastLunchEvening meal Short acting insulin injection Long Acting insulin injection 2 x daily 3 x daily

14. Limitations of conventional basal insulin Do not mimic basal insulin profile –Variable absorption (inter & intra subject variability) –Pronounced peaks –Less than 24-hr duration of action Cause unpredictable hypoglycemia –Major factor limiting insulin adjustments

15. Ideal basal insulin should be slowly & evenly absorbed with no peak have consistent bioavailability have a long half-life that permits once-daily administration have a reproducible response to allow consistent dosing Freeman SL et al. Diabetes Res Clin Pract 1991;12:187–92; White JR et al. Clinical Diabetes 2001;19:153–9 50% of insulin secretion is basal, 50% is postprandial

16. Basal bolus Therapy Administration of insulin is arranged to mimic the normal basal, prandial & post-prandial secretion of insulin. Short acting forms are usually combined with longer acting preparations to achieve this effect.

17. Basal bolus insulin therapy Patients for multiple injection therapy should: –be selected carefully –understand the relationship between insulin, food and physical exercise –be motivated and have family support –be willing to measure blood glucose several times each day –be willing to inject insulin at school

18. Flexible Bolus calculation Food bolus & correction Bolus

19. Carbohydrate Counting Insulin dosing (bolus) is based on CHO intake Permits more exact dosing of insulin Carbohydrate content can be easily determined Requires familiarity with portion sizes Requires ability to do simple calculations Direct patient to materials on CHO counting

20. Examples of some calculation All of the below contain approximately 15 grams of carbohydrate: ½ cup of fruit juice ½ cup canned fruit 1 cup of whole fresh fruit 1 slice of bread 1 cup of milk ½ cup of potatoes, rice, pasta, beans, peas

21. Reading Food Labels

22. Benefits of Rapid-Acting Insulin in Intensive Therapy

23. Rapid-acting insulin analogues reduce the risk of post-prandial hyperglycemia & late hypoglycemia Normal post-prandial values Insulin lispro, insulin aspart, or insulin glulisine Lower risk of late post-prandial hypoglycaemia Plasma-free insulin (µU/ml) Time after insulin injection or meal ingestion (hours) Regular human insulin 80 60 40 20 0 Meal 024681012 Subcutaneous insulin Better PPBG control PPBG=post-prandial blood glucose Adapted from Bolli GB. Av Diabetol 2007;23:326–32. Reproduced with permission.

24. RHI=regular human insulin; SMBG=self-monitored blood glucose; *p<0.001; † p=0.018 Ashwell SG, et al. Diabet Med 2006;23:285–92. Reproduced with permission. Once-daily insulin glargine + insulin lispro versus once- or twice-daily NPH + RHI, 54 patients Improved glycaemic control with insulin analogues compared with NPH + RHI SMBG profiles at study endpoint BreakfastLunchDinner 270 216 162 108 15 12 9 6 SMBG (mmol/l) Pre-Post-Pre-Post-Pre- Post- Bedtime Night Insulin glargine + insulin lispro NPH + RHI 8.5 8.0 7.5 7.0 HbA 1c (%) Time (weeks) 08162432 * cross-over HbA 1c * * † SMBG (mg/dl)

25. Insulin glulisine (Apidra ® ) Insulin glulisine (Apidra ® ) is a rapid-acting insulin analogue with a shorter duration of action than regular human insulin Insulin glulisine comes in a unique zinc-free formulation, which can be injected up to 15 minutes before, or soon after, each meal − providing flexibility in dosing

26. Insulin glulisine: A unique zinc-free molecular structure Capillary StructuresHexamersR-formatT-formatDimerMonomer ‘Rapid-acting’ insulin analogue: Insulin glulisine No added zinc Polysorbate 20 (Tween 20) Phenolic residues ( ) Zn 2+ ions ( ) ‘Rapid-acting’ insulin analogues: Insulin lispro Insulin aspart T T T T T T Phenol Zn 2+ T T T T T T T T T T T T T T T T T T Adapted from Brange J, et al. Diabetes Care 1990:13;923–54. Becker RH. Diabetes Technol Ther 2007;9:109–21.

27. INS-AUC= insulin infusion rate - area under the curve Adapted from Becker RH, et al. Diabetes Care 2007;30:2506–7. Reproduced with permission. INS-AUC 0–2h : p<0.05 vs RHI Time (hours) Insulin glulisine 0.15 U/kg RHI 0.15 U/kg Insulin (µU/ml) 160 140 120 100 80 60 40 20 0 Absorption of Rapid-acting insulin is twice as rapid as that of regular human insulin (RHI) Euglycemic glucose-clamp study: insulin glulisine versus RHI, 18 patients 0246810

28. PPBG=post-prandial blood glucose; RHI=regular human insulin; SMBG=self-monitored blood glucose Garg SK, et al. Endocr Pract 2005;11:11–7 and data on file. Reproduced with permission. Significantly greater improvement in HbA 1c & PPBG with pre-meal insulin glulisine versus RHI HbA 1c 7.2 7.3 7.4 7.5 7.6 7.7 7.8 BaselineWeek 8Week 12 Mean HbA 1c (%) *p<0.01 vs RHI and post-meal insulin glulisine Basal insulin glargine plus pre- or post-meal insulin glulisine or pre-meal RHI, 860 patients * * † p<0.05 vs post-meal insulin glulisine Pre-breakfast 2-h post-breakfast Pre-lunch 2-h post-lunch Pre-dinner 2-h post-dinner Bedtime Blood glucose (mmol/l) 7 8 9 10 126 144 162 180 Blood glucose (mg/dl) Seven-point SMBG profile at study endpoint † † Pre-meal insulin glulisine Pre-meal RHI Post-meal insulin glulisine

29. Similar reductions in HbA 1c and incidence of hypoglycaemia with insulin glulisine versus insulin lispro Dreyer M, et al. Horm Metab Res 2005;37:702–7. Insulin glulisineInsulin lispro Mealtime insulin glulisine versus mealtime insulin lispro (both + insulin glargine), 672 patients Rate of hypoglycaemia (events/patient-month) Incidence of hypoglycemiaHbA 1c Mean HbA 1c (%) * *p=0.9329 7.60 7.58 * 7.46 7.45 7.35 7.40 7.45 7.50 7.55 7.60 7.65 BaselineEndpoint

30. * GLU and RHI immediately pre-meal; † GLU immediately pre-meal and RHI 30-min post-meal. Children and adolescents: GLU and RHI all immediately pre-meal; PK=pharmacokinetics; PD=pharmacodynamics; GLU=insulin glulisine; RHI=regular human insulin; BG=blood glucose 1. Danne T, et al. Diabetes Care 2005:28;2100−5. 2. Rave K, et al. Diabetes Care 2006;29:1812−7. Reproduced with permission. Insulin glulisine: Similar PK/PD profiles in children and adolescents as in adults Time (minutes) 0100200300400 300 200 100 0 GLU RHI 80 60 40 20 0 GLU RHI Insulin ( µU/ml) Adults 2 * Time (minutes) 060120180240300360 Insulin ( µU/ml) Time (minutes) Adolescents 1 80 60 40 20 0 GLU RHI 060120180240300360 Time (minutes) Insulin ( µU/ml) 80 60 40 20 0 GLU RHI Adults 2† Children 1 300 200 100 0 Adolescents 1 060120180240300360 BG concentration (mg/dl) GLU RHI 300 200 100 0 Children 1 16.7 11.1 5.6 0 BG concentration (mmol/l) BG concentration (mg/dl) 16.7 11.1 5.6 0 BG concentration (mmol/l) BG concentration (mg/dl) 16.7 11.1 5.6 0 BG concentration (mmol/l 060120180240300360 GLU RHI

31. Benefits of Basal Insulin Analog in Intensive Therapy

32. Significantly greater HbA 1c reduction and less hypoglycemia with insulin glargine versus NPH *p<0.05 insulin glargine vs NPH; † HbA 1c analysis values were not aligned with the Diabetes Control and Complications Trial Porcellati F, et al. Diabet Med 2004;21:1213–20. Reproduced with permission. 024681012 Time (months) Mean HbA 1c levels during study Mean HbA 1c ± SEM (%) 6.4 6.6 6.8 7.0 7.2 7.4 7.6 NPH + insulin lispro Insulin glargine + insulin lispro Randomised, non-blinded study of once-daily insulin glargine versus four-times-daily NPH (both + mealtime insulin lispro), 121 patients † 7.2 13.2 3.2 0 2 4 6 8 10 12 14 MildNocturnal Events/patient-month Insulin glargine + insulin lispro NPH + insulin lispro Incidence of mild and nocturnal hypoglycaemia p<0.05 1.2 ** * * * Hypoglycaemia

33. 108 Switching from pre-mixed insulin to basal-bolus insulin glargine + insulin glulisine improves glycaemic control HbA 1c (%) Patients poorly controlled on previous pre-mixed insulin therapy switched to insulin glargine + insulin glulisine, 123 patients Mean HbA 1c p<0.0001 Mean FBG and PPBG Blood glucose concentration (mmol/l) FBG=fasting blood glucose; PPBG=post-prandial blood glucose Schreiber S, et al. Diabetologia 2007;50(suppl 1):S410–1. 216 90 126 144 162 198 180 Blood glucose concentration (mg/dl) Baseline12 weeksFBG2-hr PPBG

34. Insulin glargine: Flexibility in dosing whether given at breakfast, dinner or bedtime Other studies show less inter- and intra-patient variability for insulin glargine vs NPH in: –pharmacodynamic parameters 2 –fasting blood glucose 3 –average serum insulin levels 4 1.Hamann M, et al. Diabetes Care 2003;26:1738–44. Reproduced with permission. 2.Lepore M, et al. Diabetes 2000;49:2142–8. 3.Raskin P, et al. Diabetes Care 2000;23:1666–71. 4.Gerich J, et al. Diabetes Technol Ther 2006;8:237–43. 24-hour blood glucose profile of 378 patients treated with insulin glargine at breakfast, dinner or bedtime 1 Mean blood glucose (mmol/l) 12 10 8 6 4 2 0 Fasting2h afterBefore2h afterBefore2h afterBedtime03.00 breakfast lunch lunch dinner dinner Timing of blood glucose measurement Breakfast Dinner Bedtime Mean blood glucose (mg/dl) 216 180 144 108 72 36 0

35. Switching to basal-bolus insulin glargine + insulin glulisine improves metabolic control in clinical practice FBG=fasting blood glucose; PPBG=post-prandial blood glucose Ruhnau K, et al. Diabet Med 2006;23(Suppl 4):343 (Abstract P952). 1,447 patients with poorly controlled type 1 diabetes mellitus switched to basal-bolus therapy with insulin glargine + insulin glulisine HbA 1c (%) Blood glucose (mmol/l) HbA 1c during the studyFBG and PPBG 180 162 144 126 108 90 Blood glucose (mg/dl)

36. Pen Injection Force

37. + Apidra ® SoloSTAR ® Lantus ® SoloSTAR ® Apidra ® SoloSTAR ® and Lantus ® SoloSTAR ® : Same but differentiated device for ease of use and increased safety

38. Apidra ® SoloSTAR ® and Lantus ® SoloSTAR ® injection forces are lower than either FlexPen ® or Lilly Humulin ® /Humalog ® pen SoloSTAR ® has a lower injection force compared with the currently most widely used disposable insulin pens − ease of injection provides clinical benefit Clarke A, Spollett G. Expert Opin Drug Deliv 2007;49:165−74. Average force to deliver a 40 U dose in 4 seconds 30 25 20 15 10 5 0 Force (Newtons) Insulin detemir FlexPen ® Lantus ® SoloSTAR ® Lilly NPH pen Lantus ® SoloSTAR ® Insulin aspart FlexPen ® Apidra ® SoloSTAR ® Lilly insulin lispro pen Apidra ® SoloSTAR ® –54% –59% –40% –31% Basal insulinPrandial insulin

39. More patients prefer the injection force of SoloSTAR ® pen SoloSTAR ® pen FlexPen ® Humulin ® / Humalog ® pen 70 60 50 40 30 20 10 0 Patients (%) *p<0.05 vs FlexPen ® † p<0.05 vs Humalin ® /Humalog ® pen Adapted from Haak T, et al. Clin Ther 2007;29:650−60. *†*† †

40. Summary - 1 Timely initiation of insulin is critical Insulin analogs most closely match normal physiology There is a wide variety of insulin regimens and insulin delivery methods It is important to match the insulin regimen to patient lifestyle and characteristics When blood glucose goals are not met, titrate insulin in a timely manner

41. Summary -2 Basal-bolus therapy should be the treatment of choice: –Enabling FBG & PPBG to be controlled separately –Allowing for flexible dosing and timing of injections –Insulin glargine offers peak less 24-hour coverage Rapid – Acting analogue Insulin offer a fast onset of action and effective post-meal glycaemic control –As effective in children and adolescents as in adults

42. Summary - 3 Insulin glargine versus NPH in paediatrics and adolescents: –HbA 1c level is similar or better 1,2 –Fasting blood glucose is better controlled 3 –Rates of severe and nocturnal hypoglycaemia are significantly reduced 4,5 Insulin glulisine versus insulin lispro in paediatrics and adolescents: –Greater proportion of patients achieving target HbA 1c 6 1. Karagüzel G, et al. Diabetes Res Clin Pract 2006:74:15–20. 2. Chase HP, et al. Diabetes 2006;55(suppl 1):A476. 3. Murphy NP, et al. Diabetes Care 2003;26:799–804. 4. Herwig J, et al. J Pediatr Endocrinol Metab 2007;20:517–25. 5. Deiss D, et al. Pediatr Diabetes 2007;8:157–62. 6. Philotheou A, et al. Presented at Diabetes UK Annual Professional Conference 2008, 5–7 March 2008, Glasgow, Scotland.