1. An update on insulin therapy in type 2 diabetes mellitus
Jens Sandahl Christiansen, MD, DMSc, FRCPI

2. Antidiabetic treatment
Metabolic control 10 9 8 7 6 5
DCCT
Kumamoto Study 12 11 10 9 8 7 6 5
HbA1c (%)
HbA1c (%)
Time from randomization (years)
Months
N Engl J Med 1993;329:
Diab Res Clin Pract 1995;28: 9 8 7 6
UKPDS
Median HbA1c (%)
Conventional therapy
Intensive therapy
Time from randomization (years)
Lancet 1998;352:

3. Cardiovascular Disease
Kaplan-Meier estimates of the composite endpoint of cardiovascular mortality, non-fatal myocardial infarction, coronary artery bypass graft, percutaneous coronary interventions, non-fatal stroke, amputation, or vascular surgery for peripheral atherosclerotic artery disease in the conventional and the intensive therapy group.
Peter Gæde, N Engl J Med 348: 383, 2003

4. Microvascular complications
Odds ratios with 95% confidence intervals for development and/or progression of nephropathy, retinopathy, and autonommic and peripheral neuropathy during 4 ( - ) or 8 ( - ) years of follow-up.
Peter Gæde, N Engl J Med 348: 383, 2003

5. Treatment goal achieved
Percentage of patients achieving the treatment goals for the intensive group at 8 years in both the intensive and the conventional groups after 8 years of follow-up
Peter Gæde, N Engl J Med 348: 383, 2003

6. Plasma glucose (mg/dl)
The role of postprandial glycaemia (PPG)
Mealtime
glucose spikes
Fasting hyperglycaemia
Normal
0600
1200
1800
2400
300
200
100
Time (hours)
Plasma glucose (mg/dl)
Riddle MC. Diabetes Care 1990;13:676

7. Capillary glucose and CHD risk – 2-hours post-50g glucose70 60 50 40
CHD Deaths/ 1000/7.5 y 30 20
Gerstein slides 10 20 40 60 80 90 95 96 97 98 99
100
Centile
96 (5.3) 110 (6.1) 200 Glucose
*18,403 men (40-64 y). Fuller JH et al. Lancet. 1980;1:

8. Adjusted hazard ratios for death
2 hour postprandial glucose was an independent and progressive risk factor for mortality
< 140
>200
2-hour postprandial glucose (mg/dl)
Adjusted hazard ratios for death
Relative risk of death for 2 hour postprandial blood glucose
0.0
0.5
1.0
1.5
2.0
2.1
Slide 10
The Importance of Postprandial Glucose
Postprandial glucose was found to be an independent and progressive risk factor for mortality
An increase in postprandial glucose of only 1 mmol/L was shown to double the relative risk of death
DECODE Study Group. Lancet 1999;354:617–21

9. YOU WILL NOT MAKE IT TO SEVEN
Postprandial glucose > 200 mg/dl in adults with diabetes
39%
99%
< 7% %
> 8%
Hb A1c
IF PPG EXCEEDS ELEVEN
YOU WILL NOT MAKE IT TO SEVEN
NHANES III Diabetes Care 2001; 24:1734

10. Glucose
I will take the opportunity to exploit one of the San Francisco landmarks in order to make my point.
If we place and x axis of time over the day and a y-axis showing glucose levels – the typical spot measurements could look like this.
However, as all us in this audience will agree – we might not be looking at the full picture.

11. BiAsp 30 in combination with metformin in type 2 diabetes
BiAsp 30 bid + metformin (n=108)
(n=329)
BiAsp 30 bid (n=107)
Metformin failures
(HbA1c 7.5–13.0%)
glibenclamide + metformin (n=114)
BIAsp 1241
Background
NovoMix® 30 (biphasic insulin aspart 30), a premixed insulin analogue, consists of 30% soluble and 70% protamine-bound insulin aspart
Premixed insulin combination treatment can reduce daily insulin injections while achieving good glycaemic control
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

12. Superior glycaemic control with BiAsp30 + metformin in poorly controlled patients (HbA1c > 9%)
8,5 8
(%) 1c
HbA
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.
7,5 7
BiAsp
BiAsp+met
met+SU
Treatment group
Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

13. BiAsp 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:
BiAsp 30 + met 23
BiAsp 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

14. One daily injection of basal insulin may not give consistent control
Absorption of long- or intermediate-acting insulins from the subcutaneous tissue varies from day-to-day
This variability is one of the barriers to a successful outcome of the classical basal-bolus regimen

15. Variation in glucose infusion rate-time curves for 3 patients with type 1 diabetes
Following NPH injection
NPH
NPH
NPH
Subject no: 216
Subject no: 222
Subject no: 224
Lutz Heineman has discussed this study later at an earlier symposium
Clamp 1
Clamp 2
Clamp 3
Clamp 4
Heinemann et al: In press.

16. Mean Time-action profiles
0,0
0,5
1,0
1,5
2,0
2,5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Insulin glargine
Insulin detemir
NPH insulin
glucose infusion rates (mg/kg/min)
time [h]
Heinemann et al: In press.

17. NovoMix® 30 vs. NPH in type 2 patients
NPH + OHA
OHA only
No treatment
Screening
7–14 days
16 weeks
2 weeks
Twice-daily NovoMix® 30
(n = 201)
Twice-daily NPH insulin
(n = 202)
Original treatment
Randomisation
NPH monotherapy
Once or twice-daily insulin is a common insulin initiation regimen in patients with type 2 diabetes.
This 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.
Christiansen JS et al. Diabetes Obes Metab 2003;5(6):

18. NovoMix® 30 vs. NPH: lower prandial glucose increment-2
-1.5 -1
-0.5
0.5 1
*0.56
* p < 0.005
** p <
Difference in prandial glucose increment
between treatment groups (mmol/l)
-0.69
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 **
-1.26
-1.33
Total mean prandial glucose increment ** **
Breakfast Lunch Dinner
Christiansen JS et al. Diabetes Obes Metab 2003;5(6):

19. Greater HbA1c reduction with NovoMix® 30 vs. NPH
0.0
Greater reduction in HbA1c when switched to NovoMix® 30 twice-daily compared with adding another NPH injection in patients taking NPH monotherapy before the trial
-0.2
-0.4
Change in HbA1c (%)
-0.6
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 Obes Metab 2003;5(6):

20. INITIATE: INITiation of Insulin to reach A1c TargEt NovoMix® 30 (BID) vs glargine (OD)
Type 2 DM
BMI < 40 kg/m2 Body weight <125 kg
HbA1C > 8%
on metformin +/- TZD
Glargine OD (12 U, bedtime) + metformin +/- pioglitazone
NovoMix® 30, pre-breakfast (6U) and pre-dinner (6U) + metformin +/- pioglitazone
The safety and efficacy of twice-daily biphasic insulin aspart 70/30 (BIAsp 70/30,
prebreakfast and presupper) were compared to bedtime glargine in patients with
type 2 diabetes, inadequately controlled on oral antidiabetic (OAD) agents. This
randomized, 28-week, open-label, parallel-group study enrolled 233 insulin-naive
patients with A1C values >8.0%, on >1000 mg/day metformin, alone or in
combination with other OADs. At baseline, patient characteristics, prior OAD
treatment, demographics, and A1C values were similar between treatment groups.
Metformin doses were adjusted to 1500 mg/day during a 4-week run-in period.
Insulin was initiated with 5 to 6U BIAsp 70/30 twice-daily or 10 to 12 U glargine
at bedtime and then titrated to target BG (80 to 110 mg/dl) by algorithm-directed
forced titration. The dose was titrated weekly for the first 12 weeks, then every
2 weeks thereafter. Suppertime BIAsp 70/30 and bedtime glargine were titrated
based on fasting blood glucose (FBG) over the previous 3 days; morning BIAsp
70/30 was titrated on pre-dinner BG over the previous 3 days. Two hundred nine
patients completed the study. At study end, the mean A1C value in the BIAsp
70/30 group was significantly lower than in the glargine group (p=0.0026). More
BIAsp 70/30-treated patients reached target A1C values <6.5% and <7.0% than
did glargine-treated patients.
BIAsp 70/30 Glargine
(N=117) (N=116)
A1C (mean ± SD) Baseline ± ± 1.42
Study End ± ± 1.24
% Patients with A1C <6.5% Study End 42% %
% Patients with A1C < 7.0% Study End 66% %
Total Daily Insulin Dose (U/kg) Study End ± ± 0.27
One major hypoglycemic episode was reported by a subject in the glargine group.
Both groups gained weight during treatment (BIAsp, 5.4 ± 4.8 kg vs glargine,
3.5 ± 4.5 kg). Conclusion: More patients with type 2 diabetes that was poorly
controlled on OADs achieved currently recommended ADA and ACE A1C targets
with twice-daily BIAsp 70/30 before breakfast and supper than with once-daily
glargine at bedtime. (Abstract is updated from original.)
4 wk run-in:
Stop insulin secretagogues (SUs, nateglinide, repaglinide) and -glucosidase inhibitors (acarbose)
Optimize metformin to ≥1500 mg/day
Switch rosiglitazone (Avandia) for 30 mg pioglitazone (Actos)
(Weeks)
INITIATE Raskin et al
Diabetes, June 2004, vol 53, suppl. 2, p. A143

21. Blood glucose profiles
2 am
Bedtime
Lunch +90
Before lunch
Before dinner
Dinner +90
Breakfast +90
Before breakfast
INITIATE Raskin et al
Diabetes, June 2004, vol 53, suppl. 2, p. A143

22. Greater improvements in HbA1c with NovoMix® 30 than glargine
HbA1C (mean ± SD)
NovoMix® 30
(n = 100)
Glargine
(n = 109)
p-value
Baseline
Week 28
Change from baseline
9.70 1.48
6.91 1.1
-2.79 0.11
9.84 1.42
7.41 1.3
-2.36 0.11
0.4782
0.0026
0.0057
At 28 weeks, the mean A1C value in the NovoMix 30 group was lower than in the glargine group for the 171 patients completing the study to date
More NovoMix 30-treated patients reached target A1C values 6.5% and <7.0% than did glargine-treated patients (Table below).
Reduction in FPG (mean±SD)
End of trial – Baseline
-125 72.9
-125 74.4
0.1176
INITIATE Raskin et al
Diabetes, June 2004, vol 53, suppl. 2, p. A143

23. Pharmacokinetics: 28% greater AUC with NovoMix® 30 than glargine
PI AUC0-24h; p<0.01
400
NovoMix® 30
350
Glargine
300
250
Plasma Insulin (pM)
200
150
100 50 -1 4 9 14 19 24
Time (h)
NovoMix® 30 or glargine
NovoMix® 30
Luzio et al, Diabetes, June 2004, vol. 53, p. A136

24. Insulin action: NovoMix® 30 has a 34% greater glucose-lowering effect
3.5
GIR AUC0-24h; p<0.01
Glargine
3.0
2.5
2.0
GIR (mg/kg/min)
1.5
1.0
0.5
0.0 -1 4 9 14 19 24
Time (h)
NovoMix® 30 or glargine
NovoMix® 30
Luzio et al, Diabetes, June 2004, vol. 53, p. A136

25. The 1-2-3 Study: NovoMix® 30 OD, BID and TID
n = 100 Type 2 diabetes
48 weeks treat-to-target study
NovoMix® 30 pre-dinner x 16 wk If HbA1C > 6.5%, go to phase 2
Phase 1
NovoMix® 30 pre-breakfast & dinner x 16 wk If HbA1C > 6.5%, go to phase 3
NovoMix® 30 tid x 16 wk
Phase 2
Phase 3
Efficacy of Biphasic Insulin Aspart 70/30 in Patients with T2DM Not Achieving Glycemic Targets on OADs With/Without Basal Insulin Therapy
Jain R, Allen E, Wahl T, Wahlen J, Bressler P, Deng L and Garber A. Diabetes 2005; 54(1):A69
In this 48-week, multi-center, open-label trial, patients with T2DM, not achieving glycemic targets on OADs (with or without once-daily basal insulin therapy with NPH or glargine) were titrated with biphasic insulin aspart 70/30 (BIAsp 70/30) to target plasma glucose (PG) levels by the algorithm below. In Phase 1, patients initiated treatment with 12U BIAsp 70/30 qd before supper and titrated the dose based on fasting PG values. Dosing frequency was increased to bid in Phase 2 (pre-supper + pre-breakfast), and to tid in Phase 3 (pre-supper + pre-breakfast + pre-lunch) at 16 and 32 weeks, respectively, based on A1c levels. Patients attaining an A1c value ≤6.5% at the end of any phase were considered to have completed the study. Pre-breakfast insulin was adjusted based on pre-supper PG values; pre-lunch insulin, on 2-hour post-lunch PG values.
Plasma glucose (mg/dL) < to to to 180 >180
Pre-breakfast or
supper dose change (U) No change
Plasma glucose after lunch < to to 180 >180
Lunchtime dose change (U) –3 No change
Patients entering the study had mean A1c of 8.6%±0.8 and age of 56.7±11.5 yrs.
The number of patients reaching A1c targets after each phase are summarized
below.
Mean daily insulin doses for subjects who achieved an A1c≤6.5% at the end of Phases 1, 2, and 3 were 0.6, 0.9, and 1.1 U/kg, respectively.
Phase 1 Phase 2 Phase 3 Total
Subjects Enrolled
Subjects Discontinued 11* 15* 0 25
Subjects attaining A1c≤6.5% [N (%)] 21 (21) 28 (41) 8 (32) 57 (57)
Subjects attaining A1c <7.0% [N (%)] 39 (39) 47 (69) 16 (64) 76 (76)
*One subject in Phase 1 and 10 subjects in Phase 2 had A1c<7.0% when they discontinued
BIAsp30, when progressively titrated, enables a high percentage of subjects to
achieve glycemic targets when added to OAD therapy in T2DM unsuccessfully
Jain et al. Diabetes 2005; 54(Suppl 1):A69

26. The 1-2-3 study: cumulative % of patients achieving targets
HbA1C ≤ 6.5
(AACE, IDF goal)
HbA1C < 7% (ADA goal) OD
21%
41%
BID
52%
70%
TID
60%
77%
All results unless otherwise noted are intent-to-treat analyses
Baseline HbA1C was 8.6%
Jain et al. Diabetes 2005;54 (Suppl 1):A69

27. GE medical record database (USA) 112862 T2D between 1998-2004.
Basal vs. premixed insulin therapy in type 2 diabetes. A longitudinal cohort study
GE medical record database (USA)
T2D between
All patients with HbA1c records on insulin monotherapy with either
Lispro Mix (25/75), n=1569 or
Glargine , n=7036
Sun & Wang, EASD 2005

28. Mean HbA1c reductions in Lispro Mix Cohort
Duration
Mean HbA1c reductions in Lispro Mix Cohort
Mean HbA1c reductions in Glargine Corhort
Differences of mean HbA1c reductions (LM-GL)
Without Group Matching
Baseline to Q1
-0.9
-0.7
-0.1
Baseline to Q2
-0.5
-0.4
Baseline to Q3
-1.0
-0.6
With Group Matching
-2.0
-1.4
-2.4
-1.7
Note: All mean changes of HbA1c are statistically significant with p-value < 0.001
Sun & Wang, EASD 2005

29. YOU WILL NOT MAKE IT TO SEVEN
Postprandial glucose > 200 mg/dl in adults with diabetes
39%
99%
< 7% %
> 8%
Hb A1c
IF PPG EXCEEDS ELEVEN
YOU WILL NOT MAKE IT TO SEVEN
NHANES III Diabetes Care 2001; 24:1734

30. When it is time to start insulin in type 2 diabetes, why not try to mimic physiology?
Basal insulin only will not adequately deal with postprandial glucose
Rapid-acting insulin (analogues) should be added to control postprandial glucose
Premixed insulin twice- or three-times daily may be an attractive regimen for type 2 diabetes patients requiring insulin for better control