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June 10, 2020
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  1. Levemir and Novorapid safety and Efficacy

  2. What would the ideal basal insulin look like? • The

    ideal basal insulin would... • Have a long duration of action (~24 h) for OD injections • Have a flat time–action profile • Have low variability of metabolic effect • Cause minimal weight gain • Have a low risk of hypoglycaemic events OD, once daily, T1D, type 1 diabetes; T2D, type 2 diabetes Insulin detemir is indicated for the treatment of diabetes mellitus (T1D and T2D) in adults (including pregnancy), adolescents and children aged ≥1 year
  3. Safety aspects of Clinical interest Hypoglycemia Weight gain Use in

    Children Use in Pregnancy Renal and Hepatic impairment CV Safety
  4. Insulin detemir molecule: monomer Des threonine (B30) + myristic (mir)

    acid (B29) A-chain B-chain Myristic acid residue Novo Nordisk. Insulin detemir prescribing information, 2015 C14 fatty acid chain (Myristic acid) B29 A1 B1 A21 Thr Lys Pro Thr Tyr Phe Phe Gly Arg Glu Gly Cys Val Leu Tyr Leu Ala Glu Val Leu Hls Ser Gly Cys Leu Hls Gln Asn Val Phe Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn
  5. Insulin detemir molecule: dimer and hexamer The protracted action of

    insulin detemir is mediated by a combination of self-association of insulin detemir molecules at the injection site and albumin binding via the myristic acid side-chain Hexamer Di-hexamer Dimer Monomer Hamilton-Wessler et al. Diabetologia 1999;42:1254–63 A-chain B-chain Myristic acid residue Zn2+
  6. Mechanisms and sites of protraction In the subcutaneous depot: •

    Hexamer stability • Hexamer-hexamer interactions • Albumin binding In the circulation: • Albumin binding
  7. Time–action profile of basal analogues in type 2 diabetes King

    AB, Diab Obes Metab 2009;11:69-71 Prestudy Detemir Detemir Glargine Glargine Day 1 24-h glucose recording for analysis 24-h glucose recording for analysis Titration phase 2 consecutive days at target goal Day 1 Titration phase Target goal: BG 3.9–6.7 mmol/L Target goal: BG 3.9–6.7 mmol/L Week 1 Week 2 Screen Treatment crossover 2 consecutive days at target goal double-blind, randomized, crossover study in T2D subjects (n = 29)
  8. OD, once daily; CGMS, continuous glucose monitoring system CGMS confirms

    similarity of insulin detemir and glargine in OD dosing Time of day Blood glucose 250 150 200 0 8.33 100 5.56 2.78 50 11.1 13.9 20:00 22:00 24:00 02:00 04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00 mmol/L mg/dL Insulin injection 0 Insulin glargine OD Insulin detemir OD King et al. Diabetes Obes Metab 2009;11:69–71
  9. Blood glucose variability in type 2 diabetes Klein 2007: study

    objective and design • PD endpoints including within-subject and between-subject variability were measured Screening Follow-up Insulin glargine (0.4, 0.8 and 1.4 U/kg) Insulin detemir (0.4, 0.8 and 1.4 U/kg) 5–28 days 14–56 days 14–56 days 3–21 days 24-h clamp 24-h clamp 24-h clamp Randomisation Single-centre, randomised, double-blind, repeat-clamp study in type 2 diabetes (n=27) Objective: to compare the time–action profiles of insulin detemir with those of insulin glargine in individuals with type 2 diabetes Main inclusion criteria: • Male subjects with type 2 diabetes • Age 18–65 years • Diabetes duration ≥12 months • Insulin treatment ≥3 months (no OADs) • BMI ≤35 kg/m² • HbA1c ≤10% • Fasting C-peptide ≤1 nmol/L Klein et al. Diabetes Obes Metab 2007;9:290–9 BMI, body mass index; OAD, oral antidiabetic drug; PD, pharmacodynamic
  10. Insulin glargine Klein 2007: comparable time–action profile with insulin detemir

    vs. insulin glargine in type 2 diabetes 0.4 U/kg 0.8 U/kg Insulin detemir 0 2 4 6 8 10 12 14 16 18 20 22 24 0 0.5 1.0 1.5 2.0 2.5 3.0 GIR (mg/kg/min) Time from insulin injection (h) Klein et al. Diabetes Obes Metab 2007;9:290–9 GIR, glucose infusion rate
  11. Klein 2007: significantly less intra-patient variability for insulin detemir in

    type 2 diabetes Klein et al. Diabetes Obes Metab 2007;9:290–9 AUC, area under the curve; CV, coefficient of variance; GIR, glucose infusion rate p<0.00001 p=0.00001 CV in GIR-AUC0–12h (%) Insulin detemir Insulin glargine • Within-subject variability was lower for insulin detemir than for insulin glargine • Between-subject variability did not differ between treatments
  12. Once-daily insulin detemir in a cohort of insulin-naïve patients with

    type 2 diabetes: a sub-analysis from the PREDICTIVE™ study Meneghini LF, Dornhorst A, Sreenan S. Curr Med Res Opin 2009;25:1029-35
  13. March 2009 Meneghini et al. Slide 13 Once-daily Levemir® in

    insulin-naïve T2DM Introduction and methods •Intensification of therapy in T2DM is often delayed by several years for several reasons (“clinical inertia”), such as fear of hypoglycaema, weight gain etc •The result is unacceptable hyperglycemia and HbA 1C values that may exceed 9.0% before therapy is modified to include insulin •Once-daily basal insulin may be a preferred option for many patients. Introduction Meneghini LF et al. Curr Med Res Opin 2009;25:1029-35
  14. March 2009 Meneghini et al. Slide 14 Once-daily Levemir® in

    insulin-naïve T2DM Introduction and methods •This analysis reports 12-week follow-up data from the European cohort (11 countries) of the observational study PREDICTIVE™. •The cohort includes patients with T2DM who were insulin-naive, had initiated therapy on insulin detemir OD plus OADs, and were still using this regimen at12 weeks Methods and the PREDICTIVE™ study Meneghini LF et al. Curr Med Res Opin 2009;25:1029-35
  15. March 2009 Meneghini et al. Slide 15 Primary endpoint To

    evaluate the incidence of serious adverse drug reactions, including major hypoglycemic events, during Levemir therapy • HbA1c • FBG • FBG variability • Weight change • Rates of hypo events Secondary endpoint Once-daily Levemir® in insulin-naïve T2DM PREDICTIVE™ endpoints Meneghini LF et al. Curr Med Res Opin 2009;25:1029-35
  16. March 2009 Meneghini et al. Slide 16 Once-daily Levemir® in

    insulin-naïve T2DM Flow chart Pre-study regimen Study regimen EU 12-week Cohort – 11 countries n=20,5311 EU 12-week – type 2 n=12,9812 Insulin-naïve patients on OADs n=34712 Detemir OD/BD ± OADs n=23772 Rest using other regimens Detemir OD/BD ± OADs + other insulin n=10941 Rest using other regimens Detemir OD + OADs n=1653 Current analysis Meneghini LF et al. Curr Med Res Opin 2009;25:1029-35 1 Dornhorst et al Int J Clin Pract 2007;61:523–8; 2Dornhorst et al Int J Clin Pract 2008;62:659-65
  17. March 2009 Meneghini et al. Slide 17 N Mean (±SD)

    Age (years) 1649 60.8 (10.9) HbA1C (%) 1263 8.82 (1.50) FBG (mg/L) 1155 197.1 (55.8) FBG variability (mg/L) 817 22.68 (18.36) Weight (kg) 1634 84.4 (15.4) BMI (kg/m2) 1631 29.8 (4.8) Duration of diabetes (years) 1650 8.0 (5.9) Once-daily Levemir® in insulin-naïve T2DM Patient demographics Meneghini LF et al. Curr Med Res Opin 2009;25:1029-35
  18. March 2009 Meneghini et al. Slide 18 Once-daily Levemir® in

    insulin-naïve T2DM SADRs, including major hypoglycemia *SADR: Serious Adverse Drug Reactions SADRs*, including major hypoglycemia • No SADRs were reported during study • During the 4 weeks before the baseline visit, one patient reported an SADR that was described as a major hypoglycemic episode AEs – adverse events • 3 AEs reported during study (0.18%) • Injection site rash (1) • Hypoglycemia (1) • Headache (1) Meneghini LF et al. Curr Med Res Opin 2009;25:1029-35
  19. March 2009 Meneghini et al. Slide 19 Once-daily Levemir® in

    insulin-naïve T2DM Hypoglycaemia 1.0 0.1 0.3 1.3 0.0 0.3 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Total hypoglycemia Major hypoglycemia Nocturnal hypoglycemia n=1652 Events per patient-year Baseline 12-weeks Wilcoxon NS: non significant * p<0.05 NS * NS Meneghini LF et al. Curr Med Res Opin 2009;25:1029-35 Data on file
  20. March 2009 Meneghini et al. Slide 20 Once-daily Levemir® in

    insulin-naïve T2DM Glycemic control t-test ***p<0.0001 -1.25%*** -65.16mg/dL*** -8.64 mg/dL*** HbA1c FBG FBG variability Proportion of patients achieving HbA1c < 7% at 12 weeks = 30% Meneghini LF et al. Curr Med Res Opin 2009;25:1029-35
  21. March 2009 Meneghini et al. Slide 21 Once-daily Levemir® in

    insulin-naïve T2DM Patients gaining no weight or losing weight according to BMI category 30% 24% 22% 31% 48% 56% 54% 18% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% <25 (n=179) 25-<30 (n=680) 30-<35 (n=443) >=35 (n=195) Baseline BMI category (kg/m2) Patients (%) No change (+0.5 kg to -0.5 kg) Weight loss (below -0.5 kg) Note: Data missing in 14% (237/1653) of patients; by BMI category: <25: 18%; 25->30: 14%; 30-<35: 15%; ≥35: 12% Meneghini LF et al. Curr Med Res Opin 2009;25:1029-35 Data on file
  22. March 2009 Meneghini et al. Slide 22 Once-daily Levemir® in

    insulin-naïve T2DM Mean weight change from baseline to week 12 by BMI category 0,6 -0,4 -0,9 -1,2 -1,5 -1,0 -0,5 0,0 0,5 1,0 <25 (n=165) 25-<30 (n=633) 30-<35 (n=415) >=35 (n=185) Mean weight change (kg) Overall mean change in body weight = -0.5±3.3 kg, p<0.0001 Meneghini LF et al. Curr Med Res Opin 2009;25:1029-35 Data on file
  23. March 2009 Meneghini et al. Slide 23 Once-daily Levemir® in

    insulin-naïve T2DM Weight change vs baseline BMI (regression) ANOVA: p<0.001 Meneghini LF et al. Curr Med Res Opin 2009;25:1029-35
  24. March 2009 Meneghini et al. Slide 24 Levemir doses Mean

    ± SD Baseline, IU 13.00 ± 6.41 Week 12, IU 19.35 ± 11.72 Change 6.35 ± 10.81 Baseline, IU/kg 0.16 ± 0.08 Week 12, IU/kg 0.23 ± 0.13 Change 0.08 ± 0.12 Once-daily Levemir® in insulin-naïve T2DM Insulin doses Meneghini LF et al. Curr Med Res Opin 2009;25:1029-35
  25. March 2009 Meneghini et al. Slide 25 Once-daily Levemir® in

    insulin-naïve T2DM Conclusions •Empirical use of OD detemir as an insulin initiation strategy can achieve meaningful improvements in blood glucose control with remarkably good tolerability, including a low risk of hypoglycemia and possibly a weight benefit, compared to other basal insulin options, in a majority of insulin-naïve patients sub-optimally controlled on OAD therapy • OD basal insulin replacement with detemir in type 2 diabetes represents a viable therapeutic strategy that should be considered early in the management of hyperglycemia, and which may alleviate concerns over weight gain and hypoglycemia, two significant barriers to insulin initiation Meneghini LF et al. Curr Med Res Opin 2009;25:1029-35
  26. Global cohort (n=17,374; FAS) Patients with type 2 diabetes 0

    24 weeks Primary endpoint: to determine the rate of SADRs in individuals with type 2 diabetes initiating OD insulin detemir therapy Global inclusion criteria: • Previously treated with OADs • Aged ≥6 years, or ≥18 years in some countries • In some countries, patients had initiated insulin detemir or other basal insulin treatment prior to the study SOLVE: design OD insulin detemir Khunti et al. Diabetes Obes Metab 2012;14:1129–36 FAS, full analysis set; OAD, oral antidiabetic drug; OD, once daily; SADR, serious adverse drug reaction
  27. –1.3 –3.1 –0.6 –0.03 • Insulin-naïve people with type 2

    diabetes on OADs • Insulin detemir add-on to existing OAD therapy p<0.001 p<0.001 p<0.001 p<0.001 HbA1c 8.9% FPG 10.1 mmol/L Weight 80.9 kg Severe hypoglycaemia* 0.04 events/patient-year Baseline Change from baseline SOLVE: overview of results Khunti et al. Diabetes Obes Metab 2012;14:1129–36 *27 patients (0.2%) experienced SADRs, severe hypoglycaemia or both during study follow-up. 21 patients experienced a total of 31 episodes of severe hypoglycaemia. Major nocturnal hypoglycaemia decreased from 0.006 to 0.000 events/patient-year by the final visit (p<0.001) FPG, fasting plasma glucose; OAD, oral antidiabetic drug
  28. Initiation of insulin detemir (IDet) compared with insulin glargine (IGlar)

    in patients with T2DM Local results of a multinational observational study (SOLVE™) Damci et al. BMC Endocrine Disorders 2014, 14:61 BMC Endocrine Disorders, 2014 English journal, Impact factor: 2.2 Real world data in T2D:
  29. Methods Patients with T2DM Inclusion criteria • Treatment with ≥1

    OADs • ≤3 months treatment with IDet or IGlar Exclusion criteria • Children < 6 years • Pregnant, breast-feeding or intention to become pregnant • Receiving glucose lowering treatment other than diet, exercise or OAD before basal insulin therapy Final visit 24 weeks Pre-Insulin Observation Period Interim visit 12 weeks Baseline visit 0 weeks IDet OD + ≥1 OAD(s) (n=2395) IGlar OD + ≥1 OAD(s)(n=491) (n=2886)
  30. HbA1c: Similar change in HbA1c from baseline with IDet and

    IGlar. Change in HbA1c (%) -2.21 % -1.88 % CI – Confidence Interval *Adjusted for other previously identified predictors of HbA1c at final visit in the total cohort: baseline HbA1c, age, duration of diabetes, BMI, previous history of hypoglycaemia or macrovascular disease, number and change in OAD treatment, and final insulin dose IDet IGlar Difference effect on HbA1c 95% CI p value Insulin type* IDet vs. IGlar (Ref) +0.05% -0.15, +0.25% 0.6
  31. Hypoglycemia: IDet associated with lower odds of ≥ 1 hypoglycemic

    event relative to IGlar Change in Incidence of Minor Hypoglycemia (events ppy) +0.66 events ppy +2.23 events ppy OR – Odds Ratio CI – Confidence Interval *Adjusted for other previously identified predictors of hypoglycemia in the total cohort: baseline HbA1c, age, duration of diabetes, BMI, previous history of hypoglycemia or macrovascular disease, number and change in OAD treatment, and final insulin dose IDet IGlar OR 95% CI p value Insulin type* IDet vs. IGlar (Ref) 0.33 0.21, 0.52 <0.0001
  32. • Mean baseline dose for both insulin types: 0.21 U/kg

    • Mean dose at final visit for Idet: 0.30 U/kg • Mean dose at final visit for Iglar: 0.31 U/kg Similar insulin dose of Idet vs. IGlar Duration of study: 24 w Subjects Mean BMI: 29 kg/m²
  33. • The results from the SOLVE™ cohort in Turkey are

    consistent with previously reported randomized clinical trials of IDet with regards to • low incidence of hypoglycemia • weight sparing effect • effective glycemic control • Compared to patients treated with IGlar, patients treated with IDet: • had a lower risk of hypoglycemia* • greater odds of weight loss* • and achieved a similar level of glycemic control* *after correction for a number of known confounders Results
  34. Comparative benefits and harms of basal Insulin analogues for type

    2 (systemic review and network meta-analysis Medenidou AV,et al.Ann Intern Med.2018Aug7:7;169(3):165-174
  35. High to moderate quality evidence suggested that insulin Detemir had

    favorable weight profile compared to all comparators 3 5
  36. Patients with type 2 diabetes Global cohort (n=66,726) 0 24

    weeks Real world data in T2D: basal–bolus A 1 chieve Observational study of insulin treatment in type 2 diabetes • Observational, multi center, open-label prospective study • No study-prescribed procedures • No randomization • No call-in for premature discontinuation of study or missed visit • Primary objective: number of SADRs, including major hypoglycemia, from baseline to end of trial Home et al. Diabetes Res Clin Pract 2011;94:352–63 Subgroups according to treatment at baseline • Insulin detemir ± OADs (23.3%) • Biphasic insulin aspart ± OADs (61.3%) • Insulin detemir + insulin aspart ± OADs (6.2%) • Insulin aspart ± OADs (5.8%) • Others (3.4%) Current analysis OAD, oral antidiabetic drug; SADR, serious adverse drug reaction
  37. –0.16 events/ pt-yr –1.41 events/ pt-yr –2.8 % –4.9 mmol/L

    –0.0 kg –2.0 % –3.3 mmol/L –0.3 kg Insulin-naïve Insulin-experienced Patients who started or switched to insulin detemir + insulin aspart p<0.001 p<0.001 p<0.001 p<0.001 NS p<0.001 p=0.0022 p<0.0001 HbA 1c FPG Weight Major hypos 10.1% 9.4% 11.9 mmol/L 10.3 mmol/L Baseline Change from baseline 0.16 events/pt-yr 1.42 events/pt-yr 74.7 kg 79.7 kg Real world data in T2D: basal–bolus A 1 chieve Home et al. Diabetes Res Clin Pract 2011;94:352–63 FPG, fasting plasma glucose; hypos, hypoglycemic events; pt-yr, patient-year; NS, non-significant
  38. Conclusions • OD insulin detemir achieves effective glycaemic control: •

    When combined with OADs • As part of basal–bolus therapy in type 2 diabetes • In two studies in patients with type 1 diabetes • OD use of insulin detemir: • Is consistent with the pharmacological profile • Shows similar glycaemic benefits compared with BID use of insulin detemir • Maximises insulin detemir’s weight-sparing advantage • Incurs a low risk of hypoglycaemia compared with NPH insulin • Has shown favourable outcomes in routine clinical practice BID, twice daily; NPH, neutral protamine Hagedorn; OAD, oral antidiabetic drug; OD, once daily
  39. Insulin Aspart: 20 years of clinical experience

  40. The history of Insulin Aspart Launched globally at EASD in

    Brussels, Belgium First publication in Nature Måløv Research Facility Novo Nordisk A/S 1999 1988 Brange J et al
  41. The progress of Insulin Aspart Since launch, Insulin aspart has

    received approval for… Use in elderly Use in pregnancy & lactation Use in children Above 1 year Since 2016 CSII in insulin pumps Type 1 & Type 2 DM Novo Nordisk. Insulin aspart summary of product characteristics (EU). Use in renal & hepatic impairment Peri-, Intra-, Post-operative & IV use
  42. Insulin Aspart in T2DM: Reduction in PPG Bretzel. Diabetes Care

    2004;27(5):1023–7 Insulin Aspart Human insulin Human 30/70 Postprandial glucose (mg/dL) Post-breakfast Post-lunch Post-dinner Postprandial glucose (mmol/L) 10.0 140 120 8.8 7.7 6.6 160 180 0 0 Multicentre, open-label, randomised, three-arm, parallel-group study in 222 patients Better PPG control with Insulin Aspart compared to Human Insulin and Human Premix Insulin
  43. ΔHbA1c after 3 months Insulin Aspart * HI* Human 30/70**

    –0.91 –0.73 –0.65 *includes optional NPH bedtime injection **Administered once- or twice-daily Bretzel. Diabetes Care 2004;27(5):1023–7 0 –0.5 –1.0 p = 0.025 p = 0.006 p = NS Insulin Aspart in T2DM: HbA 1c control Better HbA1c control with Insulin Aspart compared to Human Insulin and Human Premix Insulin
  44. Use in special populations PK of aspart not affected by

    Hepatic impairment PK of aspart not affected in Elderly Safe and effective in children >1 yrs with the advantage of flexible dosing Holmes et al. Br J Clin Pharmacol 2005;60:469–76, Krones et al. Diabetes Obes Metab 2009;11:41–4, Danne et al. Diabetes Care 2003;26:2359–64
  45. Use in special populations: Renal impairment Kulozik F et al.

    Ther Adv Endocrinol Metab. 2013 Aug; 4(4): 113–121. Mean daily dosage of insulin lispro, insulin aspart and short-acting human insulin [IU/kg body weight (bw)/day] in relation to estimated glomerular filtration rate (eGFR, ml/min). Insulin Aspart associated with less variability of dose requirement No significant association between the eGFR and the requirements of Insulin Aspart PK of aspart not affected by Renal impairment Holmes et al. Br J Clin Pharmacol 2005;60:469–76,
  46. Insulin aspart + NPH (n=157) HI + NPH (n=165) n

    E Rate n E Rate Major 38 113 1.4 35 174 2.1 Minor 148 7197 86.4 148 7944 94.5 Symptoms only 85 1055 12.7 85 742 8.8 Use in special populations: Pregnancy Better PPG control compared to human insulin Safe for the mother: fewer Hypoglycaemic episodes during pregnancy Safe for foetus: Significantly lower risk of preterm deliveries Overall Better foetal outcomes Mathiesen et al. Diabetes Care 2007;30:771–6, Hod et al. Am J Obstet Gynecol 2008;198:e1–7
  47. Effect of Insulin Aspart in CVD: Treating patients with NR

    vs RHI CV events include myocardial infarction, angina pectoralis, PCI/CABG and TIA/cerebral infarction Nishimura. Diabetologia 2008;51(Suppl 1):S543, Pollock R. et al. Journal of Medical Economics, 2011, 14(1), 36-46 PCI, Percutaneous coronary interventions; CABG, coronary artery bypass graft; TIA, transient ischemic attack CV events Iasp: Improvement in QALY, Cost effective Significant reduction of cardiovascular disease with Insulin Aspart (43% reduction in CV outcomes)
  48. In hospital use of Insulin Aspart Safe & Effective IV

    use of insulin aspart in ICU & non ICU settings S/C aspart every 1 or 2 h: a safe and effective alternative to IV regular insulin in uncomplicated DKA Umpierrez et al. Diabetes Care 2004;27:1873–78, Udwadia et al. Diabetes Management 2012;2:103–10
  49. In hospital use of Insulin Aspart • Retrospective cohort analysis

    in 35,049 patients (mean age, 67.1 years; 53% women; 77% white): analogue bolus versus human bolus insulin. • Nonsurgical adult patients who received exclusively analogue or human bolus insulin during hospitalization were included in the study • Insulin aspart was used as bolus insulin in 76% of the patients in Analogue insulin arm 4 Does type of Bolus Insulin matter in the hospital?? Kelly J Ko et al. Clin Ther. 2010;32:1954–1966 •Analogue bolus insulin compared to human bolus insulin was associated with: 1)Lower mortality, 2)Shorter Length of stay, 3)Meaningful better Blood Glucose control
  50. Insulin Estimated probability 95% CI for probability Aspart 9.2% 4.0

    to 19.5 Lispro 15.7% 8.1 to 28.1 Glulisine 40.9% 28.0 to 55.0 Kerr at al, J. Of Diab. 2008;2(3):450-455, Weinzimer et al. Diabetes Care 2008;31:210–5,, Van Bon et al. Diab Technol Ther 2011;2:607–14, Chlup et al. Biomed Papers 2004;148:27–32 CSII of Insulin Aspart: Use of Insulin Pumps Significantly higher proportion achieving age specific HbA1c with insulin aspart & at a lower dose compared to lispro in CSII Rates of symptomatic and nocturnal hypoglycaemia significantly lower with insulin aspart than glulisine Insulin aspart: least probability for occlusions in pum use Insulin aspart more effective than Human insulin for CSII
  51. Why Insulin Aspart? 1 Diabetes is a progressive disease1 5

    Hypoglycaemia is a clinically important restricting factor 2 Mealtime insulin coverage is/will be required 3 PPG contributes up to 70% of overall daily hyperglycaemia2 4 PPG is an independent risk factor for cardiovascular disease3 6 Different individuals need insulin at different stages of life(childhood, pregnancy and elderly stage) 7 Insulin Aspart is a rapid-acting analogue for everyone 1. Holman. Diab Res Clin Pract 1998;40(Suppl):S21–25 2. Monnier. Diabetes Care 2003;26:881–5 3. DECODE Study. Lancet 1999;354:617