JSC 2006 An update on insulin therapy in type 2 diabetes mellitus Jens Sandahl Christiansen, MD, DMSc, FRCPI

JSC 2006

An update on insulin therapy in type 2 diabetes mellitus

Jens Sandahl Christiansen, MD, DMSc, FRCPI

JSC 2006

Antidiabetic treatmentAntidiabetic treatmentMetabolic controlMetabolic control

DCCT Kumamoto Study

Conventional therapy

Intensive therapy

10

9

8

7

6

50 1 2 3 4 5 6 7 8 9 10Time from randomization (years)

Hb

A1

c (%

)

121110

98765

0 12 24 36 48 60 72Months

Hb

A1

c (%

)

9

8

7

60

0 3 6 9 12 15

Med

ian

Hb

A1

c (

%)

Time from randomization (years)

UKPDS

Lancet 1998;352:837-853

Diab Res Clin Pract 1995;28:103-117N Engl J Med 1993;329:977-986

JSC 2006

Cardiovascular Disease

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0 183

365

548

730

913

1095

1278

1460

1643

1825

2008

2190

2373

2555

2738

2920

3103

Months of Study

Pro

bab

ility

for

Pri

mar

y C

om

po

site

En

d P

oin

t

12 24 36 48 60 72 84 960

Months of Follow-UpNo. at Risk

ConventionalIntensive

8080

7278

7074

6371

5966

5063

4461

4159

1319

Conventional treatment

Intensive treatment

log-rank p=0.007

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0 183

365

548

730

913

1095

1278

1460

1643

1825

2008

2190

2373

2555

2738

2920

3103

Months of Study

Pro

bab

ility

for

Pri

mar

y C

om

po

site

En

d P

oin

t

12 24 36 48 60 72 84 960

Months of Follow-UpNo. at Risk

ConventionalIntensive

8080

7278

7074

6371

5966

5063

4461

4159

1319

Conventional treatment

Intensive treatment

log-rank p=0.007

Kaplan-Meier estimates of the composite endpoint of cardiovascular mortality, non-fatal myocardial infarction, coronary artery bypass graft, percutaneous coronary interventions, non-fatal stroke, amputation, or vascular surgery for peripheral atherosclerotic artery disease in the conventional and the intensive therapy group.

Peter Gæde, N Engl J Med 348: 383, 2003

JSC 2006

Microvascular complications

Nephropathy

Retinopathy

Autonomic neuropathy

Peripheral neuropathy

0 0,5 1 1,5 2 2,5

Odds ratio

0.270.39

0.450.42

0.320.37

0.891.09

Nephropathy

Retinopathy

Autonomic neuropathy

Peripheral neuropathy

0 0,5 1 1,5 2 2,5

Odds ratio

0.270.39

0.450.42

0.320.37

0.891.09

Odds ratios with 95% confidence intervals for development and/or progression of nephropathy, retinopathy, and autonommic and peripheral neuropathy during 4 ( - ) or 8 ( - ) years of follow-up.


JSC 2006

Treatment goal achieved

Percentage of patients achieving the treatment goals for the intensive group at 8 years in both the intensive and the conventional groups after 8 years of follow-up

0

10

20

30

40

50

60

70

80

1

Pat

ien

ts o

bta

inin

g t

reat

men

t g

oal

aft

er 8

yea

rs Fat intake<30% E

Saturated fat<10% E

Non-smokers Exercise>150 min/week

Int Conv Int Conv Int Conv Int Conv

%

p=0.09

p=0.02

p=0.58

p=0.13

0

10

20

30

40

50

60

70

80

1

Pat

ien

ts o

bta

inin

g t

reat

men

t g

oal

aft

er 8

yea

rs Fat intake<30% E

Saturated fat<10% E

Non-smokers Exercise>150 min/week


%

p=0.09

p=0.02

p=0.58

p=0.13

0

10

20

30

40

50

60

70

80

1

Hyperglycemia<6.5%

Cholesterol<4.5 mmol/l

Triglycerides<1.7 mmol/l

Systolic BP<130 mmHg

Diastolic BP<80 mmHg

Int Conv

Pat

ien

ts o

bta

inin

g t

reat

men

t g

oal

aft

er 8

yea

rs

%

p=0.06

p<0.0001

p=0.19

p=0.001

p=0.21


0

10

20

30

40

50

60

70

80

1

Hyperglycemia<6.5%

Cholesterol<4.5 mmol/l

Triglycerides<1.7 mmol/l

Systolic BP<130 mmHg

Diastolic BP<80 mmHg

Int Conv

Pat

ien

ts o

bta

inin

g t

reat

men

t g

oal

aft

er 8

yea

rs

%

p=0.06

p<0.0001

p=0.19

p=0.001

p=0.21



JSC 2006Riddle MC. Diabetes Care 1990;13:676

Mealtimeglucosespikes

Fastinghyperglycaemia

Normal

0600 06001200 1800 2400

300

200

100

0

Time (hours)

Pla

sma

glu

cose

(m

g/d

l)

The role of postprandial glycaemia(PPG)

JSC 2006

Capillary glucose and CHD risk – 2-hours post-50g glucose

*18,403 men (40-64 y). Fuller JH et al. Lancet. 1980;1:1373-1376.

96 (5.3) 110 (6.1) 200 Glucose

Centile

0

10

20

30

40

50

60

70

20 40 60 80 90 95 96 97 98 99 100

CH

D D

eath

s/ 1

000/

7.5

y

JSC 2006

2 hour postprandial glucose was an independent and progressive risk

factor for mortality

< 140 140-200 >200

2-hour postprandial glucose (mg/dl)

Ad

juste

d h

aza

rd r

ati

os f

or

death

Relative risk of death for 2 hour postprandial blood glucose

0.0

0.5

1.0

1.5

2.0

2.0

2.1

1.5

1.0

DECODE Study Group. Lancet 1999;354:617–21

JSC 2006

Postprandial glucose > 200 mg/dlin adults with diabetes

NHANES III Diabetes Care 2001; 24:1734

39%39%

99%99%99%99%

< 7% 7 - 7.9% > 8%Hb A1c

IF PPG EXCEEDS ELEVENYOU WILL NOT MAKE IT TO SEVEN

JSC 2006

Glu

cose

JSC 2006

BiAsp 30 in combination withmetformin in type 2 diabetes

Weeks160

BiAsp 30 bid + metformin (n=108)

BiAsp 30 bid (n=107)

Metformin failures

glibenclamide + metformin (n=114)

(n=329)

(HbA1c 7.5–13.0%)

Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

JSC 2006

7

7,5

8

8,5

BiAsp BiAsp+met met+SU

Treatment group

Hb

A1c

(%

)

Superior glycaemic control with BiAsp30 + metformin in poorly controlled patients

(HbA1c > 9%)

p = 0.037 p = 0.033


JSC 2006

• There were no reports of major hypoglycaemia during the trial

• The total number of minor hypoglycaemic episodes was similar between groups:

• BiAsp 30 + met 23• BiAsp 30 alone 20• Met + SU 28

• No other safety concerns were raised

BiAsp 30 plus metformin is well tolerated


JSC 2006

One daily injection of basal insulin may not give consistent control

• Absorption of long- or intermediate-acting insulins from the subcutaneous tissue varies from day-to-day

• This variability is one of the barriers to a successful outcome of the classical basal-bolus regimen

JSC 2006

Variation in glucose infusion rate-time curves for 3 patients with type 1 diabetes

Clamp 1

Clamp 2

Clamp 3

Clamp 4

Subject no: 224Subject no: 222Subject no: 216

NPH NPH NPH

Following NPH injection

Heinemann et al: In press.

JSC 2006

Mean Time-action profiles

0,0

0,5

1,0

1,5

2,0

2,5

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Insulin glargine

Insulin detemir

NPH insulin

glucose infusion rates (mg/kg/min)

time [h]

Heinemann et al: In press.

JSC 2006Christiansen JS et al. Diabetes Obes Metab 2003;5(6):445-452

• NPH + OHA

• OHA only

• No treatment

Screening

7–14 days 16 weeks 2 weeks

Twice-daily NovoMix® 30 (n = 201)

Twice-daily NPH insulin (n = 202)

Original treatment

Randomisation

• NPH monotherapy

NovoMix® 30 vs. NPH in type 2 patients

JSC 2006

Breakfast Lunch Dinner

-0.69**

-1.33**

*0.56

-1.26**

-2

-1.5

-1

-0.5

0

0.5

1

Diff

eren

ce in

pra

ndia

l glu

cose

incr

emen

tbe

twee

n tr

eatm

ent

grou

ps (

mm

ol/l)

* p < 0.005** p < 0.0001

Total mean prandial glucose increment

Christiansen JS et al. Diabetes Obes Metab 2003;5(6):445-452

NovoMix® 30 vs. NPH: lower prandial glucose increment

JSC 2006

NovoMix® 30(n = 66)

NPH(n = 66)

Cha

nge

in H

bA1c

(%)

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

p = 0.03

Christiansen JS et al. Diabetes Obes Metab 2003;5(6):445-452

Greater HbA1c reduction with NovoMix® 30 vs. NPH

• Greater reduction in HbA1c when switched to NovoMix® 30 twice-daily compared with adding another NPH injection in patients taking NPH monotherapy before the trial

JSC 2006

INITIATE: INITiation of Insulin to reach A1c TargEt

NovoMix® 30 (BID) vs glargine (OD)

n = 233Type 2 DMBMI < 40 kg/m2

Body weight <125 kgHbA1C > 8%on metformin +/- TZD

Glargine OD (12 U, bedtime) + metformin +/- pioglitazone

NovoMix® 30, pre-breakfast (6U) and pre-dinner (6U) + metformin +/- pioglitazone

4 wk run-in:Stop insulin secretagogues (SUs, nateglinide, repaglinide) and -glucosidase inhibitors (acarbose)Optimize metformin to ≥1500 mg/daySwitch rosiglitazone (Avandia) for 30 mg pioglitazone (Actos)

-4 0 28

(Weeks)INITIATE Raskin et al

Diabetes, June 2004, vol 53, suppl. 2, p. A143

JSC 2006

Blood glucose profiles

INITIATE Raskin et al


Befor

e br

eakfa

st

Breakfa

st +90

Befor

e lun

ch

Lunch +

90

Before dinner

Dinner +90

Bedtime

2 am

JSC 2006

Greater improvements in HbA1c with NovoMix® 30 than glargine

HbA1C (mean ± SD) NovoMix® 30

(n = 100)

Glargine

(n = 109)

p-value

Baseline

Week 28

Change from baseline

9.70 1.48

6.91 1.1

-2.79 0.11

9.84 1.42

7.41 1.3

-2.36 0.11

0.4782

0.0026

0.0057

INITIATE Raskin et al


Reduction in FPG (mean±SD)

End of trial – Baseline -125 72.9 -125 74.4 0.1176

JSC 2006

Pharmacokinetics: 28% greater AUC with NovoMix® 30 than glargine

NovoMix® 30 or glargine

NovoMix® 30

0

50

100

150

200

250

300

350

400

-1 4 9 14 19 24

Time (h)

Pla

sm

a I

ns

uli

n (

pM

)

NovoMix® 30

Glargine

PI AUC0-24h; p<0.01

Luzio et al, Diabetes, June 2004, vol. 53, p. A136

JSC 2006

Insulin action: NovoMix® 30 has a 34% greater glucose-lowering effect

NovoMix® 30NovoMix® 30 or glargine

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

-1 4 9 14 19 24

Time (h)

GIR

(m

g/k

g/m

in)

NovoMix® 30

GlargineGIR AUC0-24h; p<0.01

Luzio et al, Diabetes, June 2004, vol. 53, p. A136

JSC 2006

n = 100 Type 2 diabetes48 weeks treat-to-target study

The 1-2-3 Study: NovoMix® 30 OD, BID and TID

Jain et al. Diabetes 2005; 54(Suppl 1):A69

NovoMix® 30 pre-dinner x 16 wkIf HbA1C > 6.5%, go to phase 2

Phase 1

NovoMix® 30 pre-breakfast & dinner x 16 wkIf HbA1C > 6.5%, go to phase 3

NovoMix® 30 tid x 16 wk

Phase 2

Phase 3

JSC 2006

HbA1C ≤ 6.5

(AACE, IDF goal)

HbA1C < 7%(ADA goal)

OD 21% 41%

BID 52% 70%

TID 60% 77%

Baseline HbA1C was 8.6%

The 1-2-3 study: cumulative % of patients achieving targets

Jain et al. Diabetes 2005;54 (Suppl 1):A69

JSC 2006

Basal vs. premixed insulin therapy in type 2 diabetes.

A longitudinal cohort study

• GE medical record database (USA)

• 112862 T2D between 1998-2004.

• All patients with HbA1c records on insulin monotherapy with either– Lispro Mix (25/75), n=1569 or– Glargine , n=7036

Sun & Wang, EASD 2005

JSC 2006

Duration Mean HbA1c reductions in Lispro Mix Cohort

Mean HbA1c reductions in Glargine Corhort

Differences of mean HbA1c reductions (LM-GL)

Without Group Matching

Baseline to Q1 -0.9 -0.7 -0.1

Baseline to Q2 -0.9 -0.5 -0.4

Baseline to Q3 -1.0 -0.4 -0.6

With Group Matching

Baseline to Q1 -2.0 -1.4 -0.6

Baseline to Q2 -2.4 -1.7 -0.7

Baseline to Q3 -2.4 -1.7 -0.6

Sun & Wang, EASD 2005

Note: All mean changes of HbA1c are statistically significant with p-value < 0.001

JSC 2006

Postprandial glucose > 200 mg/dlPostprandial glucose > 200 mg/dlin adults with diabetesin adults with diabetes

NHANES III Diabetes Care 2001; 24:1734

39%39%

99%99%99%99%

< 7% 7 - 7.9% > 8%Hb A1c

IF PPG EXCEEDS ELEVENYOU WILL NOT MAKE IT TO SEVEN

JSC 2006

When it is time to start insulin in type 2 diabetes, why not try to mimic physiology?

• Basal insulin only will not adequately deal with postprandial glucose

• Rapid-acting insulin (analogues) should be added to control postprandial glucose

• Premixed insulin twice- or three-times daily may be an attractive regimen for type 2 diabetes patients requiring insulin for better control

JSC 2006

Documents

JSC 2006 An update on insulin therapy in type 2 diabetes mellitus Jens Sandahl Christiansen, MD, DMSc, FRCPI