The Role of Modern Premixed Analogues in Clinical Practice

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 Aspart30: Superior glycaemic control & Safety profile Biphasic Insulin Aspart30: improved convenience Conclusion

4. 43% 37% 19% 16% 14% 12% Stroke Myocardial infarction Heart failure Cataract extraction Microvascular disease Lower extremity amputation or fatal peripheral vascular disease Improving control reduces risks oflong-term complications • Every 1% drop in HbA1c can reduce long-term diabetes complications UKPDS: Stratton et al. BMJ 2000;32:405–12

5. HbA1c & Microvascular Complications Retinopathy 15 Nephropathy 13 11 9 Neuropathy Relative Risk 7 5 Microalbuminuria 3 1 6 7 8 9 10 11 12 HbA1c (%) Skyler JS. Endocrinol Metab Clin. 1996;25:243–254.

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

7. ­12 ­8 0 -4 4 8 12 Why is insulin initiation inevitable? Type 2 diabetes is a progressive disease 100 50% beta-cells declined at time of diagnosis 75 Diagnosis Beta-cellfunction (%) 50 25 0 Years from diagnosis 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.

8. Glycaemic control deteriorates over time in type2 diabetic patients Glibenclamide 9 Chlorpropamide 8 Metformin Recommended target ≤ 6.5† 7 6 Typical range of HbA1cin people without diabetes 5 Median HbA1c (%) 4 3 2 1 0 0 2 4 6 8 10 Years from randomisation †Diabetes UK guidelines UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854–65

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

10. Insulin use is often delayed, despite poor glycaemic control1,2 2.9 years 4.7 years 2.5 years 2.7 years Mean HbA1c at last visit(%) 10 9.4% 9.1% 8.8% 9 8 3 OADs 2 OADs 1 OAD Diet OAD, oral antidiabetic drug 1Novo Nordisk. Type 2 Diabetes Market Research. 2Roper Starch US Study, 2000.

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

13. Psychological Barriers for insulin initiation 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

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

15. Targets for glycaemic control

17. PPGThe peak glucose level FPG The basal glucose level HbA1c The long-term average glucose level For Optimal Management Should We Target……

18. Postprandial glucose (PPG) Fasting plasma glucose (FPG) Relative contributions of PPG and FPG to diurnal hyperglycaemia 100 30% 90 80 70 60 Relative contribution of PPG and FPG to diurnal hyperglycaemia (%) 70% 50 40 30 FPG increases with worsening diabetes 20 10 0 7.3–8.4 >10.2 <7.3 8.5–9.2 9.3–10.2 HbA1c quintiles Monnier et al. Diabetes Care 2003;26:881–5

19. Treatment should cover meal times glucose peaks

21. NovoMix30 (Biphasic insulin aspart) What is Insulin aspart? Pro Asp Phe Gly Arg Phe Tyr Glu Thr Gly Asp Cys B28 Lys B30 Thr A21 Asn Cys Val Tyr Leu Gly Asn Tyr Ile Glu Leu Val Leu Ala Glu Gln Glu Gln Tyr Val Cys Leu Ser Cys Thr Ser Ile Leu Cys His Ser Gly Cys Leu B1 Phe Val Asn Gln His

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

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

24. Physiological insulin profile: • basal component • meal-related peaks • Rapid-acting insulin analogues together with a basal insulin provide physiological insulin replacement Physiological insulin profile Soluble insulin aspart • NovoMix® 30 replace both meal-related and basal insulin Protamine crystallised insulin aspart NovoMix® 30 Rationale for NovoMix 30 faster onset, more effective control and lower risk of hypoglycaemia • Better PPG control • Lower risk of hypoglycemia (30%) (70%) 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 HbA1c • Conclusion: • This trial demonstrates that initiation of NovoMix30 to type 2 patients poorly controlled on OAD was an effective treatment approach Garber et al. Diabetes Obes Metab 2006;8(1):58-66

27. HbA1c reduction using NovoMix 30 in 6 international studies 9.7% 6.9% 9.4% 9.2% 7.5% 8.6% 8.4% 7.2% 8.1% 6.5% 7.2% 7.1% HbA1c 10.0 9.5 *5 *2 9.0 *6 8.5 *4 *3 HbA1c (%) 8.0 *1 7.5 7.0 6.5 INITIATE EuroMix ACTION PREFER 1-2-3 IMPROVETM 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

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

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

30. FPG reduction using NovoMix 30 in 6 international studies 14.0 FPG 14 250 13 *5 12 11.0 11.0 10.9 200 11 *2 *3 9.6 10 FPG(mg/dL) *6 9.2 FPG(mmol/L) 9 *1 150 *4 8.6 8 8.1 7 7.1 7.2 6.6 6.4 6 100 0 0 INITIATE EuroMix ACTION PREFER 1-2-3 IMPROVETM 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

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

32. Mean plasma glucose (mg/dl) After preprandial injection After postprandial injection -15 60 120 180 240Time (minutes) Blood glucose levels did not differ between injection times Warren ML et al.Diabetes Res Clin Pract 2004;66(1):23-29

33. Next Generation FlexPen® Next Generation FlexPen® has lower injection force than SoloSTAR® and KwikPen®With NovoFine® 32G Tip needle APROM ID: 1062 Created: October 2009 Mean injection force of Next Generation FlexPen®, SoloSTAR® and KwikPen® at three different injection speeds 37-41% lower injection force than KwikPen® 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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