1. The Role of Modern Premixed Analogues in Clinical Practice Raef M. Botros Professor of Medicine Ain Shams University

2. Facts & Figures about Diabetes 285 Million Diabetic patients 2010 439 Million Diabetic patients 2030 70% of diabetics live in developing countries 3.8 Million deaths per year 1 Million amputations per year 2.5 Million cases of retinopathy per year Source: IDF Diabetes Atlas 2010 - WHO

3. Presentation overview Does strict glycaemic control matter? Why and when should insulin be initiated? Psychological barriers for Insulin initiation Targets for glycaemic control Contribution of FPG & PPG to overall glycaemic control Biphasic Insulin Aspart 30: Superior glycaemic control & Safety profile Biphasic Insulin Aspart 30: improved convenience Conclusion

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: Stratton et al. BMJ 2000;32:405–12

5. HbA1c & Microvascular Complications Relative Risk Retinopathy Nephropathy Neuropathy Microalbuminuria HbA 1c (%) 15 13 11 9 7 5 3 1 6789101112 Skyler JS. Endocrinol Metab Clin. 1996;25:243–254.

6. Poor glycaemic control leads to Long-term complications… Diabetic nephropathy Proliferative diabetic retinopathy Atherosclerosis Diabetic foot

7. Beta-cell function (%) Years from diagnosis 50% beta-cells declined at time of diagnosis 0 50 100 75 25 Diagnosis ­12­8 0 4812 The beginning of the beta-cell loss was estimated by extrapolation back to 100% function and the lack of significant insulin secretion by extrapolation forward. IGT=impaired glucose tolerance. Modified from Lebovitz HE. Diabetes Reviews. 1999;7:139-153. Why is insulin initiation inevitable? -4 Type 2 diabetes is a progressive disease

8. Glycaemic control deteriorates over time in type2 diabetic patients Median HbA 1c (%) Years from randomisation Recommended target ≤ 6.5 † 2468100 Glibenclamide Chlorpropamide Metformin 6 7 8 9 0 5 4 3 2 1 †Diabetes UK guidelines UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854–65 Typical range of HbA 1c in people without diabetes

9. Not only OAD Mono-therapy fails but also Combination OADs fail too Cook et al. Diabetes Care 2005; 28:995-1000 2220 patients with T2DM treated with SU+MET were studied in a retrospective analysis of electronic medical records from U.K.

10. Insulin use is often delayed, despite poor glycaemic control1,2 1 OAD 2 OADs 3 OADs Diet 2.9 years4.7 years2.5 years2.7 years Mean HbA 1c at last visit (%) 8 9 10 8.8% 9.4% 9.1% 1 Novo Nordisk. Type 2 Diabetes Market Research. 2 Roper Starch US Study, 2000. OAD, oral antidiabetic drug

11. Insulin use is often delayed, despite it is the most effective anti diabetic agent Nathan DM. N Engl J Med. 2007;356:437-40.

12. 12 Patient Concerns: 1.Anxiety about pain and proper injection technique 1.Fear of hypoglycaemia 2.Perceived restriction in lifestyle 3.Social embarrassment with pre-meal injections 4.Concern that disease has progressed to a serious level Hunt et al. Diabetes Care 20(3):292, 1997 Psychological Barriers for insulin initiation

13. Patient Concerns: Continue 6.Timing of pre-meal injections 7.Sense of failure 8.Need for careful blood glucose monitoring 9.Concern that insulin will cause weight gain Hunt et al. Diabetes Care 20(3):292, 1997 Psychological Barriers for insulin initiation

14. Physician Concerns: 1.Time requirement for teaching insulin therapy 2.Increased risk of severe hypoglycaemia 3. Worsened insulin resistance 4.Concern that insulin will cause weight gain Hunt et al. Diabetes Care 20(3):292, 1997 Psychological Barriers for insulin initiation

15. ADA 1 ACE/IDF 2 HbA 1c (%) <7.0 6.5 Fasting/ preprandial 90-130 mg/dl 5.0-7.2 mmol/l <100 mg/dl <5.6 mmol/l 2-hour postprandial <180 mg/dl <10.0 mmol/l <135 mg/dl <7.5 mmol/l Targets for glycaemic control

17. For Optimal Management Should We Target…… FPG The basal glucose level PPG The peak glucose level HbA 1c The long-term average glucose level

18. Relative contributions of PPG and FPG to diurnal hyperglycaemia Monnier et al. Diabetes Care 2003;26:881–5 0 10 20 30 40 50 60 70 80 90 100 <7.3 7.3–8.4 8.5–9.29.3–10.2 >10.2 HbA 1c quintiles Relative contribution of PPG and FPG to diurnal hyperglycaemia (%) Postprandial glucose (PPG) Fasting plasma glucose (FPG) 70% FPG increases with worsening diabetes 30%

19. Treatment should cover meal times glucose peaks

21. NovoMix30 (Biphasic insulin aspart) What is Insulin aspart?

22. Absorption: human insulin vs. Insulin aspart Insulin aspart Insulin concentration (M) Absorption Monomer Capillary membrane T-type hexamer Dimer R-type hexamer 10 –3 10 –4 10 –6 10 –8 Human insulin This is purely schematic to illustrate absorption of molecules

23. Dual-release insulin concept: BHI 30 Physiological insulin profile: basal component meal-related peaks Physiological insulin profile Hyperglycaemia Hypoglycaemia Biphasic Human Insulin fails to re-create the physiological insulin profile BHI 30 Jacobsen L et al. Eur J Clin Pharm 2000;56:399–403

24. Rationale for NovoMix 30 faster onset, more effective control and lower risk of hypoglycaemia Physiological insulin profile: basal component meal-related peaks Physiological insulin profile Protamine crystallised insulin aspart Rapid-acting insulin analogues together with a basal insulin provide physiological insulin replacement Soluble insulin aspart NovoMix ® 30 replace both meal-related and basal insulin NovoMix ® 30 (30%) (70%) Better PPG control Lower risk of hypoglycemia Jacobsen L et al. Eur J Clin Pharm 2000;56:399–403

25. Improved Glycaemic control with NovoMix 30 Once or twice-daily Garber study (1-2-3) Aim: To assess whether addition of NovoMix30 could achieve AACE, IDF and ADA guidelines in type 2 diabetic patients failed on OADs Method: –100 patients had diabetes > 12 months –Using 2 OADs or at least one OAD plus once-daily basal insulin –HbA1c level is between (7.5% and <10%) and the average is 8.6% Garber et al. Diabetes Obes Metab 2006;8(1):58-66

26. HbA1c reduction with NovoMix 30 Once- & twice-daily Garber et al. Diabetes Obes Metab 2006;8(1):58-66 HbA1c Conclusion: This trial demonstrates that initiation of NovoMix30 to type 2 patients poorly controlled on OAD was an effective treatment approach

27. HbA1c reduction using NovoMix 30 in 6 international studies INITIATE EuroMix ACTION PREFER 1-2-3 IMPROVE TM 9.7% 6.9% 9.2% 7.5% 8.1% 6.5% 8.4% 7.2% 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 8.6% 7.2% HbA 1c (%) 9.4% 7.1% HbA1c 1- McSorley PT et al. Clin Ther 2002;24(4):530–539 2- Kann PH et al. Insulin Therapy in Type 2 Diabetes... Exp Clin Endocrinol Diabetes 2006; 114: 527–532 3- Diabetes, Obesity and Metabolism, 2008 4- Garber et al. Diabetes Obes Metab 2006;8(1):58-66 5-The American Journal of Medicine (2009) 122, 1043-1049 6- P.Valensi,2009 Int J Clin Pract *1 *3 *2 *4 *5 *6

28. Boehm B et al. Diabet Med 2002;19(5):393–399 Significantly lower prandial glucose increment with NovoMix® 30 0 0.5 1 1.5 2 2.5 3 BiAsp 30BHI 30 Mean prandial glucose increment (mmol/l) p < 0.02 between treatment groups (n = 128) (n = 141) 29% reduction PPG

29. Reduced glucose excursions vs. Lispro Mix25TM and BHI 30 p < 0.05 –10% p < 0.001 –17% 0 13 14 15 16 17 18 19 20 21 Lispro Mix 25 TM NovoMix ® 30BHI 30 Blood glucose excursion 0– 5h (mmol/l h) Hermansen K et al. Diabetes Care 2002;25:883–888 PPG

30. FPG reduction using NovoMix 30 in 6 international studies 14.0 INITIATE EuroMix ACTION PREFER 1-2-3 IMPROVE TM 11.0 9.6 0 6 7 8 9 10 11 12 FPG (mmol/L) 9.2 6.4 13 14 7.1 8.6 7.2 8.1 10.9 6.6 0 100 150 200 250 FPG (mg/dL) FPG 1- McSorley PT et al. Clin Ther 2002;24(4):530–539 2- Kann PH et al. Insulin Therapy in Type 2 Diabetes... Exp Clin Endocrinol Diabetes 2006; 114: 527–532 3- Diabetes, Obesity and Metabolism, 2008 4- Garber et al. Diabetes Obes Metab 2006;8(1):58-66 5-The American Journal of Medicine (2009) 122, 1043-1049 6- P.Valensi,2009 Int J Clin Pract *5 *2 *1 *3 *4 *6

31. Reduced major hypoglycaemia after 3 months Number of hypoglycaemic episodes 0 5 10 15 20 25 30 35 40 45 NovoMix ® 30BHI 30 42 events 20 events 52% relative risk reduction Boehm B et al. Diabet Med 2002;19(5):393–399 (n = 138) (n = 153)

32. Warren ML et al. Diabetes Res Clin Pract 2004;66(1):23-29 After preprandial injection After postprandial injection Mean plasma glucose (mg/dl) -15 60120 180 240 Time (minutes) Blood glucose levels did not differ between injection times

33. 37-41% lower injection force than KwikPen ® Next Generation FlexPen ® APROM ID: 1062 Created: October 2009 Next Generation FlexPen® has lower injection force than SoloSTAR® and KwikPen® With NovoFine® 32G Tip needle Mean injection force of Next Generation FlexPen ®, SoloSTAR ® and KwikPen ® at three different injection speeds 15-22% lower injection force than SoloSTAR ® Asakura et al. Evaluation of injection force of three insulin delivery pens. Expert Opin Pharmacother 2009;10:1389-1393

34. How to start NovoMix30 Simple intensification with the same insulin in the same device NovoMix 30 core data sheet June 2008

35. Conclusion: Strong relation exists between A1C reduction and reduction of microvascular complications Glycaemic control deteriorates over time in type2 patients using OADs Insulin use is often delayed, despite poor glycaemic control ` NovoMix® 30 FlexPen® provides superior glycaemic control & significant reduction in major hypoglycemia NovoMix® 30 FlexPen® offers convenient mealtime flexibility

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