ueda2013 basal insulin versus premixed insulin-d.salah

Basal insulin

versus premixed insulin

for the treatment of T2DM

Professor Salah Shelbaya

Head of Endocrine Department

Ain Shams University

2

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

1. Background on

insulin analogues

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

Blo

od g

lucose

(m

mol/

l)

15

5

0

8

Monnier L, et al. Diabetes Care 2003;26:881–5.

0

10

20

30

40

50

60

70

<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2

Rela

tive c

ontr

ibuti

on (

%)

HbA1c (%)

Insulin regimen to be implemented depends on

the level of overall hyperglycaemia

Postprandial hyperglycaemia Fasting 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

9

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

Insulin therapy should mimic endogenous

insulin action In

su

lin

(U

/l)

0.08

0.04

0

Glucose homeostasis

08.00 13.00 19.00 16.00

Time (hours)

Pla

sm

a g

luc

os

e (m

mo

l/L)

8

6

4

2

0

Plasma glucose profiles Endogenous insulin secretion

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

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

Insu

lin l

evel

0 4 8 12 16 20 24 Hours post dose

Insu

lin l

evel

0 4 8 12 16 20 24 Hours post dose

Insu

lin l

evel

1. Rave K, et al. Diabetes Care 2006;29:1812–7.

2. Becker RHA, et al. Exp Clin Endocrinol Diabetes 2005;113:435–43.

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.

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**

Basal and prandial insulin

analogues

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

Insu

lin l

evel

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

Insu

lin l

evel

0 4 8 12 16 20 24 Hours post dose

Insu

lin l

evel

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

Glu

cose

infu

sion r

ate

(m

g/kg/m

in)

Glu

cose

infu

sion ra

te (µ

mol/

kg/m

in)

Time (hours)

0 4 8 12 16 20 24

SC

injection

Glu

cose

infu

sion r

ate

(m

mol/

kg/m

in) G

lucose

infu

sion ra

te (m

mol/

kg/m

in)

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

22

8 0 24 4 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

Glu

co

se

in

fus

ion

ra

te

(mg

/kg

/min

)

0

2

4

Time (h)

1

3

Insulin glargine 0.3 U/kg

Time (h)

Ins

uli

n (

µU

/mL

)

160

80

10 8 6 4 2 0

Premixed insulin analogues

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

Insu

lin l

evel

0 4 8 12 16 20 24

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

Pla

sma insu

lin (

pM

)

Time (hours)

Premix injection Premix injection

Hyperglycemia risk

Hypoglycemia risk

meal

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

Week 1

6

Week 3

2 W

eek 4

8

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

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

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

Summary

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

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

Guidance on initiating

insulin therapy

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

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


2. IDF global guideline for type 2 diabetes, www.idf.org/webdata/docs/IDF%20GGT2D.pdf

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

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 phase Screening

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.

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

*

*

*

*

*

Blo

od

glu

co

se

(m

mo

l/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.

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‡

We

igh

t g

ain

(k

g)

1.4

2.1

2.5

2.0

1.5

1.0

0.5

0

-1.64

Hb

A1c c

ha

ng

e f

rom

ba

se

lin

e (

%)

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.

48

0.51

0

2

4

6

8

10

12

Lower incidence of hypoglycaemia with

insulin glargine versus premix E

ve

nts

pe

r p

ati

en

t p

er

ye

ar

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

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

Change f

rom

base

line (

%)

HbA1c

Incid

ence

(epis

odes/

pati

ent-

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

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

61

5

6

7

8

9

10

HbA1c was reduced in both groups with a

significantly greater effect with premix

HbA

1c (

%)

Glargine

Lispro mix

Baseline 24 weeks

p = 0.005


9,1

7,3 7.2

9.0

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


28

23

Premixed

insulin

Insulin

glargine

Ep

iso

de

s p

er

pa

tie

nt

ye

ar

3,6

2,5

0

1

2

3

4

Premixed

insulin

Insulin

glargine

kg

0,47

0,40

At

stu

dy e

nd

(U

/kg

/da

y)

Treatment satisfaction

with insulin glargine

vs premixed insulin analogues

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

DTSQ

c s

core

at

endpoin

t

11.5

14.0

At 24 weeks insulin glargine was associated with a greater increase

in patient treatment satisfaction

Summary

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

THANK YOU

67

2.2. Intensifying insulin therapy

in T2DM

69

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.

8

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

Time (h)

Insu

lin (

µU

/mL

)

160

0

80

0 10 8 6 24

20 subjects with Type 1 diabetes1

Glu

co

se

in

fusio

n r

ate

(mg

/kg

/min

)

0

2

4

Time (h)

1

3

Insulin glargine 0.3 U/kg

4 12 16 20 4 2 0

The basal-plus approach

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

72

New approaches for intensifying insulin

therapy: basal-plus

Basal

e.g. insulin glargine Premixed insulin x1

Premixed insulin x3

Basal–bolus


Premixed insulin x2 Basal-plus


Basal-plus


Lifestyle modification and OHAs

As per ADA/EASD guidelines

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


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.

75

Basal-plus approach facilitates individualised care

compared with premixed insulin

Time of day

Prandial insulin

at dinner

16:00 08:00 12:00 20:00 0:00 04:00 08:00

Prandial insulin

at breakfast

BG

(m

mol/

l)

12

10

8

6

4

Patient B

Patient A

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).

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.

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

Clinical evidence for the

basal-plus approach

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

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

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)

Hb

A1

c (

%)

7,35 7,29 7,32

7,03 6,94 6,99

Breakfast Main meal Overall

Baseline

Endpoint


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

Res

po

nd

er

rate

wit

h H

bA

1c <

7%

(%

)

27,8

33,8

0

10

20

30

40

Breakfast Main meal

Re

sp

on

de

r ra

te w

ith

Hb

A 1c

< 6

.5%

(%

)


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

Blo

od

glu

co

se

(m

g/d

L)

5.6

6.7

7.8

8.9

10.0

11.1

Blo

od

glu

co

se

(mm

ol/L

)

†

*

†

†

†

†

*

Baseline

Endpoint

200


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

Blo

od

glu

co

se

(m

g/d

L)

Blo

od

glu

co

se

(mm

ol/L

) 200

Calculated for the per-protocol analysis set (n=316)

Data are means; *p<0.05; †p<0.0001


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†

Severe

Confirmed

nocturnal†

Eve

nts

pe

r p

ati

en

t-ye

ar

p=0.70

p=0.31

p=0.27

p=0.18

p=0.97

Hypoglycaemia


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

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

Switch strategies

• From Premix to insulin glargine

• From Premix to insulin glargine ± prandial

• From human insulin to Premix or insulin glargine

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.

Pati

ents

achie

vin

g t

arg

et

(%)

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

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)

Change f

rom

base

line (

%)

Change f

rom

base

line (

mm

ol/

l)

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

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

0.6In

cid

ence

(epis

odes/

pati

ent-

year)

0.8

0.6

0.4

0.2

0

Hypoglycaemia

0.1

0.8

Change f

rom

base

line (

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

Change f

rom

base

line (

%)

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

Basal-plus and basal-bolus

approaches with

insulin glargine + insulin glulisine


94

06.00 12.00 24.00 18.00 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

Insu

lin

(m

U/l

)

0

15

30

45 Breakfast Lunch Dinner

Time (hours)

95

LACE – basal-bolus insulin glargine + insulin glulisine

is more effective than premixed insulin

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

Change f

rom

base

line (

%) 0

–0.5

–1.0

–1.5

-2.0

-2.5 –2.3

–1.7

HbA1c Hypoglycaemia

Incid

ence (

% p

ati

ents

)

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

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

Change f

rom

base

line (

%) 0

–0.5

–1.0

–1.5 –1.3

–0.8

p=0.0001 In

cid

ence

(epis

odes/

pati

ent-

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

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 PPBG FBG

9.9

11.7

6.8

8.0

5

6

7

8

9

10

11

128.6

7.3

5

6

7

8

9

HbA

1c (

%)

p<0.0001

BG

(m

mol/

l)

Baseline 12 weeks after switching


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

Change f

rom

base

line (

%)

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

Treatment satisfaction with

insulin glargine ± insulin glulisine

vs premixed insulin

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%

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

DTSQ

score

p<0.0001


Baseline 12 weeks

Basal-plus and basal-bolus insulin therapy provided

better patient treatment satisfaction

Summary

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

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

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

-cell m

ass

(% o

f m

ax)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

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

-cell m

ass

(% o

f m

ax)

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

HbA

1c (%

)

0

50

100

HbA1c pre-diagnosis1

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)

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.

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.

Basal-bolus regimen with

insulins glargine and glulisine

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.

113

8.0

7.16.9

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).

HbA

1c (

%)

BG

(m

mol/

l)

HbA1c PPBG FBG

Basal-plus and basal-bolus insulin therapy improved

glycaemic control with a low risk of hypos

Basal-bolus approach


115

LADI – switching from premixed insulin to insulin glargine +

insulin glulisine improves glycaemic control in T1DM


9.7

10.7

6.5

7.7

5

6

7

8

9

10

11

128.7

7.2

5

6

7

8

9

HbA

1c (

%)

p<0.0001

BG

(m

mol/

l)

HbA1c PPBG FBG


Baseline 12 weeks after switching

116

LADI – switching from premixed to insulin glargine + insulin

glulisine improves treatment satisfaction in T1DM


17

31

0

5

10

15

20

25

30

35

DTSQ

score

p<0.0001

Baseline 12 weeks

Basal-plus and basal-bolus insulin therapy provided

better patient treatment satisfaction

Summary

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.

4. Overall conclusions

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

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

Back-up

123

Kazda et al. – insulin glargine vs intensive premixed

insulin lispro 50/50

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

HbA1c

p<0.001

–0.3

–1.2

Incid

ence

(epis

odes/

100 p

ati

ent-

days)

2.0

1.5

1.0

0.5

0

Hypoglycaemia

Change f

rom

base

line (

kg)

2.0

1.5

1.0

0.5

0

Weight

p=0.0013

0

–0.5

–1.0

–1.5

Change f

rom

base

line (

%)

(p not published)

Insulin glargine was associated with

fewer hypos and less weight gain

Insulin glargine Premixed insulin lispro 50/50 TID

Insulin glargine was not

optimally titrated

1.0

1.5

0.7

1.8

Premixed insulin was given TID

ueda2013 basal insulin versus premixed insulin-d.salah

Health & Medicine

basal insulin therapy

insulin regimen

prandial insulin analogues

percentage of prandial

initiating insulin therapy

mealtimes premixed insulin

percentage of basal

basal insulins