1. Insulin Therapy In The Treatment Of T2DM Prof. Ibrahim El-Ebrashy Cairo University Head Of Diabetes & Endocrinology Center

2. T2DM is insulin resistance + insulin deficiency Type 2 diabetes –Characterised by insulin resistance and insulin deficiency –Degrees of resistance and deficiency vary but insulin deficiency is key to developing diabetes Adapted from Bergenstal et al. In: Degroot & Jameson (eds). Endocrinology 2001;821–35

3. Slide No 3 Natural history: insulin secretion and blood glucose control IFG, impaired fasting glucose 350 300 250 200 150 100 50 Postprandial glucose Fasting glucose ObesityIFGDiabetesUncontrolled hyperglycaemia 250 200 150 100 50 Insulin resistance Insulin level Years of diabetes –102520151050–530 Beta-cell failure Glucose level (mg/dL) Relative function (%) Normal Adapted from Bergenstal et al. In: Degroot & Jameson (eds). Endocrinology 2001;821–35

4. Improving control reduces risks of long-term complications Every 1% drop in HbA 1c can reduce long-term diabetes complications 43% Lower extremity amputation or fatal peripheral vascular disease 37% Microvascular disease 19% Cataract extraction 14% Myocardial infarction 16% Heart failure 12% Stroke UKPDS 35: Stratton et al. BMJ 2000;321:405–12 Slide no 4

5. Positive legacy effect of early, intensive glucose control RRR = Relative Risk Reduction Red indicates significant reduction on intensive therapy vs. conventional therapy At end of post-trial follow up (median 8.5 years) Aggregate endpoint19972007 Any diabetes-related endpoint RRR:12%9% Microvascular diseaseRRR:25%24% Myocardial infarctionRRR:16%15% All-cause mortalityRRR:6%13% UKPDS 80. Holman et al. N Engl J Med 2008; 359:1577-89 Slide no 5

6. Insulin is the most effective anti-diabetic agent Nathan DM. N Engl J Med. 2007;356:437-40 Slide no 6 1.5 1.0-1.50.5-0.90.8-1.0 ≥2.5 Sulfonylureas Biguanides (metformin) Glinides DPP-IV inhibitors TZDsInsulin 0.0 0.5 1.0 1.5 2.0 2.5 3.0 HbA 1c reduction (%) Efficacy as mono therapy Anti diabetic agents

7. Insulin use is often delayed, despite poor glycaemic control Slide no 7 1 OAD 2 OADs 3 OADs Diet 2.9 years4.7 years2.5 years2.7 years 8 9 10 8.8% 9.4% 9.1% OAD, oral antidiabetic drug Mean HbA 1c at last visit (%) Novo Nordisk. Type 2 Diabetes Market Research Roper Starch US Study, 2000

8. Better treatment extends and improves lives Age at diagnosis Signs of advanced complications† Early signs of complications† 71 years 52 68 years Patient #1 60-6266-68 69-71 Patient #2 65-6852 Average glycaemic control for life (HbA 1c = 9.1%) Enhanced treatment (HbA 1c = 7.0%) 5-6 year delay 3 year delay † If complications were to occur UKPDS Risk Engine: modelled data based on newly diagnosed cohort at age 52 Slide no 8

9. T2DM treatment patterns in Egypt 2010-14, thousand patients Slide no 9 2010-12 Change 16% 11% 3% 16% 100%

10. There is resistance to insulin despite efficacy and guideline recommendations In a survey of insulin-naïve T2DM patients, 28.2% of respondents reported that they would be unwilling to take insulin if it were prescribed 3 UKPDS 27% of T2DM patients randomized to insulin initially refused treatment 1 DAWN More than half of insulin-naïve T2DM patients expressed anxiety about starting insulin therapy 2 1 UKPDS 33, 1998; 2 Peyrot et al. 2005; 3 Polonsky et al. 2005 Kunt and Snoek Int J Clin Pract 2009; 63:6-10 Slide no 10

11. Barriers to starting insulin Fear of hypoglycaemia Fear of reduced quality of life Reluctance to inject in public Perception that the disease is becoming more severe Fear of needles/pain from injections Patients do not feel empowered to take control of their diabetes Korytkowski. Int J Obes Relat Metab Disord 2002;26:S18–S24 Polonsky et al. Diabetes Care 2005;28(10):2543-2545 Rubin and Peyrot. J Clin Psychol 2001;57:457– 478 Slide no 11

13. Clinical inertia: delay in treatment initiation and optimisationTherapyN=66726 Diabetes duration (years) Mean (SD) HbA 1c (%) Mean (SD) No therapy (9%) 2.1 (8.6)10.0 (2.2) OGLD only (58%) 8.3 (6.3)9.5 (1.7) Insulin +/- OGLD (33%) 12.0 (7.7)9.4 (1.8) Home et al. Diabetes Res Clin Pract 2011; 94: 352-63 Slide no 13

14. Often there is a failure to advance therapy even when required Time to insulin initiation in patients on >1 OAD is 7.7 yrs † Percentage Patients (%) Delay in insulin initiation (years) †95% CI = 7.4 to 8.5 years Calvert et al. Br J Gen Pract 2007;57:455-460 Slide no 14

15. Common reasons for clinical inertia Insulin makes one fat Fear of hypos Pain from injection Pain from blood tests Insulin makes one fat Fear of hypos Pain from injection Pain from blood tests * Percentage of patients/physicians interviewed who provided this as a reason for not starting insulin Insulin naïve patientsPrimary care physicians Nakar et al. J Diabetes Complications 2007;21:220–6 Slide no 15

16. Patient concerns still exist after insulin initiation 0 10 20 30 40 50 60 70 80 Diabetes has progressed Less flexibility Injection fear Weight gain Seen as sick p<0.001 for all Percentage of subjects who agree or strongly agree Insulin naïve Insulin-treated Increased risk of hypoglycaemia Snoek et al. Health and Quality of Life Outcomes 2007;5:69 Slide no 16

19. Sequential Insulin Strategies in T2DM Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

20. Algorithm for initiating insulin therapy.

22. Patient-Based Insulin Regimens

24. Starting Dosages Start Low and Titrate Steadily

25. Dosage Titration for Once-Daily or Twice-Daily Insulin Regimens

26. Transition From One Regimen to Another

31. Data about Premixed Insulin Aspart in treatment of Diabetes

32. Nazia Raja-Khan, Sarah S Warehime, and Robert A Gabbay Vasc Health Risk Manag. 2007 December; 3(6): 919–935.

36. Percentage of subjects achieving HbA1c target values at the end of the study. Raskin P et al. Dia Care 2005;28:260-265 Copyright © 2011 American Diabetes Association, Inc.

37. Eight-point SMPG readings before breakfast, lunch, and supper [BB, BL, and BD] and 90 min after breakfast, lunch, and supper [B90, L90, and D90]; at bedtime [Bed]; and at 3:00 a.m.). Raskin P et al. Dia Care 2005;28:260-265 Copyright © 2011 American Diabetes Association, Inc.

47. Case 1

48. q A 49-years-old male patient with T2DM 8 years ago, being treated with Insulin Glargine 20 unites at 11 pm and glimpride 3mg before breakfast and metformin 2g/day since 2 years BMI 30 q Lifestyle: High-carbohydrate meals is fond of rice or bread and potatoes. Does not exercise.

49. HbA1c = 7.5% On antihypertensive for several years. Recently, a statin has been added to his medications

50. He wants to fast in ramadan? Yes No

51. What due think you should first ask before deciding the his treatment regimen in ramadan ? 1. His blood glucose analysis during the day

52. Blood glucose levels over the day: FBG 145mg/dl PPG (Post-breakfast) 165 mg/dl Pre Lunch 133 mg/dl PPG (Post-Lunch) 167 mg/dl Pre Dinner 166 mg/dl After Dinner ( main meal ) 261 mg/dl

53. What are the option to control his blood glucose ? Increase the dose of glargine? Add a mealtime bolus? Shift to basal-bolus insulin regimen? Switched to premixed analogue insulin before eftar and SU at a lower dose before sohoor and the same metformin doses?

54. What dietary advice you have to give him in Ramadan ? 1. Eftar starting with a lot of fluids and no sugar 2.Snack after praying taraweeh 3.Lot of fluid during the time allowed to eat 4.Late sohoor

55. Thank You