Designer Insulins. History case 1. Follow up - case 1. Follow up - case 1. History - case hr glucose profile - case 1

Transcription

1 History case 1 33 yr old male bank manager Designer Insulins Dr A Qureshi MB ChB (Edin), MD (Lon), CCT (Lon), FRCP (Lon) Consultant in Endocrinology, Diabetes and General Internal Medicine w w w. e n d o c r i n o l o g y s p e c i a l i s t. c o m Type I diabetes since age 6 Actrapid U tds and Ultratard 3units nocte Wt 7.7kg, BMI 3 No evident microvascular complications BP 15/92 HbA1c 7.% Private practice Clementine Churchill Garden Hospital Wellington Hospital NH practice Northwick Park Hospital Commenced on Humalog 6U tds and Ultratard 36U to improve control Follow up - case 1 24 hr glucose profile - case Weight 3.kg Fall in HbA1c. To Nocturnal hypos Weight.2kg HbA1C.4%??? Check results on Additional insulin Glucose - mmol/l ugar Follow up - case 1 Ultratard substituted with Glargine 32U At follow up HbA1C.1% BP 13/1 Wt 2.4kg No further hypoglycaemic episodes History - case 2 61 yr old woman with Type II diabetes (1997) Maculopathy Hypothyroidism Mixtard 3/7 24U bd Weight 71.3kg, BP 17/ HbA1C 1.5% Plan Humalog mix 25 2U bd to improve control 1

2 Follow up - case 2 24 Weight 7kg BMI 3Kg/m 2 HbA1c 11.5% For poor control switched to Basal bolus Novorapid 1U tds and Glargine 1U nocte 25 HbA1c 9.5% ummary Case 1 Type I diabetes with poor control and hypos hort acting analogues failed to improve HbA1c Nocturnal hypos improved with long acting analogue Case 2 Type II with poor control Twice daily insulin analogue failed to improve HbA1c Basal bolus regime was more successful Weight 73.kg tructure of insulin erum insulin in normal individuals C Chain Breakfast Lunch Dinner nack Alpha Chain Beta Chain Ala Lys Pro erum insulin conc. (micromol/l) Galloway JA, Chance RE. Improving insulin therapy: achievements and challenges. Horm Metab Res Dec;26(12):591-. Review 2

3 History of insulin preparations Frederick Grant Banting Born in Nov 191 urgeon in Ontario Fond of dogs earched for the anti-diabetic component of the pancreas Isolated insulin in 1921 with Charles Best Died 1941 History of insulin preparations 193s 195s 197s 19s 19s 199s Protamine zinc insulin Neutral protamine Hagedorn and insulin zinc plit-mix insulins Purified pork insulins Recombinant human insulins Insulin analogues Insulin preparations available in UK Principle of bd mixed-insulins HORT-ACTING (n>) Actrapid Humulin MEDIUM AND LONG-ACTING INULIN (n>13) Insulatard Ultratard Humulin I MIXED INULIN (n>16) Mixtard 3/7 Humulin M3 RAPID-ACTING ANALOGUE NovoRapid (Aspart) Humalog (Lispro) Apidra (Glulisine) LONG-ACTING ANALOGUE MIXTURE Lantus (Glargine) Levemir (Detemir) ANALOGUE MIXTURE Humalog Mix 25, Mix 5 NovoMix Breakfast Tea 1 3

4 Basal bolus (1) Basal bolus (2) Breakfast Lunch Tea Bed Breakfast Lunch Tea Pre-mixed insulin tds Breakfast Lunch Tea Why develop new insulin preparations? Insulin uptake Adipose tissue per 1 patient years Risk of severe hypoglycaemia Risk of retinopathy 12 6 per 1 patient years Hexamers Capillary membrane Dimers Monomers HbA 1c (%) Insulin in blood Adapted from: The DCCT tudy Group, NEJM, 1993; Vol. 329, No. 14:

5 hort acting analogues Insulin analogues Adipose tissue Lys C Chain Alpha Chain Arg Arg Gly Dimers Monomers Pro Lys Asp Beta Chain Hexamers Capillary membrane Insulin in blood Aspart Lispro Glargine Detemir Clinical effectiveness of Lispro and Aspart hort acting analogues In type I diabetes 1 Aspart Humalog Regular insulin erum insulin conc. (micromol/l) 9 Better postprandial glucose 13,14 Reduced severe hypoglycaemic episodes Improved HbA1c versus regular insulin when used in pumps No or little improvement in HbA1c In type II diabetes 2 25% reduction in severe hypos No improvement in HbA1c15-1 Long acting analogues Glargine Adipose tissue PH Dimers Monomers Plasma Insulin Hexamers Glargine C injection NPH insulin B Capillary membrane L 1 12 D Time of Day (hr) Insulin in blood N. Younis, H. oran and D. Bowen-Jones. Insulin Glargine: a new basal insulin analogue Q J Med 22; 95:

6 Glargine The Thomas Addison Unit Patients (%) With 1 Hypoglycaemia Episode Basal insulin * * * * * Lantus NPH insulin B L D Time of Day (hr) * 2 Percentage of patients Type I Regular insulin Type II Insulin analogues n=92 M. Riddle, J. Rosenstock, and J. Gerich. The Treat-to-Target Trial: Randomized Addition of Lantus or Human NPH Insulin to Oral Therapy of Type 2 Diabetes Patients for the Insulin Glargine.Diabetes Care 23;26:11 n=92, Type I =17% and type II=3% of all patients hort acting analogues HbA1c in type I diabetes hort acting analogues hypoglycaemic episodes in type I diabetes Bode (22) Bode (22) Ciofetta (1999) Home (2) Iwamoto (21) Raskin (2) Recasens (23) Annuzzi (21) Ferguson (21) Favours analogues Favours regular Bode (22) Bode (22) Ciofetta (1999) Del indaco (199) Del indaco (199) Gale (2) Renner (1999) chmauss (199) Vignati (1997) Favours analogues Favours regular iebenhofer A et al. hort acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Review. Issue 3, 24 iebenhofer A et al. hort acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Review. Issue 3, 24 hort acting analogues HbA1c in type II diabetes hort acting analogues hypoglycaemic episodes in type II diabetes Ross (21) Vignati (1997) Herz (22) Ross (21) Vignati (1997) Favours analogues Favours regular Favours analogues Favours regular iebenhofer A et al. hort acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Review. Issue 3, 24 iebenhofer A et al. hort acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Review. Issue 3, 24 6

7 Insulin analogues in type I (summary) Why develop new insulin preparations? HbA1c evere Noct Minor Overall Weight hypos hypos hypos hypos gain Lispro / Aspart / Glargine / / Rate of severe hypoglycemia per 1 person years DCCT HbA1c (%) Hypoglycemia rates Humalog HbA1c (%) Detemir HbA1c Chase HP, Lockspeiser T, Peery B, hepherd M, MacKenzie T, Anderson J, Garg K. The impact of the diabetes control and complications trial and Humalog insulin on glycohemoglobin levels and severe hypoglycemia in type 1 diabetes. Diabetes Care. 21 Mar;24(3):43-4. Insulin analogues in type II (summary) Cost HbA1c evere Noct Minor Overall Weight hypos hypos hypos hypos gain Lispro Aspart Glargine Detemir Approximate annual costs* hort acting insulins Aspart (NovoRapid) 36 Lispro (Humalog) 36 Actrapid 27 Humulin 31 Long acting insulins Levemir (Detemir) 19 Lantus (Glargine) 19 Longer-acting Humulin I 13 Insulatard 11 Biphasic insulins NovoMix 3 36 Humalog Mix25 36 Humulin M3 31 Mixtard 3 27 * Based on information in Chemist & Druggist. Calculated using cartridge costs, and assuming the patient is using 5 units daily of a short-acting insulin, 2 units daily of a longer-acting insulin or 5 units daily of a biphasic insulin. Future preparations New insulin analogues Inhaled insulin Oral Modified insulin ublingual insulins Buccal insulins Rectal insulins 7

8 Inhaled insulins aliva Enzymes Enzymes Mucosa PH Enzymes Unpleasant Inhaled insulin profile Breakfast Lunch Dinner nack erum insulin conc. (micromol/l) Plasma insulin concentration with Inhaled administration Plasma insulin concentration with Inhaled administration Inhaled insulin Insulin analogue recommendations Type I diabetes mellitus with frequent severe hypoglycaemia 1 Type II diabetes mellitus Not first line 1 12 control non-diabetic subjects 1 non-obese subjects with type I diabetes 3 smoker, 5 ex-smokers and 2 non-smokers (±D) If significant recurrent hypos 1 (require assistance to administer insulin) 2 Almer LO, Wollmer P, Jonson B, Troedsson Almer A. Insulin inhalation with absorption enhancer at meal-times results in almost normal postprandial insulin profiles. Clin Physiol Funct Imaging. 22 May;22(3): DTB Dec (24) 2.NICE (22)