Basal insulin

versus premixed insulin

for the treatment of
T2DM

Professor Salah Shelbaya

Head of Endocrine Department
Ain Shams University
Contents

1. Background on insulin analogues

2. Insulin therapy for T2DM

1. Initiating insulin therapy in T2DM
2. Intensifying insulin therapy in T2DM

3. Conclusions

2
1. Background on
insulin
analogues
Both fasting and postprandial hyperglycaemia
contribute to overall hyperglycaemia

15
Postprandial
Blood glucose (mmol/l)

hyperglycaemia

10 Fasting
hyperglycaemia Diabetes profile

5
Healthy profile

0
06:00 12:00 18:00 24:00 06:00
Time of day

Riddle M. Diabetes Care 1990;13:676−86.

7
Insulin regimen to be implemented depends on
the level of overall hyperglycaemia
Initiate basal insulin therapy
when glycaemic control is very
poor
Fasting hyperglycaemia
70
Intensify insulin therapy with
the stepwise addition of
prandial insulin as HbA1c
approaches target value
Postprandial hyperglycaemia

60
Relative contribution (%)

50

40

30

20

10

0
>10.2 9.3–10.2 8.5–9.2 7.3–8.4 <7.3
HbA1c (%)
Monnier L, et al. Diabetes Care 2003;26:881–5.
8
Insulin therapy should mimic endogenous
insulin action

Plasma glucose profiles Endogenous insulin secretion

Glucose homeostasis
0.08

Plasma glucose (mmol/L)

8
Insulin (U/l)

0.04 6

2
0 0

08.00 13.00 16.00 19.00

Time (hours)

Owens DR, et al. Lancet 2001;358:739−46.

9
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
10
Basal, prandial and premixed insulin have different
action profiles
Basal insulin Prandial insulin Premixed insulin
Reduces fasting Reduces postprandial Reduces fasting and
hyperglycaemia postprandial
hyperglycaemia Short duration hyperglycaemia
Long duration of action Long biphasic
of action Inject at duration of action
Inject morning and/or mealtimes Inject at
evening mealtimes
Insulin level

Insulin level
Insulin level

0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24
Hours post dose Hours post Hours post dose
dose
1. Rave K, et al. Diabetes Care 2006;29:1812–7.
2. Becker RHA, et al. Exp Clin Endocrinol Diabetes 2005;113:435–43.
11
Available insulin analogues

Generic Marketed name

Type of insulin
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,

Adis R&D Insight, 16 Jun 2008.
respectively.
12
Available human insulins

Marketed
Type of insulin Generic name
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**

*Numbers refer to percentage of basal and prnadial insulins in the formulation, respectively; US brand
name.
**Number refers to
Pharmaprojects, the 2008.
5 Nov percentage of prandial insulin in the formulation.
13
Basal and prandial insulin
analogues
Properties of the ideal basal insulin

 Peakless profile1
 Long duration of action1

Insulin level
 Flexible dosing
 Simple titration
 Suitable for treat-to-target
schedules
0

8
1. Rosenstock J. Clin Cornerstone 2001;4:50–64.
15
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
Insulin analogue Human insulin
(long acting) (intermediate acting)
Insulin level

Insulin level
0 4 8 12 0 4 8 12 16 20 24
16 20 24 Hours post dose
Hours post dose
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. 16
Insulin glargine has a more physiological action
profile than other basal insulins

T1DM patients (n=20)1 T1DM patients (n=24)2

Glucose infusion rate (mmol/kg/min)

Glucose infusion rate (µmol/kg/min)

Glucose infusion rate (mol/kg/min)

Glucose infusion rate (mg/kg/min)

4 SC 24 4 SC injection
injection NPH 0.3 IU/kg 0.35 IU/kg
20
3 3
16
CSII (insulin lispro)
2 0.3 IU/kg/24h 12 2

8 9
Insulin glargine
1 1 6
4 3
Insulin glargine Insulin detemir
0 0.3 IU/kg 0 0 0

0 4 8 12 16 20 24
0 4 8 12 16 20
24
Time (hours)
Time (hours)

1. Lepore M, et al. Diabetes 2000;49:2142–8.

2. Porcellati F, et al. Diabetes Care 2007;30:2447–52.
17
 Insulin glargine and insulin glulisine have
complementary physiological profiles

20 subjects with Euglycaemic glucose-clamp study:

Type 1 diabetes1 insulin glulisine vs RHI, 18
patients2

Insulin glargine 0.3 U/kg Insulin glulisine 0.15 U/kg

160
4
RHI 0.15 U/kg
Glucose infusion rate

Insulin (µU/mL)
INS-AUC0–2h: p < 0.05 vs RHI
(mg/kg/min)

2 80

0
0
0 4 8 12 16 20 24 0 2 4 6 8 10
Time (h) Time (h)

INS-AUC, insulin infusion rate – area 1. Lepore M, et al. Diabetes 2000;49:2142–8.

under the curve 2. Becker RH, et al. Diabetes Care 2007;30:2506–7.
Premixed insulin analogues
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

Insulin level
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 0 4 8 12 16 20 24
 Simple regimen with few Hours post dose

injections
24
Premixed insulin analogues profile exposes to an increase
risk of post-prandial hyper and hypoglycemia

Isoglycaemic clamp study using twice-daily premixed insulin aspart 30/70

400 Hyperglycemia risk

Plasma insulin (pM)

300
Hypoglycemia risk

200

100

meal meal
Plasma glucose profiles
0 Premix injection Premix injection

0 4 8 12 20 24

Luzio S et al. Diabetologia 2006;49:1163–8. 16

25
 1-2-3 Study – multiple daily injections of premixed insulin
are required to achieve blood-glucose control

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

Premixed insulin
aspart
30/70

Week 16
Once daily 21

Week 32
Twice daily 31

Week 48
Three times daily 8

0 20 40 60 80

Garber A, et al. Diabetes Obes Metab 2006;8:5866.

Patients achieving HbA1c ≤6.5% (%)
26
New premixed insulin aspart formulations
are being investigated
Versus premixed in s lin aspart 30/70 BID:
Premixed insulin u Premixed insulin aspart
aspar t 70/30 TID
50/50 TID

–0.3 –0.07
Change in HbA1c (%) ns
p=0.004
Relative risk of 1.20 1.58
hypoglycaemia ns p=0.0002
More effective than As effective as 30/70,
Conclusion 30/70, and same f but higher risk of
risk o hypoglycaemia
Almost 50% of patientshypoglycaemia
receiving 50/50 and 70/30
required a switch to evening 30/70 to manage their
FBG levels
Cucinotta D, et al. 43rd Annual Meeting of the EASD, 2007. Abstract 0988.
27
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
28
Summary
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

30
2. Insulin therapy for T2DM
Stepwise intensification of insulin treatment is
required as diabetes progresses

FBG at target Basal-bolus

HbA1c above target Additional prandial insulin
doses as needed

FBG at target Basal-plus

HbA1c above target Add prandial insulin at main meal

FBG above target

HbA1c above target
Basal only
Add basal insulin and titrate

Progressive deterioration of -cell function

Raccah D, et al. Diabetes Metab Res Rev 2007;23:257–64.

37
Guidance on initiating
insulin therapy
ADA/EASD and IDF recommend early initiation of
insulin therapy to meet HbA1c targets

ADA/EASD 2008 1

 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 2005 2

 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
40
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
41
Insulin glargine has proven efficacy in
combination with OHAs

Reduction Final HbA1c Patients with

Trial
in HbA1c (%) achieved (%) 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
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.
44
 LAPTOP study: Comparison of insulin glargine
added to an OHA regimen versus switching
to premixed insulin
R
Insulin glargine + OHAs (n = 177)
A Initial dose: 10 IU once daily in
Patients with T2DM the morning
HbA1c: 7.5% to 10.5% N

and FBG: ≥6.7 mmol/L D

(≥120 mg/dL) and
treated with OHAs O
Human premixed insulin (70/30) (n
(n = 364) M = 187)
I Initial dose: 10 IU before
S breakfast and 10 IU before dinner

Screening Run-in phase A Treatment phase

T
I
3–14 weeks O 24 weeks
Subjects taking sulphonylurea and metformin for at least a month were enrolled. Sulphonylurea was
N
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

45 2005;28:254–9.
Significantly greater reduction in FBG and
PPBG with insulin glargine vs premix

16
Premixed insulin twice daily
Blood glucose (mmol/L)

Insulin glargine + OHAs

14 Baseline

12

10
*
8
*
6 *
*
Endpoint
*
4
Fasting After Lunch After Dinner After Bedtime 03.00
breakfast lunch dinner
Time of day
*p < 0.05 for treatment comparison
of 46 Janka H, et al. Diabetes Care 2005;28:254–9.
 Insulin glargine provided better glycaemic
control and less weight gain than premix

Premixed Insulin Final daily dose:

insulin† glargine‡
0 2.5 Premixed insulin 64.5 IU
HbA1c change from baseline (%)

2.1 Insulin glargine 28.2

IU
2.0
-0.5 p = NS

Weight gain (kg)

1.4
1.5
-1.0
1.0
-1.31
-1.5
0.5
-1.64

-2.0 p = 0.0003
0 Premixed Insulin
insulin† glargine‡
† Twice daily; ‡plus OHAs
Janka H, et al. Diabetes Care 2005;28:254–9.
47
 Lower incidence of hypoglycaemia with
insulin glargine versus premix
Events per patient per year

12 p < 0.0001 Premixed insulin

10
9.87 Insulin
glargine*
8 p = 0.0009
5.73
6
4.07
4
2,62
p = 0.0449
2 1,04
0.51
0
All confirmed Confirmed Confirmed
hypoglycaemia symptomatic nocturnal

Hypoglycaemia confirmed by blood glucose <60 mg/dL (3.3

mmol/L)
*Plus OHAs Janka H, et al. Diabetes Care 2005;28:254–9.
48
Insulin glargine provided better glycaemic control with
fewer hypoglycemia than premix in elderly patients

Sub-population of patients aged ≥65 years (n=130)

HbA1c Hypoglycaemia
Insulin glargine Premixed human insulin 30/70 BID
0
10 9.1
Change from baseline (%)

(episodes/patient-year)
–0.5 8
p<0.008

Incidence
6
–1.0
3.7
4
–1.5 –1.4
2
p=0.003
–2.0 –1.9 0

Insulin glargine was well titrated Insulin glargine was associated

and more effective with fewer hypos

Janka H, et al. J Am Geriatr Soc 2007;55:182−8.

49
DURABLE trial: Comparison of starting insulin
glargine versus lispro mix added to an OHA regimen

R
Insulin glargine + OHAs
A Once daily
Insulin-naïve patients
with T2DM on at N
least 2 OHAs D
HbA1c >7%
(n = 2,091) O
Lispro mixture (25% lispro / 75%
M lispro protamine suspension) +
I OHAs: Twice daily
S

A
T
Initiation
I phase Maintenance phase
O
24 weeks 104 weeks
N

Wolffenbuttell BH, et al. Diabetologia 2008;51(Suppl. 1):S386.

60
HbA1c was reduced in both groups with a
significantly greater effect with premix

Glargine
Lispro mix
10
9,1 9.0 p = 0.005
9
HbA1c (%)

8
7.2 7,3
7

5
Baseline 24 weeks

Wolffenbuttell BH, et al. Diabetologia 2008;51(Suppl. 1):S386.

61
 Hypoglycaemia, weight gain and daily dose
all lower with glargine vs premix

Hypoglycaemia Weight gain Daily insulin dose

30 28 4 0,6
p = 0.007 3,6 p < 0.0001 p < 0.001
0,47

At study end (U/kg/day)

23 0,5
Episodes per patient year

3 0,40
2,5 0,4
20
kg

2 0,3

10 0,2
1
0,1

0 0 0
Premixed Insulin Premixed Insulin Premixed Insulin
insulin glargine insulin glargine insulin glargine

Wolffenbuttell BH, et al. Diabetologia 2008;51(Suppl. 1):S386.

62
Treatment satisfaction
with insulin glargine
vs premixed insulin
analogues
 Treatment satisfaction is higher with insulin
glargine than with premixed human insulin

15 14.0
DTSQc score at endpoint

p = 0.0012 11.5

10

0
Insulin glargine Premixed human
+ OHAs insulin 30/70
BID
At 24 weeks insulin glargine was associated with a greater increase
in patient treatment satisfaction
Bradley C, et al. Diabetes 2005;54(Suppl):Abstract 1246-P.
64
Summary
Key learning points – initiating insulin therapy
in T2DM
 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

66
THANK YOU

67
2.2. Intensifying insulin therapy
in T2DM
Insulin glargine and insulin glulisine have
complementary physiological profiles
20 subjects with Euglycaemic glucose-clamp study:
Type 1 diabetes1 insulin glulisine vs RHI, 18
patients2

Insulin glargine 0.3 U/kg Insulin glulisine 0.15 U/kg

160
4
RHI 0.15 U/kg
Glucose infusion rate

Insulin (µU/mL)
3
INS-AUC0–2h: p < 0.05 vs RHI
(mg/kg/min)

2 80

0
0
0 4 8 12 16 20 24 0 2 4 6 8 10
Time (h) Time (h)

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.
The basal-plus approach
Traditional approaches for intensifying insulin
therapy: basal-bolus and premixed insulin

Lifestyle modification and OHAs

Basal
e.g. insulin glargine Premixed insulin x1

Premixed insulin x2

Premixed insulin x3

Basal–bolus
e.g. insulin glargine + insulin glulisine x3

Hirsch I, et al. Clin Diabetes 2005;23:78−86.

71
New approaches for intensifying insulin
therapy: basal-plus

Lifestyle modification and OHAs

Basal
e.g. insulin glargine Premixed insulin x1

Basal-plus
e.g. insulin glargine + insulin glulisine x1 Premixed insulin x2

Basal-plus
e.g. insulin glargine + insulin glulisine x2 Premixed insulin x3

Basal–bolus
e.g. insulin glargine + insulin glulisine x3

As per ADA/EASD guidelines

72
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.

73
 ADA/EASD guidelines: Insulin intensification
starts with adding 1 prandial insulin injection

If FBG is in range check pre-meal BG levels.

Add 1 prandial insulin injection, at a selected meal

Start or Add 1 injection of rapid-acting insulin

HbA1c intensify • At BREAKFAST if pre-lunch BG is out of range*
≥ 7% insulin • or LUNCH if pre-dinner BG is out of range
therapy
• or At DINNER, if pre-bedtime BG is out of range*

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.

*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

Nathan D, et al. Diabetes Care

74
Basal-plus approach facilitates individualised care
compared with premixed insulin

12
Prandial insulin Prandial insulin
at breakfast at dinner

10
BG (mmol/l)

8 Patient B

6
Patient A

4
08:00 12:00 16:00 20:00 0:00 04:00 08:00
Time of day

75
Basal-plus approach is more flexible than a
premixed insulin analogue approach
Basal-plus approach Premixed insulin
e.g. insulin glargine e.g. premixed insulin
+ insulin glulisine aspart 30/70
Initial number of 2 21
injections daily
Daily initial dose Insulin glargine: 10 U 6 U + 6 U1
Insulin glulisine: 4 U
Timing of injections Insulin glargine: morning/evening Breakfast
Insulin glulisine: main meal and dinner1
Monitoring for Insulin glargine: FPG (once daily) FBG and preprandial BG
titration targets Insulin glulisine: preprandial, (twice daily)1
bedtime or 2-hour
postprandial BG (once daily)
Lifestyle Flexible mealtimes Scheduled mealtimes
and meal content and set meal plans
Intensification Stepwise progression Increase to 3 times daily,
to basal-bolus 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).
76
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.

77
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

78
Clinical evidence for the
basal-plus approach
Six clinical trials supporting the Basal Plus
strategy in T2DM
Study Purpose Lead country

OPAL Equivalence between breakfast and main meal for the Germany
primary bolus

ELEONOR Success of Telecare System to support Italy

Basal / Basal Plus strategy

OSIRIS Basal / Basal Plus strategy 18 countries

as safe and effective as basal bolus

1-2-3 Addition of 1 x glulisine as effective USA

as 2 x or 3 x glulisine

Proof-of-Concept Efficacy of Basal / Basal Plus strategy after USA/UK

basal insulin optimisation

All-to-Target Basal / Basal Plus strategy more effective than USA

premixed insulin

80 www.clinicaltrials.gov
OPAL: First study supporting the Basal Plus approach

Stratification Randomisation

Insulin glargine Main meal

+ OHA Breakfast Breakfast group
Insulin glargine + OHA +
Inclusion criteria once-daily insulin
• T2DM glulisine
• HbA1c >6.5 to  9% Lunch
• Pre-treatment with Main meal group
insulin glargine and
Insulin glargine + OHA +
OHAs for >3 months Dinner
• FBG 120 mg/dL once-daily insulin glulisine

Pre-screening Screening Treatment Follow up

1–2 weeks 1–3 24 1 week
weeks weeks
2h-pp, 2-hour postprandial Titration target values
FBG, fasting blood glucose
2h-pp blood glucose: 135 mg/dL FBG:
100 mg/dL
Lankisch M, et al. Diabetes Obesity and Metabolism 2008; 10: 1178-1185
81
OPAL: A single injection of glulisine (at breakfast OR main
meal) + once-daily glargine results in significant HbA1c
improvement
p=NS
Baseline
8.0 p<0.0001 p<0.0001 p<0.0001
Endpoint
7,35 7,29 7,32 Overall HbA1c
7,03
reduction
HbA1c (%)

6,94 6,99
–0.33%
7.0

6.0

0.0
Breakfast Main meal Overall
(n=162) (n=154) (n=316)
Per-protocol population
Main meal is defined as the meal including the highest
2-h postprandial BG excursion
Lankisch M, et al. Diabetes Obesity and Metabolism 2008; 10: 1178-1185
82
OPAL: Main meal group after 6 months

52% achieved HbA1c <7%; 34% achieved HbA1c <6.5%

p=0.028
p=0.21
Responder rate with HbA1c < 7% (%)

Responder rate with HbA1c < 6.5% (%)

60 40
52,2
33,8
50
30 27,8
40 36,5

30 20

20
10
10

0 0
Breakfast Main meal Breakfast Main meal
(n=162) (n=154) (n=162) (n=154)

Lankisch M, et al. Diabetes Obesity and Metabolism 2008; 10: 1178-1185

83
OPAL: 8-point blood glucose profile – breakfast
group

200 11.1

†
180 † 10.0

Blood glucose (mmol/L)

Blood glucose (mg/dL)

†
*
160 8.9
*
140 † 7.8

120 6.7
Baseline
Endpoint
100 † 5.6

3:00 am Fasting 2h-post 2h-post Pre-dinner 2h-post Bedtime

Pre-lunch breakfast lunch dinner

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
84
 OPAL: 8-point blood glucose profile – main
meal group
200 11.1
†

180 † † 10.0

Blood glucose (mmol/L)

Blood glucose (mg/dL)

160 8.9

*
140 7.8

120 * 6.7
Baseline
Endpoint
100 5.6
*
3:00 a.m. Fasting 2h-post Pre-lunch 2h-post Pre-
dinner 2h-post Bedtime breakfast lunch dinner
Calculated for the per-protocol analysis set (n=316)
Data are means; *p<0.05; †p<0.0001
Lankisch M, et al. Diabetes
Obesity 85
 OPAL: The rate of hypoglycaemia was similar
in both groups*

p=0.70
6
5.34
Weight gainBreakfast group
5 4.76 Main meal
Breakfast group: group
+ 1.02 kg
p=0.31
Events per patient-year

Main meal group: + 0.85 kg

4 3.69
p=0.97
3
2.50 2.55 2.58
2
p=0.18
1 p=0.27
0.52
0.27 0.1 0.03
0
Overall Confirmed† Confirmed Confirmed Severe
symptomatic†
nocturnal†
Hypoglycaemia
*Calculated for the safety analysis set (n=393)
†blood glucose ≤60 mg/dL (3.3 mmol/L)
Lankisch M, et al. Diabetes Obesity and Metabolism 2008; 10: 1178-1185
86
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

87
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 88
 Switch strategies
• From Premix to insulin glargine
• From Premix to insulin glargine ± prandial
• From human insulin to Premix or insulin glargine
Hammer & Klinge – switching from premixed insulin
to insulin glargine improves glycaemic control

100
Patients achieving target (%)

83
80 74  Only 16 episodes of
hypoglycaemia were
60 reported
49
 A significant reduction in
40 weight was observed
(p<0.001)
20
 The increase in mean daily
0 insulin dose was low
HbA1c FBG 2h PPBG
<7.5% <6.7 mmol/l <8.9 mmol/l

Insulin glargine improved glycaemic control,

and was associated with fewer hypos and weight loss

Hammer H and Klinge A. Int J Clin Pract 2007;61:2009–18.

90
AT.LANTUS – switching from premixed insulin to insulin
glargine ± prandial insulin improves glycaemic control

Sub-population of patients previously treated with premixed insulin (n=686)

HbA1c FBG
Insulin glargine Insulin glargine + 1, 2 or >2 prandial
insulin
0 0

Change from baseline (mmol/l)

Change from baseline (%)

-1
-0.5
–0.7 -2
-1 p<0.001
-3
–1.2 -3.1
-1.5 p=0.004 –1.4 -4 p<0.001 -3.7 –3.6
–1.6 p<0.001 p<0.001
p<0.001
p<0.001 -4.4
-2 -5 p<0.001

Basal-plus and basal-bolus insulin therapy provided better glycaemic control

Davies M, et al. Diabetes Res Clin Pract 2008;79:368–75.

91
 Malone et al. 2005 – switching from human insulin
to insulin glargine or premixed insulin lispro 25/75

HbA1c Hypoglycaemia Weight

Insulin glargine Premixed insulin lispro 25/75 BID

0 0.8 1.0

Change from baseline (kg)

0.8
Change from baseline (%)

(episodes/patient-year) 0.6 0.8

0.6 p=ns
–0.5 –0.4
Incidence

0.4 0.6
p<0.001 0.4 p=0.001
0.4
–1.0
–1.0 0.2
0.2 0.1

–1.5 0 0

Insulin glargine was not optimally Insulin glargine was associated

titrated in a treat-to-target manner, with a similar risk of hypos
and cross-over design was flawed and less weight gain
Malone J, et al. Diabet Med 2005;22:374–81.
92
Basal-plus and basal-bolus
approaches with
insulin glargine + insulin
glulisine vs premixed
insulin analogues
In advanced T2DM, insulin therapy should
mimic physiological patterns
Endogenous insulin secretion
Ideal basal insulin
Ideal prandial insulin

45 Breakfast Lunch Dinner

Insulin (mU/l)

30

15

06.00 12.00 18.00 24.00 06.00

Time (hours)

Adapted from Kruszynska YT, et al. Diabetologia 1987;30:16–21.

94
LACE – basal-bolus insulin glargine + insulin glulisine
is more effective than premixed insulin

HbA1c Hypoglycaemia
Insulin glargine + insulin glulisine Premixed insulin

0 50
43
Change from baseline (%)

Incidence (% patients)
–0.5 40 36

–1.0 30 p=ns

–1.5 20

-2.0 –1.7 10

-2.5 –2.3 0

Basal-bolus insulin therapy provided better glycaemic control

and a similar risk of hypos

Lee F, et al. EASD 2008: Abstract 1003 (poster).

95
GINGER – switching from premixed insulin to basal-bolus
insulin glargine + insulin glulisine improves glycaemic control

HbA1c Hypoglycaemia
Insulin glargine + insulin glulisine Premixed insulin

0 20 18.5
Change from baseline (%)

(episodes/patient-year)
15 14.0
–0.5

Incidence
p=ns
10

–1.0 –0.8
5
p=0.0001

–1.5 –1.3 0

Basal-bolus insulin therapy provided better glycaemic control

and a similar risk of hypos

Fritsche A, et al. EASD 2008: Abstract 186 (oral).

96
LADI – switching from premixed insulin to insulin glargine +
insulin glulisine improves glycaemic control in T2DM

HbA1c FBG PPBG

Baseline 12 weeks after switching

9 12 11.7
8.6

p<0.0001 11
8 9.9
10

BG (mmol/l)
HbA1c (%)

7.3
9
7 8.0
8
6.8
7
6
6

5 5

Basal-plus and basal-bolus insulin therapy provided better glycaemic control

Schreiber S, et al. Diabetologia 2007;50(suppl 1):S410–1.

97
Basal-bolus regimen with insulin glargine is more
effective than twice-daily premixed insulin lispro

HbA1c
Premixed insulin
Basal-bolus lispro 50/50  Hypoglycaemia rates and
0
weight gain were similar in
the two groups
Change from baseline (%)

–0.5

–1.0
 55% of patients in the
premixed insulin group
–1.5 switched from premixed
insulin lispro 50/50 to
-2.0 –1.9 25/75 at dinner to achieve
–2.1 the FBG target
-2.5 p<0.021 for 0.2% difference

Basal-bolus insulin therapy provided a better efficacy profile

and a similar safety profile
Rosenstock J, et al. Diabetes Care 2008;31:20–5.
98
 Treatment satisfaction with
insulin glargine ± insulin glulisine
vs premixed insulin
High physician satisfaction with switching from
premixed insulin to insulin glargine

Efficacy Safety

46%
42% 54%
41% Very good
Good
Satisfactory
Unsatisfactory
No response
given

Most physicians rated the efficacy and safety

of insulin glargine as ‘very good’ or ‘good’
Hammer H and Klinge A. Int J Clin Pract 2007;61:2009–18.
100
LADI – switching from premixed insulin to insulin glargine + insulin
glulisine improves treatment satisfaction in T2DM

30 29

25 p<0.0001

20 18
DTSQ score

15

10

0
Baseline

12 weeks

Basal-plus and basal-bolus insulin therapy provided

better patient treatment
101 satisfaction
Summary
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
103
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
104
3. Insulin therapy for T1DM
Pathophysiology and progression of T1DM (1)

Infectious or environmental Progressive

Near-absolute Exogenous
stimulus triggers auto-immune destruction of
endogenous insulin insulin supply
attack on pancreatic insulin- beta cells over
deficiency necessary
producing beta cells1 months to years

Birth Tim
e
Immunologic
(ye abnormalities
ars) Progressive impairment
100
Beta-cell mass (% of max)1

Genetic of insulin release

predisposition
Overt diabetes
Immunologic trigger 'Honeymoon'
50 period
(1–2 years)
No diabetes
Diabetes
0

1. Adapted from Powers AC. In: Harrison’s Principles of Internal Medicine, Kasper DL et al (Eds). New
York: McGraw-Hill; 2005:p2152−80.
106
Pathophysiology and progression of T1DM (2)

Infectious or environmental Progressive

Near-absolute Exogenous
stimulus triggers auto-immune destruction of
endogenous insulin insulin supply
attack on pancreatic insulin- beta cells over
deficiency necessary
producing beta cells months to years

100 7
Beta-cell mass (% of max)

HbA1c (%)
50
5
HbA1c post-diagnosis2
HbA1c pre-diagnosis 1

4
0
–8 –7 –6 –5 –4 –3 –2 –1 0/Diagnosis
Years prior to diagnosis

1. Adapted from Stene LC, et al. Pediatr Diabetes 2006;7:247–53.

2. Garg S. Data on file.
107
Guidelines provide HbA1c, FBG and PPBG targets
for T1DM

AACE/
Parameter ADA1 IDF3
ACE2
HbA1c, % <7.0 6.5 <6.5

FBG, mmol/l (mg/dl) 3.9–7.2 <6.1 <5.5

(70–130) (<110) (<100)

PPBG, mmol/l (mg/dl) <10.0 <7.8 <7.8

(<180) (<140) (<140)

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.
108
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.
109
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.

110
 Basal-bolus regimen with
insulins glargine and glulisine
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. 4. Becker RH, et al. Diabetes Care 2007;30:2506–7.
2. Porcellati F, et al. Diabetes Care 2007;30:2447–52. 5. Rave K, et al. Diabetes Care 2006;29:1812–7.
3. Pieber T, et al. Diabet Med 2007;24:635–42. 6. Dreyer M, et al. Horm Metab Res 2005;37:7027.
112
Basal-bolus insulin glargine + insulin glulisine
improves glycaemic control

HbA1c FBG PPBG

Baseline 12 weeks 6 months
9.0 10 .0 9.8

8.0 9 .0
8.0 8 .5

7.1 8 .0

BG (mmol/l)
6.9 7. 5 7. 5
HbA1c (%)

7.0
7 .0
6. 5 6 . 4
6.0
6 .0

5.0 5 .0

Basal-plus and basal-bolus insulin therapy improved

glycaemic control with a low risk of hypos
Ruhnau K, et al. Diabet Med 2006;23(Suppl 4):343 (Abstract P952).
113
 Basal-bolus approach
vs premixed insulin analogues
LADI – switching from premixed insulin to insulin glargine +
insulin glulisine improves glycaemic control in T1DM

HbA1c FBG PPBG

Baseline 12 weeks after
9 8.7 switching
12

11 10.7

8
p<0.0001
10 9.7
HbA1c (%)

BG (mmol/l)
7.2
9
7
8 7.7

7 6.5
6
6

5 5

Basal-plus and basal-bolus insulin therapy provided better glycaemic control

Schreiber S, et al. Diabetologia 2007;50(suppl 1):S410–1.

115
LADI – switching from premixed to insulin glargine + insulin
glulisine improves treatment satisfaction in T1DM

35
31
30
p<0.0001
25
DTSQ score

20 17

15

10

0
Baseline
12 weeks

Basal-plus and basal-bolus insulin therapy provided

better patient treatment satisfaction
Schreiber S, et al. Diabetologia 2007;50(suppl 1):S410–1.
116
Summary
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.
118
4. Overall conclusions
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
120
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
121
Back-up
Kazda et al. – insulin glargine vs intensive premixed
insulin lispro 50/50
HbA1c Hypoglycaemia Weight
Insulin glargine Premixed insulin lispro 50/50 TID

0 2.0 2.0
1.8

(episodes/100 patient-days)

Change from baseline (kg)

Change from baseline (%)

1.5
–0.3 1.5 1.5
–0.5 p=0.0013
(p not published)
Incidence
1.0
p<0.001 1.0 1.0
0.7
–1.0
0.5 0.5
–1.2
–1.5 0 0

Insulin glargine was not Insulin glargine was associated with

optimally titrated fewer hypos and less weight gain

Premixed insulin was given TID

Kazda C, et al. J Diabetes Complic 2006;20:145−52.
123