Hypoglycemia a barrier to normoglycemia Are long acting analogues and pumps the answer to the barrier??

Transcription

1 Hypoglycemia a barrier to normoglycemia Are long acting analogues and pumps the answer to the barrier?? Moshe Phillip Institute of Endocrinology and Diabetes National Center of Childhood Diabetes Schneider Children s Medical Center

2 Diabetes is Devastating and Deadly Leading cause of blindness in adults Cardiovascular disease and stroke 2-4x Amputations 15-40x Leading cause of end-stage renal disease Diabetes is the 4th leading cause of death by disease; 7th leading cause of death in US American Diabetes Association, Vital Statistics 1996

3 Trade-off Between Hypoglycemia & Complications Rate pf progression of retinopathy (per 100 patient years) Relative risk Severe hypoglycemia 120 of retinopathy HbA1c (%) Rate of severe hypoglycaemia (per 100 patient years) DCCT Research Group, 1993

4 Hypoglycemia during insulin Rx 50% of severe episodes of hypoglycemia in the DCCT patients occurred during sleep Children with type 1 diabetes appear to be at an increased risk of severe hypoglycemia, with prevalence rates of up to 85.7 episodes per hundred patient years Porter PA, et al. J Pediatr 1997; 130:

5 New clinical information with CGMS, 2000

6 Methods 52 Children and adolescents with type 1 diabetes ages participated in the study. All children received intensive insulin therapy. Glucose sensors were used for 52 measurements of 72 hours each. Children were asked to perform self monitoring of blood glucose 4-7 times a

7 Methods II Frequency of hypoglycemia, hyperglycemia, maximum and minimum readings were compared between the sensor and the selfmonitored records

8 Sensor records vs. self-blood glucose measurements (SBGM) Variable Hypoglycemic episodes/night Hypoglycemic episodes/day Hyperglycemic episodes/night Hyperglycemic episodes/day Post-prandial hyperglycemia Sensor 0.41 (0.38) 0.74 (0.68) 0.96 (0.69) 1.72 (0.80) 2.19 (0.90) SBGM 0.13 (0.25) 0.33 (0.33) 0.79 (0.51) 1.47 (0.85) 0.86 (0.65) P <0.001 < <0.001 Amir Schechter,Naomi Weintrob, Hadassa Benzaquen, Moshe Phillip

9 Distribution of Blood Glucose Levels During Daytime 4% Hypoglycemia duration Hyperglycemia duration Normoglycemia duration 51% 45%

10 Distribution of Blood Glucose Levels During Night Time 14% 41% Hypoglycemia duration Hyperglycemia duration Normoglycemia duration 45%

11 At least one event of hypoglycemia was recorded in 42% of the nights

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13 Multicenter randomized parallel-group study 534 type 1 diabetic subjects, aged 38.5 ± 12 (18 80) years Regular insulin and either insulin glargine (at bedtime) or NPH insulin (once/twice-daily) Duration, 28 weeks (one month titration) Glycemic control: Reduction of GHb were similar in both groups. Ratner RE et al Diabetes Care. 2000;23:

14 Patients P=.022 P=.012 Insulin Glargine (n=264) NPH Insulin (n=270) P= All Symptomatic Nocturnal Severe Ratner RE et al Diabetes Care. 2000;23: Type of Hypoglycaemia Adult patients experiencing 1 1 episode of hypoglycaemia confirmed by a blood glucose level <2.0 mmol/l

15 P=NS P=0.44 1Ashwell et al Diabet Med. 2006;23: Pieber TR et al Diabetes Care. 2000;23: Raskin P et al Diabetes Care. 2000;23:

16 100 Insulin Glargine (n=174) % 78.9% NPH Insulin (n=175) Patients (%) % 28.6% 48.3% 50.9% 12.6% 17.7% 0 All Symptomatic Severe Nocturnal Severe Nocturnal Schober et al. J Pediatr E. M. 2002;15:

17 Study N HbA1c Sever Hypo Aspart vs 16w, 18-65y No change Regular (1) PRCT 0.85 NS Detemir vs 12mo, 18-74y No change NPH (2) Pros randomized 0.12 NS Detemir vs 16w, 38-56y NS NPH (3) PRCT NS CSII vs 12mo, 2-40y P<0.001 NPH(4) retrospective P=0.002* Education program(5) 12mo,3-18y Pros randomized No change P= Heller SR et al Diabet Med 21:769-75, Standl E el al Diabetes Tech & Therap 6:579-88, Kolendrof K et al Diabet Med. 23:729-35, Nimri R et al Pediatrics. 70:1-7, Nordfeidt S et al Arch Dis Chaild. 88:240-5,2003 *Adolescents group 127 patients

18 PUMPS

19 24-h profiles of blood insulin and glucose concentrations in non-diabetic subjects.

20 Insulin Pump Therapy Basal Rate Continuous flow of insulin Takes the place of NPH or Ultralente insulin 6 Meal Boluses Insulin needed with meal, based on: Pre-meal BG, carbohydrates in meal, & activity level Supplemental insulin for high BG 5 4 Meal Boluses Units Basal Rate 12 am 12 pm 12 am

21 Randomized controlled crossover trail

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25 There was a marked reduction in the frequency of hypoglycemic events using CSII compared to MDI Hypoglycemic events per patient year in the CSII group: Mild hypoglycemia (Vs 55.4 in MDI) 0.2 Sever hypoglycemia (Vs 0.5 in MDI)

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33 Ped. Sept 2003 The Schneider Group, 2001

34 Design Open, randomized, crossover study comparing 3.5 months of CSII with 3.5 months of MDI A (11) Run in 2 weeks CSII: 3.5 months Run in 2 weeks MDI: 3.5 months Patients included in the study Randomized Crossover (12) B Run in 2 weeks MDI: 3.5 months Run in 2 weeks CSII: 3.5 months Cohen D et al, J Pediatr Endocrinol Meta 2003 Sep;116(7): Weintrob N et al, Pediatrics Sep;112(3 Pt 1):559-64

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37 Results: Comparison Between CSII & MDI Variable CSII MDI P Hypoglycemia No. of events 24 hours 1.1 (0.8) 1.1 (1.0) 0.90 AUC-night 198 (300) 433 (544) 0.01 AUC-24 hours 377 (377) 638 (727) 0.04 AUC postprandial 24 (42) 64 (113) 0.03 AUC before breakfast 16 (32) 36 (58) 0.06 Hyperglycemia No. of events 24 hours 3.4 (1.2) 2.9 (1.0) 0.04 AUC 24 hours (5528) (6495) 0.15 AUC postprandial 1454 (1292) 2282 (2174) 0.05 AUC before breakfast 390 (461) 566 (548) 0.11 Weintrob N et al Arch Pedi Adolesc Med 158(7):677-84, 2004

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41 Pumps in youth with type 1 DM Nimri et al ; Pediatrics Jun; 117(6): ; 2006

42 Pumps in youth with type 1 DM Nimri et al ; Pediatrics Jun; 117(6): ; 2006

43 Pumps in youth with type 1 DM Nimri et al ; Pediatrics Jun; 117(6): ; 2006

44 A significant decrease in HbA1c was demonstrated after the start of CSII in all age groups. The rate of sever hypoglycemic episodes decreased significantly in the adolescent group from 36.5 to 11.1 events per 100 patient-year and in the young adult group, from 58.1 to 23.3 Nimri et al ; Pediatrics Jun; 117(6): ; 2006

45 Hypoglycemia Better insulin delivery Hyperglycemia Better glucose monitoring

46 β-cell and I.V. I.V. Route Insulin Action (~30 min) I.V. I.P. Route Absorption of I.P. Regular Insulin (~40 min) Insulin Action (~30 min) S.C. S.C. Route Absorption of S.C. Short-Acting Insulin (~50 min) Insulin Action (~30 min) IG-PG Kinetics (~10 min) Transport Lag (~15 min) Hovorka R, Diabetic Medicine 23,1-2, 2005 Time (min)

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48 Admon G, Pediatrics Sep;116(3):e348-55, 2005

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51 Pumps Vs MDI

52 Cryer PE,N Engl J Med 2004;350:

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54 Sensing Arm Insulin Delivery Arm (Response and Action)

55 Diabetes Control Hyperglycemia Hypoglycemia

56 Physician Educator Nurse Dietitian Social Worker Psychologist THE DIABETES TEAM

57 Institute of Endocrinology and Diabetes National Center of Childhood Diabetes Schneider Children s s Medical Center

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59 Multi-center, randomized, cross-over study. 56 patients, aged 41.1 ± 12.2 years, treated with insulin glargine and rapid insulin analog or NPH insulin (once/twice-daily) and regular insulin for 32 weeks period. Ashwell et al Diabet Med. 2006;23: Multi-center, randomized study. 333 patients. Aged years ( mean 35.8). 110 patients received NPH insulin treatment (once/twice-daily) and 223 patients received glargine insulin treatment (two formulations ) as basal insulin and regular insulin at meal time for 4 weeks.

60 Multi-center, randomized study. 619 patients aged 39.2 ± 12.2 years, were randomized to treatment with insulin glargine or to NPH insulin treatment (once/twice-daily) as basal insulin and rapid insulin analog at meal time for 16 weeks period.