The dual-release insulin preparation

The dual-release insulin preparation
Overview of published studies

Contents NovoMix® 30 – the dual release insulin Contents Slides
Insulin aspart 34 Dual-release kinetics 512 Postprandial glycaemic control 1336 Hypoglycaemia 3750 Combination with oral medications 5176 Convenience & flexibility 7794 Use in adolescents 9596

Return to contents slide
Insulin aspart – a rapid acting analogue Brange J et al. Nature 1988;333:679–682 Clinical proof of concept study for insulin aspart Return to contents slide

Insulin aspart: preclinical proof-of-concept
4.5 Insulin aspart IRI (10-10 M) 3.0 Human insulin 1.5 5 Insulin aspart is a rapid-acting insulin analogue that has been shown in crystallographic studies to have a structure virtually identical to that of human insulin. The substitution of one amino acid for another (proline for aspartic acid) at position B28 creates a molecule designed to retain the advantages of human insulin, whilst minimising the undesirable properties. Insulin aspart achieves a diurnal insulin profile resembling as closely as possible that of native human insulin, in which rapid absorption provides early limitation of the postprandial glucose excursion. The ideal insulin replacement must not only control meal-related blood glucose excursions, but must also provide glycaemic control over a more protracted period to fulfil the basal requirement for insulin. Hence the need for a ‘dual-release’ insulin in which both meal-related and basal insulin are replaced as physiologically as possible. 4 Plasma glucose (mM) 3 Injection 2 1 2 3 4 5 hours Adapted from Brange J et al. Nature 1988;333:679–682

Dual-release kinetics Jacobsen L et al. Eur J Clin Pharm 2000;56: 399–403 Weyer C et al. Diabetes Care 1997;10:1612–1614 PK studies in healthy volunteers PD studies in healthy volunteers Return to contents slide

The dual-release insulin concept
Physiological insulin profile: basal component meal-related peaks Soluble insulin fails to match normal insulin peak Intermediate-acting insulin provides basal insulin replacement but… …together these fail to re-create the physiological insulin profile

The dual-release insulin concept
Physiological insulin profile: basal component meal-related peaks Rapid-acting insulin analogues together with a basal insulin provide physiological insulin replacement Analogue premixes such as NovoMix® 30 replace both meal-related and basal insulin

Benefits of dual-release insulin replacement
Mimics physiological insulin release Early release of rapid-acting insulin targets postprandial glucose Delayed release of intermediate-acting insulin fulfils basal insulin requirement Reduces hypoglycaemic risk < Conventional premix Improves HbA1c in combination with oral medications Simplifies dosing Option of postprandial dosing

NovoMix® 30: PK/PD studies in healthy volunteers
Comparison PK and PD profiles of NovoMix® 30 vs. BHI 30 Design Randomised, double-blind, two-way single dose crossover1 Randomised, double-blind, crossover single dose euglycaemic clamp2 Studies 031 and 033 were designed to compare the pharmacokinetic and pharmacodynamic properties of NovoMix® 30 with biphasic human insulin 30 (BHI 30), in healthy volunteers. Study 031 was a double-blind, single-dose, two-way crossover trial in which 24 healthy male subjects (age years) were randomised to receive one single injection of either NovoMix® 30 or BHI 30 (0.2 IU/kg body weight) on two different study days, separated by a washout period of 4-10 days. Study 033 compared the pharmacodynamic properties of NovoMix® 30 and BHI 30 in a single centre, double-blind, euglycaemic clamp crossover study. 24 healthy male volunteers were randomised to receive a single dose of either NovoMix® 30 on the first treatment day and BHI 30 on the second visit (0.3 U/kg body weight) or vice versa. 1. Jacobsen L et al. Eur J Clin Pharm 2000;56:399– Weyer C et al. Diabetes Care 1997;10:1612–1614

Proof of concept: rapid absorption and higher peak concentration
BHI 30 NovoMix® 30 25 *** 20 ***p < n = 24 15 Serum insulin (mU/l) 10 ANA 031 The soluble fraction of NovoMix® 30 was absorbed significantly faster than that of BHI 30 (p < ), and reached higher peak concentration (p < ). Pharmacokinetic data from the 033 study similarly demonstrated faster absorption and greater peak serum concentration reached in a shorter time with NovoMix® 30 than BHI 30, and corroborated the equivalent pharmacokinetic behaviour of the intermediate-acting protaminated fraction of both insulins. 5 8:00 11:00 14:00 17:00 20:00 23:00 2:00 5:00 8:00 Time of day Jacobsen L et al. Eur J Clin Pharm 2000;56:399–403

Proof of concept: faster onset and more effective
n = 24, dose = 0.3 U/kg 12 NovoMix® 30 10 BHI 30 (Actraphane) 8 Glucose infusion rate (mg/kg/min) 6 4 ANA 033 NovoMix® 30 had a significantly faster onset and reduced variability of glucose-lowering effect compared with BHI 30, reflecting the more rapid and predictable absorption of the soluble component of NovoMix® 30. NovoMix® 30 demonstrated more efficient insulin-mediated glucose disposal as evidenced by a significantly greater maximum glucose infusion rate, reached in a shorter time. The protaminated, longer-acting component of NovoMix® 30 had less long-lasting hypoglycaemic effect between 6 and 24 hours after injection. 2 240 480 720 960 1200 1400 Time (min) Weyer C et al. Diabetes Care 1997;10:1612–1614

PK/PD conclusions: NovoMix® 30 vs. BHI 30
Faster absorption1,2 Higher peak concentrations1,2 More rapid and pronounced glucose-lowering effect1,2 Similar duration of action of basal component1,2 Faster onset and greater glucose-lowering effect of insulin aspart are retained in dual-release NovoMix® 30 ANA 031 & 033 1. Jacobsen L et al. Eur J Clin Pharm 2000;56:399– Weyer C et al. Diabetes Care 1997;10:1612–1614

Improved postprandial glycaemic control McSorley PT et al. ClinTher 2002;24(4):530–539 Hermansen K et al. Metabolism 2002;51(7):896–900 Hermansen K et al. Diabetes Care 2002;25:883–888 Boehm B et al. Diabet Med 2002;19(5):393–399 Christiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6): Meal study in type 2 patients vs. BHI 30 Comparison vs. BHI 30 in type 1 patients Comparison vs. BHI 30 and lispro mix 25 in type 2 patients Comparison vs. BHI 30 in type 1 and type 2 patients Comparison vs. NPH in type 2 patients Return to contents slide

Twice-daily NovoMix® 30 in patients with type 2 diabetes
BHI 30 Screening visit (n = 13) Follow-up +3 to 7 days –3 to14 days ANA 046 Randomised, double-blind, two period crossover study to compare the pharmacokinetic, pharmacodynamic and safety profiles of NovoMix 30 with biphasic human insulin 30/70 (BHI 30) in patients with type 2 diabetes. 13 subjects, all previously controlled on a twice-daily 30/70 biphasic insulin, were randomised and completed the trial. Subjects, aged between 55 and 70 yrs, with body mass index (BMI) of kg/m2, were considered representative of insulin-treated type 2 diabetic subjects. Subjects remained on their usual pre-trial insulin regimen until screening, after which they were randomised to receive NovoMix 30 or BHI 30 twice daily for 2 weeks. Injections were performed immediately before dinner and breakfast throughout both treatment periods. Although BHI 30 is ideally given 30 minutes before meals, evidence has shown that up to two thirds of patients on human insulins inject immediately before meals. It was therefore felt appropriate not to use a double-dummy technique, and to reflect ‘real-life’ dosing by injecting insulin immediately before meals. Endpoints: PK – AUCinsulin, Cmax and tmax after dinner and breakfast PD – Cmax and tmax after dinner, breakfast and lunch Hypoglycaemic events and AE’s 2 4 Weeks McSorley PT et al. Clin Ther 2002;24(4):530–539

NovoMix® 30 is rapidly absorbed
* * NovoMix® 30 120 Biphasic human insulin 100 n = 13 * p < 0.05 in favour of NovoMix® 30 for mean serum insulin level and insulin Cmax after dinner and breakfast 80 Total serum insulin (mU/l) 60 40 ANA 046 Summary: NovoMix 30 was absorbed more rapidly than BHI 30, reached higher peak serum concentrations, and fell to a lower level more rapidly after dinner and breakfast, supporting proof of principle. In the NovoMix 30 group, mean serum insulin level was 17% greater in the 2 hours after dinner (136 vs. 134 mU/Lh), and 44% greater after breakfast (144 vs. 102 mU/Lh) than equivalent measurements for BHI 30 (p < 0.05). Insulin Cmax was 18% higher in the NovoMix 30 group than the BHI 30 group after dinner, (96 vs. 79mU/L; p < 0.05), and 35% higher after breakfast the following morning (108 vs. 81 mU/L; p < 0.05). Subjects receiving NovoMix 30 reached Cmax in a significantly shorter time after breakfast than those receiving BHI 30 (62 minutes earlier), but this was not the case after dinner. There was no significant treatment difference with respect to AUC(insulin 0-24 h), indicating that the degree of absorption of both study medications over 24 hours was similar. During the night, insulin concentration was lower in the NovoMix 30 group, although the difference did not reach statistical significance, and was not reflected in the pharmacodynamic results. Total daily insulin AUC was similar for both treatment groups, but the shape of the curves were significantly different, reflecting the different pharmacokinetic profiles attained with each, and supporting proof of principle for insulin aspart and NovoMix 30. 20 18:00 22:00 08:00 13:00 18:00 Time McSorley PT et al. Clin Ther 2002;24(4):530–539

Improved postprandial glucose control with NovoMix® 30
20 Biphasic human insulin * * n = 13 15 Blood glucose (mmol/l) 10 ANA 046 Summary: Postprandial glucose excursions were significantly lower in the NovoMix 30 group after dinner and breakfast, but higher after lunch. Subjects receiving NovoMix 30 had lower mean postprandial glucose concentrations than those receiving BHI 30 in the first 4 hours after dinner (9.1 vs mmol/Lh; p < 0.05) and breakfast (14.0 vs mmol/Lh; p < 0.05). Pre-lunch glucose values were lower in the NovoMix 30 group, but after lunch - the only meal not preceded by an insulin injection - glucose concentration was higher in the NovoMix 30 group (25.4 vs mmol/Lh; p < 0.05). Maximum blood glucose concentrations (Cmax) after breakfast were significantly lower in the NovoMix 30 group (14.0 vs mmol/L; p < 0.05). Maximum blood glucose concentrations after breakfast were reached 31.3 minutes earlier in the NovoMix 30 group (102 vs. 133 mins; (p < 0.05) There were no significant differences in Cmax,glu or Tmax,glu after lunch or dinner Nocturnal blood glucose profiles were similar in both treatment groups. Concentrations below 4 mmol/L were very few (5 in total); excursions above 7 mmol/L were more frequent (10 vs. 9 in NovoMix 30 and BHI 30 groups respectively). When blood glucose concentration was averaged over 24h there was no significant difference between treatment groups (10.06 vs mmol/L) in NovoMix 30 and BHI 30 groups respectively. 5 * p < 0.05 in favour of NovoMix® 30 for lower PPG levels after dinner and breakfast 18:00 22:00 08:00 13:00 18:00 Time McSorley PT et al. Clin Ther 2002;24(4):530–539

NovoMix® 30 is well tolerated
Both insulins were well tolerated Both insulins had comparable adverse-event profiles No major hypoglycaemic episodes or serious adverse events were reported No other safety concerns ANA 046 Summary: Safety evaluation revealed no major hypoglycaemic episodes or serious adverse events (AEs) in either treatment group. Four subjects reported 7 minor hypoglycaemic episodes whilst on NovoMix 30, whilst three subjects reported 5 minor episodes on BHI 30. Three mild nocturnal hypoglycaemic episodes were recorded. Overall, hypoglycaemia was rare and no treatment difference was seen. Nine subjects reported 18 AEs during treatment with NovoMix 30, three of which could possibly have been due to study medication. In comparison, six subjects reported 14 AEs during treatment with BHI 30, seven of which might have resulted from the trial drug. All but one were rated as mild. Injection site reactions were rare – only one case in each group, and all other AEs were sporadic in nature. Laboratory testing indicated no adverse effect of either study medication. McSorley PT et al. Clin Ther 2002;24(4):530–539

NovoMix® 30 twice daily improves postprandial glucose control
Compared with BHI 30, NovoMix® 30 given immediately before a meal (twice daily) in type 2 diabetic patients resulted in: Significantly faster absorption Significantly higher peak concentrations 2 hours after injection Smaller postprandial glucose excursions No safety concerns ANA 046 Conclusion This trial confirmed that the pharmacokinetics of insulin aspart are maintained not only in single-dose studies using NovoMix 30 in healthy volunteers (4), but also when NovoMix 30 is used in a twice-daily regimen in patients with type 2 diabetes. The benefits of insulin aspart over soluble human insulin on postprandial glycaemic control are maintained when NovoMix 30 is compared to BHI 30. The pharmacokinetic and pharmacodynamic results from this study are mutually supportive. Results suggest that immediate preprandial injection of NovoMix 30 provides improved postprandial glycaemic control compared to BHI 30, for four hours following those meals before which injections were given. When no lunchtime injection was given, postprandial glycaemic control was poorer in patients receiving NovoMix 30. Evidence from trials involving rapid-acting insulin analogues suggest it may be advisable to supplement the basal insulin level during the day (5) or to adjust mealtime dosing. McSorley PT et al. Clin Ther 2002;24(4):530–539

Type 1 diabetes: single dose crossover
NovoMix® 30 at meal Screening Follow-up BHI 30 at meal (n = 50) Study 1070 Comparison of postprandial blood glucose excursions following administration of NovoMix® 30 immediately before a meal with BHI 30 given immediately or 30 minutes before a meal. The study was a multicentre, open-labelled, randomised three-period crossover trial in which 50 type 1 patients with at least a one year history of human insulin treatment. Efficacy of each insulin dosing strategy was evaluated by per protocol analysis of blood glucose excursions in the 4 hours following the start of the standard meal. Secondary efficacy endpoints included maximum concentration reached (Cmax), time to achieve maximum concentration (tmax), area under the curve (AUC), and half-life (t1/2) of variables including glucose, insulin and lipids. Safety and tolerability of the different insulin regimens were evaluated by documentation of the nature, severity and outcome of any adverse events, and the probability that they were attributable to trial medication. Frequency, severity and timing of hypoglycaemic episodes were documented. Major hypoglycaemic episodes were defined as those that required third party assistance or provision of IV glucose or glucagon. Minor episodes were those in which the patient experienced hypoglycaemic symptoms, with or without confirmation by blood glucose measurement. BHI 30 at –30 minutes Study day Study day Study day 3 3–21 days 5–21 days 7–14 days Hermansen K et al. Metabolism 2002;51(7):896–900

Blood glucose (mmol/l)
Reduced glucose exposure in type 1 patients after a meal NovoMix® 30 ( t = 0) BHI 30 (t = 0) 20 Max glucose concn 15% lower at t = 0 * BHI 30 (t = –30) Max glucose concn 20 min earlier * * p < n = 50 15 Blood glucose (mmol/l) 10 BIAsp 1070 Summary: Exposure to postprandial glucose was significantly lower in patients receiving NovoMix® 30 than BHI 30, irrespective of when BHI 30 was administered. Total glucose exposure in the 4 hours after insulin injection was 2189 mmol.min.l-1 in the group receiving immediate pre-meal NovoMix® 30, compared with 2847 and 2401 mmol.min.l-1 in those taking BHI 30 immediately, or 30 minutes, before the meal, respectively. This represents a 23% reduction in AUC compared with BHI 30 (t = 0; p < ), and a 9% reduction compared with BHI 30 at t=-30 (p<0.05). The maximum glucose concentration reached (Cmax) was 15% lower in the NovoMix® 30 group than in those taking BHI 30 immediately before the meal (13.7 versus 16.2 mmol/l respectively; p < ); there was no significant difference when NovoMix® 30 was given immediately before the meal and BHI 30, 30 minutes before. Maximum glucose concentration (tmax) was reached 20 minutes earlier in the NovoMix® 30 group than in participants taking BHI 30, irrespective of timing (68.5 versus 91.7 and 90.2 min, respectively; p < ). 5 23% lower glucose exposure than BHI at t = 0 * –30 30 60 90 120 150 180 210 240 Nominal time (min) Hermansen K et al. Metabolism 2002;51(7):896–900

Reduced glucose excursion irrespective of timing of BHI 30 injection
3000 BHI 30 2800 23% 9% NovoMix® 30 2600 Blood glucose excursion 4 h after injection (mmol.min.l-1) 2400 2200 BIAsp 1070 Summary: Compared with BHI 30 injected at t = 0, NovoMix® 30 reduced the blood glucose excursion by 23% (p < ). When BHI 30 was injected 30 minutes before the meal, the reduction was of 9% in favour of NovoMix 30 (p=0.013). For the primary endpoint (EXC(glucose 0-4h)), separate analyses were made based on the intention-to-treat (ITT) and the per protocol (PP) populations. All secondary endpoints were based on the ITT population only. 2000 t = 0 t = 0 t = –30 Injection time in relation to meal Hermansen K et al. Metabolism 2002;51(7):896–900

NovoMix® 30 is more effective than BHI 30
Superior efficacy in controlling postprandial glucose levels Higher reduction in blood glucose concentrations when injected immediately before meals Significantly larger insulin concentrations achieved regardless of the time of BHI 30 administration BIAsp 1070 Hermansen K et al. Metabolism 2002;51(7):896–900

Comparison of NovoMix® 30, Humalog® Mix25TM and BHI 30
NovoMix® 30 at meal Humalog® Mix25TM at meal (n = 45) BHI 30 at –15 min Objective To compare the postprandial blood glucose excursion between treatment groups Design Randomised, open-labelled, three-period crossover trial Method Single dose meal test, NovoMix® 30 and Humalog® Mix25TM immediately before meal, BHI min before meal Population 45 type 2 patients Primary test EXC (glucose 0–5h) BIAsp 1235 NovoMix 30 is comprised of 30% aspart, 70& protaminated aspart Mix25 is comprised of 25% lispro, 75% protaminated lispro BHI 30 is comprised of 30% regular insulin, 70% NPH insulin Population allocation: 77 screened 61 exposed 55 completed 45 per protocol. This population were used for statistical analyses Hermansen K et al. Diabetes Care 2002;25:883–888

Reduced glucose excursions vs. Humalog® Mix25TM and BHI 30
p < 0.001 21 –17% p < 0.05 (mmol/l h) 20 –10% 19 0– 5h 18 17 16 BIAsp 1235 In this randomised, cross-over single-dose trial 61 type 2 diabetic patients were exposed on 3 separate study days to the following treatments in random order: NovoMix 30, Mix 25, and BHI 30, the latter injected 15 minutes before a standard breakfast (0.4 U/kg for all three insulins). No intermediate or long-acting insulin or OHAs were allowed for the 24 hours preceding the trial days. Mean pre-test FPG levels were similar for all 3 groups ( mmol/L). The PPG excursion over 5 hours was reduced for NovoMix 30 by 10% compared with Mix25, and by 17% compared with BHI 30. EXC0-5(glu) (mmol/l h) for the different treatment groups were: Humalog Mix 25 – NovoMix 30 – BHI 30 – 20.1 Blood glucose excursion 15 14 13 Humalog® Mix 25TM NovoMix® 30 BHI 30 Hermansen K et al. Diabetes Care 2002;25:883–888

Improved postprandial control vs. Humalog® Mix25TM and BHI 30
Glucose parameter EXC0–5h (mmol/l h) Cmax tmax (min) NovoMix® 30 16.6  4.4a,b 15.9  2.7c 75.1  22.2c,d Humalog® Mix25TM 18.9  6.1 16.4  3.2 86.5  26.9 BHI 30 20.1  4.9 16.7  2.6 88.0  26.4 BIAsp 1235 Cmax glucose was higher for BHI 30 than for NovoMix 30 (p<0.05) No significant difference of Cmax between Mix25 and NovoMix Time to max blood glucose concentration was significantly shorter for NovoMix 30 than for Mix25 (-11 minutes; p < 0.05) and BHI 30 (–13 minutes; p<0.01). a NovoMix® 30 significantly less than Humalog® Mix25TM (p < 0.05) b NovoMix® 30 significantly less than BHI (p < 0.001) c NovoMix® 30 significantly earlier than BHI (p < 0.05) d NovoMix® 30 significantly earlier than Humalog® Mix25TM (p < 0.01) Hermansen K et al. Diabetes Care 2002;25:883–888

Larger and more rapid increase in serum insulin with NovoMix® 30
Insulin parameter AUC (ins0–5h) (pmol/l h) Cmax(ins) Tmax(ins) (min) NovoMix® 30 1079  535a 415  244a 115  59a Humalog® Mix25TM 1031  621 360  211 100  41 BHI 30 741  426 237  156 169  71 BIAsp 1235 A larger AUC (0-5 h) and an approximately twofold higher Cmax(ins) were seen after injection with NovoMix 30 than after injection with BHI 30 (p < in both cases). Tmax(ins) was significantly shorter with NovoMix compared with BHI 30 (p < 0.001) Cmax(ins) was 12% higher and AUC0-5 h(ins) was 7% higher for NovoMix compared with Mix25 but this did not reach statistical significance. Safety No safety concerns for any of the three treatments were raised during the study period. a Values for NovoMix® 30 are significantly different from BHI 30 (p < 0.001) Hermansen K et al. Diabetes Care 2002;25:883–888

Improved postprandial glucose vs. BHI 30 and Humalog® Mix25TM
Superior postprandial glucose control to BHI 30 and Humalog® Mix25TM in type 2 patients Higher maximum serum insulin with BHI and Humalog® Mix25TM Well tolerated with no serious adverse events occurring related to treatment BIAsp 1235 Hermansen K et al. Diabetes Care 2002;25:883–888

Insulin-using type 1 and type 2 diabetic patients
Comparison of efficacy and safety of NovoMix® 30 vs. BHI 30: study design NovoMix® 30 (n = 140) Insulin-using type 1 and type 2 diabetic patients (n = 294) One screening visit; patients already using a twice-daily insulin regimen ANA 038 Comparison of the efficacy and safety of NovoMix® 30 and BHI 30 in a twice-daily meal-related regimen, in a mixed population of patients with type 1 and type 2 diabetes. In this 12-week, randomised, open labelled, parallel-group comparison, 294 adult male and female subjects who had been using insulin in a twice-daily regimen were randomised to receive NovoMix® 30, injected within 10 minutes before breakfast and dinner (n = 143), or BHI 30 injected approximately 30 minutes prior to breakfast and dinner (n = 151). Of these, 140 patients were exposed to NovoMix 30, and 151 were expose to BHI 30. Three patients withdrew from the study after randomisation, but before exposure, as it was found that had not been treated with insulin for the required minimum of 2 years. The treatment comparison, which used HbA1c after 12 weeks as the primary efficacy endpoint, was based on a non-inferiority criterion for the difference between the two biphasic insulins All pharmacokinetic and pharmacodynamic endpoints were similarly analysed on the basis of a null hypothesis that there was no difference between treatments. Safety and tolerability of the two regimens was evaluated by measurement of the frequency, severity and timing of hypoglycaemic episodes. BHI 30 (n = 151) 12 weeks Boehm B et al. Diabet Med 2002;19(5):393–399

Improved postprandial glucose after 3 months
NovoMix® 30 * p < 0.05 * 12 BHI 30 * * 10 * 8 Blood glucose (mmol/l) 6 ANA 038 Summary: Blood glucose concentration was significantly lower after breakfast and dinner, before lunch and at bedtime in the NovoMix® 30 group. Analysis of 8-point blood glucose profiles revealed significantly lower blood glucose concentrations after breakfast and dinner, before lunch and at bedtime in the NovoMix® 30 group. At 12 weeks, values were approximately 1% lower in the NovoMix® group after breakfast and dinner (10.4 versus 11.4 mmol/l in NovoMix® 30 and BHI 30 groups respectively after breakfast, and 9.22 versus 10.2 mmol/l after dinner; p < 0.05 between groups for breakfast and p < 0.02 for dinner). Before lunch, blood glucose concentrations of 6.64 mmol/l in the NovoMix® 30 group compared favourably with 7.57 mmol/l in the BHI 30 group (p < 0.02), while at bedtime, concentrations of 8.22 versus 9.10 mmol/l in the NovoMix® 30 and BHI 30 groups, respectively, again favoured NovoMix® 30 (p < 0.05). At other time points, between-treatment differences did not reach statistical significance. Importantly, mean prandial glucose concentration was significantly lower in the NovoMix® 30 group after 12 weeks (1.66 versus 2.34 mmol/l in NovoMix® 30 and BHI 30 groups, respectively; p < 0.02). Pre- Post- Pre- Post- Pre- Post- Bedtime 0200 h Breakfast Lunch Dinner Boehm B et al. Diabet Med 2002;19(5):393–399

Significantly lower prandial glucose increment with NovoMix® 30
0.5 1 1.5 2 2.5 3 p < 0.02 between treatment groups (mmol/l) Mean prandial glucose increment ANA 038 Summary: At 12 weeks, mean prandial glucose excursion was significantly less (p < 0.02) in the NovoMix 30 group compared with the BHI 30 group. Postprandial glycaemic control was significantly better with NovoMix® 30 when analysed on the basis of mean prandial blood glucose increment - mean increment (post-meal minus pre-meal blood glucose) over the three meals including lunch, when no insulin was given. After 12 weeks, mean prandial glucose increment was 1.66 ± 0.20 mmol/l in the NovoMix® 30 group versus 2.34 ± 0.19 mmol/l for BHI 30 (p < 0.02). After three months treatment, levels of HbA1c did not differ between the two treatment groups. Only subjects who had a complete set of values for each of the 8-point blood glucose time points were included in the analysis. NovoMix® 30 BHI 30 (n = 128) (n = 141) Boehm B et al. Diabet Med 2002;19(5):393–399

Improved postprandial control with NovoMix® 30
Superior postprandial glycaemic control achieved compared with BHI 30 No increased risk of hypoglycaemia with NovoMix® 30 Trend for reduction in nocturnal hypoglycaemic episodes with NovoMix® 30 ANA 038 See slides 40 and 41 for hypoglycaemia data for this trial Boehm B et al. Diabet Med 2002;19(5):393–399

NovoMix® 30 vs. NPH in type 2 patients
OHA only Twice-daily NovoMix® 30 (n = 201) NPH + OHA NPH monotherapy No treatment Original treatment Twice-daily NPH insulin (n = 202) Manuscript submitted BIAsp 1069 Once or twice-daily insulin is a common insulin initiation regimen in patients with type 2 diabetes. BIAsp-1069 was a multicentre, randomised controlled, double-blind, parallel group trial, investigating the potential advantages to glycaemic control of using NovoMix® 30 instead of NPH insulin as a starting insulin in this patient group. 403 patients were randomised and exposed to either NovoMix® 30 or NPH insulin, injected subcutaneously immediately before breakfast and evening meal, for 16 weeks. Subjects were eligible for inclusion if they were already receiving NPH insulin or were insulin-naïve, but would benefit from starting insulin. There was no differentiation between patients who received either NPH once- or twice-daily before the start of the trial. 7–14 days 16 weeks 2 weeks Screening Randomisation Christiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6):

NovoMix® 30 vs. NPH: lower prandial glucose increment
* 1 0.56 * p < 0.005 ** p < Favours NPH Favours NovoMix® 30 0.5 Difference in prandial glucose increment between treatment groups (mmol/l) -0.5 -1 -0.69 Manuscript submitted For the total population, the mean prandial glucose increment (ie, average taken for breakfast, lunch and dinner) was significantly less in patients treated with NovoMix 30 twice-daily compared with those receiving NPH twice-daily ** -1.5 -1.26 -1.33 Mean prandial glucose increment ** ** -2 Breakfast Lunch Dinner Christiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6):

Greater HbA1c reduction with NovoMix® 30 vs. NPH
0.0 -0.2 -0.4 Change in HbA1c (%) -0.6 Manuscript submitted BIAsp 1069 Summary: Subjects who had been taking NPH insulin monotherapy before the trial achieved significantly greater reductions in HbA1c when switched to NovoMix® 30 twice-daily compared to those who added another NPH injection (p < 0.005). As expected, subjects who were receiving NPH monotherapy (once- or twice-daily) or who were insulin-naïve prior to the study responded more favourably to both NovoMix® 30 and NPH insulin than those who had been taking combination therapy since they did not discontinue any component of treatment before starting on trial medication. Total population: HbA1c concentration decreased by > 0.6 % (p < versus baseline), in parallel, in both groups; metabolic control continued to improve throughout the trial without reaching a stable level -0.8 p = 0.03 -1.0 Christiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6):

NovoMix® 30 offers better glycaemic control than NPH
Mean prandial glucose increment lower in NovoMix® 30 group (p < ) Patients receiving NPH monotherapy benefit from switching to NovoMix® 30 (bid) Manuscript submitted BIAsp 1069 NPH monotherapy = once- or twice-daily NPH. The study did not distinguish between patients taking NPH either once a day or twice a day. Christiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6):

Superior postprandial control
Higher plasma insulin levels with NovoMix® 30 vs. BHI 30 Improved postprandial control vs. BHI 30 Superior postprandial control vs. Humalog® Mix25TM Lower postprandial increment and HbA1c vs. NPH No safety concerns

Superior hypoglycaemia profile Boehm B et al. Diabet Med 2002;19(5):393–399 Boehm et al. Submitted to Eur J Int Med Boehm B et al. Diabetologia 2003;46(Suppl 2):A269 Safety comparison vs. BHI 30 in type 1 and type 2 patients 2-year safety data in type 2 patients vs. BHI 30 4-year safety data in type 2 patients vs. BHI 30 Return to contents slide

Insulin-using type 1 and type 2 diabetic patients
Comparison of efficacy and safety of NovoMix® 30 vs. BHI 30: study design NovoMix® 30 (n = 140, 39% type 1) Insulin-using type 1 and type 2 diabetic patients (n = 294) One screening visit; patients already using a twice-daily insulin regimen ANA 038 Comparison of the efficacy and safety of NovoMix® 30 and BHI 30 in a twice-daily meal-related regimen, in a mixed population of patients with type 1 and type 2 diabetes. In this 12-week, randomised, parallel-group, open labelled comparison, 294 adult male and female subjects who had been using insulin in a twice-daily regimen were randomised to receive NovoMix® 30, injected within 10 minutes before breakfast and dinner (n = 143), or BHI 30 injected approximately 30 minutes prior to breakfast and dinner (n = 151). Of these, 140 patients were exposed to NovoMix 30, and 151 were expose to BHI 30. Three patients withdrew from the study after randomisation, but before exposure, as it was found that had not been treated with insulin for the required minimum of 2 years. The treatment comparison, which used HbA1c after 12 weeks as the primary efficacy endpoint, was based on a non-inferiority criterion for the difference between the two biphasic insulins Safety and tolerability of the two regimens was evaluated by measurement of the frequency, severity and timing of hypoglycaemic episodes. BHI 30 (n = 151, 32% type 1) 12 weeks Boehm B et al. Diabet Med 2002;19(5):393–399

Improved postprandial glucose after 3 months
NovoMix® 30 * p < 0.05 * 12 BHI 30 * * 10 * 8 Blood glucose (mmol/l) 6 ANA 038 Summary: Blood glucose concentration was significantly lower after breakfast and dinner, before lunch and at bedtime in the NovoMix® 30 group. Analysis of 8-point blood glucose profiles revealed significantly lower blood glucose concentrations after breakfast and dinner, before lunch and at bedtime in the NovoMix® 30 group. At 12 weeks, values were approximately 1% lower in the NovoMix® group after breakfast and dinner (10.4 versus 11.4 mmol/l in NovoMix® 30 and BHI 30 groups respectively after breakfast, and 9.22 versus 10.2 mmol/l after dinner; p < 0.05 between groups for breakfast and p < 0.02 for dinner). Before lunch, blood glucose concentrations of 6.64 mmol/l in the NovoMix® 30 group compared favourably with 7.57 mmol/l in the BHI 30 group (p < 0.02), while at bedtime, concentrations of 8.22 versus 9.10 mmol/l in the NovoMix® 30 and BHI 30 groups, respectively, again favoured NovoMix® 30 (p < 0.05). At other time points, between-treatment differences did not reach statistical significance. Importantly, mean prandial glucose concentration was significantly lower in the NovoMix® 30 group after 12 weeks (1.66 versus 2.34 mmol/l in NovoMix® 30 and BHI 30 groups, respectively; p < 0.02). Pre- Post- Pre- Post- Pre- Post- Bedtime 0200 h Breakfast Lunch Dinner Boehm B et al. Diabet Med 2002;19(5):393–399

Significantly lower prandial glucose increment with NovoMix® 30
0.5 1 1.5 2 2.5 3 p < 0.02 between treatment groups (mmol/l) Mean prandial glucose increment ANA 038 Summary: At 12 weeks, mean prandial glucose excursion was significantly less (p < 0.02) in the NovoMix 30 group compared with the BHI 30 group. Postprandial glycaemic control was significantly better with NovoMix® 30 when analysed on the basis of mean prandial blood glucose increment - mean increment (post-meal minus pre-meal blood glucose) over the three meals including lunch, when no insulin was given. After 12 weeks, mean prandial glucose increment was 1.66 ± 0.20 mmol/l in the NovoMix® 30 group versus 2.34 ± 0.19 mmol/l for BHI 30 (p < 0.02). After three months treatment, levels of HbA1c did not differ between the two treatment groups. Only subjects who had a complete set of values for each of the 8-point blood glucose time points were included in the analysis. NovoMix® 30 BHI 30 (n = 128) (n = 141) Boehm B et al. Diabet Med 2002;19(5):393–399

Reduced major hypoglycaemia after 3 months
50% relative risk reduction 45 40 35 30 hypoglycaemic episodes Number of 42 events 25 20 ANA 038 Summary: Subjects in the NovoMix® 30 group experienced nearly half as many major hypoglycaemic episodes as those in the BHI 30 group, as well as a trend towards reduced nocturnal hypoglycaemia. Based on actual exposure, analysis of hypoglycaemic episodes was based on 138 patients in the NovoMix® 30 group and 153 in the BHI 30 group. This is explained by a pharmacy dispensing error, where two patients who were randomised to receive NovoMix® 30 actually received BHI 30: therefore, these two patients were moved to the BHI 30 group. 8% of patients in the NovoMix® 30 group reported a total of 20 major hypoglycaemic episodes, whereas 12% of the BHI 30 group reported 42 major events. The relative risk (RR) of major hypoglycaemia when NovoMix® 30 was compared with BHI 30 throughout the 24 hour period was 0.66, indicating a trend towards greater risk reduction in the NovoMix® 30 group, although this figure failed to reach statistical significance. For both major and minor hypoglycaemic episodes the RR between 06:00 and 24:00 hours was not significantly different between treatments (RR = 1.02). 15 20 events 10 5 NovoMix® 30 BHI 30 (n = 138) (n = 153) Boehm B et al. Diabet Med 2002;19(5):393–399

Trend towards reduced minor nocturnal hypoglycaemic episodes
60 55 50 45 40 35 58 events hypoglycaemic episodes Number of 30 25 ANA 038 Summary: A trend toward reduced nocturnal minor hypoglycaemic episodes was seen in the NovoMix 30 group (p = 0.06). Minor hypoglycaemic events were reported by 54% of patients receiving NovoMix® 30 (362 events) and 56% receiving BHI 30 (361 events). The difference between groups in terms of daily relative risk was non-significant. However, a trend towards reduced minor nocturnal hypoglycaemia was observed with NovoMix® 30 between 00:00 and 00:60 hours (39 events vs. 58 events; RR = 0.63; p = 0.06). 39 events 20 15 10 5 NovoMix® 30 BHI 30 Boehm B et al. Diabet Med 2002;19(5):393–399

Reduced hypoglycaemic profile with NovoMix® 30
Superior postprandial glycaemic control achieved compared with BHI 30 No increased risk of hypoglycaemia with NovoMix® 30 Trend for reduction in nocturnal hypoglycaemic episodes with NovoMix® 30 ANA 038 Boehm B et al. Diabet Med 2002;19(5):393–399

NovoMix® 30 vs. BHI 30: 2-year safety in type 2 diabetes
NovoMix® 30 bid (n = 58) Insulin-using type 2 diabetic patients (n = 125) BHI 30 bid (n = 67) This trial (067) was an extension of the 3-month 038 study. Subjects who participated in the extension trial continued to receive twice-daily treatment with either NovoMix30 or BHI 30, as previously randomly allocated. The primary objective was to evaluate the long-term safety profile of biphasic NovoMix30 as measured by the number of major hypoglycaemic episodes occurring over time. These analysis were planned for the entire cohort, but separate analyses were also planned for patients with type 1 and type 2 diabetes. Of the 268 subjects who completed trial 038, 204 (76%) elected to continue in the extension trial; The type 2 population comprised 58 in the NovoMix30 group and 67 in the BHI30 group. The dosage of the trial products was adjusted throughout the trial according to local practice based on the subject’s self-measured blood glucose. 24 Months Boehm et al. Submitted to Eur J Int Med

Reduced major hypoglycaemia after 2 years
12 p = 0.04 NovoMix® 30 BHI 30 p = NS 10 8 Patients with at least one major episode (%) 6 4 ANA 067, Manuscript in preparation This was part of a 24-month randomised parallel-group study (continuation of the 3-month study shown before), including type 1 and type 2 diabetes patients taking either NovoMix 30 b.i.d. or BHI 30 b.i.d. (the latter 30 minutes before the meal). All analyses shown from this study correspond to the type 2 subgroup (n=125) 95 patients (76%) completed the two year treatment period. The proportion of patients experiencing major hypoglycemia was also similar during the first year (BIAsp, 5%; BHI, 8%; NS) but significantly lower with NovoMix 30 than with BHI during the second (BIAsp, 0%; BHI, 10%; P = 0.04). The frequency of major hypoglycaemic episodes was: 1st yr N x % E NovoMix BHI 2nd yr NovoMix BHI p = 0.04 N Number of subjects exposed X Number of subjects with at least one episode (%) Proportion of subjects with episodes relative to the total number of subjects E Number of episodes Minor episodes were also fewer in the Nmix 30 group, especially in the second year First treatment year: 265 Nmix in BHI 30 Second year: 133 and 222, respectively (p < 0.05). 2 1st year 2nd year Year of study Boehm et al. Submitted to Eur J Int Med

2-year efficacy and tolerability of NovoMix® 30 in type 2 diabetes
Compared with BHI 30, NovoMix® 30 is associated with: A reduced risk of major hypoglycaemia An equivalent level of efficacy More favourable balance between hypoglycaemia and hyperglycaemia in insulin-treated type 2 diabetes ANA 067, manuscript in preparation Boehm et al. Submitted to Eur J Int Med

NovoMix® 30 vs. BHI 30: 4-year safety in type 2 diabetes
Insulin-using type 2 patients (n = 73) NovoMix® 30 bid (n = 32) BHI 30 bid (n = 41) ANA 067 – 4 year extension study This was a randomised, open-label, parallel group trial comparison of BIAsp 30 and BHI 30. After an initial 3-month efficacy and safety study (ANA 038 study), there was a 21-month safety (and efficacy) study. (Data presented in earlier slides) This was extended twice – initially to 42 months then to 48 months. Efficacy assessments (HbA1c and insulin dose) are presented only up to the end of the first safety extension (42 months). In the second extension, visits were too irregular and the number of measurements at each visit were too small to provide meaningful data. Months Boehm B et al. Diabetologia 2003;46(Suppl 2):A269

Twice-daily NovoMix® 30 and BHI 30 gives stable metabolic control
9.0 8.5 8.0 HbA1c (%) 7.5 7.0 067 – 4-year extension HbA1c profiles are presented as mean with 2 SEM Months Boehm B et al. Diabetologia 2003;46(Suppl 2):A269

Hypoglycaemic episodes in patients completing the 4-year trial
NovoMix® 30 (n = 32) BHI 30 (n = 41) p-value People with major episodes First 2 years 1 7 0.04 Entire period 4 11 0.08 People with nocturnal episodes 6 0.02 Major nocturnal episodes are defined as those occuring between 24:00 and 06:00 Boehm B et al. Diabetologia 2003;46(Suppl 2):A269

Superior hypoglycaemic profile vs. BHI 30
No major hypoglycaemic episodes during second year of treatment No nocturnal hypoglycaemic events during 4 years’ treatment

Superior HbA1c control with oral medication Kvapil M et al. Diabetes 2002;51(Suppl 2):A104 Kilo C et al. J Diabetes Complications 2003;17(6):30713 Raz I et al. Submitted to Diabetes, Obesity and Metabolism Raz I et al. Clin Ther 2003;25:31093123 Raz I et al. Manuscript in preparation Raz I et al. Diabetologia 2003;46(Suppl 2):A8 Addition of twice-daily NovoMix® 30 to metformin vs. addition of SU Addition of once-daily NovoMix® 30 to metformin Addition of twice-daily NovoMix® 30 or metformin to glibenclamide Addition of rosiglitazone to glibenclamide vs. switch to NovoMix® 30 plus rosiglitazone Addition of NovoMix® 30, NovoMix® 30 plus repaglinide or glibenclamide to metformin Comparison of NovoMix® 30, NovoMix® 30 plus pioglitazone and glibenclamide plus pioglitazone in SU failures Return to contents slide

NovoMix® 30 in combination with metformin
NovoMix® 30 bid + metformin (n = 108) (n = 329) NovoMix® 30 bid (n = 107) Metformin failures (HbA1c 7.5–13.0%) glibenclamide + metformin (n = 114) BIAsp 1241 Aim To compare the efficacy of: - NovoMix® 30 monotherapy - NovoMix® 30 plus metformin, and - sulphonylurea plus metformin, in type 2 diabetes Trial design Multinational, randomised, open-label, parallel group trial Duration of treatment was 16 weeks Treatment was administered BID (before morning and evening meals) NovoMix 30 was injected 0-5 minutes before the test meal All of the 329 patients involved in the trial had type 2 diabetes Poorly controlled patients (n = 193) had HBA1c levels of  9.0% A total of 136 patients had good-to-moderate control, and their HbA1c levels were less than 9.0% 16 Weeks Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

Demographic characteristics (total population)
NovoMix® 30 plus metformin in type 2 diabetes Demographic characteristics (total population) NovoMix® 30 + met Met + SU No of patients 107 108 114 Mean age (yrs ± SD) 55.2 ± 10.3 56.4 ± 9.0 58.1 ± 8.8 Male/Female 50/57 53/55 52/62 BMI (kg/m2 ± SD) 30.9 ± 4.5 30.4 ± 4.0 30.5 ± 4.4 BIAsp 1241 Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

Improved HbA1c with NovoMix® 30 combination in total population
8.5 p = 0.004 HbA1c difference of 0.6% 8 (%) following 16 weeks' treament 7.5 BIAsp 1241 In the total population, mean HbA1c was reduced from 9.6 at baseline to 8.1 after 16 weeks in NM group, from 9.3 to 7.5 in Group MB and from 9.4 to 7.8 in Group MS. After 16 weeks, the mean HbA1c was significantly lower in Group MB than in Group B. 1c HbA 7 NM NM+met Met+su Treatment group Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

Superior glycaemic control with NovoMix® 30 + metformin in poorly controlled patients (HbA1c > 9%) p = 0.037 p = 0.033 8.5 8 (%) 1c HbA 7.5 BIAsp 1241 In the poorly-controlled population (HbA1c >9%), 16 weeks’ treatment with NovoMix 30 in combination with metformin resulted in a significantly lower HbA1c level compared with the other treatment groups. 7 NM NM+met Met+SU Treatment group Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

Lower insulin dose when used with metformin
NovoMix® 30 NovoMix® + met Met + SU 1 2 3 4 5 6 7 0.6 0.4 NovoMix® 30 dose (IU/mg/day) SU dose (mg/day) 0.2 BIAsp 1241 Throughout the course of the study, the metformin dose was approximately 1660 mg per day in both the MB and MS treatment groups. The dose of BIAsp 30, when used in combination with metformin, was less than the dose required in the BIAsp 30 monotherapy treatment group. 1 2 3 4 Time (months) Time (months) Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

Significantly lower body weight* for NovoMix® 30 + met vs. NovoMix® 30
p = p = 0.05 120 100 80 weight (kg) End of trial mean body 60 40 * Mean body weights adjusted for baseline 20 NovoMix® 30 NovoMix® 30 + met Met + SU Kvapil M et al. Diabetologia 2002;45(Suppl 2):A18

NovoMix® 30 plus metformin is well tolerated
There were no reports of major hypoglycaemia during the trial The total number of minor hypoglycaemic episodes was similar between groups: NovoMix® 30 + met 23 NovoMix® 30 alone 20 Met + SU No other safety concerns were raised BIAsp 1241 The percentage of patients experiencing at least one adverse event was also similar between treatment groups: BIAsp 30 + met 31% BIAsp only 42% Met + SU 24% Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

Improved glycaemic control with NovoMix® 30 combination
In poorly controlled patients: NovoMix® 30 plus metformin achieved better glycaemic control than NovoMix® 30 alone or sulphonylurea plus metformin The end of trial mean weight was not different between the NovoMix® 30 plus metformin group and SU plus metformin group NovoMix® 30 plus metformin is well tolerated There was no difference in hypoglycaemia between the two groups BIAsp 1241 No safety concerns were raised during the trial period The pattern of hypoglycaemic episodes did not differ between the groups No major hypoglycaemic events were reported for any treatment group The rate of hypoglycaemia (minor and symptoms only) was ~ 0.04 episodes per patient week in the total population Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

Once-daily (dinnertime) NovoMix® 30 with metformin
Metformin + NovoMix® 30 od (n = 45) Run-in period – metformin (up to 2550 mg/day) Metformin + human insulin NPH od (n = 47) Follow-up Metformin + BHI 30 od (n = 46) BIAsp 1088 Aim To compare three combinations of metformin with 1) NovoMix 30, within 10 minutes before the meal, 2) biphasic human insulin, 30 minutes before the meal, 3) human insulin NPH, at bedtime Trial design The study was an open-label, randomised, parallel-group, multicentre, 3-arm trial with a 4 week run-in period and 2 week follow-up. The trial involved 138 type 2 patients who were receiving either metformin or metformin in combination with sulphonylurea or repaglinide for at least 3 months. Both men and women enrolled, and had a BMI of < 40 kg/m2 and HbA1c of > 7.5%. Eligible patients: FPG  126 mg/dl – Weeks Kilo C et al. J Diabetes Complications 2003;17(6):307-13

Addition of insulin to metformin improves glycaemic control
Treatment group (+metformin) NovoMix® 30 NPH BHI 30 -1 (%) 1c -1.2 BIAsp 1088 Results No significant difference in reduction in HbA1c between treatment groups in the total trial population However, when divided into groups according to fasting plasma glucose……see next slide Reduction in HbA -1.4 Kilo C et al. J Diabetes Complications 2003;17(6):307-13

Benefits of reaching fasting glycaemic targets with NovoMix® 30
FPG (mmol/l) 5–8 (n = 54) Treatment (+metformin) Change in HbA1c from baseline (%) NovoMix® 30 NPH BHI 30 -3 -2.5 -2 -1.5 -1 -0.5 BIAsp 1088 The total population was divided into sub-groups according to the fasting plasma glucose level (mmol/l). Patients in the 5-8 mg/dl sub-group who were treated with NovoMix 30 had a significantly larger reduction in HbA1c compared with the other two treatment groups (p < vs NPH + met and BHI 30 + met). Patient numbers: NovoMix® 30 group – n = 12 NPH group – n = 23 BHI 30 group – n = 19 Kilo C et al. J Diabetes Complications 2003;17(6):307-13

Fewer nocturnal hypoglycaemic events with NovoMix® 30 combination
NPH BHI 30 Patients (n) 45 46 47 Major events Symptomatic nocturnal events 9 18 14 Minor nocturnal events 1 6 BIAsp 1088 Results (cont) There were no significant differences among groups for any lipid parameters. The rate of hypoglycaemia in the trial was low, and did not differ between treatment groups. No major hypoglycaemic events were reported during the study. There were fewer nocturnal hypoglycaemic events in the NovoMix + metformin group compared with the other two treatment groups. Total hypoglycaemic events: NovoMix® 30: minor – 23; symptoms only – 36 NPH: minor 8; symptoms only 28 BHI 30: minor – 13; symptoms only 23. The high incidence of minor and symptoms only hypoglycaemic events may be due to the aggressive therapy. There were no major hypoglycaemic events reported during the study. There were numerically fewer nocturnal hypoglycaemic events in the NovoMix® 30 group Kilo C et al. J Diabetes Complications 2003;17(6):307-13

Once-daily (dinnertime) NovoMix® 30 with metformin is effective and well tolerated
With metformin non-responders, starting NovoMix® 30 once-daily and continuing metformin is effective and well tolerated. Reaching FPG target with NovoMix® 30 plus metformin achieves greater benefits than NPH or BHI 30 groups Less nocturnal hypoglycaemic events occurred in the NovoMix® 30 combination group compared to NPH or BHI 30 groups BIAsp 1088 Kilo C et al. J Diabetes Complications 2003;17(6):307-13

Addition of second therapy when glibenclamide fails (I)
NovoMix® 30 (BID) + glibenclamide (n = 22) Glibenclamide (7.5–15 mg/day) Type 2 patients, HbA1c 813% Metformin (850 mg OD) + glibenclamide (n = 24) BIAsp 1269 In this multi centre, open, 6-week, parallel group trial, 46 patients (HbA1c 8-13%) were randomised to add on either metformin (MET) or NovoMix® 30 to existing (and failing) glibenclamide therapy Patients adding NovoMix 30 injected prior to breakfast and dinner Patients took their metformin dose at dinner Weeks Raz I et al. Submitted to Diabetes, Obesity and Metabolism

Improved glycaemic control with addition of NovoMix® 30 vs. metformin
GLI+ NovoMix® 30 GLI+ NovoMix® 30 GLI+MET GLI+MET 0.0 0.0 –0.5 –0.3 –1.0 –1.5 Mean glucose reduction (mmol/l) –0.6 –2.0 HbA1c reduction (%) –0.9 –2.5 BIAsp 1269 The overall (derived from the daily 7-point profiles) mean blood glucose change was greater for those treated with GLIB + NovoMix 30 than those with GLIB + MET; -2.85mmol/l vs mmol/l, p = 0.03. The reduction in HbA1c was numerically greater when NovoMix 30 was added to glibenclamide compared with when metformin was added (-1.4% vs. -0.8%; p=NS) –3.0 –1.2 –3.5 * p < 0.05 –4.0 –1.5 Raz I et al. Submitted to Diabetes, Obesity and Metabolism

Addition of second therapy when glibenclamide fails (II)
NovoMix® 30 (BID) + rosiglitazone (4 mg OD) (n = 26) Glibenclamide (7–15 mg) Type 2 patients, HbA1c (813%) Glibenclamide + rosiglitazone (4mg OD) (n = 23) 1271 In this multi centred, open-label, 6-week, parallel group trial, 49 patients (HbA1c 8-13%) were randomised either to replace glibenclamide therapy with NovoMix 30 (BID) plus rosiglitazone (OD) or to add rosiglitazone (OD) to pretrial doses of glibenclamide. Weeks Raz I et al. Clin Ther 2003;25:

Improved glycaemic control with NovoMix® 30 combination
ROS+ NovoMix® 30 ROS+ NovoMix® 30 ROS+GLI ROS+GLI 0.0 0.0 –0.5 –0.3 –1.0 –1.5 Mean glucose reduction (mmol/l) –0.6 –2.0 HbA1c reduction (%) –2.5 –0.9 1271 There was a significant difference between treatments in mean change in daily blood glucose HbA1c was lowered in both treatment groups, however, there was no between-treatment difference –3.0 –1.2 –3.5 –4.0 –1.5 * p < 0.05 Raz I et al. Clin Ther 2003;25:

Treatment options when metformin fails
NovoMix® 30 (BID) + metformin (OD) (n = 23) Metformin (1700–2550 mg) NovoMix® 30 (BID) + repaglinide 1 mg (OD) + metformin (OD) (n = 24) 1270 In this multi centred, open-label, three-armed, 6-week parallel group study, 71 patients were randomised to add one of the following treatment options to their pretrial doses of metformin: NovoMix 30 (BID) Glibenclamide (OD) and NovoMix 30 (BID) Glibenclamide (OD) Glibenclamide 5 mg (OD) + metformin (OD) (n = 23) Weeks Raz I et al. Manuscript in preparation

Reduction in HbA1c after 6 weeks’ treatment
MET+ REP+ NovoMix® 30 MET+ REP+ NovoMix® 30 MET+ GLI MET+ NovoMix® 30 MET+ NovoMix® 30 MET+ GLI 0.0 0.0 –0.5 –0.3 –1.0 Mean glucose reduction (mmol/l) –1.5 –0.6 –2.0 HbA1c reduction (%) –0.9 –2.5 –3.0 BIAsp 1270 Despite lowering the change in mean blood glucose and HbA1c, there were no between-treatment differences –1.2 –3.5 –1.5 –4.0 Raz I et al. Manuscript in preparation

NovoMix® 30 + oral agent is preferable to a second oral agent
The addition of NovoMix® 30 to an oral agent was more effective in lowering average glucose than when a second oral agent was added Addition of NovoMix® 30 also showed a trend to decrease HbA1c All treatment therapies showed improvements in HbA1c BIAsp 1269,1270,1271 Raz I et al. Diabetologia 2002;45(Suppl 2):A263

Treatment options with NovoMix® 30 when SU therapy fails
NovoMix® 30 (BID) + pioglitazone (30 mg OD) SU mono or combination therapy (HbA1c 7.513.0%) NovoMix® (BID) Glibenclamide (515 mg, OD) + pioglitazone (30 mg OD) Time (weeks) 1237 This was an 18-week, international, multi-centred, randomised, open-label, parallel group trial. Three treatment regimens were compared in patients with type 2 diabetes who were inadequately controlled on sulphonylurea mono-or combination therapy: NovoMix 30 (BID) plus pioglitazone NovoMix 30 (BID) Glibenclamide + pioglitazone Screening Randomisation (SU therapy discontinued) Discontinuation of trial product Raz I et al. Diabetologia 2003;46(Suppl 2):A8

Lower HbA1c with NovoMix® 30 combination treatment
11.0 NovoMix® 30 10.5 NovoMix® 30 + pioglitazone Glibenclamide + pioglitazone 10.0 9.5 HbA1c (%) * * 9.0 8.5 1237 Data are for the ITT population 8.0 7.5 *p < 0.01 7.0 Screening Visit 6 End of Trial Raz I et al. Diabetologia 2003;46(Suppl 2):A8

Superior glycaemic control with NovoMix® 30 combination therapy
At end of trial, NovoMix® 30 + pioglitazone was superior to glibenclamide + pioglitazone on almost all measures of blood glucose (p < 0.05–p < 0.001) Significantly lower prandial BG increment for NovoMix® 30 + pioglitazone versus glibenclamide + pioglitazone (p < 0.05) NovoMix® + pioglitazone superior to NovoMix® 30 in reducing dinner-related glucose Raz I et al. Diabetologia 2003;46(Suppl 2):A8

NovoMix® 30 + pioglitazone is effective in type 2 diabetes
NovoMix® 30 and pioglitazone is an effective treatment combination in type 2 diabetic patients The combination of NovoMix® 30 and pioglitazone offers better glycaemic control than the combination of glibenclamide and pioglitazone and NovoMix® 30 only The combination of NovoMix® 30 and pioglitazone is well tolerated and associated with a low incidence of nocturnal hypoglycaemia Raz I et al. Diabetologia 2003;46(Suppl 2):A8

NovoMix® 30 is an effective add-on therapy
Superior glycaemic improvements when NovoMix® 30 added to metformin vs. addition of SU Adding NovoMix® 30 (once-daily) to metformin is more effective for controlling blood glucose levels compared with adding NPH or BHI 30 Overall, adding NovoMix® 30 to a failing oral agent provides superior glycaemic control than adding another oral therapy

Convenience and flexibility Kapitza C et al. In press Diabet Med Postprandial dosing vs. BHI 30 Warren et al. Submitted to Diabet Res Clin Prac Postprandial dosing vs. BHI 30 in the elderly Vora JP et al. Diabetologia 2002;45(Suppl 2):A255 NovoMix® 30 FlexPen® vs. Humalog® Mix25TM Pen Asakura T & Seino H Diabetes Metab 2003;29:4S236 NovoRapid® FlexPen® vs. Humalog® KitTM Pen Korytkowski M et al. Clin Ther 2003;25(11): in press FlexPen® vs. vial/syringe with NovoMix® 30 Return to contents slide

Postprandial dosing with NovoMix® 30
NovoMix® 30, 0 min NovoMix® 30, +15 min BHI 30, –15 min BHI 30, 0 min BIAsp 1238 Investigation of postprandial glycaemic control in type 2 diabetes patients, specifically whether NovoMix® 30, injected 15 minutes after the beginning of a test meal, was inferior to: Biphasic human insulin (BHI), injected 15 mins before test meal BHI, injected immediately before test meal NovoMix® 30, injected immediately before test meal Single centre, open-label, randomised, four-period crossover trial Trial patients (n=31) with type 2 diabetes had received insulin for at least 6 months before trial commencement Patients attended four meal visits (3–21 days apart) and received a different treatment at each visit Blood samples (for blood glucose measurements) were taken at intervals for 5 hours after the onset of the test meal Visit (Screening) (Randomisation) (Follow-up) Days between visits 5– – – – –14 Kapitza C et al. In press Diabet Med

Postprandial dosing efficacy with NovoMix® 30
BHI 30(t = –15 min) 6 BHI 30(t = 0 min) NovoMix® 30(t = 0 min) 4 NovoMix® 30( t= +15 min) 2 Blood glucose (mmol/l) BIAsp 1238 Postprandial dosing AUC and glucose Cmax analysis showed no difference NovoMix® 30 (t=+15min) compared with the two BHI treatments No major hypoglycaemic episodes were recorded during the trial Incidence of minor hypo’s was comparable between the four treatment groups No safety concerns were raised during the trial –2 –4 60 120 180 240 300 Time (min) Kapitza C et al. In press Diabet Med

Postprandial dosing with NovoMix® 30
NovoMix® 30 (t = 0 min) NovoMix® 30 (t = +15 min) BHI 30 (t = –15 min) BHI 30 (t = 0 min) *AUC (0–240mins) (mM/min) 2563a 2864 2958 2777 *Cmax (mM) 13.47b 15.28 15.08 14.42 Tmax (median, min) 75 90 BIAsp 1238 AUC and glucose Cmax analysis showed no difference NovoMix® 30 (t=+15min) compared with the two BHI treatments No major hypoglycaemic episodes were recorded during the trial Incidence of minor hypo’s was comparable between the four treatment groups No safety concerns were raised during the trial * Values are expressed as geometric means a AUC for NovoMix® 30 significantly smaller than both BHI treatments (p = and p = for t = – 15 min and t = 0 min, respectively) b Cmax is smaller for NovoMix® 30 (t = 0 min) compared with both BHI treatments, but only significantly smaller than BHI (t = 0 min) (p = 0.007) Kapitza C et al. In press Diabet Med

NovoMix® 30 allows flexible dosing
Superior postprandial blood glucose control compared with either of BHI 30 injection regimens Comparable postprandial blood glucose control when injected after meal to BHI 30 (either injection regimen) Gives advantage of increased flexibility in injection timing Opportunity to alter insulin dose according to meal size and composition BIAsp 1238 Kapitza C et al. In press Diabet Med

Postprandial NovoMix® 30 dosing in elderly patients
Run-in (n = 91) Preprandial dosing Preprandial dosing Postprandial dosing Postprandial dosing NovoMix® 30, bid, preprandial BIAsp 1239 This study compared pre- and postprandial bid injections of NovoMix in elderly patients with type 2 diabetes. In this open-label, randomised, 12-week, crossover study, 92 elderly patients (age ≥ 65 yrs) with type 2 diabetes were assessed. HbA1c was measured at baseline and at the end of the study period. Self-measured blood glucose testing was measured before and 2 hours after breakfast and before and 2 hours after dinner. Run in period consisted of four weeks, where patients were treated with bid preprandial injections of NovoMix 30 After randomisation, patients received either pre- or postprandial injections bid of NovoMix 30 for four weeks. At crossover, patients followed the alternative dosing regimen for a further four weeks. Weeks Warren et al. Submitted to Diabet Res Clin Prac

Blood glucose levels did not differ between treatment groups
200 Preprandial dosing (NovoMix® 30, bid) 180 Postprandial dosing (NovoMix® 30, bid) 160 140 120 n = 91 p = NS in all cases Blood glucose levels (mg/dl) 100 80 BIAsp 1239 Blood glucose levels (mg/dl): Preprandial dosing (NovoMix® 30, bid) Postprandial dosing (NovoMix® 30, bid) Before Breakfast 139 ± ± 55 Dinner 143 ± ± 65 2 hrs after Breakfast 159 ± ± 61 Dinner 143 ± ± 59 Plasma glucose profiles during test meals were also similar: AUC 0-240min ± vs ± mg/dL/min-1 There was no difference in the number of hypoglycaemic episodes for either treatment group (47 vs 55 episodes during pre- vs. postprandial treatment periods, respectively; p=ns) 60 40 20 Before breakfast Before dinner 2 hrs after breakfast 2 hrs after dinner Warren et al. Submitted to Diabet Res Clin Prac

Postprandial NovoMix® 30 is effective in elderly type 2 patients
Postprandial NovoMix® 30 offers acceptable alternative to standard preprandial injections No significant difference in hypoglycaemic episodes between treatment groups Postprandial injections appear to be well tolerated BIAsp 1239 Warren et al. Submitted to Diabet Res Clin Prac

Comparison of NovoMix® 30 FlexPen® with Humalog® Mix25TM Pen
Weeks –3 24 12 NovoMix® 30 FlexPen® Humalog® Mix25TM Pen Run-in (n = 133) BIAsp 1236 Background NovoMix® 30 (biphasic insulin aspart 30) is a premixed insulin analogue consisting of 30% soluble and 70% protamine-bound insulin aspart Mix25 is effective in achieving good glycaemic control in patients with type 2 diabetes Aim To compare the effectiveness of NovoMix® 30 with Mix25 administered with NovoMix 30 FlexPen and Humalog Mix25 Pen, respectively. Study overview Multinational, multicentre, open-label, randomised, crossover trial in patients with type 2 diabetes (n = 133) Following a screening period, patients followed a 2-week run-in period with biphasic human insulin 30/70 BID During period 1, patients administered either NovoMix® 30 BID with NovoMix® 30 FlexPen® or Mix25 BID with Humalog® Mix25TM Pen for 12 weeks. At crossover (period 2), patients administered the alternative treatment for 12 weeks Patient satisfaction with each device and their overall pen preference were assessed using a device specific questionnaire HbA1c, prandial BG increment and hypoglycaemic events were measured after each treatment period Vora JP et al. Submitted to Diabetes, Obesity and Metabolism

NovoMix® 30 FlexPen® is simple to use
Device specific, and comparative questionnaires assessed patients’ opinion about attributes of the devices Features included: confidence in setting and injecting the correct dose readability of the dose scale confidence in managing daily insulin injections using the pen device For all 16 device features assessed NovoMix® 30 FlexPen® was statistically superior to Humalog® Mix25™ Pen, p < 0.001 BIAsp 1236 Vora JP et al. Submitted to Diabetes, Obesity and Metabolism

NovoMix® 30 FlexPen® is preferred over Humalog® Mix25TM Pen
Equally easy/ either NovoMix® 30 FlexPen® Humalog® Mix25TM Equally difficult/ neither 100 90 * * 80 70 60 50 % of patients 40 30 BIAsp 1236 Pen device preference was assessed using a comparative questionnaire. Regarding overall ease of use, 73.6% of patients preferred the NovoMix 30 FlexPen, while 9% preferred the Humalog Mix25 Pen 20 10 Overall, which pen device do Overall, which pen device would you find easiest to use? you prefer to continue to use after this trial? * p < compared with Humalog® Mix25TM Pen Vora JP et al. Submitted to Diabetes, Obesity and Metabolism

Comparable efficacy and safety vs. Humalog® Mix25TM
A similar reduction in HbA1c was seen in the NovoMix® 30 and Humalog® Mix25TM treatment groups Both treatments lowered postprandial glucose to a similar extent The number of hypoglycaemic events did not differ significantly between treatment groups Both treatment groups experienced few adverse events BIAsp 1236 Vora JP et al. Submitted to Diabetes, Obesity and Metabolism

Higher patient satisfaction with NovoMix® 30 FlexPen®
Patients were more satisfied and experienced fewer problems than with the Humalog® Mix25TM Pen More patients found the NovoMix® 30 FlexPen® the easiest device to use More patients (75%) would continue to use the NovoMix® 30 FlexPen® while only 14% of Humalog® Mix25TM Pen users would Efficacy and safety of NovoMix® 30 and Humalog® Mix25TM were comparable BIAsp 1236 Vora JP et al. Submitted to Diabetes, Obesity and Metabolism

Comparison of FlexPen® with Humalog® KitTM
”Device-naïve” patients Run-in (n = 58) FlexPen® FlexPen® Humalog® KitTM Humalog® KitTM 58 inpatients were randomised to test either NovoRapid FlexPen or Humalog Kit for 2 days. Patients crossed over to use the alternative device for 2 days. None of the trial participants had previous experience of insulin devices. Injections were simulated using a sponge on the abdomen; no insulin was injected during the trial. 2 4 Days Both pens contained rapid-acting analogues, however, no insulin was injected during the testing procedure Asakura T & Seino H Diabetes Metab 2003;29:4S236

FlexPen® is more user-friendly than Humalog® Kit
** ** * * * 250 FlexPen® 200 Humalog® Kit * p < 0.01 ** p < 0.001 150 Total score 100 50 Number legibility Ease of dose setting Ease of pressing release button Simplicity Injection confirmation Pen feature Asakura T & Seino H Diabetes Metab 2003;29:4S236

More patients prefer FlexPen® to Humalog® Kit
90 80 70 60 50 Patients (%) 40 30 20 10 FlexPen® Humalog® Kit No preference Device preference Asakura T & Seino H Diabetes Metab 2003;29:4S236

FlexPen® is simple to use
Patients preferred FlexPen® to Humalog® Kit for: Readability of the dosing scale Ease of dose setting Ease of pressing the release button Stability during injection Simplicity Confirmation of injection No difference between the devices regarding grip and portability Asakura T & Seino H Diabetes Metab 2003;29:4S236

Comparison of FlexPen® vs vial/syringe
Run-in Type 1 and type 2 patients (using vial/syringe) FlexPen® FlexPen® Vial/syringe Vial/syringe Randomisation (n = 108) 1280 Randomised, open-label, comparative, 2-period crossover trial in patients with type 1 and 2 DM. Conducted in 9 sites in the US. All patients were syringe/vial users but naïve to the use of other insulin delivery devices. During the 4-week run-in period, patients used their previous mode of insulin delivery to administer NovoMix 30. Dose optimisation was determined during the run-in period. Patients were randomly assigned to use either FlexPen or vial/syringe for 4 weeks, then they crossed over to use the alternate delivery system. All patients continued to use NovoMix 30 (twice or four times daily). Weeks Korytkowski M et al. Clinical Therapeutics 2003;25(11):

Patients prefer FlexPen® to vial/syringe
6% FlexPen 20% Vial/syringe Q: Overall, which device would you prefer to continue using? No difference * Significantly more patients (p<0.05) preferred to continue using FlexPen® vs. vial/syringe 74%* Korytkowski M et al. Clinical Therapeutics 2003;25(11):

FlexPen® is preferred to vial/syringe in a number of injection parameters
Easier to read dose FlexPen® Vial/syringe No preference Confidence in setting dose Confidence in injecting correct dose Injection parameters More discreet in public More stable Easier to handle Confidence in glycaemic control Easier to use 10 20 30 40 50 60 70 80 90 100 Patients expressing preference (%) Korytkowski M et al. Clinical Therapeutics 2003;25(11):

Reduction in HbA1c with NovoMix® 30
* p<0.05 9.5 9 (%) 8.5 1c 8 7.5 Absolute HbA 7 6.5 Baseline (week 0) End of trial (week 12) Time point Korytkowski M et al. Clinical Therapeutics 2003;25(11):

FlexPen® is preferred to vial/syringe
Both injection devices demonstrated high acceptance by the patients according to the Diabetes Treatment Satisfaction Questionnaire (DTSQ) Efficacy and safety profiles were similar between treatment groups Given the choice, more patients expressed a preference to continue using FlexPen® to vial/syringe Korytkowski M et al. Clinical Therapeutics 2003;25(11):

Health care professionals’ opinion
82% of healthcare professionals preferred FlexPen® compared with two other prefilled pens 100 * p<0.01 vs. Humalog® pen and OptiSet® (n=102) 82%* 80 Proportion of patients (%) 60 40 14% 20 3% FlexPen® Humalog® Pen** OptiSet® ** Same device as Humalog® Mix 25 pen Lawton S et al. Diabetes 2001;50 (Suppl 2):A440

Convenient and flexible dosing with NovoMix® 30 FlexPen®
NovoMix® 30 offers flexible dosing times while maintaining good postprandial glycaemic control Patients prefer NovoMix® 30 FlexPen® to Humalog® Mix25TM Patients with impaired manual dexterity and vision prefer FlexPen® to Humalog® Kit

Efficacy and safety of NovoMix® 30 in type 1 adolescents
NovoMix® 30 (TID) (n = male female 49) Type 1 patients, yrs HI + BHI (n = male 43 female 38) In this multi centred, open labelled, parallel group, 4-month trial, 167 adolescents (10-17 yrs) were randomised to receive either NovoMix® 30 thrice daily (37 male, 49 female) or human insulin (HI) and biphasic human insulin 30 (BHI 30) (43 male, 38 female). BHI 30 was used once daily (usually before breakfast), and HI twice daily before lunch and dinner. weeks weeks (Time) Mortensen H et al. Diabetes Metab 2003;29:4S227

Efficacy of NovoMix® 30 in adolescents
NovoMix® 30 significantly improved BMI in boys, but not in girls Both treatments improved glycaemic control during the 16-week period : HbA1c decreased by ~0.2% NovoMix® 30 tended to improve prandial glucose control more in boys than in girls There was no between-treatment difference in rate of hypoglycaemia Mortensen H et al. Diabetes Metab 2003;29:4S227

NovoMix® 30: NovoMix® 30 provides improved postprandial glycaemic control compared to biphasic human insulin and Humalog® Mix25TM NovoMix® 30 provides a superior hypoglycaemic profile to biphasic human insulin NovoMix® 30 improves HbA1c when used in combination with oral medications NovoMix® 30 is simple and convenient to use in clinical practice NovoMix® 30 is effective and well tolerated in adolescents

Publications/abstracts used in this slide kit
Brange J et al. Nature 1988;333:679–682 Jacobsen L et al. Eur J Clin Pharm 2000;56:399–403 Weyer et al. Diabetes Care 1997;20: 1612–1614 McSorley PT et al. Clin Ther 2002;24(4):530–539 Hermansen K et al. Metabolism 2002;51(7):896–900 Hermansen K et al. Diabetes Care 2002; 25:883–888 Boehm B et al. Diabet Med 2002;19(5):393–399 Christiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6): Boehm B et al. Submitted to Eur J Int Med Boehm B et al. Diabetologia 2003;46(Suppl 2):A269 Kvapil M et al. Diabetes 2002;51(Suppl 2):A104 Kilo C et al. J Diabetes Complications 2003;17(6):307-13 Raz I et al. Submitted to Diabetes, Obesity and Metabolism Raz I et al. Clin Ther 2003;25:3109–3123 Raz I et al. Manuscript in preparation Raz I et al. Diabetologia 2002;45(Suppl 2):A263 Raz I et al. Diabetologia 2003;46(Suppl 2):A8 Kapitza C et al. In press Diabet Med Warren et al. Submitted to Diabet Res Clin Prac Vora JP et al. Submitted to Diabetes, Obesity and Metabolism Asakura T & Seino H Diabetes Metab 2003;29:4S236 Korytkowski M et al. Clinical Therapeutics 2003;25(11): Lawton S et al. Diabetes 2001;50 (Suppl 2):A440 Mortensen H et al. Diabetes Metab 2003;29:4S227

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