4. 7
Riddle M. Diabetes Care 1990;13:676−86.
Both fasting and postprandial hyperglycaemia
contribute to overall hyperglycaemia
10
06:00 12:00 18:00 24:00 06:00
Time of day
Healthy profile
Fasting
hyperglycaemia
Postprandial
hyperglycaemia
Diabetes profile
Bloodglucose(mmol/l)
15
5
0
5. 8
Monnier L, et al. Diabetes Care 2003;26:881–5.
0
10
20
30
40
50
60
70
<7.37.3–8.48.5–9.29.3–10.2>10.2
Relativecontribution(%)
HbA1c (%)
Insulin regimen to be implemented depends on
the level of overall hyperglycaemia
Postprandial hyperglycaemiaFasting hyperglycaemia
Initiate basal insulin therapy
when glycaemic control is very
poor
Intensify insulin therapy with
the stepwise addition of
prandial insulin as HbA1c
approaches target value
7. 10
Insulin therapy should meet patients’ needs to
improve treatment compliance
Efficacy
• Short term: FBG and PPBG
• Long term: HbA1c
Low risk of hypoglycaemia
Minimal weight gain
Ease of use
• Simple titration
• Flexible dosing
Quality of life
• Treatment satisfaction
8. 11
Basal, prandial and premixed insulin have different
action profiles
Basal insulin
Reduces fasting
hyperglycaemia
Long duration
of action
Inject morning and/or
evening
Prandial insulin
Reduces postprandial
hyperglycaemia
Short duration
of action
Inject at mealtimes
Premixed insulin
Reduces fasting and
postprandial hyperglycaemia
Long biphasic
duration of action
Inject at mealtimes
0 4 8 12 16 20 24
Hours post dose
Insulinlevel
0 4 8 12 16 20 24
Hours post dose
Insulinlevel
0 4 8 12 16 20 24
Hours post dose
Insulinlevel
1. Rave K, et al. Diabetes Care 2006;29:1812–7.
2. Becker RHA, et al. Exp Clin Endocrinol Diabetes 2005;113:435–43.
9. 12
Available insulin analogues
Type of insulin
Generic
name
Marketed name
in Europe
Basal Glargine Lantus
Detemir Levemir
Prandial Glulisine Apidra
Lispro Humalog
Aspart Novolog
Premixed Lispro 25/75* Humalog Mix 25
Lispro 50/50*
Aspart 30/70* NovoMix 30
*Numbers refer to percentage of prandial and basal insulins in the formulation, respectively.
Adis R&D Insight, 16 Jun 2008.
10. 13
Available human insulins
*Numbers refer to percentage of basal and prnadial insulins in the formulation, respectively; US brand name.
**Number refers to the percentage of prandial insulin in the formulation.
Pharmaprojects, 5 Nov 2008.
Type of insulin Generic name
Marketed
name/s
Basal NPH Humulin N
Novolin R
Insulatard
Protophane
Prandial RHI Humulin R
Actrapid
Novolin R
Premixed RHI + NPH Humulin 70/30
and 50/50*
Novolin 70/30* Mixtard 30, 40
and 50**
12. 15
Properties of the ideal basal insulin
Peakless profile1
Long duration of action1
Flexible dosing
Simple titration
Suitable for treat-to-target
schedules
1. Rosenstock J. Clin Cornerstone 2001;4:50–64.
0 4 8 12 16 20 24
Hours post dose
Insulinlevel
13. 16
Basal insulin analogues offer advantages over
basal human insulins
Compared with human basal insulins, basal insulin analogues:
Have more physiological action profiles
Exhibit less variability
Reduce the risk of hypoglycaemia
Are associated with less weight gain
Tibaldi J and Rakel R. Int J Clin Pract 2007;61:633–44.
Choe C, et al. J Natl Med Assoc 2007;99:357–67.
Insulin analogue
(long acting)
Human insulin
(intermediate acting)
0 4 8 12 16 20 24
Hours post dose
Insulinlevel
0 4 8 12 16 20 24
Hours post dose
Insulinlevel
14. 17
0 4 8 12 16 20 24
Insulin glargine has a more physiological action
profile than other basal insulins
1. Lepore M, et al. Diabetes 2000;49:2142–8.
2. Porcellati F, et al. Diabetes Care 2007;30:2447–52.
T1DM patients (n=20)1 T1DM patients (n=24)2
Glucoseinfusionrate(mg/kg/min)
Glucoseinfusionrate(µmol/kg/min)
Time (hours)
0 4 8 12 16 20 24
SC
injection
Glucoseinfusionrate(mmol/kg/min)
Glucoseinfusionrate(mmol/kg/min)
Time (hours)
Insulin detemir
Insulin glargine
SC injection
0.35 IU/kg
0
8
16
4
12
20
24
0
2
4
1
3
0
2
4
1
3
0
6
3
NPH 0.3 IU/kg
CSII (insulin lispro)
0.3 IU/kg/24h
Insulin glargine
0.3 IU/kg
9
15. 22
80 244 12 16 20
Insulin glargine and insulin glulisine have
complementary physiological profiles
INS-AUC, insulin infusion rate – area
under the curve
1. Lepore M, et al. Diabetes 2000;49:2142–8.
2. Becker RH, et al. Diabetes Care 2007;30:2506–7.
INS-AUC0–2h: p < 0.05 vs RHI
Insulin glulisine 0.15 U/kg
RHI 0.15 U/kg
Euglycaemic glucose-clamp study:
insulin glulisine vs RHI, 18
patients2
0
20 subjects with
Type 1 diabetes1
Glucoseinfusionrate
(mg/kg/min)
0
2
4
Time (h)
1
3
Insulin glargine 0.3 U/kg
Time (h)
Insulin(µU/mL)
160
80
1086420
17. 24
Premixed insulin combines a fixed ratio of a basal
and a prandial insulin
Combines a basal and a
prandial insulin in a fixed
ratio
Basal insulin is a modified
form of the prandial insulin
• e.g. premixed insulin aspart
30/70 = 30% soluble insulin
aspart (prandial) +
70% protamine-crystallised
insulin aspart (basal)
Biphasic action profile
Simple regimen with few
injections
Hours post dose
Insulinlevel
0 4 8 12 16 20 24
18. 25
Plasma glucose profiles
meal
Premixed insulin analogues profile exposes to an increase
risk of post-prandial hyper and hypoglycemia
Luzio S et al. Diabetologia 2006;49:1163–8.
Isoglycaemic clamp study using twice-daily premixed insulin aspart 30/70
0
100
200
300
400
0 4 8 12 16 20 24
Plasmainsulin(pM)
Time (hours)
Premix injection Premix injection
Hyperglycemia risk
Hypoglycemia risk
meal
19. 26
1-2-3 Study – multiple daily injections of premixed insulin
are required to achieve blood-glucose control
Garber A, et al. Diabetes Obes Metab 2006;8:5866.
0 40 80
Three times daily
Twice daily
Once daily
Premixed insulin
aspart 30/70
Patients achieving HbA1c ≤6.5% (%)
21
31
8
Week16
Week32
Week48
20 60
100 patients uncontrolled T2DM treated with OHAs +/- basal insulin
Basal insulin was discontinued and patients received premixed insulin
aspart 30/70 once daily with dinner
20. 27
New premixed insulin aspart formulations
are being investigated
Cucinotta D, et al. 43rd Annual Meeting of the EASD, 2007. Abstract 0988.
Versus premixed insulin aspart 30/70 BID:
Premixed insulin aspart
50/50 TID
Premixed insulin aspart
70/30 TID
Change in HbA1c (%)
–0.3
p=0.004
–0.07
ns
Relative risk of
hypoglycaemia
1.20
ns
1.58
p=0.0002
Conclusion
More effective than
30/70, and same risk of
hypoglycaemia
As effective as 30/70,
but higher risk of
hypoglycaemia
Almost 50% of patients receiving 50/50 and 70/30 required
a switch to evening 30/70 to manage their FBG levels
21. 28
Disadvantages of premixed insulin analogues in
clinical practice
Fixed ratio of the basal and prandial insulin components
• Treatment not individualised
• Difficult to monitor and titrate
• Not suitable for treat-to-target schedules
More than one daily injection usually required
More than one type of premixed insulin may be needed each day
Structured meal content and timing
Do not mimic physiological insulin action
• Risk of hypoglycaemia
• Weight gain
Must be converted to a basal-bolus regimen if a three-times-daily
regimen fails
23. 30
Key learning points – background on
insulin analogues
Insulin analogues offer advantages over human insulins
Premixed insulin analogues combine basal and prandial
insulins in a fixed ratio
• Dosing up to 3 times daily
• Structured regimens
• Non-physiological action profile
Basal and prandial insulin analogues can be combined to
suit patients’ needs
• Dosing : 2 to 4 times daily
• Flexible regimens
• Physiological action profile
• Good safety profile
25. 37
Stepwise intensification of insulin treatment is
required as diabetes progresses
Progressive deterioration of -cell function
Basal only
Add basal insulin and titrate
Basal-plus
Add prandial insulin at main meal
Basal-bolus
Additional prandial insulin
doses as needed
FBG at target
HbA1c above target
Raccah D, et al. Diabetes Metab Res Rev 2007;23:257–64.
FBG above target
HbA1c above target
FBG at target
HbA1c above target
27. 40
ADA/EASD and IDF recommend early initiation of
insulin therapy to meet HbA1c targets
ADA/EASD 20081
Basal insulin therapy can be initiated when lifestyle
modification plus metformin does not maintain a
HbA1c value of <7.0%
Insulin therapy may be particularly beneficial in patients
with HbA1c values of >8.5%
IDF 20052
Insulin therapy should be initiated before HbA1c values
are >7.5% on maximum OHAs
1. Nathan D, et al. Diabetes Care 2008;31:1−11.
2. IDF global guideline for type 2 diabetes, www.idf.org/webdata/docs/IDF%20GGT2D.pdf
28. 41
ADA/EASD and IDF provide treat-to-target
algorithms for the initiation of insulin therapy
ADA/EASD 20081
Basal insulin once daily
Titrate 2U every 3 days until FBG 3.9–7.2mmol/l
(70–130mg/dl)
Titrate 4U every 3 days if FBG >10mmol/l (>180mg/dl)
IDF 20052
Self titrate 2U every 3 days, or use a scaled algorithm
with frequent clinic visits
Aim for both pre-breakfast and pre-dinner glucose levels
of <6.0mmol/l (<110 mg/dl)
Guidelines do not include initiating insulin therapy with
premixed insulin
1. Nathan D, et al. Diabetes Care 2008;31:1−11.
2. IDF global guideline for type 2 diabetes, www.idf.org/webdata/docs/IDF%20GGT2D.pdf
29. 44
1. Riddle M, et al. Diabetes Care 2003;26:3080–6. 2. Janka H, et al. Diabetes Care 2005;28:254–9.
3. Raskin P, et al. Diabetes Care 2005;28:260–5. 4. Yki-Järvinen H, et al. Diabetologia 2006;49:442–51.
5. Rosenstock J, et al. Diabetes Care 2006;29:554–9. 6. Gerstein HC, et al. Diabet Med 2006;23:736-42.
7. Schreiber S, et al. Diabetes Technol Ther 2008;10:121–7. 8. Bretzel R, et al. Lancet 2008;371:1073–84.
9. Bickle J, et al. 68th Scientific Sessions of the ADA, 2008: Abstract 467.
Insulin glargine has proven efficacy in
combination with OHAs
Trial
Reduction
in HbA1c (%)
Final HbA1c
achieved (%)
Patients with
HbA1c <7% (%)
Treat-To-Target1 1.6 7.0 60
LAPTOP2 1.6 7.2 50
INITIATE3 2.4 7.4 40
LANMET4 2.4 7.1 –
Triple Therapy5 1.7 – 48
INSIGHT6 1.6 7.0 58
Schreiber, et al.7 1.6 7.0 –
APOLLO8 1.7 7.0 57
TULIP9 0.8 6.8 66
30. 45
R
A
N
D
O
M
I
S
A
T
I
O
N
Patients with T2DM
HbA1c: 7.5% to 10.5%
and FBG: ≥6.7 mmol/L
(≥120 mg/dL) and
treated with OHAs
(n = 364)
Insulin glargine + OHAs (n = 177)
Initial dose: 10 IU once daily in
the morning
Human premixed insulin (70/30) (n
= 187)
Initial dose: 10 IU before
breakfast and 10 IU before dinner
Treatment phaseScreening
24 weeks
Run-in phase
3–14 weeks
LAPTOP study: Comparison of insulin glargine
added to an OHA regimen versus switching to
premixed insulin
Subjects taking sulphonylurea and metformin for at least a month were enrolled. Sulphonylurea was
replaced with 3 or 4 mg glimepiride during run-in phase. OHA dose remained the same throughout the
study in the insulin glargine arm, while OHAs were discontinued in the premixed insulin arm.
Janka H, et al. Diabetes Care 2005;28:254–9.
31. 46
4
6
8
10
12
14
16
Endpoint
Fasting After
breakfast
Lunch After
lunch
Dinner After
dinner
Bedtime 03.00
Significantly greater reduction in FBG and
PPBG with insulin glargine vs premix
*
*
*
*
*
Bloodglucose(mmol/L)
Baseline
Insulin glargine + OHAs
Premixed insulin twice daily
Time of day
*p < 0.05 for treatment comparison of
changes from baseline to endpoint Janka H, et al. Diabetes Care 2005;28:254–9.
32. 47
Premixed
insulin†
Insulin
glargine‡
0
-0.5
-1.0
-1.5
-2.0
-1.31
Insulin glargine provided better glycaemic
control and less weight gain than premix
Premixed
insulin†
Insulin
glargine‡
Weightgain(kg)
1.4
2.1
2.5
2.0
1.5
1.0
0.5
0
-1.64
HbA1cchangefrombaseline(%)
Final daily dose:
Premixed insulin 64.5 IU
Insulin glargine 28.2 IU
p = 0.0003
p = NS
†Twice daily; ‡plus OHAs
Janka H, et al. Diabetes Care 2005;28:254–9.
33. 48
0.51
0
2
4
6
8
10
12
Lower incidence of hypoglycaemia with
insulin glargine versus premixEventsperpatientperyear
Premixed insulin
Insulin glargine*
All confirmed
hypoglycaemia
Confirmed
symptomatic
Confirmed
nocturnal
p < 0.0001
p = 0.0009
p = 0.0449
Hypoglycaemia confirmed by blood glucose <60 mg/dL (3.3 mmol/L)
Janka H, et al. Diabetes Care 2005;28:254–9.
*Plus OHAs
1,04
2,62
9.87
5.73
4.07
34. 49
Premixed human insulin 30/70 BID
Insulin glargine provided better glycaemic control with
fewer hypoglycemia than premix in elderly patients
p=0.003
Janka H, et al. J Am Geriatr Soc 2007;55:182−8.
–1.4
–1.9
Changefrombaseline(%)
HbA1c
Incidence
(episodes/patient-year)
10
8
6
4
2
0
Hypoglycaemia
p<0.008
3.7
9.1
Sub-population of patients aged ≥65 years (n=130)
0
–0.5
–1.0
–1.5
–2.0
Insulin glargine was well titrated
and more effective
Insulin glargine was associated
with fewer hypos
Insulin glargine
35. 60
Maintenance phase
R
A
N
D
O
M
I
S
A
T
I
O
N
Insulin-naïve patients
with T2DM on at least
2 OHAs
HbA1c >7%
(n = 2,091)
Insulin glargine + OHAs
Once daily
Lispro mixture (25% lispro / 75%
lispro protamine suspension) +
OHAs: Twice daily
Initiation phase
24 weeks
Wolffenbuttell BH, et al. Diabetologia 2008;51(Suppl. 1):S386.
104 weeks
DURABLE trial: Comparison of starting insulin
glargine versus lispro mix added to an OHA regimen
36. 61
5
6
7
8
9
10
HbA1c was reduced in both groups with a
significantly greater effect with premix
HbA1c(%) Glargine
Lispro mix
Baseline 24 weeks
p = 0.005
Wolffenbuttell BH, et al. Diabetologia 2008;51(Suppl. 1):S386.
9,1
7,37.2
9.0
37. 62
0
0,1
0,2
0,3
0,4
0,5
0,6
Premixed
insulin
Insulin
glargine
0
10
20
30
Hypoglycaemia, weight gain and daily dose
all lower with glargine vs premix
p = 0.007
Hypoglycaemia Weight gain
p < 0.0001 p < 0.001
Daily insulin dose
Wolffenbuttell BH, et al. Diabetologia 2008;51(Suppl. 1):S386.
28
23
Premixed
insulin
Insulin
glargine
Episodesperpatientyear
3,6
2,5
0
1
2
3
4
Premixed
insulin
Insulin
glargine
kg
0,47
0,40
Atstudyend(U/kg/day)
39. 64
Treatment satisfaction is higher with insulin
glargine than with premixed human insulin
p = 0.0012
Bradley C, et al. Diabetes 2005;54(Suppl):Abstract 1246-P.
0
5
10
15
Insulin glargine
+ OHAs
Premixed human
insulin 30/70 BID
DTSQcscoreatendpoint
11.5
14.0
At 24 weeks insulin glargine was associated with a greater increase
in patient treatment satisfaction
41. 66
Some recent trials have shown that initiation with insulin glargine plus
OHAs had a smaller effect on HbA1c than premix plus OHAs
• Optimal insulin glargine titration was not achieved in most of these studies
• Premixed insulin was associated with significant increases in hypoglycaemia,
weight gain and insulin dose
LAPTOP demonstrated the superiority of insulin glargine plus OHAs vs
premix for insulin initiation:
• Improved glycaemic control and reduced hypoglycaemia
• Lower insulin dose requirements and weight gain
• Improved treatment satisfaction
Insulin glargine in combination with OHAs is more effective than
premixed insulins for initiating insulin in line with ADA/EASD
recommendations
Key learning points – initiating insulin therapy
in T2DM
46. 71
Traditional approaches for intensifying insulin
therapy: basal-bolus and premixed insulin
Hirsch I, et al. Clin Diabetes 2005;23:78−86.
Lifestyle modification and OHAs
Basal
e.g. insulin glargine Premixed insulin x1
Basal–bolus
e.g. insulin glargine + insulin glulisine x3
Premixed insulin x2
Premixed insulin x3
47. 72
New approaches for intensifying insulin
therapy: basal-plus
Basal
e.g. insulin glargine Premixed insulin x1
Premixed insulin x3
Basal–bolus
e.g. insulin glargine + insulin glulisine x3
Premixed insulin x2
Basal-plus
e.g. insulin glargine + insulin glulisine x1
Basal-plus
e.g. insulin glargine + insulin glulisine x2
Lifestyle modification and OHAs
As per ADA/EASD guidelines
48. 73
ADA/EASD guidelines recommend the addition of
prandial insulin to intensify a basal insulin regimen
ADA/EASD 20081
Basal insulin regimen intensified by the addition of prandial
insulin injections at selected meals
Premixed insulins not recommended during titration of
prandial insulin
1. Nathan D, et al. Diabetes Care 2008;31:1−11.
49. 74
ADA/EASD guidelines: Insulin intensification
starts with adding 1 prandial insulin injection
*Premixes are not recommended during adjustment dose; they can be used before breakfast
and dinner if the proportion of rapid and intermediate is similar to the fixed proportions available
Start or
intensify
insulin
therapy
HbA1c
≥ 7%
Add 1 injection of rapid-acting insulin
• At BREAKFAST if pre-lunch BG is out of range*
• or LUNCH if pre-dinner BG is out of range
• or At DINNER, if pre-bedtime BG is out of range*
If FBG is in range check pre-meal BG levels.
Add 1 prandial insulin injection, at a selected meal
If still uncontrolled after titration, add another injection. Add a
third prandial injection for full basal–bolus Rx.
If A1C is still out of range check postprandial glucose and adjust
premeal rapid acting insulin.
Nathan D, et al. Diabetes Care 2008;31:1−11.
50. 75
Basal-plus approach facilitates individualised care
compared with premixed insulin
Time of day
Prandial insulin
at dinner
16:0008:00 12:00 20:00 0:00 04:00 08:00
Prandial insulin
at breakfast
BG(mmol/l)
12
10
8
6
4
Patient B
Patient A
51. 76
Basal-plus approach is more flexible than a
premixed insulin analogue approach
Basal-plus approach
e.g. insulin glargine
+ insulin glulisine
Premixed insulin
e.g. premixed insulin
aspart 30/70
Initial number of
injections daily
2 21
Daily initial dose Insulin glargine: 10 U
Insulin glulisine: 4 U
6 U + 6 U1
Timing of injections Insulin glargine: morning/evening
Insulin glulisine: main meal
Breakfast
and dinner1
Monitoring for
titration targets
Insulin glargine: FPG (once daily)
Insulin glulisine: preprandial,
bedtime or 2-hour
postprandial BG (once daily)
FBG and preprandial BG
(twice daily)1
Lifestyle Flexible mealtimes
and meal content
Scheduled mealtimes
and set meal plans
Intensification Stepwise progression
to basal-bolus
Increase to 3 times daily,
then switch to basal-bolus
1. Summary of product characteristics for NovoMix 30, 50 and 70. Available at
http://www.emea.europa.eu/humandocs/Humans/EPAR/novomix/novomix.htm (last accessed 2 Jul 2008).
52. 77
Basal Plus strategy:
When to add the first prandial bolus?
The need for prandial insulin despite optimal
titration of basal insulin is indicated by
• FBG at target <5.5 mmol/L, but HbA1c ≥7%
• FBG controlled, but PPBG consistently high
• Unacceptably frequent or severe hypoglycemia during basal
insulin titration
Add one injection of prandial insulin (4 IU)
• Starting with the main meal
Nathan DM, et al. Diabetes Care 2006;29:1963–72.
Nathan DM, et al. Diabetes Care 2008;31:173–5.
Raccah D, et al. Diabetes Metab Res Rev 2007;23:257−64.
53. 78
Basal-plus approach – stepwise addition of prandial
insulin to a basal insulin regimen
1. Optimise basal insulin dose
2. Identify the main meal of the day
3. Introduce prandial insulin once daily at the main meal
4. Discontinue concomitant insulin secretagogues
5. Titrate the prandial insulin dose to achieve target blood-
glucose levels
6. Add further prandial insulin injections, as required
55. 80 www.clinicaltrials.gov
Six clinical trials supporting the Basal Plus
strategy in T2DM
Study Purpose Lead country
OPAL Equivalence between breakfast and main meal for the
primary bolus
Germany
ELEONOR Success of Telecare System to support
Basal / Basal Plus strategy
Italy
OSIRIS Basal / Basal Plus strategy
as safe and effective as basal bolus
18 countries
1-2-3 Addition of 1 x glulisine as effective
as 2 x or 3 x glulisine
USA
Proof-of-Concept Efficacy of Basal / Basal Plus strategy after
basal insulin optimisation
USA/UK
All-to-Target Basal / Basal Plus strategy more effective than
premixed insulin
USA
56. 81
Screening
1–3 weeks
Pre-screening
1–2 weeks
Treatment
24 weeks
Follow up
1 week
OPAL: First study supporting the Basal Plus approach
Titration target values
2h-pp blood glucose: 135 mg/dL FBG:
100 mg/dL
Stratification
Main meal
Dinner
Lunch
Breakfast
Insulin glargine
+ OHA
Inclusion criteria
• T2DM
• HbA1c >6.5 to 9%
• Pre-treatment with
insulin glargine and
OHAs for >3 months
• FBG 120 mg/dL
Main meal group
Insulin glargine + OHA +
once-daily insulin glulisine
Breakfast group
Insulin glargine + OHA +
once-daily insulin glulisine
Randomisation
2h-pp, 2-hour postprandial
FBG, fasting blood glucose
Lankisch M, et al. Diabetes Obesity and Metabolism 2008; 10: 1178-1185
57. 82
OPAL: A single injection of glulisine (at breakfast OR main
meal) + once-daily glargine results in significant HbA1c
improvement
Per-protocol population
Main meal is defined as the meal including the highest
2-h postprandial BG excursion
0.0
6.0
7.0
8.0
Overall HbA1c
reduction
–0.33%
p<0.0001
p=NS
p<0.0001 p<0.0001
(n=162) (n=154) (n=316)
HbA1c(%)
7,35 7,29 7,32
7,03
6,94 6,99
Breakfast Main meal Overall
Baseline
Endpoint
Lankisch M, et al. Diabetes Obesity and Metabolism 2008; 10: 1178-1185
58. 83
OPAL: Main meal group after 6 months
52% achieved HbA1c <7%; 34% achieved HbA1c <6.5%
(n=162) (n=154) (n=162) (n=154)
p=0.028
p=0.21
36,5
52,2
0
10
20
30
40
50
60
Breakfast Main meal
ResponderratewithHbA1c<7%(%)
27,8
33,8
0
10
20
30
40
Breakfast Main meal
ResponderratewithHbA1c<6.5%(%)
Lankisch M, et al. Diabetes Obesity and Metabolism 2008; 10: 1178-1185
59. 84
3:00 am Fasting 2h-post
breakfast
Pre-lunch 2h-post
lunch
Pre-dinner 2h-post
dinner
Bedtime
OPAL: 8-point blood glucose profile – breakfast
group
Calculated for the per-protocol analysis set (n=316)
Data are means; *p<0.05; †p<0.0001
100
120
140
160
180
Bloodglucose(mg/dL)
5.6
6.7
7.8
8.9
10.0
11.1
Bloodglucose(mmol/L)
†
*
†
†
†
†
*
Baseline
Endpoint
200
Lankisch M, et al. Diabetes Obesity and Metabolism 2008; 10: 1178-1185
60. 85
2h-post
breakfast
2h-post
lunch
2h-post
dinner
3:00 a.m. Fasting Pre-lunch Pre-dinner Bedtime
OPAL: 8-point blood glucose profile – main
meal group
100
120
140
160
180
5.6
6.7
7.8
8.9
10.0
11.1
†
*
*
*
†
†
Baseline
Endpoint
Bloodglucose(mg/dL)
Bloodglucose(mmol/L)
200
Calculated for the per-protocol analysis set (n=316)
Data are means; *p<0.05; †p<0.0001
Lankisch M, et al. Diabetes Obesity and Metabolism 2008; 10: 1178-1185
61. 86
6
5
4
3
2
1
0
OPAL: The rate of hypoglycaemia was similar
in both groups*
*Calculated for the safety analysis set (n=393)
†blood glucose ≤60 mg/dL (3.3 mmol/L)
Breakfast group
Main meal group
Weight gain
Breakfast group: + 1.02 kg
Main meal group: + 0.85 kg
4.76
2.55
0.27
0.1
3.69
2.58
0.52
0.03
2.50
5.34
Overall Confirmed† Confirmed
symptomatic†
SevereConfirmed
nocturnal†
Eventsperpatient-year
p=0.70
p=0.31
p=0.27
p=0.18
p=0.97
Hypoglycaemia
Lankisch M, et al. Diabetes Obesity and Metabolism 2008; 10: 1178-1185
62. 87
OPAL: Main findings
A single bolus of insulin glulisine added to once-daily
basal insulin glargine results in an improvement of both
HbA1c and PPBG levels
The change in HbA1c is independent of the time of
insulin glulisine administration, i.e. breakfast or main
meal
• Slightly better responder rate in main meal group
Low risk of hypoglycaemia in both groups
No major weight gain with a Basal Plus approach
63. 88
Summary
T2DM is best treated in a stepwise fashion
Prandial insulin can be added before the main meal if the
HbA1c target is not maintained despite control of FBG on
basal insulin
This approach allows an easy transition to a complete basal–
bolus regimen
The Basal Plus strategy is a flexible, ‘patient friendly’,
stepwise approach to managing progressive diabetes in
clinical practice
Ongoing trials will further refine the Basal Plus approach
64. Switch strategies
• From Premix to insulin glargine
• From Premix to insulin glargine ± prandial
• From human insulin to Premix or insulin glargine
65. 90
Hammer & Klinge – switching from premixed insulin
to insulin glargine improves glycaemic control
Hammer H and Klinge A. Int J Clin Pract 2007;61:2009–18.
Patientsachievingtarget(%)
FBG
<6.7 mmol/l
2h PPBG
<8.9 mmol/l
HbA1c
<7.5%
100
80
60
40
20
0
49
83
74 Only 16 episodes of
hypoglycaemia were
reported
A significant reduction in
weight was observed
(p<0.001)
The increase in mean daily
insulin dose was low
Insulin glargine improved glycaemic control,
and was associated with fewer hypos and weight loss
66. 91
-5
-4
-3
-2
-1
0
HbA1c FBG
AT.LANTUS – switching from premixed insulin to insulin
glargine ± prandial insulin improves glycaemic control
Davies M, et al. Diabetes Res Clin Pract 2008;79:368–75.
-2
-1.5
-1
-0.5
0
p<0.001
–0.7
–1.4
-3.1
–3.6
–1.2
–1.6
-4.4
-3.7
Insulin glargine Insulin glargine + 1, 2 or >2 prandial insulin
p=0.004
p<0.001
p<0.001
p<0.001
p<0.001
p<0.001 p<0.001
Sub-population of patients previously treated with premixed insulin (n=686)
Changefrombaseline(%)
Changefrombaseline(mmol/l)
Basal-plus and basal-bolus insulin therapy provided better glycaemic control
67. 92
Malone et al. 2005 – switching from human insulin
to insulin glargine or premixed insulin lispro 25/75
Malone J, et al. Diabet Med 2005;22:374–81.
HbA1c
p<0.001
–0.4
–1.0
0.4
0.6
Incidence
(episodes/patient-year)
0.8
0.6
0.4
0.2
0
Hypoglycaemia
0.1
0.8
Changefrombaseline(kg)
1.0
0.8
0.6
0.4
0.2
0
Weight
p=ns
p=0.001
0
–0.5
–1.0
–1.5
Changefrombaseline(%)
Insulin glargine was associated
with a similar risk of hypos
and less weight gain
Insulin glargine Premixed insulin lispro 25/75 BID
Insulin glargine was not optimally
titrated in a treat-to-target manner,
and cross-over design was flawed
69. 94
06.00 12.00 24.0018.00 06.00
In advanced T2DM, insulin therapy should
mimic physiological patterns
Adapted from Kruszynska YT, et al. Diabetologia 1987;30:16–21.
Endogenous insulin secretion
Ideal basal insulin
Ideal prandial insulin
Insulin(mU/l)
0
15
30
45 Breakfast Lunch Dinner
Time (hours)
70. 95
LACE – basal-bolus insulin glargine + insulin glulisine
is more effective than premixed insulin
Lee F, et al. EASD 2008: Abstract 1003 (poster).
Changefrombaseline(%)
0
–0.5
–1.0
–1.5
-2.0
-2.5 –2.3
–1.7
HbA1c
Hypoglycaemia
Incidence(%patients)
50
40
30
20
10
0
p=ns
36
43
Basal-bolus insulin therapy provided better glycaemic control
and a similar risk of hypos
Insulin glargine + insulin glulisine Premixed insulin
71. 96
GINGER – switching from premixed insulin to basal-bolus
insulin glargine + insulin glulisine improves glycaemic control
Fritsche A, et al. EASD 2008: Abstract 186 (oral).
HbA1c
Hypoglycaemia
Changefrombaseline(%)
0
–0.5
–1.0
–1.5 –1.3
–0.8
p=0.0001 Incidence
(episodes/patient-year)
20
15
10
5
0
p=ns
14.0
18.5
Insulin glargine + insulin glulisine Premixed insulin
Basal-bolus insulin therapy provided better glycaemic control
and a similar risk of hypos
72. 97
LADI – switching from premixed insulin to insulin glargine +
insulin glulisine improves glycaemic control in T2DM
Schreiber S, et al. Diabetologia 2007;50(suppl 1):S410–1.
HbA1c PPBGFBG
9.9
11.7
6.8
8.0
5
6
7
8
9
10
11
12
8.6
7.3
5
6
7
8
9
HbA1c(%)
p<0.0001
BG(mmol/l)
Baseline 12 weeks after switching
Basal-plus and basal-bolus insulin therapy provided better glycaemic control
73. 98
Basal-bolus regimen with insulin glargine is more
effective than twice-daily premixed insulin lispro
Rosenstock J, et al. Diabetes Care 2008;31:20–5.
p<0.021 for 0.2% difference
–1.9
–2.1
Basal-bolus
Changefrombaseline(%)
HbA1c
Premixed insulin
lispro 50/50
0
–0.5
–1.0
–1.5
-2.0
-2.5
Hypoglycaemia rates and
weight gain were similar in
the two groups
55% of patients in the
premixed insulin group
switched from premixed
insulin lispro 50/50 to
25/75 at dinner to achieve
the FBG target
Basal-bolus insulin therapy provided a better efficacy profile
and a similar safety profile
75. 100
High physician satisfaction with switching from
premixed insulin to insulin glargine
Hammer H and Klinge A. Int J Clin Pract 2007;61:2009–18.
Efficacy Safety
Very good
Good
Satisfactory
Unsatisfactory
No response given
Most physicians rated the efficacy and safety
of insulin glargine as ‘very good’ or ‘good’
46%
41%
54%42%
76. 101
LADI – switching from premixed insulin to insulin glargine + insulin
glulisine improves treatment satisfaction in T2DM
18
29
0
5
10
15
20
25
30
DTSQscore
p<0.0001
Schreiber S, et al. Diabetologia 2007;50(suppl 1):S410–1.
Baseline 12 weeks
Basal-plus and basal-bolus insulin therapy provided
better patient treatment satisfaction
78. 103
Key learning points – intensifying insulin therapy
in T2DM
Basal-plus is a simple, flexible approach to intensifying a
basal insulin regimen
The basal-plus approach can be easily progressed to a
basal-bolus regimen, if required
Premixed insulin regimens are less flexible, and
must be switched to a more physiological basal-bolus
regimen if further intensification is required
Switching from premixed insulin regimens to basal ±
boluses improves patient satisfaction
Ongoing trials are directly comparing the basal-plus
approach with premixed insulin regimens
79. 104
Key learning points – intensifying insulin therapy
in T2DM
Basal-bolus therapy with glargine plus glulisine effectively achieves and
maintains glycaemic targets in patients requiring regimen
intensification
In GINGER and LACE, a basal-bolus regimen of glargine and glulisine
achieved significantly greater reductions in HbA1c compared with
premixed insulins
Basal-bolus regimen with glargine lower HbA1c more than 50:50
premixed given 3 times per day
Insulin doses can be adjusted using simple titration algorithms and CHO
counting, both with significant improvements in HbA1c and similar
hypoglycaemia rates
The basal-bolus regimen offers patients flexible treatment that
responds to different needs and lifestyles and reduces glucose
variability
81. 106
Progressive
destruction of
beta cells over
months to years
Near-absolute
endogenous insulin
deficiency
Exogenous
insulin supply
necessary
Pathophysiology and progression of T1DM (1)
Infectious or environmental
stimulus triggers auto-immune
attack on pancreatic insulin-
producing beta cells1
Beta-cellmass(%ofmax)1
Time (years)
Genetic
predisposition
Immunologic abnormalities
Progressive impairment
of insulin release
Overt diabetes
'Honeymoon'
period
(1–2 years)
No diabetes
Diabetes
Immunologic trigger
Birth
1. Adapted from Powers AC. In: Harrison’s Principles of Internal Medicine, Kasper DL et al (Eds). New York:
McGraw-Hill; 2005:p2152−80.
0
50
100
82. 107
HbA1c post-diagnosis2
Progressive
destruction of
beta cells over
months to years
Near-absolute
endogenous insulin
deficiency
Exogenous
insulin supply
necessary
Pathophysiology and progression of T1DM (2)
Infectious or environmental
stimulus triggers auto-immune
attack on pancreatic insulin-
producing beta cells
Beta-cellmass(%ofmax)
1. Adapted from Stene LC, et al. Pediatr Diabetes 2006;7:247–53.
2. Garg S. Data on file.
Years prior to diagnosis
7
6
5
4
–8 –7 –6 –5 –4 –3 –2 –1 0/Diagnosis
HbA1c(%)
0
50
100
HbA1c pre-diagnosis1
83. 108
Guidelines provide HbA1c, FBG and PPBG targets
for T1DM
1. ADA. Diabetes Care 2008;31(suppl 1):S12–S54.
2. AACE/ACE Position Statement, 2005: www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
3. IDF. Guideline for management of postmeal glucose: www.idf.org/webdata/docs/Guideline_PMG_final.pdf.
Parameter ADA1 AACE/
ACE2 IDF3
HbA1c, % <7.0 6.5 <6.5
FBG, mmol/l (mg/dl) 3.9–7.2
(70–130)
<6.1
(<110)
<5.5
(<100)
PPBG, mmol/l (mg/dl) <10.0
(<180)
<7.8
(<140)
<7.8
(<140)
84. 109
Commonly used insulin strategies in T1DM
Basal-bolus insulin regimen
1–2 basal insulin injections
+ 2–3 mealtime insulin injections
Pre-mixed insulin regimens
≥2 premixed insulin injections
Continuous subcutaneous insulin infusion (CSII)
Continuous basal insulin infusion
+ 3 or more mealtime doses
DeWitt DE, Hirsch IB. JAMA 2003;289:2254–64;
Rosenstock J. Clin Cornerstone 2001;4:50–64.
Dave JA, Delport SV. SA Fam Pract 2006;48:30–6.
85. 110
Guidelines recommend basal-bolus insulin
regimen or CSII
ADA 2008
Use a basal-bolus regimen of 3–4 injections daily or
CSII
Use insulin analogues, especially if hypoglycaemia
is a problem
Match prandial insulin dose to carbohydrate
intake, premeal blood-glucose level and exercise
ADA. Diabetes Care 2008;31(Suppl 1):S12−54.
87. 112
Insulins glargine and glulisine are appropriate
components of a basal-bolus regimen
Insulin glargine provides:
Good control over 24 hours with one injection daily1,2
Flexible dosing at breakfast, dinner or bedtime1
Similar efficacy and safety profiles to twice-daily
insulin detemir3
Insulin glulisine provides:
Rapid onset and short duration of action4
Flexible dosing just before or after a meal5
Similar efficacy and safety profiles to insulin lispro6
1. Hamann M, et al. Diabetes Care 2003;26:1738–44.
2. Porcellati F, et al. Diabetes Care 2007;30:2447–52.
3. Pieber T, et al. Diabet Med 2007;24:635–42.
4. Becker RH, et al. Diabetes Care 2007;30:2506–7.
5. Rave K, et al. Diabetes Care 2006;29:1812–7.
6. Dreyer M, et al. Horm Metab Res 2005;37:7027.
88. 113
8.0
7.1
6.9
5.0
6.0
7.0
8.0
9.0
Baseline 12 weeks 6 months
8.5
9.8
6.5
7.5
6.4
7.5
5.0
6.0
7.0
8.0
9.0
10.0
Basal-bolus insulin glargine + insulin glulisine
improves glycaemic control
Ruhnau K, et al. Diabet Med 2006;23(Suppl 4):343 (Abstract P952).
HbA1c(%)
BG(mmol/l)
HbA1c PPBGFBG
Basal-plus and basal-bolus insulin therapy improved
glycaemic control with a low risk of hypos
93. 118
Basal-bolus insulin regimen – physiological
approach to diabetes management
Intensive, physiological therapy
Combines separate basal and prandial insulins
• 1–2 basal and 3 prandial insulin injections per day
Patient education needed
Required by most T1DM patients
Required by some T2DM patients
• Improves PPBG control
• Allows tighter overall BG control
• Provides regimen flexibility
Insulins glargine and glulisine are an appropriate combination for basal-
bolus therapy
Switching from premixed insulin to a basal-bolus regimen with insulins
glargine and glulisine improves glycaemic control
Tibaldi J and Rakel R. Int J Clin Pract 2007;61:633–44.
Choe C, et al. J Natl Med Assoc 2007;99:357–67.
95. 120
Key learning points – basal and prandial insulin
analogues
Reduce HbA1c values
Mimic physiological insulin action
Associated with low hypoglycaemia rates
Suitable for treat-to-target titration schedules
Required 1 to 4 times daily
Can be easily progressed a basal-bolus regimen,
if required
Provide meal plan and schedule flexibility
Can be individualised to suit a patient’s lifestyle
96. 121
Key learning points – premixed insulin analogues
Reduce HbA1c values
Do not mimic physiological insulin action
Associated with hypoglycaemia
Fixed ratio of the basal and prandial insulin components
Difficult to monitor and titrate
Not suitable for treat-to-target titration schedules
Usually required 2–3 times daily
Must be switched to a basal-bolus regimen if further
intensification is required
Require structured meal plans and schedules
Cannot be easily individualised
