Basal Bolus Regimen in T2DM Prof. Dr. Hala Aly Gamal El Din Professor Of internal medicine Faculty of Medicine - Cairo University

Goals of Glucose Management Targets for glycemic (blood sugar) control ADA AACE A1c (%) <7* ≤6.5 Fasting (preprandial) plasma glucose 70-130 mg/dL <110 mg/dL Postprandial (after meal) plasma glucose <180 mg/dL <140 mg/dL R36/p34/P1/L15 Both the ADA and the AACE recommend tight glucose control for persons with diabetes, although their definitions vary. Despite the findings of two large-scale trials, the DCCT and UKPDS, a universally agreed-upon set of glucose management goals has yet to be defined. While almost every diabetes management guideline includes the hallmark variables of A1c and fasting plasma glucose, there are slight variations in specific target values. The American Diabetes Association (ADA) currently recommends a target A1c of <7%, while the American Association of Clinical Endocrinologists (AACE) suggests aiming for a value of 6.5% or lower. The ADA proposes a target range for fasting plasma glucose levels between 90 and 130 mg/dL, while the AACE recommends levels below 110 mg/dL. Postprandial plasma glucose recommendations put forth by the two organizations are <180 and <140 mg/dL, respectively. In addition to these standard variables, there are other important aspects of diabetes management that deserve consideration. Other important issues identified in the two landmark trials, both medically and from a quality of life perspective, include reducing the frequency of hyperglycemic excursions, minimizing the risk of hypoglycemia, especially nocturnal, and minimizing weight gain. Addressing these issues could have an impact on patient motivation and/or treatment compliance, increasing the chance of attaining A1c and plasma glucose goals. References: American Diabetes Association. Standards of medical care in diabetes – 2006. Diabetes Care. 2006;29(suppl 1):S4-S42. Implementation Conference for ACE Outpatient Diabetes Mellitus Consensus Conference Recommendations: Position Statement at http://www.aace.com/pub/pdf/guidelines/Outpatient ImplementationPositionStatement.pdf. Accessed January 6, 2006. R5/pS10/T6 *<6 for certain individuals Implementation Conference for ACE Outpatient Diabetes Mellitus Consensus Conference Recommendations: Position Statement at http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf. Accessed January 6, 2006. AACE Diabetes Guidelines – 2002 Update. Endocr Pract. 2002;8(suppl 1):40-82. American Diabetes Association. Diabetes Care. 2009;32(suppl 1) R2/p3/P2 3 3

Relation between PPG control & Achieving A1C Goal Adapted from Monnier L, Lapinski H, Collette C. Contributions of fasting and postprandial plasnma glucose increments to the overall diurnal hyper glycemia of Type 2 diabetic patients: variations with increasing levels of HBA(1c). Diabetes Care. 2003;26:881-885. 4 4

Difficult and Important!! Moving from A1C 8.0% to 7.0% Difficult and Important!! 20-25% of Patients Have A1Cs between 8.0% and 7.0% Moving from A1C 8.0% to 7.0% - Reduces Serious Complications UKPDS Study Results Reduced microvascular complications (kidney, eye, etc.) by 17-33% Reduced risk of heart attack by 16% Reduced diabetes-related deaths by 21% Challenge: More difficult to make improvements as A1C gets closer to 7.0%

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

Parenteral/inhaled agents A1C reduction with glucose – lowering medications Oral agents A1C (%)* Sulfonylureas 1.5 Biguanides (metformin) Glinides 1.0–1.5 Thiazolidinediones 0.8–1.0 DPP-IV inhibitors 0.5–0.9 α-Glucosidase inhibitors 0.5–0.8 Parenteral/inhaled agents Insulin ≥2.5 Inhaled insulin GLP analogues 0.6 Amylin analogues *Monotherapy DPP = dipeptidyl peptidase; GLP = glucagon-like peptide Nathan DM. N Engl J Med. 2007;356:437-40.

Insulin is the most effective anti diabetic agent Nathan DM. N Engl J Med. 2007;356:437-40.

Insulin therapy in T2DM indications Significant hyperglycemia at presentation Hyperglycemia on maximal doses of oral agents Decompensation Acute injury, stress, infection, myocardial ischemia Severe hyperglycemia with ketonemia and/or ketonuria Uncontrolled weight loss Use of diabetogenic medications (eg, corticosteroids) Surgery Pregnancy

A clinical fact Most Patients with T2DM will eventually need exogenous insulin to maintain recommended targets for glycaemic control Starting insulin treatment in adults with Type 2 diabetes RCN guidance for nurses 2004

When to Start Insulin First ADA-EASD Consensus SEVERELY CATABOLIC PATIENT Hemoglobin A1C > 10% FBS > 250 mg/dl (13.9 mmol/l) Random consistently > 300 mg/dl (16.7 mmol/l) Nathan et al. Diabetes Care 2006;29: 1963-1972

T2DM treatment Old paradigm by A1C level 7% 8% 9% 10% 7% Insulin Diet and exercise Combination oral agents 7% Monotherapy Insulin

New ADA/EASD treatment algorithm for Type 2 diabetes Tier 1: Well validated core therapies Lifestyle + Metformin + Basal insulin Lifestyle + Metformin + Intensive insulin At diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Sulfonylureaa STEP 1 STEP 2 STEP 3 Tier 2: Less well validated therapies Lifestyle + Metformin + Pioglitazone No hypoglycaemia Oedema/CHF Bone loss Lifestyle + Metformin + Pioglitazone Sulfonylureaa Nathan DM, Buse JB, Davidson MB, et al. Diabetologia. 2009;52:17-30 Lifestyle + Metformin + GLP-1 agonistb No hypoglycaemia Weight loss Nausea/vomiting Lifestyle + Metformin + Basal insulin Reinforce lifestyle interventions at every visit and check HbA1c every 3 months until HbA1c is <7 % and then at least every 6 months. The interventions should be changed if HbA1c is ≥7 % aSulfonylureas other than glibenclamide (glyburide) or chlorpropamide bInsufficient clinical use to be confident regarding safety

The Ideal Basal Insulin Mimics normal pancreatic basal insulin secretion Long-lasting effect – 24 hours Smooth, peakless profile Reproducible and predictable effects Reduced risk of nocturnal hypoglycemia Once-daily administration 14

Levemir® FlexPen® ? Welcome! Thank you for joining us here today… This is a momentous day for Levemir® because, unusually, we now have a second chance for a new beginning… And just in case you’re thinking… here we go again, same old, same old… Let me set you straight. When we tell you this is a new beginning for Levemir®, we mean just that. Nothing will ever be the same again… Are you ready to hear more…? 15

Insulin Detemir (Levemir®) LysB29(N-tetradecanoyl)des(B30)human insulin Detemir Properties: Neutral pH Albumin binding Long extended action More within patient consistency Less hypoglycemia Less weight gain Thr Glu Lys Val Phe Asn Leu Gln Tyr Ser Cys Ile Gly Pro Arg Ala His B1 A21 A1 B29 C14 fatty acid chain (Myristic acid) In insulin detemir, a 14-carbon (myristic acid) FA side chain is attached to Lysine at residue B29, with threonine at residue B30 removed. Insulin detemir takes its name from: Des threonine + myristic (mir) acid 16

Mode of Action Injection site Blood Tissue Use of Serum Carrier Protein (e.g. Albumin) to Extend time of action Injection site Blood Tissue Carrier Protein Receptor Carrier Protein Receptor Hormone Hormone Hormone Hormone Carrier Protein

Levemir® FlexPen® Designed to bind specifically to albumin Albumin binding protracts: Absorption of insulin detemir from the subcutaneous depot Residency of insulin detemir in the circulation Albumin binding buffers variability of action of insulin detemir There are no safety concerns with albumin binding of insulin detemir or with changes to its insulin structure

Albumin binding of Levemir® Myristic acid binds at fatty-acid binding sites of albumin 98.8% binding in human plasma Safety of albumin binding At therapeutic doses, insulin detemir occupies a tiny fraction of available albumin binding sites, with more than 60,000-fold excess albumin over insulin This 3D cartoon illustrates albumin binding in a capillary. It can be used alongside the other screen grabs from the insulin detemir animation if a more ‘graphic’ presentation is required.

Mode of prolonging action Self association (hexameric) Fatty acid side chains bind to albumin in injection depot Albumin binding in circulation Protracted absorption ‘Buffering’ effect and minor contribution to protraction

Why do we say Levemir™ is “predictable”? Solution, acid pH, pain Precipitation & de-precipitation is the mechanism of protraction: so factors of precipitation and absorption remain Glargine Precipitation Solution, neutral pH, no pain No precipitation mechanism of protraction depends on increased self -association Levemir™ Precipitation No absorption factor – albumin binding buffers absorption

Variability in time-action profile of basal insulin Study 1450. Importantly, the time-action profile of insulin detemir has also been shown to be reproducible – significantly more so than NPH insulin or insulin glargine. These data are taken from a comparative study in which patients underwent glycaemic clamps following 4 injections on 4 separate visits. Here we see three typical examples of the GIR curves required to maintain a glycaemic target following injection in three patients – one receiving insulin glargine, one NPH insulin and one insulin detemir. Abstract: Lower Within-Subject Variability of Insulin Detemir in Comparison to NPH Insulin and Insulin Glargine in Subjects with Type 1 Diabetes TIM C. HEISE 1 , LESZEK NOSEK 1 , EBERHARD DRAEGER 2 , ANNETTE STENDER 2 , BIRGITTE BIILMANN RØNN 2 , CHRISTOPH KAPITZA 1 , LUTZ HEINEMANN 1 . 1 Neuss, Germany, 2 Bagsvaerd, Denmark. We compared the within-subject variability of the effect of the novel long-acting insulin analogue insulin detemir (IDet) with that of NPH insulin and insulin glargine (GL) in a randomized, controlled, parallel group, double blind study. Fifty-four patients with type 1 diabetes (32 males; age 38±10 years (mean±SD); BMI 24±2 kg/m 2 ; HbA 1c 7.5±1.2%; diabetes duration 18±9 years) received the same dose (0.4 U/kg) of either NPH insulin, GL or IDet s.c. on four identical study days under euglycemic glucose clamp conditions (target blood glucose concentration 5.5 mmol/L). The pharmacodynamic and pharmacokinetic effects of the basal insulin preparations were recorded for 24 and 28 hours post-dose, respectively. IDet showed significantly less within-subject variability compared to NPH and GL (2.5 and 1.8 fold lower CV for GIR-AUC(0–24h), respectively), see table. Similar findings were also observed for pharmacokinetic parameters. In conclusion, this first systematic investigation of the variability in the pharmacodynamic and pharmacokinetic properties of the most commonly used basal insulin preparations in type 1 diabetes shows significantly less within-subject variability for insulin detemir. This suggests that this novel basal insulin will provide a more predictable therapeutic effect compared to both NPH insulin and insulin glargine. Within-Subject Variability, expressed as Coefficients of Variations (CV) in % Insulin Detemir NPH Insulin Insulin Glargine Pharmacodynamics (assessed by Glucose Infusion Rates (GIR)) GIR-AUC (0–12h) 27 59* 46* GIR-AUC (0–24h) 27 68* 48* GIR max 23 46* 36* Pharmacokinetics (assessed by plasma concentrations of insulin (INS), insulin glargine and insulin detemir) INS-AUC (0–12h) 15 26 34 INS-AUC (0–) 14 28 33 *: p<0.001 compared with insulin detemir (no statistical analyses were performed to compare pharmacokinetic CVs). CVs were determined using an ANOVA model after log-transformation of the parameters. GIR profiles following four non-consecutive injections of identical doses (0.4U/kg, thigh) in three patients Heise T et al. Diabetes 2004;53: 1614-20

TITRATE™Study Levemir® once daily Self-adjusted target FPG 70-90 mg/dl Main inclusion criteria: Type 2 diabetes, ≥3 months 7%≤HbA1c≤9% BMI ≤45 kg/m2 Age ≥18 years Insulin naïve Prior OAD therapy (n=122) Levemir® once daily Self-adjusted target FPG 80-110 mg/dl Screening period (n=122) Levemir® was initiated at 0.1 to 0.2 unit/kg or 10 units once daily at dinner or bedtime Dose titration was based on the PREDICTIVE® 303 patient-directed self-titration algorithm Patients continued on OAD therapy Study Design: Treat to Target This study was designed to prove that Levemir® can be successfully dosed once daily in Type 2 patient population and to investigate the use of the 303 algorithm using lower target fasting glucose levels 244 insulin-naïve patients with type 2 diabetes treated with OAD therapy (metformin± sulfonylurea ± glinides ± TZDs) were randomized to 1 of 2 FPG target–titration arms: 3.9-5.0 mmol/L or 4.4-6.1 mmol/L 1 Levemir 0.1 to 0.2 unit/kg or 10 units was used once daily at dinner or bedtime1 Patients continued their OAD use and self-titrated their insulin dose every 3 days according to the mean of self-measured FPG values the 3 previous days, using the forced titration algorithm described in the PREDICTIVE® (Predictable Results and Experience in Diabetes Through Intensification and Control to Target: An International Variability Evaluation) 303 study2 Blonde L et al. 2009; [manuscript under review]. 2. Meneghini L., Koenen C., Weng W., Selam J.L. The usage of a simplified self-titration dosing guideline (303 Algorithm) for Levemir in patients with type 2 diabetes - Results of the randomized, controlled PREDICTIVE 303 study. Diabestes obes metab 2007; 9:902-913. Blonde L et al; Diabetes Obes Metab. 2009 Jun;11(6):623-31 23

HbA1C Improvement Mean HbA1c (%) 8.2 -1.22% reduction in HbA1C 7.99 6.93 6.77* Mean HbA1c (%) 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 7.94 7.04 7.00* FPG 70-90 mg/dl Mean HbA1C Reduction by Week: ITT population Mean HbA1c at the end of study was 6.9% for the combined target groups. In the 3.9-5.0 mmol/L target group, HbA1c values decreased by 1.22% from baseline, while HbA1cvalues decreased by 0.94% from baseline in the 4.4-6.1 mmol/L group at Week 20, LOCF Decreases in HbA1c were significantly different both from baseline and between the 2 target groups (LS mean difference = ‑0.271; 95% CI: -0.441, -0.101; P=0.0019) Once-daily Levemir® decreased HbA1c to a mean of 6.9% A reduction in HbA1C of -1.2% in patients as high as 9% (range 7-9) FPG 80-110 mg/dl Baseline 12 20 Time (study week) *Change in both groups , p=0.019 at 20 weeks Blonde L et al; Diabetes Obes Metab. 2009 Jun;11(6):623-31 Reference Data on file. Novo Nordisk Inc., Princeton, NJ.

Low rates of hypoglycaemia with once-daily Levemir® Hypoglycaemic Events Low rates of hypoglycaemia with once-daily Levemir® p=NS FPG 80-110 mg/dl FPG 70-90 mg/dl Events per subject/year p=NS Hypoglycaemia occurred with very low rates Rates of Overall and Nocturnal Hypoglycemia: Safety Analysis The overall rates of hypoglycemia episodes were low and comparable between target groups Nearly all hypoglycemic events were considered minor or symptoms only A single major hypoglycemic event was reported by a subject in the 70-90 mg/dL target group Hypoglycaemic events One major hypoglycaemic event was reported by subject in the 70-90 mg/dl target group Blonde L et al; Diabetes Obes Metab. 2009 Jun;11(6):623-31 References Blonde L et al. 2009; [manuscript under review]. Data on file. Novo Nordisk Inc., Princeton, NJ.

Change in weight Insulin detemir NPH insulin 1 0.55 -0.06 -0.56 -1 25 >25-30 >30-35 >35 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 1 0.55 -0.06 -0.56 -1 -0.96 -1.51 Data from the clinical study shown on the left side of the graph illustrates how insulin detemir incurs a weight sparing advantage that is correlated with BMI; patients in the highest BMI categories, gained the least weight. On the right side of the slide, we can see how these data from a randomised controlled trial are, in fact, also seen in the everyday clinical setting.   -2 n= 270 395 374 341 640 <25 25–<27 27–<29 29–<31 ≥31 Baseline BMI Baseline BMI Philis-Tsimikas et al. Clin Ther 2006 Dornhorst et al. Int J Clin Pract 2008 26

Titration at a once-daily dose Mean 3-day FPG 3 3 units Increase dose 3 Units Above target FPG Target range 70-90 mg/dL or 80-110 mg/dL no adjustment Maintain dose The 303 algorithm was shown to be effective and simple to use in the PREDICTIVE 303 study. This was therefore adopted in a study of patients driven titration with Levemir. 303 Titration Algorithm In the original version of the 303 chart, the FPG titration target used by Meneghini et al (4.4-6.1 mmol/L ) is represented as the target range with titration instructions positioned to the right of “0 maintain dose.” In this newly adapted version, the dual FPG targets from the Blonde trial are included, allowing physicians to choose the target (3.9-5.0 mmol/L or 4.4-6.1 mmol/L ) to better customize therapy for each patient. Physicians can help their patients with type 2 diabetes get to goal with either FPG target. 3 Below target Units Decrease dose 3 units Patients who experienced hypoglycaemia reduced their daily dose by 3 units Reference Data on file. Novo Nordisk Inc., Princeton, NJ.

Insulin analogues compared Insulin receptor affinity IGF-1R affinity Insulin receptor off rate Metabolic potency Mitogenic potency Human insulin =100 Insulin aspart 92 ± 6 81 ± 9 81 ± 8 101 ± 2 58 ± 22 Insulin detemir 18 ± 3 16 ± 1 204 ± 9 27 11 Kurtzhals P, et al. Diabetes 2000; 49: 999 28 28

Insulin analogues compared Insulin receptor affinity IGF-1R affinity Insulin receptor off rate Metabolic potency Mitogenic potency Human insulin =100 Insulin aspart 92 ± 6 81 ± 9 81 ± 8 101 ± 2 58 ± 22 Insulin lispro 84 ± 6 156 ± 16 100 ± 11 82 ± 3 66 ± 10 Insulin glargine 86 ± 3 641 ± 51 152 ± 13 60 ± 3 783 ± 13 Insulin detemir 18 ± 3 16 ± 1 204 ± 9 27 11 Kurtzhals P, et al. Diabetes 2000; 49: 999 29 29

ONCE- DAILY DOSING1,3 OPTIMAL HbA1c Control1,2 LOW RISK OF HYPOS3,4 FlexPen® TRUSTED BY MILLIONS6,7 LESS WEIGHT GAIN4,5 LOW RISK OF HYPOS3,4 OPTIMAL HbA1c Control1,2 ONCE- DAILY DOSING1,3

Summary Treatment with basal analogues enables patients to reach HbA1c target with low rate of hypoglycaemia HbA1c improves but some patients need more Levemir® + OD is associated with: reduced hypoglycemia in comparison to NPH, and reduced weight gain in comparison to any other basal insulin. Initiation of Levemir® + OD with 3-0-3 algorithm is effective, simple and safe.

Bolus Insulin Today I’m going to show you results from real-world observational studies that analyzed Levemir® compared to glargine. 32

Physiologic Insulin Secretion: 24-hour Profile (µU/mL) Basal insulin Breakfast Lunch Dinner 50 25 Prandial insulin 150 Time of day Glucose (mg/dL) 100 50 7 8 9 10 11 12 1 2 3 4 5 6 AM PM Basal glucose Prandial glucose When we consider glucose control, we need to focus on both postprandial and basal requirements. This slide illustrates the normal physiologic response of glucose and insulin to meals, which highlights the need for both basal and meal-time insulin. Meal insulin release occurs in response to nutrient ingestion. Basal insulin is continuously secreted over a 24-hour period. In the past, we have had to make due with various insulin formulations that did not have adequate pharmacokinetics to duplicate these profiles. However, within the past few years, new insulin analogs that provide more physiologic profiles have been developed. 33

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 34

Structure of insulin aspart (NovoRapid®) NovoRapid® is designed for low self-association to allow rapid absorption Read from slide. 35 35

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

NovoRapid® is designed for rapid, flexible control Rapid absorption Meal time flexibility Rapid time to maximum effect Efficacy Rapid return to baseline insulin level Safety (Less Hypos) BI Yu- fang, ZHAO Lie-bin et al. Compare efficacy and safety of insulin aspart and Novolin R delivered with CSII in 21 Chinese diabetic patients.Chin Med 2007;120(19):1700-1703 37

Estimated Pharmacokinetics of Current Insulin Preparations Onset Peak Effective Duration Rapid acting analog <15 min 0.5-1.5 hr 3 hr Human Regular Insulin 0.5-1 hr 2-3 hr 3-6 hr Barnett AH, Owens DR. Lancet. 1997;349:97-51. White JR, et al. Postgrad Med. 1997;101:58-70. Kahn CR, Schechter Y. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 1990:1463-1495. Coates PA, et al. Diabetes. 1995;44(Suppl 1):130A. 38

Bolus Insulin for Pre-prandial Administration Clinical Benefits Precise dosing Optimal glucodynamics Reduced risk of hypoglycemia (day and night) Desirable Kinetic Characteristics Predictable, reproducible time- action profile Rapid onset of action Short duration of action In type 2 diabetes there is an impairment of beta cell (ß-cell) function resulting in a decrease in insulin secretion and an impairment of insulin with subsequent insulin resistance. 39

NovoRapid® FlexPen® Today I’m going to show you results from real-world observational studies that analyzed Levemir® compared to glargine. 40

Insulin Aspart vs. Regular Human Insulin: Effect on A1C 8.5 8.0 7.5 Insulin Aspart Regular Insulin A1C (%) • * 3 6 Time (months) Data represent mean ± SEM * P < 0.05 41

Effect of NovoRapid® versus Actrapid® on PP myocardial perfusion in type 2 diabetes Blood- Flow Healthy group people T2D Patients Fasting Posprandial Scognamiglio R et. al. Diab Care 2006;29:95–100

Cumulative CV events in 374 Japanese T2 patients after 4.5 years Nippon ultrarapid Insulin and diabetic Complication Evaluation (NICE) Studie Cumulative CV events in 374 Japanese T2 patients after 4.5 years Nishimura M et al. Diabetologia 2008;51(Suppl1):S5432008;51(Suppl1):S543

NovoRapid®: approved for every stage of life, from children aged 2 years to the elderly2 Approved for use in abroad range of patients For patients with Type 1 diabetes2 For patients with Type 2 diabetes2 For patients using an insulin pump2 Even patients requiring special consideration For use in pregnancy- can be used during lactation2 For use in the elderly2 For use in children aged 2 years and above2 For use in special population with renal or hepatic imparement2,3 Read from slide. 44 44

NovoRapid® : helps T2DM patients attain and maintain their HbA1c goals4 6.9% median HbA1c achieved by patients at 3 years 1.2% reduction in HbA1c from baseline4 63% of patients achieved ADA target <7% over 3 years4 Reduced mean PPG levels4 The addition of NovoRapid® significantly reduced the mean PPG level by 67 mg/dL (3.72 mmol/L)4 45

NovoRapid® : Reduced rate of nocturnal hypoglycaemia 72% less major nocturnal hypoglycaemia in patients with type 1 diabetes6 24% Lower risk of nocturnal hypoglycaemia was confirmed by a meta-analysis of 3,727 T1DM patients in randomized, controlled trials conducted over 10 years of clinical experience with NovoRapid®7 Reduced rates of hypoglycaemia, even in pregnant women8 Initiation of NovoRapid® preconception may result in lower risk of severe hypoglycaemia in pregnant women with type 1 diabetes8 Nocturnal events 46

NovoRapid® :pre and post meal dosing allows patients to treat according to lifestyle9 Depending on their lifestyle and eating habits, some patients require more treatment flexibility10-12 NovoRapid® enabled an overall improved quality of life with increased flexibility compared with regular human insulin T1DM10 Since children may have unpredictable eating habits, parents preferred NovoRapid® over regular human insulin11 Pregnant women with T1DM preferred NovoRapid® for more flexibility12 in their treatment9 Read from slide. 47 47

FlexPen® : trusted by millions worldwide13,14 Next Generation FlexPen® from Novo Nordisk offers Read from slide. 48 48

New features of FlexPen

Glulisine “zinc-free” counter - what data do we have? Approved shelf-life: aspart vs. glulisine The approved shelf-life is greater for NovoRapid® than for Apidra® in both the Europe and US Furthermore, once in use NovoRapid® remain stable for 28 days at 30°C while Apidra® must be stored at no greater than 25°C European Label US Label Shelf-life (2-8°C) In-use NovoRapid®/NovoLog® 30 months 28 days <30°C Insulin glulisine 24 months 28 days <25°C Glulisine US label April 07, European label July 05 NovoRapid Core Data Sheet, version 10, 2007

After 10 years of study and use2, no other rapid- acting insulin is part of so many lives1 Approved for every stage of life, from children aged 2 years to the elderly2 Helps patients attain and maintain their HbA1c goals4 NovoRapid® significantly reduced major nocturnal hypoglycaemia versus regular human insulin by 72%6,7 Pre- and post-meal dosing allows patients to treat according to lifestyle10 FlexPen®: trusted by millions worldwide14,15 Read from slide. 51 51

Summary Today I’m going to show you results from real-world observational studies that analyzed Levemir® compared to glargine. 52

Timely addition of prandial insulin reflects a meal plus basal insulin coverage Tight glycaemic control can be achieved and maintained with low rates of hypoglycaemia and minimal weight gain, using insulin Detemir (Levemir®) OD first, then adding short acting analogue insulin (insulin Aspart, NovoRapid®), stepwise or with all meals according to 1-0-1 Initiation and intensification of insulin therapy in type 2 diabetes can be done safely, effectively and conveniently

References: 1. IMS Health Inc. IMS MIDAS (MATQ209). 2. NovoRapid [summary of product characteristics]. Bagsværd, Denmark: Novo Nordisk A/S; 2009. 3. Holmes G, Galitz L, Hu P, Lyness W. Pharmacokinetics of insulin aspart in obesity, renal impairment, or hepatic impairment. Br J Clin Pharmacol. 2005;60(5):469-476. 4. Holman RR, Farmer AJ, Davies MJ, et al, for the 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med. 2009;361(18):1736-1747. 5. Holman RR, Thorne KI, Farmer AJ, et al, for the 4-T Study Group. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med. 2007;357(17):1716-1730. 6. Heller SR, Colagiuri S, Vaaler S, et al. Hypoglycaemia with insulin aspart: a double-blind, randomised, crossover trial in subjects with type 1 diabetes. Diabet Med. 2004;21(7):769-775. 7. Heller S, Bode BW, Kozlovski P, Svendsen A. Examining the glycaemic and hypoglycaemic benefits with rapid-acting insulin analogues: a meta versus regular human insulin in randomised controlled trials [poster 916]. Diabetologia . 2009;52(suppl 1):S359-S360. 8. Heller S, Damm P, Mersebach H, et al. Hypoglycemia in type 1 diabetic pregnancy: role of preconception insulin aspart treatment in a randomized study. Diabetes Care. 2010;33(3):473-477. 9. Brunner GA, Hirschberger S, Sendlhofer G, et al. Post-prandial administration of the insulin analogue insulin aspart in patients with type 1 diabetes mellitus. Diabet Med. 2000;17(5):371-375. 10. Bott U, Ebrahim S, Hirschberger S, Skovlund SE. Effect of the rapid-acting insulin analogue insulin aspart on quality of life and treatment satisfaction in patients with type 1 diabetes. Diabet Med. 2003;20(8):626-634. 11. Danne T, Råstam J, Odendahl R, et al. Parental preference of prandial insulin aspart compared with preprandial human insulin in a basal-bolus scheme with NPH insulin in a 12-wk crossover study of preschool children with type 1 diabetes. Pediatr Diabetes. 2007;8(5):278-285. 12. Mathiesen ER, Kinsley B, Amiel SA, et al, on behalf of the Insulin Aspart Pregnancy Study Group. Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insulin aspart versus human insulin in 322 pregnant women. Diabetes Care. 2007;30(4):771-776. 13. IMS Health Inc. IMS MIDAS (12 months ending September 2009). 14. Reimer T, Hohberg C, Pfützner AH, Jørgensen C, Jensen KH, Pfützner A. Intuitiveness, instruction time, and patient acceptance of a prefilled insulin delivery device and a reusable insulin delivery device in a randomized, open-label, crossover handling study in patients with type 2 diabetes. Clin Ther. 2008;30(12):2252-2262. 15. Asakura T, Seino H, Kageyama M, Yohkoh N. Evaluation of injection force of three insulin delivery pens. Expert Opin Pharmacother. 2009;10(9):1389-1393. 16. Rissler J, Jørgensen C, Rye Hansen M, Hansen N-A. Evaluation of the injection force dynamics of a modified prefilled insulin pen. Expert Opin Pharmacother. 2008;9(13):2217-2222.17. Sommavilla B, Jørgensen C, Jensen KH. Safety, simplicity and convenience of a modified prefilled insulin pen. Expert Opin Pharmacother. 2008;9(13):2223-2232. 18. Weise A, Pfützner JW, Borig J, et al. Comparison of the dose accuracy of prefilled insulin pens. J Diabetes Sci Technol.2009;3(1):149- 153.