Lecture powerpoint novomix Feb2023 update

Powerpoint for novomix Feb2023 update.pptx

1. Role of Premixed Insulin Analogue in Diabetes treatment พญ . กิ เริ่น โซนี่ อา ยุร แพทย์ต่อมไร้ท่อและเมตะบอลิสม รพ . เชียงรายประชานุเคราะห์

2. Table of contents Overview of Diabetes mellitus Benefits and risks of insulin Short update in Diabetes Guideline 2023 Pharmacology of premixed insulin analogue Efficacy and safety of premixed insulin analogue Switching insulin to BIAsp 30 Hypoglycaemia meta-analysis TID dosing Premixed insulin analogue dose titration Summary , Q&A

3. 1 Overview of Diabetes Mellitus

4. 2010 2000 171 million 1 2030 552 million 2 2011 366 million 2 Diabetes is a global disease Estimated global prevalence of diabetes Wild. Diabetes Care. 2004. 27:1047-1053. International Diabetes Federation. IDF Diabetes Atlas . Fifth Edition. 2011

5. Pathophysiology and Pathologic changes T2DM

6. T2D clinical burden ADA. Standards of Medical Care in Diabetes - 2019. Diabetes Care . 2019;42. ADA. Living with diabetes: complications. http://www.diabetes.org/living-with-diabetes/complications/. Accessed: 9 Sept 2018. Klimek P, et al. PLoS Comput Biol . 2015;11:e1004125; Pantalone KM, et al. BMJ Open Diabetes Res Care . 2015;3:e000093; Song et al. Qjm . 2009;102(11):799-806; Tancredi M, et al. N Engl J Med . 2015;373:1720-1732. Obesity; cancer; gastroparesis Cerebrovascular disease; emotional and cognitive challenges Diabetic retinopathy Hypertension; cardiovascular disease Polyuria; nephropathy; chronic kidney disease Peripheral vascular disease; neuropathy ; s kin/foot complications and amputation Comorbidities Cardiovascular death 14% All-cause mortality 15% Mortality T2D is a complex, multifactorial disorder with pathophysiological deficits that lead to comorbidities and mortality

7. For people with diabetes, it can have a wide-ranging impact on their lives Nicolucci et al. Diabet Med 2013;30:767–77

8. T2D economic burden Baxter M, et al. Diabet Med . 2016;33:1575-1581; Dieleman JL, et al. JAMA . 2016;316:2627-2646; IDF Diabetes Atlas. 8 th ed. 2017; Kanavos. Diabetes expenditure, burden of disease and management in 5 EU countries. LSE. 2012; NHS. The cost of diabetes: report. 2014; Diabetes.co.uk. Cost of diabetes. https://www.diabetes.co.uk/cost-of-diabetes.html. Accessed: 10 Oct 2018 ; Seuring T, et al. Pharmacoeconomics . 2015;33:811-831. Annual mean healthcare expenditure per adult (20-79 years) with diabetes Per IDF Atlas 2017 and Seuring 2015 Annual cost: up to ~$12,000 (ID) per person, with substantial variation depending on the country; the highest cost was in the US Worldwide healthcare expenditure by adults (20-79 years) with diabetes 800 700 600 500 400 300 200 100 Billion dollars (US) 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 232 376 465 548 673 727 Per IDF Atlas 2017 T2D is financially expensive for patients and healthcare systems, and strategies for cost avoidance should be considered T2D spending consumes a large percentage (~9%) of the healthcare budget, and most of this is spent on care for complications (~80%) rather than direct treatment costs (~20%) Per NHS 2010-2012 estimates Did you know?

9. The cost of treating diabetes was as high as Thai Baht a year* 6 In Thailand, hospital care is the main cost driver *data from 2003 5. Adapted from Chatterjee S. et al., Health and Social Care in the community, 2011;Cost of diabetes and its complications in Thailand:a complete picture of economic burden 6. Adapted from Sintawanarong , P., in:Bangkok Post,31 Oct 2013:Diabetes kills 8,000 Thai each year, http://www.bankokpost.com/print/377376/ 47.6 billion

10. Long-term complications drive the cost of diabetes Adapted from Riewpaiboon A. et al., Int J Pharm Pract , 2001; 19: 342-9 Adapted from Chatterjee S. et al., Health Social Care Comm , 2011; 11pp

11. Sources: 1. Thai National Health Examination Survey V Study Group. Thai National Health Examination Survey, NHES V. Nonthaburi, Thailand: National Health Examination Survey Office, Health System Research Institute, 2016. 2. Official Statistics Registration Systems. Thai population 2016. stat.dopa.go.th/stat/ statnew / upstat_age_disp.php . Accessed May 2017. 3. Rangsin R, MedResNet . An assessment on quality of care among patients diagnosed with type 2 diabetes and hypertension visiting hospitals of Ministry of Public Health and Bangkok Metropolitan Administration in Thailand. Bangkok, Thailand: National Health Security Office, 2014. The Diabetes Rule of Halves in Thailand Of those who are diagnosed and received care, 35.6% achieve treatment targets Achieve treatment
targets (HbA1c ) Receive care Diagnosed Diabetes million people Of those people living with diabetes 1,2 ... 57% are diagnosed 1 ... 97% of those who are diagnosed receive care 1 ... 35.6% of those who received care achieve recommended treatment targets. 3 4.8 million Thai people live with diabetes, and many will develop complications at some point in life

12. Importance of good glycaemic control Long-term benefits in reducing cardiovascular risk can be achieved with good glycaemic control 1 -14% risk -37% risk -21% risk Myocardial infarction Microvascular complications Death related to diabetes Each HbA 1c percentage point reduction counts 2 HbA 1c -1% Holman et al. NEJM 2008;359:1577–89 Stratton et al. BMJ 2000;321(7258):405-12

13. Insulin remains the most efficacious glucose lowering agent 1 Decrease in HbA 1c : Potency of monotherapy Adapted from: Nathan D, et al. Diabetes 2007;56( Suppl 1):Abstract 0996-P HbA 1c % -2.5 -2.0 -1.5 -1.0 -0.5 0.0 AGIs DPPIV inh SGLT2-i Exenatide TZD SU/GLIN Metformin Insulin GLP-1

14. 2 Benefits and risks of insulin

15. Benefits of insulin Frederick Banting and J.J.R. Macleod awarded the Nobel Prize in Physiology of medicine in 1923

16. Developments in insulin therapy Advancements Animal Insulin Preparations Recombinant Human Insulin Rapid-acting Insulin Analogues Basal Insulin Analogues Isolation of Insulin ( Banting & Best) Time 1922 1977 Biphasic Insulin 1990s 2000s

17. Impact of Intensive Therapy for Diabetes Summary of Major Clinical Trials Study Microvasc CVD Mortality UKPDS       DCCT / EDIC*       ACCORD    ADVANCE    VADT    Long Term Follow-up Initial Trial * in T1DM Kendall DM, Bergenstal RM. © International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med . 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med . 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024)

18. Lower HbA 1c also correlates with higher rates of all-cause mortality Cohort 1 Metformin and SUs Cohort 2 Insulin-based regimens Currie et al. Lancet 2010;375:481–9

19. Medical complications of severe hypoglycaemia Central nervous system events 2 Cardiac implications 1 Vascular events 1 Death 1,2 Desouza CV, et al. Diabetes Care 2010;33(6):1389-1394 Boyle et al. South Med J 2007;100(2):183-194 Stroke, myocardial infarction, acute cardiac failure, ventricular arrhythmia Decreased heart rate, cardiac output, myocardial contractility Seizures, convulsions, coma

20. Which patients are at risk? Special populations at risk: Elderly 2,3,5 Young 2 Pregnant women 1,3 Unaware of hypoglycaemia 2,4,5 History of CVD 3 Comorbid conditions: Hypopituitarism 1 Renal impairment 2,3 Hypothyroidism 3 Liver failure 2,3 Barbour. Management of Diabetes in Pregnancy 2010: chpt 20 Briscoe. Clinical Diabetes 24(3):115-121 CDA. Can J Diabetes 2008;32:S29–31 Cryer. Diabetes 2008;57(12):3169-3176 Frier. Diab Metab Res Rev 2008;24:87-92

21. 3 Update Diabetes Guidelines 2023

22. Case Scenario 55 years old Thai male Type 2 DM diagnosed for 5 years Co-morbid diseases HTN Dyslipidemia No pre-existing cardiovascular disease No microalbuminuria and retinopathy

23. Question What is the most appropriate glycemic target? HbA1C < 6.0% HbA1C < 6.5% HbA1C < 7.0% HbA1C < 7-8%

24. 2/20/2023 25

25. HbA1C target should be individualized based on numerous factors, including age, life expectancy, comorbid conditions, duration of diabetes, risk of hypoglycemia or adverse consequences from hypoglycemia, patient motivation, and adherence 1,2 Test Glycemic Control Targets ADA AACE HbA1c <7% ≤6.5% 3 FPG 80-130 mg/dL <110 mg/dL 3 PPG <180 mg/dL (measured within 1 to 2 hours after the start of a meal) <140 mg/dL 3 (2-hour value) AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association PG , fasting plasma glucose; PPG, postprandial glucose. 1. American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S135. 2. Garber AJ, et al. Endocr Pract. 2017;23(2):207-238. 3. Handelsman Y et al. Endocr Pract. 2015;21(suppl 1):1-87. ADA and AACE Glycemic Targets

26. Case Scenario Currently on Glipizide 20 mg once daily Metformin 2000 mg a day (max tolerated dose) Pioglitazone 30 mg a day Follow up: 3 mos ago: HbA1C 8.8%,FPG 240 mg/dl This visit: HbA1C 8.5%,FPG 220 mg/dl Next Step?

27. Decline in - Cell Function with Diabetes Progression: UKPDS Lebovitz H. Diabetes Rev. 1999;7(3):139-153. UKPDS 16. Diabetes. 1995;44(11):1249-1258. Rx: Insulin, Metformin, Sulfonylurea  -Cell Function (%) Postprandial Hyperglycemia IGT Type 2 Diabetes Phase II Type 2 Diabetes Phase III 25 100 75 50 -12 -10 -6 -2 2 6 10 14 Years from Diagnosis Type 2 Diabetes Phase I Dashed line shows extrapolation forward and backward from years 0 to 6 based on HOMA data from UKPDS.

28. Current Concepts in Diabetes Treatment

29. A1C, glycated hemoglobin; CVD, cardiovascular disease; DSMES, diabetes self-management education and support; FPG, fasting plasma glucose; GLP-1 RA, glucagon-like peptide 1 receptor agonist; NPH, Neutral Protamine Hagedorn American Diabetes Association (ADA). Diabetes Care 2023 Jan; 46(Supplement 1):S150. Use Principles in Figure 9.3 including reinforcement of behavioral interventions (weight management and physical activity) and provision of DSMES to meet individualized treatment goals If injectable therapy is needed to reduce A1C 1 Consider GLP-1 RA or GIP/GLP-1RA in most patients prior to insulin 2 INITIATION: Initiate appropriate starting dose for agent selected (varies within class) TITRATION: Titration to maintenance dose (varies within class) If already on GLP-1 RA or dual GIP and GLP-1RA or if these are not appropriate OR insulin preferred If above A1C target Add basal insulin 3 Choice of basal insulin should be based on patient-specific considerations, including cost. Refer to Table 9.4 for insulin cost information. Consider prescri ption of glucagon for emergent hypoglycaemia . Add basal analog or bedtime NPH insulin INITIATION: Start 10 IU a day OR 0.1-0.2 IU/kg per day TITRATION: Set FPG target (see Section 6: Glycemic Targets) Choose evidence-based titration algorithm, e.g., increase 2 units every 3 days to reach FPG target without hypoglycaemia For hypoglycaemia determine cause, if no clear reason lower dose by 10-20% Assess adequacy of basal insulin dose 4 Consider clinical signals to evaluate for overbasalization and need to consider adjunctive therapies (e.g., basal dose >0.5 IU/kg, elevated bedtime-morning and/or post- preprandial differential, hypoglycaemia [aware or unaware], high variability) Consider insulin as the first injectable if evidence of ongoing catabolism, symptoms of hyperglycaemia are present, when A1C levels (>10% [86 mmol/mol]) or blood glucose levels ( ≥ 300 mg/dL [16.7 mmol/L]) are very high, or a diagnosis of type 1 diabetes is a possibility. When selecting GLP-1 RA, consider: patient preference, A1C lowering, weight-lowering effect, or frequency of injection. If CVD, consider GLP-1 RA with proven CVD benefit. Oral or injectable GLP-1 RA are appropriate. For patients on GLP-1 RA and basal insulin combination, consider use of a fixed-ratio combination product ( iDegLira or iGlarLixi ). Consider switching from evening NPH to a basal analog if the patient develops hypoglycaemia and/or frequently forgets to administer NPH in the evening and would be better managed with an AM dose of a long-acting basal insulin. TO AVOID THERAPEUTIC INERTIA REASSESS AND MODIFY TREATMENT REGULARLY (3-6 MONTHS) 2023 ADA: Algorithm for intensifying to injectable therapies (1/2)

30. 5. If adding prandial insulin to NPH, consider initiation of a self-mixed or premixed insulin regimen to decrease the number of injections required. A1C, glycated hemoglobin; FPG, fasting plasma glucose; GLP-1 RA, glucagon-like peptide 1 American Diabetes Association (ADA). Diabetes Care 2023 Jan; 46(Supplement 1):S150. If above A1C target and not already on GLP-1 RA or dual GIP and GLP-1RA, consider these classes, either in free combination or fixed-ratio combination, with insulin If A1C remain above target If on bedtime NPH, consider converting to twice-daily NPH regimen Conversion based on individual needs and current glycemic control. The following is one possible approach: INITIATION: Total dose = 80% of current bedtime NPH dose 2/3 given in the morning 1 /3 given at bedtime TITRATION: Titrate based on individualized needs Add prandial insulin 5 Usually one dose with the largest meal or meal with greatest PPG excursion; prandial insulin can be dosed individually or mixed with NPH as appropriate INITIATION: 4 IU a day or 10% of basal insulin dose If A1C <8% (64 mmol/mol) consider lowering the basal dose by 4 IU a day or 10% of basal dose TITRATION: Increase dose by 1-2 IU or 10-15% twice weekly For hypoglycaemia determine cause, if no clear reason lower corresponding dose by 10-20% If above A1C target If above A1C target Consider self-mixed/split insulin regimen Can adjust NPH and short/rapid-acting insulins separately INITIATION: Total NPH dose = 80% of current NPH dose 2/3 given before breakfast 1/3 given before dinner Add 4 IU of short/rapid-acting insulin to each injection or 10% of reduced NPH dose TITRATION: Titrate each component of the regimen based on individualized needs Consider twice daily premix insulin regimen INITIATION: Usually unit per unit at the same total insulin dose, but may require adjustment to individual needs TITRATION: Titrate based on individualized needs Stepwise additional injections of prandial insulin (i.e., two, then three additional injections) Proceed to full basal-bolus regimen (i.e., basal insulin and prandial insulin with each meal) 2023 ADA: Algorithm for intensifying to injectable therapies (2/2)

31. When to start insulin All patients with type 1 diabetes Type 2 diabetes . During pregnancy. High dose of glucocorticoid therapy . Perioperative/intensive care setting . Acute infections or other serious illnesses. Post myocardial infarction. Ketoacidosis or severe hyperglycemia. Failure to achieve ideal glycemic control with two or three agents . Inability to tolerate or contraindication to oral anti-glycemic agents .

32. Case Scenario 55 yrs old man ,T2D for 5 yrs , no diabetes related complications BW 65 kg BMI 22 kgm 2 สิทธิ UC Currently on Glipizide 20 mg once daily Metformin 2000 mg a day (max tolerated dose) Pioglitazone 30 mg a day Follow up: 3 mos ago: HbA1C 8.8%,FPG 240 mg/dl This visit: HbA1C 8.5%,FPG 220 mg/dl Next Step?

33. Question What injectable regimen should be started? Bedtime basal insulin Premixed insulin twice a day Premeal prandial insulin GLP1-analogue

34. INSULIN THERAPY OPTIONS Basal insulin administration Prandial insulin supplementation Premixed formulations Basal-plus /bolus regimen

35. Types of insulin Insulin may categorized by differences in: Onset Peak Duration Concentration Route of administration

36. What we have in CRH? Basal Insulins NPH Lantus/ Toujeo Bolus Insulins Human Regular (RI) Novorapid Premixed Human 70/30 Novomix 70/30 (70% Protaminated aspart + 30% aspart ) Ryzodeg 70/30 (70% Insulin Degludec+30% aspart )

37. Basal insulin Titration

38. Oral hypoglycaemic agents (OHA) and basal insulin Metformin useful agent to continue in most patients Reduces insulin resistance Treats post- prandial hyperglycaemia No hypoglycaemia due to Metformin itself Continue at same dose

39. Suphonylureas and basal insulin Reduced to 50% maximum dose if using NPH at bedtime or premixed insulin at dinner To 25 % if using insulin analogues at bedtime

40. Other OHA Pioglitazone: usually discontinued at insulin commencement Increased risk of fluid retention But…. In young overweight patient maybe continued to help minimise the insulin dose Acarbose: can be continued if useful DPP4-inhibitors/SGLT2-inhibitors/GLP1-analoques: can be continued

41. Case Scenario 55 yrs old man ,T2D for 5 yrs , no diabetes related complications BW 65 kg BMI 22 kgm 2 สิทธิ UC Currently on Glipizide 10 mg once daily Metformin 2000 mg a day (max tolerated dose) Pioglitazone 30 mg a day NPH 10 units sc hs was started and titrated

42. Case Scenario 1 55 yrs old man ,T2D for 5 yrs , no diabetes related complications BW 66 kg สิทธิ UC Currently on Glipizide 10 mg once daily Metformin 2000 mg a day (max tolerated dose) NPH 20 units sc hs Follow up: 6 mos ago: HbA1C 8.8%,FPG 240 mg/dl 3 mos ago: HbA1C 8.5%,FPG 220 mg/dl This visit HbA1C 7.9%, FPG 110 mg/dl ,no hypoglycemic symptoms, weight gain of 1 kg. Next Step?

43. Next step Titrate dose of b edtime basal insulin Switch to basal insulin analogue Premixed insulin twice a day Premeal prandial insulin Premeal prandial plus bedtime basal insulin

44. 24-week randomized study; N = 4823 Tanenberg RJ, et al. Diabetes . 2006;55(suppl 1):A135 [abstract 567-P]. Mean Insulin Dose, units/day FPG Goal, mg/dL Mean HbA1c, % Severe Hypoglycemia, rate / year 0.13 0.08 0.05 0.03 0.02 80 60 40 120 110 100 90 80 6 7 8 9 0.05 0.1 0.15 78.2 74.9 69.6 62.2 59.4 7.6 7.5 7.4 7.4 7.3 Mean basal insulin dose, units/day Mean HbA1C, % Severe hypoglycemia, rate/year Aggressive Basal Dose Titration May Increase Severe Hypoglycemia Without Improving HbA1c

45.  Shaefer C, Reid T, Vlajnic A, Zhou R, DiGenio A. Fasting versus postprandial hyperglycemia as a treatment target to lower elevated hemoglobin A1C.  Endocr Pract  2015;21:1323–1332 2.  LaSalle JR, Berria R. Insulin therapy in type 2 diabetes mellitus: a practical approach for primary care physicians and other health care professionals. J Am Osteopath Assoc 2013;113:152–162 3.Shaefer C, Traylor L, Gao L, Dex T, Sepe P, Skolnik N. Exploratory study of a dose-response curve for basal insulin. Diabetes 2015;64(Suppl. 1):A253  4.  Reid T, Gao L, Gill J, et al.. How much is too much? Outcomes in patients using high-dose insulin glargine. Int J Clin Pract  2016;70:56–65  When to Stop Titrating Basal Insulin and Consider Prandial Control Options

46. Both fasting & mealtime glucose contribute to HbA 1c Clinical evidence suggests that reducing PPG excursions is as important, or perhaps more important than fasting blood glucose (FBG), for achieving HbA 1c goals

47. PPG control is vital for achieving HbA 1c targets 1,2 FPG PPG HbA 1c quintiles <7.1 100 60 40 20 80 7.1–7.5 7.6–8.0 8.1–8.7 8.8-12.7 Asians 2 Relative contribution to overall hyperglycaemia (%) <7.3 Relative contribution to overall hyperglycaemia (%) 100 60 40 20 80 7.3–8.4 8.5–9.2 9.3–10.2 >10.2 FPG PPG HbA 1c quintiles Caucasians 1 0.7 0.5 0.5 0.4 0.3 1 . Adapted from Monnier L et al. Diabetes Care 2003;26:881–885. 2. Adapted from Wang JS et al. Diab Metab Res Rev 2011; 27: 79–84.

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

49. Case Scenario 55 yrs old man ,T2D for 5 yrs , no diabetes related complications BW 66 kg สิทธิ UC Currently on Glipizide 10 mg once daily Metformin 2000 mg a day (max tolerated dose) NPH 20 units sc hs Off NPH Start Humulin70/30 bid

50. Pre-Mixed Insulin

51. For pre mixed insulins (70/30 preparations) Step1: First calculate the total daily starting requirement of insulin body weight(kg)/2 eg . For a 66 kg patient, total daily dose =33 units Step 2: Then divide this dose into 3 equal parts: 11+11+11 Step 3: Give 2 parts in the morning and 1 part in the evening Morning=22U Evening=11 U

52. Case Scenario 1 55 yrs old man ,T2D for 5 yrs , no diabetes related complications BW 70 kg สิทธิ UC Currently on Metformin 2000 mg a day (max tolerated dose) Humulin70/30 22-0-11 units Follow up: 9 mos ago: HbA1C 8.8%,FPG 240 mg/dl 6 mos ago: HbA1C 8.5%,FPG 220 mg/dl 3 mos ago HbA1C 7.9%, FPG 110 mg/dl This visit HbA1C 7.5 % FPG 158 mg/dl complaints of frequent hypoglycemic symptoms at night time, 3 kg weight gain . Next Step?

53. Question Patient ’ s A1C is 7.5% and SMBG diary reveals high fasting and post-dinner glucose, and nocturnal hypoglycemia. The next step for this patient to gain control is to: Continue with the twice-daily premix and increase dose Continue with premixed and discontinue metformin Switch to a long-acting insulin analog alone Switch to premix analogue

54. Case Scenario 55 yrs old man ,T2D for 5 yrs , no diabetes related complications BW 68 kg สิทธิ UC Currently on Metformin 2000 mg a day (max tolerated dose) Novomix 70/30 22-0-11 units Follow up: 12 mos ago: HbA1C 8.8%,FPG 240 mg/dl 9 mos ago: HbA1C 8.5%,FPG 220 mg/dl 6 mos ago HbA1C 7.9%, FPG 110 mg/dl 3 mos ago HbA1C 7.5%, FPG 168 mg/dl This visit HbA1C 7.0 % FPG 110 mg/dl , no hypoglycemic symptoms . Weight loss 2 kgs .

55. Limitations of Human Regular Insulin Slow onset of action Requires inconvenient administration: 20 to 40 minutes prior to meal Risk of hypoglycemia if meal is further delayed Mismatch with postprandial hyperglycemic peak Long duration of activity Up to 12 hours’ duration Increased at higher dosages Potential for late postprandial hypoglycemia 6-26

56. The benefits of insulin use in those who need it outweight the risks INSULIN USE Weight gain Side-effects of insulin use Maintaining glycaemic control Hypoglycaemia

57. 4 Pharmacology of premixed insulin analogue

58. The dual-release insulin concept 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 BIAsp, biphasic insulin aspart Physiological insulin profile Protamine crystallised insulin aspart Soluble insulin aspart BIAsp 30 Schematic presentation

59. Insulin aspart Insulin aspart differs from human insulin by the single amino-acid substitution of a proline by an aspartic acid residue at B28 The B28 position is implicated in the formation of dimers but not implicated in pharmacological activity Insulin aspart is monomeric at pharmacological concentrations, allowing rapid absorption into the bloodstream Brange et al. Nature 1988;333:679–82 How is BIAsp 30 different from BHI 30? 30 % Protamine-crystallised insulin aspart Soluble insulin aspart BIAsp 30 A premixed suspension of: 30 % NPH insulin ( protaminated human insulin) BHI 30 BIAsp 30 70 % 70 % Regular human insulin BHI 30 A premixed suspension of: BIAsp 30 SPC. http://ec.europa.eu/health/documents/community-register/2000/200008013730/anx_3730_en.pdf BHI, biphasic human insulin; BIAsp, biphasic insulin aspart; NPH, neutral protamine Hagedorn

60. * Human premix insulin 30/70 1. Adapted from Garber AJ et al. Diabetes Obes Metab 2007;9:630–639. 2. BIAsp 30 Summary of Product Characteristics. 3 . Davidson J. et al., Clin Therap , 2009;31(8):1641-1651. 4. Hermansen K et al. Diabeties Care 2002;25:883–888. Relative action of insulin Physiological insulin profile Human premix insulin 30/70 30 minutes before a meal 1 BIAsp 30 Immediately before a meal 2 Time 30 minutes Higher maximum concentration More effective PPG control 4 Shorter acting Reduces risk of hypoglycaemia 3 Faster start action Flexible mealtime injection – no need to wait 30 minutes before eating 1,2 Pharmacokinetic profile BIAsp 30 vs. BHI

61. Pharmacological profile Compared with biphasic human insulin, BIAsp 30 has: Faster absorption Higher peak concentration More rapid and pronounced glucose-lowering effect Similar duration of action of basal component Jacobsen et al . Eur J Clin Pharmacol 2000;56:399–403 BIAsp, biphasic insulin aspart

62. 5 Efficacy and safety of premixed insulin analogue 20 Years of clinical experience

63. 2000–2020 BIAsp 30 has been studied in at least 63 RCTs *1 2007–2010 PRESENT observational study 2–4 >22,000 patients 2008–2012 IMPROVE observational study 5–7 >51,000 patients 2010–2012 A 1 chieve observational study 8,9 >66,000 patients of clinical experience *2–9 Tolerability profile demonstrated over 20 YEARS * Literature search on 2016.03.09: PubMed search string based on MeSH search strings: (“biphasic insulins” [ MeSH Terms] or “insulin aspart ” [ MeSH Terms]) AND (“ randomised controlled trial” [Publication Type] OR “ randomised controlled trials as topic” [ MeSH Terms]):resulting in 63 hits for biphasic insulin aspart 1. Data on file. 2. Adapted from Sharma SK et al. Curr Med Res Opin 2008;24:645–652. 3. Almustafa M et al. Diabetes Res Clin Pract 2008;81(Suppl. 1):S10–15. 4. Güler S et al. Arch Drug Inf 2009;2:23–33. 5. Valensi P et al. Int J Clin Pract 2009;63:522–531. 6. Yang W et al. Curr Med Res Opin 2009;25:2643–2654. 7. Gumprecht J et al. Int J Clin Pract 2009;63:966–972. 8. Home P et al. Diabetes Res Clin Pract 2011;94:352–363. 9. El Naggar NK et al. Diabetes Res Clin Pract 2012;93:408–413. A well-documented tolerability profile 1–8

64. 5.1 Efficacy and safety in type 2 diabetes Switching insulin to BIAsp 30

65. Significantly lower prandial glucose increment with BIAsp 30 0.5 1 1.5 2 2.5 3 BIAsp 30 BHI 30 Mean prandial glucose increment (mmol/l) p < 0.02 between treatment groups (n = 128) (n = 141) At 12 weeks Mean prandial glucose excursion was significantly less 29% ( p < 0.02) in the BIAsp 30 compared with the BHI 30. -29% Boehm et al . Diabet Med 2002;19:393–99

66. Iwamoto 2003 (n=428) BIAsp 30 associated with a significantly lower rate of major hypoglycaemia compared with BHI 30 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 <0.05 100 0.1 1 10 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 BIAsp 30, biphasic insulin aspart 30; BHI, biphasic human insulin; CI, confidence interval reduction in the likelihood of major hypoglycaemic events vs human premix insulin 1† 55% 

67. BIAsp 30 associated with a significantly lower rate of nocturnal hypoglycaemia compared with BHI 30 Iwamoto 2003 (n=428) 20 0.2 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) Favours BIAsp 30 Favours BHI 30 Trial Rate ratio [95% CI] Davidson et al . Clin Ther 2009;31:1641–51 BIAsp 30, biphasic insulin aspart 30; BHI, biphasic human insulin; CI, confidence interval reduction in the likelihood of nocturnal hypoglycaemic events vs human premix insulin 1† 50% 

68. Hypoglycaemia is costly Direct medical and informal caregivers of diabetes management 2,3,4 1,155 – 3,007 2,133 – 6,789 13,971 – 15,483 Total cost: THB 3,288 – 6,789 Total cost: THB 13,971 – 15,483 THB per patient per year Drug cost Other direct medical cost Informal caregivers Direct medical cost Informal caregivers Novo Nordisk. The Blueprint for change: Partnering to innovate diabetes care in Thailand 2017. Permsuwan U, et al. Appl Health Econ Health Policy 2016;14(3):281-92. Riewpaiboon A, et al. Int J Pharm Pract 2011;19(5):342-9. Chatterjee S, et al. Prim Care Diabetes 2011;5(2):109-15. THB 10,574 – 28,494 Per episode could be saved from severe and very severe hypoglycaemia treatment 1

69. 5.2 Efficacy and safety in type 2 diabetes BIAsp 30 for TID dosing

70. American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S135. Therapeutic Options in Patients Not Achieving Glycemic Goals

71. BIAsp 30 BID + metformin (n=217) Duration 24 weeks Treat-to-target Key exclusion criteria Previous insulin intensification regimen for more than 14 days Anticipated initiation or change in concomitant medications known to affect weight or glucose metabolism Impaired liver function Titration Weekly SMBG target 4.4−6.1 mmol/L (80−110 mg/dl) Trial information Randomised Open-labelled Treat-to-target Intensification with TID vs BID BiAsp 30 Trial design *Within each participating country, the aim was to include a maximum of 20% of randomised subjects on treatment with NPH prior to screening. Key inclusion criteria Age > 18 yrs T2DM > 12 mo Basal insulin (NPH * or analogue) > 90 days + Metformin + 1 OAD > 90 days HbA 1c 7.5%-10% (both inclusive) Randomisation (1:1) End of treatment BIAsp 30 TID + metformin (n=220) F-U 30 d -2 W screening Randomisation Stratified according to : HbA 1c 7.5%-8.5% and 8.6%-10.0% Metformin and metformin + 1 OAD Yang 2019 Diabetes Res Clin Pract, 150, 158-166

72. Objectives Primary objective To compare the efficacy of thrice daily BIAsp 30 versus twice daily BIAsp 30, both in combination with metformin, in subjects with T2DM inadequately controlled on basal insulin combined with OADs Secondary objectives To compare between the 2 treatment arms: Safety Patient reported treatment satisfaction Yang 2019 Diabetes Res Clin Pract, 150, 158-166

73. ETD: − 0.09 [−0.23;0.06] 95% CI 7-point SMBG profiles were similar for BIAsp 30 TID and BIAsp 30 BID and none of the derived endpoints were statistically significantly different between the two treatment arms Summary of efficacy results after 24 weeks * Subjects achieving HbA 1c <7.0% after 24 weeks of randomised treatment. Missing HbA 1c value at week 24 is imputed using t he predicted value from an MMRM analysis . CI, confidence interval; ETD, estimated treatment difference ( BIAsp 30 TID – BIAsp 30 BID); OR, odds ratio ( BIAsp 30 TID / BIAsp 30 BID); PPG, post-prandial glucose; SMBG, self-measured blood glucose. −1.71 −1.62 HbA 1c (%) BIAsp 30 TID BIAsp 30 BID The odds for HbA 1c responders after 24 weeks of treatment were not statistically significantly different for BIAsp 30 TID vs BIAsp 30 BID Estimated OR: 1.36 [0.92; 2.01] 95% CI* Change from baseline in FPG after 24 weeks of treatment was not statistically significantly different for BIAsp 30 TID vs BIAsp 30 BID ETD: − 0.25 mmol /L [ − 0.67; 0.16] 95% CI Yang 2019 Diabetes Res Clin Pract, 150, 158-166

74. Summary of safety results after 24 weeks BG, blood glucose; BID, twice daily; ERR, estimated rate ratio ( BIAsp 30 TID / BIAsp 30 BID); ETD, estimated treatment difference ( BIAsp 30 TID – BIAsp 30 BID). Daily insulin dose Mean actual total daily dose at week 24 BIAsp 30 TID: 0.970 U/kg (69.8 U) BIAsp 30 BID: 0.899 U/kg (64.8 U) Severe or BG-confirmed hypoglycaemic episodes Overall ERR: 0.98 [0.72; 1.33] 95% CI Nocturnal ERR: 0.71 [0.35; 1.46] 95% CI The overall rates of adverse events were similar for the two treatment arms Both treatment arms were well tolerated and no new safety issues were identified 1.53 ETD: −0.21 [−0.79; 0.37] 95% CI Body weight (kg) BIAsp 30 TID BIAsp 30 BID 1.74 BIAsp 30 TID BIAsp 30 BID Yang 2019 Diabetes Res Clin Pract, 150, 158-166

75. Observational Studies TID Dosing

76. 1-2-3 Study: design and methods HbA 1c ≤6.5% Pre-dinner × 16 weeks Start with 12 U at dinner End of study If HbA 1c >6.5%, go to BID, stop secretagogues Pre-breakfast and dinner × 16 weeks Add 3 U at breakfast if FBG ≤110 mg/dL Add 6 U at breakfast if FBG >110 mg/dL End of study HbA 1c ≤6.5% If HbA 1c >6.5%, go to TID TID × 16 weeks Add 3 U at lunch and titrate Phase 1 Phase 2 Phase 3 OD BID TID Titrate according to schedule every 3 days n=100 patients with type 2 diabetes (≥12 months), HbA 1c ≥7.5≤10%, ≥2 OADs or ≥1 OAD plus basal insulin OD (max 60 U) Garber et al . Diabetes Obes Metab 2006;8:58–66 BID, twice daily; FBG, fasting blood glucose; OAD, oral antidiabetic drug; OD, once daily; TID, three-times daily

77. 1-2-3 Study: 2% reduction in HbA 1c with OD, BID or TID BIAsp 30 6.6% 8.6% 2 4 6 8 10 Baseline OD, BID, TID HbA 1c (%) Garber et al . Diabetes Obes Metab 2006;8:58–66 BIAsp, biphasic insulin aspart; BID, twice daily; OD, once daily; TID, three-times daily Patients achieving HbA 1c target, % OD OD, BID OD, BID, TID

78. Similar low hypoglycaemia rate between phases with BIAsp 30 Stepwise regression showed that t here was no correlation between hypoglycaemia and number of injections   Phase 1 OD Phase 2 BID Phase 3 TID Number of patients with major hypoglycaemic events 3 3 1 Rate of minor hypoglycaemic events (events per patient-year) 15 22 12 Number of major nocturnal hypoglycaemic events Garber et al . Diabetes Obes Metab 2006;8:58–66 BIAsp, biphasic insulin aspart; BID, twice daily ; OD, once daily; TID, three-times daily

79. 6 Premixed insulin analogue dose titration

80. BIAsp 30: titration algorithm FBG or pre-dinner SMBG BIAsp 30 dose adjustment (mg/ dL ) ( mmol /L) <80 <4.4 –2 U 80 – 110 4.4 –6.1 – 111 – 140 6.2–7.8 +2 U 141 – 180 7.9–10 +4 U >180 >10 +6 U Adapted from Raskin et al. Diabetes Care 2005;28:2811 BIAsp , biphasic insulin aspart ; BID, twice daily; FBG, fasting blood glucose; OD, once daily; SMBG, self-measured blood; TID, three-times daily Dose to titrate Timing of blood glucose measurements used for dose titration BIAsp 30 OD BIAsp 30 BID BIAsp 30 TID Breakfast – Pre-dinner Pre-lunch Lunch – – Pre-dinner Dinner Pre-breakfast Pre-breakfast Pre-breakfast

81. In insulin-naïve patients 1 Breakfast Dinner Once-daily start ̶̶ Twice-daily start 12 units 6 units 6 units BIAsp 30 : titration algorithm *Guideline for the recommended adjustment is included in the NovoMix ® 30 Summary of Product Characteristics 1. Adapted from the NovoMix ® 30 Summary of Product Characteristics. 2. Garber AJ et al. Diabetes Obes Metab 2006;8:58–66. FBG or pre-dinner SMBG BIAsp 30 dose adjustment (mg/ dL ) ( mmol /L) <80 <4.4 –2 U 80 – 110 4.4 –6.1 – 111 – 140 6.2–7.8 +2 U 141 – 180 7.9–10 +4 U >180 >10 +6 U When transferring from human premix insulin, start with the same dose and regimen * unit of human premix insulin † Transfer to unit of BIAsp 30

82. Three times daily dosing 1,2,3 breakfast same total dose split break-fast dose lunch   dinner = breakfast add 2 to 6 units add lunch-time dose lunch -4 dinner = 6 or:   1. Adapted from Garber A.J. et al., Diab Obes Metab , 2006; 8: 58-66 2. Adapted from Unnikrishnan A.G. et al., Int J Clin Pract , 2009; 63 (11): 1571-77 3. Heise T. et al., Diabetes Care, 2009; 32 (8): 1431-33

83. 7 Summary

84. Biphasic insulin aspart 30 Available in 2 dosage forms : Penfill ® (cartridge 300 i.u. / 3 mL use with NovoPen ® 4 ) Flexpen ® (prefilled pen 30 i.u. / 3 mL) 30% rapid acting + 70% intermediate-acting insulin aspart Cloudy & white Resuspending needed Onset: 10-20 minutes Peak: 1-4 hours Duration: up to 24 hours BIASp30 Professional leaflet STF-Dec-2017

85. Human insulin Modern insulin* Biphasic insulin aspart 30 When hypoglycaemia occurs 1,2 When PPG control is needed 2 1. Adapt from Zanariah H. et al., Diab Res Clin Pract , 2013; 100: S24-9 2. Adapt from National List Essential Medicine , 07 August 2013; www.nlem.in.th *ANNOUNCED SINCE 13 AUGUST.2013 Available in 2 dosage forms : Penfill ® (cartridge 300 i.u. / 3 mL use with NovoPen ® 4 ) Flexpen ® (prefilled pen 30 i.u. / 3 mL)

86. Versus human premix insulin * : Flexible injection timing – can be taken just before or immediately after a meal vs 30 minutes before a meal with human insulin 1,2 Better HbA 1c , FPG and PPG control after upgrading from human premix insulin 3-6† 29% lower PPG 3 Significantly lower risk of major (55%) or nocturnal (50%) hypoglycaemia vs human premix insulin 7 Listed on Thailand NLEM 8 1. Garber AJ et al . Diabetes Obes Metab 2007;9:630−639. 2. NovoMix ® 30 Summary of Product Characteristics. 3. Boehm P.O. et al., Diab Med, 2002; 19: 393-9 . 4. Shestakova M et al. Curr Med Res Opin 2007;23(12):3209−3214. 5. Shah S et al. Int J Clin Pract 2009;63(4):574−582. 6. El Nagger NK et al. Diabetes Res Clin Pract 2012;98:408-413. 7. Davidson JA et al . Clin Ther 2009;31(8):1641−1651. 8.Thailand National List Essential Medicine, 28 May 2015 *Human premix insulin 30/70 †Data from observational studies

87. Questions and answers