1. NN-Iran/MIP/001/Jan 2010/1 Position of “Premix Insulin” in the Management of Type 2 diabetes Dr. Khalilzadeh /Endocrinologist

2. Novo Nordisk A/SSlide no 220 December 2015 World Health Organization’s (WHO) definition of diabetes A metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both

3. Novo Nordisk A/SSlide no 320 December 2015 Classification of Diabetes Type 1 Type 2 10% of diabetes Younger usually <20 years Normal body weight Normal blood pressure Absolute insulin deficiency May or may not have lipid anomalies 90 to 95% of diabetes Older usually > 30 years Relative insulin deficiency Insulin resistance syndrome, obesity High BP Dyslipedemia HDL, TG LDL (increased small, dense particles)

4. Novo Nordisk A/SSlide no 420 December 2015Slide no 4Date Diabetes (today – tomorrow) Rapid growth in diabetes prevalence 284.6 million 438.4 million 54% increase in 20 years 2010 2030

5. Slide no 5Date Diabetes Prevalence was underestimated… The number of people with diabetes in 2011 has reached a staggering 366 million IDF Fact Sheet updated in EASD 2011

6. The Clock is ticking for the world’s leaders One person is dying from diabetes every seven seconds! IDF 2011 Fact Sheet 4.6 million deaths due to diabetes in 2011!

7. Novo Nordisk A/SSlide no 720 December 2015 Rule of halves T2D Diabetes population in Iran 3,237,559 (age 25-64) 1,717,889 (apprx. 53%) 860,000 430,000 208,000 3,237,559 208,000 *Esteghamati A, et al. Third national surveillance of risk factors of non-communicable diseases (SuRFNCD-2007) in Iran: methods and results on prevalence of diabetes, hypertension, obesity, central obesity, and Dyslipidemia. BMC Public Health 2009, 9:167

8. Final visit GLOBAL Data collection overview IRAN A 1 chieve Interim visit Baseline visit Week 0~Week 24~Week 12 Weight Current diabetes treatment regimen Blood glucose control parameters Hypoglycaemia AE and ADR Quality of life - EQ5D Weight Current diabetes treatment regimen Blood glucose control parameters Hypoglycaemia AE and ADR Informed consent Eligibility Demographics Medical history Diabetes treatment history Quality of life – EQ5D 3166 investigators 66726 subjects Iran 84 investigators 919 subjects AE, adverse event; ADR, adverse drug reaction

9. HbA 1c - by pre-study therapy IRAN A 1 chieve 5725049223371718611 n= GlobalIran 71722453242

10. Diabetes-related complication prevalence : IRAN A 1 chieve Complications Global n=65513 Iran n=919 Cardiovascular (%)27.227.7 Neuropathy (%)38.457.7 Renal (%)27.9 Eye (%)26.338.0 Foot ulcer (%)5.47.9 A patient can have multiple complications

11. Novo Nordisk A/SSlide no 1120 December 2015 FPG The basal glucose level PPG The peak glucose level HbA 1 C The long-term average glucose level For Optimal Management We Should Target……

12. Novo Nordisk A/SSlide no 1220 December 2015 UKPDS-Stratton IM et al. BMJ 2000;321:405-412. Correlation between a 1% HbA 1 C decrease and reduced risk of complications (T2DM) 43%37%19%14% Lower extremity amputation or fatal peripheral vascular disease Microvascular disease Cataract extraction Myocardial infarction 16% Heart failure 12% Stroke Cardiovascular complications 1% drop in HbA 1 C

13. Management of Type 2 Diabetes 13

14. The different diabetes management guidelines all target HbA 1 c of < 7% ADA (US) 1 HbA 1c < 7% IDF (Europe) 3 HbA 1c  6.5% CDA (Canada) 4 HbA 1c  7% NICE (UK) 5 HbA 1c 6.5–7.5% AACE (US) 2 HbA 1c  6.5% ALAD (Latin America) 6 HbA 1c < 6 – 7% APPG (Asia Pacific) 7 HbA 1c < 6.5% Australia 8 HbA 1c  7% 1 American Diabetes Association. Diabetes Care 2009; 32 (Suppl. 1):S13–S61. 2 American Association of Clinical Endocrinologists. Endocr Pract 2009; 15 (6):540-559. 3 European Diabetes Policy Group. Diabet Med 1999; 16:716–730. 4 Canadian Diabetes Association. Can J Diabetes 2008; 32 (Suppl. 2):S1–S201. 5 National Institute for Clinical Excellence. 2002. Available at: http://www.nice.org.uk. 6 ALAD. Rev Asoc Lat Diab 2000; Suppl. 1. 7 Asian-Pacific Policy Group. Practical Targets and Treatments (3rd Edition). 8 NSW Health Department. 1996. NN-Iran/MIP/001/Jan 2010/1

15. ADA – EASD Guideline 2012 15

16. Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) April 19, 2012

23. More Stringent HbA1c Targets (6.0 – 6.5%) Short disease duration Long life expectancy No significant CVD If this can be achieved without significant hypoglycemia or other adverse effects of treatment 23

24. History of severe hypoglycemia Limited life expectancy Advanced complications Extensive comorbid conditions In whom the target is difficult to attain despite intensive self-management education, repeated counseling, and effective doses of multiple glucose-lowering agents, including insulin 24 Less Stringent HbA1c Targets (7.5 – 8.0% or even slightly higher)

26. Lifestyle Interventions: At diagnosis, highly motivated patients with HbA1c already near target (<7.5%) could be given the opportunity to engage in lifestyle change for a period of 3–6 months before embarking on pharmacotherapy (usually metformin) 26

32. Perhaps more convenient but less adaptable method involves “premixed” insulin Traditionally, administered twice daily, before morning and evening meals In comparison with basal insulin alone, premixed regimens tend to lower HbA1c to a larger degree, but often at the expense of slightly more hypoglycemia and weight gain 32 Transitions to and titrations of Insulin:

33. “premixed” insulin approach This strategy may be appropriate for certain patients who eat regularly and may be in need of a simplified approach beyond basal insulin Disadvantages: inability to titrate the shorter- from the longer-acting component 33 Transitions To and Titrations of Insulin:

34. Key Message Again, individualization of therapy is key, incorporating the degree of hyperglycemia needing to be addressed and the overall capacities of the patient. 34

43. 2011 IDF Guideline

45. NovoMix ® 30 - Abbreviated prescribing information Abbreviated Prescribing Information NovoMix ® 30 (biphasic insulin aspart). Refer to the Summary of Product Characteristics (SPC) before prescribing. Presentations: NovoMix ® 30 FlexPen ®. All presentations contain soluble insulin aspart/ protamine-crystallised insulin aspart 100 units/ml in the ratio of 30/70. Indication: Treatment of diabetes mellitus. Dosage: Individual by subcutaneous injection. NovoMix ® 30 has a faster onset of action than biphasic human insulin and should generally be given immediately before a meal. When necessary, NovoMix ® 30 can be given soon after start of a meal. In patients with type 2 diabetes, NovoMix ® 30 can be given in monotherapy or in combination with metformin when the blood glucose is inadequately controlled with metformin alone. Contraindications: Hypoglycaemia, hypersensitivity to insulin aspart or to any other of the ingredients. Warnings and precautions: Inadequate dosages or discontinuation of treatment may lead to hyperglycaemia and ketoacidosis, which are potentially lethal. A change in the usual early warning symptoms of hypoglycaemia may be seen upon tightening control. The fast onset of action should be considered in patients where a delayed absorption of food might be expected. Transferring to a new type or brand of insulin should be done under strict medical supervision. Too much insulin, omission of a meal or strenuous exercise may lead to hypoglycaemia. Compared with biphasic human insulin, NovoMix ® 30 may have a stronger hypoglycaemic effect up to 6 hours after injection. This may need to be compensated for through adjustment of dose and/or food intake. Hypoglycaemia may constitute a risk when driving or operating machinery. Elderly patients: NovoMix ® 30 can be used in elderly patients; however there is limited experience with the use of NovoMix ® 30 in combination with OADs in patients older than 75 years. Pregnancy and lactation: Limited clinical experience in pregnancy. No restrictions on use during lactation. Side effects: Most of the following undesirable effects are uncommon, rare or very rare. Hypoglycaemia. Oedema, refraction anomalies and local hypersensitivity can occur on instituting therapy and are usually transitory in nature. Acute painful peripheral neuropathy may occur upon fast improvement in blood glucose control but is usually reversible. Generalised hypersensitivity reactions are rare but potentially life-threatening. Lipodystrophy, worsening of diabetic retinopathy. Major drug interactions: Oral Hypoglycemic Agents (OHAs), Monoamine Oxidase Inhibitors (MAOIs) and non-selective beta-adrenergic blocking agents may reduce the patient’s insulin requirements. Oral contraceptives and thyroid hormones may increase the patient’s insulin requirements. Please refer to the patient information leaflet for more information. Prescription only medicine Full prescribing information can be obtained free of charge from Novo Nordisk. IRC number: 1228066993 Novo Nordisk Pars 11 th flr. Kian Tower, No.1387 Naseri St. Vali e Asr Ave.Tehran Tel: 88645221-28

46. Novo Nordisk Pars 11 th floor, Kian Tower No. 1387, Vali-e-Asr Ave. TehranIran NN-Iran/MIP/001/Jan 2010/1