1. Dr Ravi Kant Premix Analogue VS. Premix Human Insulin In Clinical Practice

2. Agenda Objectives The pharmacological differences between premixed insulin analogue and premixed human insulin BHI 30 Efficacy and safety with BIAsp 30 and BHI 30: evidence from RCT and meta-analysis Switching from BHI 30 to BIAsp 30 Cost- effectiveness Case Study BHI, biphasic human insulin; BIAsp, biphasic insulin aspart

3. Objectives To explore the rationale for treating with premix insulin analogues with focus on: The difference between premixed insulin analogue and BHI 30 Evidence from clinical practice for BIAsp 30 as a switch option for individuals on BHI 30

4. The dual-release insulin concept Physiological insulin profile Protamine crystallised insulin aspart Soluble insulin aspart BIAsp 30 Schematic presentation Garber et al. Diabetes Obes Metab 2007;9:630–9 Physiological insulin profile: Basal component Meal-related peaks Rapid-acting insulin analogues together with a basal insulin provide physiological insulin replacement Analogue mix insulins such as BIAsp 30 replace both meal-related and basal insulin

5. 30% Protamine-crystallised insulin aspart Soluble insulin aspart BIAsp 30 A premixed suspension of: 30% NPH insulin How is BIAsp 30 different from BHI 30? BHI 30BIAsp 30 70% Regular human insulin BHI 30 A premixed suspension of: Novo Nordisk. BIAsp 30 SPC. http://ec.europa.eu/health/documents/community-register/2000/200008013730/anx_3730_en.pdf BIAsp, biphasic insulin aspart; BHI, biphasic human insulin; NPH, neutral protamine Hagedorn

6. Proof of concept: rapid absorption and higher peak concentration Adapted from Jacobson et al. Eur J Clin Pharm 2000;56:399–403 ***p<0.0001; n=24 BIAsp 30 BHI 30

7. Faster absorption of BIAsp 30 is reflected in the earlier onset of serum glucose lowering Adapted from Jacobson et al. Eur J Clin Pharm 2000;56:399–403 BIAsp 30 BHI 30

8. *p<0.05 in favour of BIAsp 30 for lower PPG levels after dinner and breakfast; n=13 PPG, postprandial plasma glucose Twice-daily BIAsp 30 in patients with type 2 diabetes: improved PPG control 18:00 Adapted from McSorley et al. Clin Ther 2002;24:530–9 BIAsp 30 BHI 30

9. Pharmacological profile Compared with BHI, BIAsp 30 has: Faster absorption Higher peak concentration More rapid and pronounced glucose- lowering effect Similar duration of action of basal component Jacobson et al. Eur J Clin Pharm 2000;56:399–403

10. Efficacy and safety with BIAsp 30 and BHI 30: evidence from RCTs and meta-analysis RCT, randomised controlled trial.

11. Long-term comparison of efficacy and safety of BIAsp 30 vs. BHI 30 Insulin-using patients with type 1 and type 2 diabetes (n=294) BIAsp 30 (n=140) BHI 30 (n=151) 3 months One screening visit; patients already using a twice-daily insulin regimen Adapted from Boehm et al. Diabet Med 2002;19:393–99; Boehm et al. Eur J Intern Med. 2004;15:496-502. BHI, biphasic human insulin; BIAsp, biphasic insulin aspart 21 months Extension period Initial period

12. Long-term comparison of efficacy of BIAsp 30 vs. BHI 30 HbA1c at 24 months (%) BIAsp 30 BHI 30 BHI, biphasic human insulin; BIAsp, biphasic insulin aspart; NS, not significant Boehm et al. Eur J Intern Med. 2004;15:496-502.

13. Improved postprandial blood glucose with BIAsp 30 vs. BHI 30 After 12 weeks of treatment, levels of HbA 1c did not differ between the two treatment groups Mean difference: −0.01 (90% CI: −0.14;0.12) *p<0.05 Boehm et al. Diabet Med 2002;19:393–99 BHI, biphasic human insulin; BIAsp, biphasic insulin aspart; CI, confidence interval

14. Reduced major hypoglycaemia with BIAsp 30 vs. BHI 30 Patients with at least one major hypoglycaemic episode (%) BIAsp 30 BHI 30 p=NS p=0.04 BHI, biphasic human insulin; BIAsp, biphasic insulin aspart; NS, not significant Boehm et al. Eur J Intern Med. 2004;15:496-502. 0 events

15. Similar change in HbA 1c with premixed human insulin vs. BIAsp 30 Superior with premix insulin analogues vs. long-acting insulin analogues or non-insulin therapy -1.2-0.8-0.6-0.4-0.200.20.4 Favours premixed analogue Favours comparator Comparison Long-acting insulin analogue vs.: All premixed insulin analogues Insulin aspart 70/30 Insulin lispro 75/25 Insulin lispro 50/50 All premixed insulin analogues Insulin aspart 70/30 Insulin lispro 75/25 † Insulin lispro 50/50 † Premixed human insulin vs.: All premixed insulin analogues Insulin aspart 70/30 Insulin lispro 75/25 Insulin lispro 50/50 All premixed insulin analogues Insulin aspart 70/30 Mean difference of change in HbA 1c level (95% CI), % Studies (participants), n -0.39 (-0.50;-0.28) -0.48 (-0.61;-0.34) -0.33 (-0.48;-0.17) -0.40 (-0.65;-0.15) 11 (3108) 4 (976) 5 (1720) 3 (530) -0.05 (-0.15;-0.04) 0.06 (-0.04;0.16) -0.06 (-0.26;0.14) -0.06 (-0.35;0.23) 9 (2717) 4 (708) 3 (1499) 3 (226) 10 (2422) 9 (1921) 7 (1510) 6 (1009) 3 (912) No data -0.49 (-0.86;-0.12) -0.55 (-0.94;-0.16) -0.52 (-1.00;-0.04) -0.61 (-1.13;-0.10) -0.42 (-1.00;0.16) Noninsulin antidiabetic agents vs.: † Pooled results include those of a study that administered insulin lispro 50/50 in the morning and insulin lispro 75/25 in the evening. CI, confidence interval Adapted from Qayyum et al. Ann Intern Med 2008;149:549–59

16. Iwamoto 2003 (n=428) BIAsp 30 associated with a significantly lower rate of major hypoglycaemia compared with BHI 30 Version June 2014 Overall 0.50 (0.12;1.98), p=0.32 0.34 (0.01;8.28), p=0.50 0.57 (0.16;2.00), p=0.38 0.25 (0.01;6.62), p=0.41 0.53 (0.03;8.63), p=0.66 0.31 (0.06;1.54), p=0.15 0.45 (0.22;0.93), p<0.05 1000.1110 0.01 I 2 =32% Favours BIAsp 30 Favours BHI 30 McNally et al. 2007 (n=160) Kilo et al. 2003 (n=93) 1394 (n=292) 3002 bioequivalence trial (n=36) Boehm et al. 2002 (n=187) Trial Rate ratio (95% CI) Davidson et al. Clin Ther 2009;31:1641–51

17. BIAsp 30 associated with a significantly lower rate of nocturnal hypoglycaemia compared with BHI 30 Version June 2014 Iwamoto 2003 (n=428) 200.2 0.57 [0.20;1.58], p=0.28 0.89 [0.25;3.16], p=0.86 0.44 [0.22;0.89], p=0.02 1.03 [0.42;2.53], p=0.95 1.03 [0.38;2.76], p=0.96 1.05 [0.11;10.09], p=0.97 1536 (n=195) 2.43 [0.31;18.90], p=0.39 0.1 1 10 3006 (n=103) Overall 0.33 [0.21;0.51], p<0.01 0.44 [0.11;1.47], p=0.17 0.50 [0.38;0.67], p<0.01 I 2 =32% McNally et al. 2007 (n=160) Kilo et al. 2003 (n=93) 1394 (n=292) Bioequivalence trial (n=36) Boehm et al. 2002 (n=187) 1234 (n=180) Davidson et al. Clin Ther 2009;31:1641–51 Trial Rate ratio (95% CI) Favours BIAsp 30 Favours BHI 30

18. Switching from BHI 30 to BIAsp 30 BHI, biphasic human insulin; BIAsp, biphasic insulin aspart

19. Real-life switching from BHI 30 to BIAsp 30: HbA 1c HbA 1c change after 6 months (%) -2.21*-2.13*-2.24*-2.27* IMPROVE 2 HbA 1c change after 6 months (%) -1.8*** -1.6*** *p<0.05 for all comparisons vs. baseline; **p<0.001; ***p<0.0001. BIAsp, biphasic insulin aspart; BHI, biphasic human insulin 1. Shestakova et al. Curr Med Res Opin 2007;23:3209–14; 2. Shah et al. Int J Clin Pract 2009;63:574–82; 3. El Naggar et al. Diabetes Res Clin Pract 2012;98:408–13 PRESENT 1 Overall population A 1 chieve 3 -1.9** -1.6 -1.8*** HbA 1c change after 6 months (%) Baseline value 9.1% Baseline value 9.2% Baseline value 9.3% -1.7**

20. Real-life switching from BHI 30 to BIAsp 30: FPG -2.21*-2.13*-2.24*-2.27* IMPROVE 2 -1.8*** -1.6*** **p<0.001; BIAsp, biphasic insulin aspart; BHI, biphasic human insulin 1. Shestakova et al. Curr Med Res Opin 2007;23:3209–14; 2. Shah et al. Int J Clin Pract 2009;63:574–82; 3. El Naggar et al. Diabetes Res Clin Pract 2012;98:408–13 PRESENT 1 Overall population A 1 chieve 3 -1.9** -2.92 -3.48** Baseline value 10.2 (mmol/L) Baseline value 10.3 (mmol/L) Baseline value 11.0 (mmol/L) -3.0** FPG change after 6 months (mmol/L) FPG change after 6 months (mmol/L) FPG change after 6 months (mmol/L)

21. Real-life switching from BHI 30 to BIAsp 30: PPG -2.21*-2.13*-2.24*-2.27* IMPROVE 2 -1.8*** -1.6*** **p<0.001; BIAsp, biphasic insulin aspart; BHI, biphasic human insulin 1. Shestakova et al. Curr Med Res Opin 2007;23:3209–14; 2. Shah et al. Int J Clin Pract 2009;63:574–82; 3. El Naggar et al. Diabetes Res Clin Pract 2012;98:408–13 PRESENT 1 Overall population A 1 chieve 3 -1.9** -4.75 -5.48** Baseline value 14.2 (mmol/L) Baseline value 14.9 (mmol/L) Baseline value 15.3 (mmol/L) -4.3** PPG change after 6 months (mmol/L) PPG change after 6 months (mmol/L) PPG change after 6 months (mmol/L)

22. Real-life switching from BHI 30 to BIAsp 30: Minor hypoglycaemia rates -2.21*-2.13*-2.24*-2.27* IMPROVE 2 -1.8*** -1.6*** BIAsp, biphasic insulin aspart; BHI, biphasic human insulin 1. Shestakova et al. Curr Med Res Opin 2007;23:3209–14; 2. Shah et al. Int J Clin Pract 2009;63:574–82; 3. El Naggar et al. Diabetes Res Clin Pract 2012;98:408–13 PRESENT 1 Overall population A 1 chieve 3 -1.9** -6.0 -5.7 Baseline value 5.3 (events/patient/year) Baseline value 7.7 (events/patient/year) Baseline value 8.2 (events/patient/year) -3.1 Hypoglycaemia rate change after 6 months (events/patient/year) Hypoglycaemia rate change after 6 months (events/patient/year) Hypoglycaemia rate change after 6 months (events/patient/year)

23. A 1 chieve: quality of life following switch from BHI 30 to BIAsp 30 02010 50 407080100309060 Worst Best Visual analogue scale 0 = worst imaginable health state 100 = best imaginable health state Baseline 64.0 (SD 16.3) Week 24 76.5 (SD 11.9) BIAsp, biphasic insulin aspart; BHI, biphasic human insulin; SD, standard deviation Improvement 12.5 points El Naggar et al. Diabetes Res Clin Pract 2012;98:408–13

24. Cost-effectiveness of switching from BHI 30 to BIAsp 30 BHI, biphasic human insulin; BIAsp, biphasic insulin aspart

25. Switching from therapy with BHI 30 or insulin glargine ± OADs to BIAsp 30 ± OADs improves life expectancy Increase in life expectancy (years) 0.7 India 1.5 0.5 –1.5 –0.5 Indonesia Saudi Arabia 0.9 1.2 Change in life expectancy following change from therapy with BHI 30 or insulin glargine ± OADs to BIAsp 30 ± OADs † India Saudi Arabia –1.7 0.9 1.0 0 –1.0 BHI 30 ± OADs to BIAsp 30 ± OADs Insulin glargine ± OADs to BIAsp 30 ± OADs Decrease in life expectancy (years) † Simulated over 30 years OAD, oral antidiabetic drug Gupta et al. J Med Econ 2015;18:263–72

26. Switching from BHI 30 to BIAsp 30: incidence of complications (CORE Diabetes Model simulation) Gupta et al. J Med Econ 2015;18(4):26372 Reduction in incidence (% people) BHI, biphasic human insulin; BIAsp, biphasic insulin aspart; CORE, The Centre of Outcomes Research

27. Switching from BHI 30 to BIAsp 30 results in a projected delay in onset of complications Gupta et al. J Med Econ 2015;18(4):26372 BHI, biphasic human insulin; BIAsp, biphasic insulin aspart; Any complication Myocardial infarction Ulcer Severe vision loss End-stage renal disease Death Macrovascular complications Microvascular complications Age at diagnosis 44.6 56.3 56.1 65.1 64.2 66.9 66.2 66.867.267.3 65.9 66.4 66.6 General population 74.9

28. Switching from BHI 30 to BIAsp 30: sensitivity analyses show cost-effectiveness to be robust Gupta et al. J Med Econ 2015;18(4):26372 BHI, biphasic human insulin; BIAsp, biphasic insulin aspart; CORE, The Centre of Outcomes Research Base effect Median treatment effect (HbA1c) No HbA1c deterioration 50-year time horizon 30-year analyses 1-year analyses

29. Case Study

30. Mr Omkar Age: 52 Diagnosis: type 2 diabetes since 2008 Current employment: Shopkeeper HbA 1c : 7.9% Weight: 77 kg Height: 1.61 m BMI: 29.7 kg/m 2 Diabetes treatment: human premix insulin 25 for 2 years (9 kg weight gain since start of insulin treatment), metformin, sitagliptin Medical history: asthma (inhaled steroids), symptomatic hypoglycaemia nearly every day during his morning work Lifestyle: occasional alcohol intake; stressful job; early morning starts Case Study

31. Mr Omkar Blood glucose profile 1 Human premix insulin 30, 28-0-16 IU JanuMet 50/1000 bid bid, twice daily Case Study

32. Interactive question How would you intensify treatment, and why? Add a third dose of regular human insulin. Switch to analogue premix insulin (e.g. BIAsp 30) BID Add Acarbose Add Repaglinide Switch to basal-bolus therapy Stop insulin and switch to GLP-1 s.c. (e.g. liraglutide) in combination with metformin Case Study

33. Mr Omkar Blood glucose profile 2 In the evening (4 weeks later) he consumes alcohol, and his wife has to call the emergency ambulance during the night due to severe hypoglycaemia. It is totally unclear what insulin he had injected and when. NPH, neutral protamine Hagedorn; RHI, regular human insulin What is the cause of the severe hypoglycaemia? Case Study Switched to: Prandial insulin 18- 8-10 Basal insulin 0-0-0- 12 Still experiencing minor hypoglycaemic events before noon; Has to snack every day

34. Mr Omkar Blood glucose profile 3 We change the regimen to insulin BIAsp 30 14-0-14 IU. In the following weeks the dose is titrated to 16-0-18 IU Case Study

35. How did Mr Omkar fare? No more hypoglycaemia, especially in the morning HbA1c after 4 months: 6.9% Weight decreases by 5 kg  No more snacking No carbohydrate counting, two blood glucose profiles per week, singular blood glucose self-measurements in between With heavy lunch he has 6 IU BiAsp 30 before lunch Happy and very satisfied patient! Case Study

36. Thanks for patient hearing