The value of measuring and treating post-prandial hyperglycaemia – Evidence from

prospective studies

M. Hanefeld

Zentrum für Klinische Studien, GWT TU Dresden

Hanefeld@gwtonline-zks.de

Breakfast Lunch Dinner 0:00 4:00

Legend:

Postprandial state

Postabsorptive state

Fasting state

Monnier L. Eur J Clin Invest 2000;30(Suppl 2):3–11.

Most of our life we are spending in

the postprandial state

Breakfast

24h plasma glucose profile in healthy (n=18) and in type

2 diabetic (n=75) subjects

0

5

10

15

20

25

07:00 10:00 13:00 16:00 19:00 22:00 01:00 04:00 07:00

time

pla

sm

a g

luco

se (

mm

ol/l) NGT T2D

meals

Hanefeld M Diabetes & Stoffwechsel 1998

The GLUCO-TRIAD and risk of

atherosclerosis

FPG The basal

glucose level

PPGThe peak

glucose level

HbA1cThe long-term average glucose level

Blood Glucose and Risk of CVD in the

Asia-Pacific RegionDiab. Care 27: 2836, 2004

Evidence for 2-hour

postprandial/postchallenge to be an

independent risk factor

*As assessed by intima-media thickness

AUC = area under the curve

Significance

FPG 1.30 (0.92–1.82) NS

30-minute plasma glucose 1.11 (0.80–1.56) NS

60-minute plasma glucose 1.48 (1.06–2.07) p<0.05

90-minute plasma glucose p<0.05

Two-hour plasma glucose 1.88 (1.34–2.63) p<0.05

Plasma glucose peak 1.47 (1.05–2.05) p<0.05

Plasma glucose increment 1.50 (1.08–2.10) p<0.05

Plasma glucose AUC 1.63 (1.16–2.29) p<0.05

Glycaemic parameter Odds ratio

HbA1c 1.24 (0.82–1.89) NS

1.45 (1.03–2.02)

Temelkova-Kurktschiev TS et al. Diabetes Care 2000;23:1830–1834.

Relationship of parameters PGR to IMT

PPG, not FPG, determined risk of abnormal arteries*

Model 1 Model 2

Variable ß-coefficient p Variable ß-coefficient p

Age 0.326 < 0.001 Age 0.322 < 0.001

Sex - 0.242 < 0.001 Sex - 0.230 < 0.001

Plasma glucose

2h

0.140 0.001 Plasma glucose

2h

0.178 < 0.001

HDL cholesterol - 0.103 0.025 HDL cholesterol - 0.124 0.013

Albuminuria 0.098 0.021 Albuminuria 0.112 0.011

Leukocytes

count

0.083 0.045 Leukocytes

count

0.104 0.016

Total cholesterol 0.101 0.019

DeterminantsDeterminants of of carotidcarotid IMTIMTmeanmean: :

thethe RIAD RIAD StudyStudy

Temelkova-Kurktschiev T et al. Diabetes Care 2000; 23:1830-34

Relation between postprandial blood glucose levels and cardiovascular mortality

DECODE

19991Pacific and

Indian Ocean

19992

Funagata

Diabetes Study

19993

Whitehall, Paris and

Helsinki Study

19984

Diabetes

Intervention Study

19965

The

Rancho–Bernardo

Study 19986

ppBG

Honolulu

Heart Programme

19877

CVD death

4 Balkau B et al. Diabetes Care 19985 Hanefeld M et al. Diabetologia 1996

6 Barrett-Connor E et al. Diabetes Care 19987 Donahue R. Diabetes 1987

1 DECODE Study Group. Lancet 19992 Shaw J et al. Diabetologia 1999

3 Tominaga M et al. Diabetes Care 1999

Evidence from intervention

studies

Development of first cardiovascular events

Risk

red.

(%)

p

Ac

(n=682)

Pl

(n=686)

No. of patients

Favoursacarbose

Favoursplacebo

0 0.5 1.0 1.5 2.0

Coronary heart disease

myocardial infarction 1 12 91

angina 5 12 55

revascularisation 11 20 39

cardiovascular death 1 2 45

Congestive heart failure 0 2 –

Cerebrovascular accident/ 2 4 44

stroke

Peripheral vascular 1 1 –

disease

Any prespecified 15 32 49

cardiovascular event

0.0226

0.1344

0.1806

0.6298

–

0.5061

0.9255

0.0326

Cardiovascular event

STOPNIDDM

Chiasson JL et al. JAMA 2003; 290: 486-94

Changes of IMTmean and IMTmax between baseline and

endpoint of the study: Effect of acarbose in STOP-NIDDM

subgroup analysis

(average time of treatment 3.9 years)

Acarbose (A) Placebo (Pl) p

Baseline Endpoint Baseline Endpoint

IMTmean (mm)* 0.91

(0.18)

0.93

(0.18)

0.93

(0.19)

0.97

(0.20)

A 0.02

Pl<0.001

∆IMTmean(mm) † 0.02 (0.07) 0.05 (0.06) 0.027

∆IMTmean/year †

(mm/y)

0.007 (0.019) 0.013 (0.018) 0.021

IMTmax (mm)* 1.03

(0.24)

1.05

(0.23)

1.05

(0.22)

1.08

(0.22)

A 0.044

Pl 0.007

∆IMTmax (mm) † 0.02 (0.08) 0.03 (0.08) n.s.

* Differences between baseline and endpoint † Differences between the groups

Hanefeld M et al Stroke 2004

Adapted from Esposito K et al. Circulation 2004;110:214-219.

Repaglinide vs. glyburide:

significant regression of

atherosclerosis despite no

significant change in other risk

factors:

(eg, BMI, blood pressure, total

cholesterol, triglycerides)

Targeting PPG slows progression of

atherosclerosis in carotid arteries

The decrease in IMT was associated with

changes in postprandial but not fasting

hyperglycaemia

0

5

10

15

20

25

30

35

40

45

50

Repaglinide Glyburide

Treatment group

Perc

enta

ge o

f pa

tients

achie

vin

g

glu

cose p

eak <

140 m

g/d

L

p=0.01

0

10

20

30

40

50

60

Repaglinide Glyburide

Treatment group

Perc

enta

ge o

f pa

tients

achie

vin

g

fasting g

lucose level <

110 m

g/d

L

p=0.01

Esposito K et al. Circulation 2004;110:214-219.

Incidence of MI and Mortality-Rate according to categories of

the NIDDM-Policy Group: 11 years follow-up(Hanefeld et al. Diab Med 1997)

Incidence of MI and Mortality-Rate according to categories of

the NIDDM-Policy Group: 11 years follow-up(Hanefeld et al. Diab Med 1997)

0

50

100

150

200

250

good borderline poor 0

50

100

150

200

250

300

good borderline poor

0

50

100

150

200

250

good borderline poor

FBG pp BG

0

50

100

150

200

250

good borderline poor

Triglycerides Blood pressure

Rate

pe

r 1000

Rate

pe

r 1000

Rate

pe

r 1000

Rate

pe

r 1000

MI

Mortality

*

** ** **

*) p < 0.05

**) p < 0.01

*

Effect of acarbose on developing cardiovascular events during the treatment phase: MeRIA7 study

M. Hanefeld et al. Eur Heart J 2004 Cox proportional hazards model

Inflammation as link between

postprandial hyperglycemia and

atherogenesis

0

1

2

3

4

5

6

7

Fibrinogen (g/l) CRP (mg/l) Leukocytes count (GPt/l)

NGT

IGT

Diabetes

*

*

*

*

*

Inflammatory Parameters in Glucose Tolerance Stages

Temelkova-Kurktschiev T et al. Diabetologia 2002

Postprandial excursions of glucose, triglycerides, leucocytes and PAI1 after a mixed meal in drug naive type 2 diabetes patients (N=55)

Unpublished results

time (min)

2401200

trig

lyce

rid

es (

me

an

+S

D)

mm

ol/l

5

4

3

2

1

0

-1

time (min)

2401200

PA

I 1 (

me

an

+S

D)

ng

/ml

200

100

0

-100

time (min)

2401200

pla

sm

a g

lucose (

mean +

SD

) m

mol/l

16

14

12

10

8

6

4

2

time (min)

2401200

Leucocyte

s c

ount (m

ean+

SD

) G

Pt/l

12

10

8

6

4

2

# ** #

# ** ##

**#

#

**#

Impact of postprandial glucose control by acarbose on

postprandial leucocyte excursion: AIDA-study

unpublished

5

6

7

8

9

0 2 4

Time after testmeal (h)

leu

co

cyte

s (

GP

t/l)

Placebo V2

Acarbose V2

Placebo V5

Acarbose V5

*

*Acarbose: V2 vs. V5 p=0.01

Pathopysiology of pp state due to excessive hyperglycemia

excessive pp

hyperglycemia

blood

coagulation ↑HDL-C catabolism ↑

plaque stability ↓

TG-rich lipoproteins

LDL removal ↓

endothelial

dysfunction

(NO release ↓)

insulin

resistance ↑

FFA ↑fibrinolysis ↓

B-cell function ↓

oxidative

stress ↑

Hanefeld M. 1999 Diabetes & Stoffw.

subclinical

inflammtion ↑

Practical consequences

Insulin treatment guided by pp (2h)

glucose value

Variable Preprandial Monitoring (n=33)

Postprandial Monitoring (n=33)

p-value

Gestational age at delivery (wk)

37.6 37.9 0.16*

Maternal weight gain (kg)

10.7

10.5

0.94*

Success in glycemic control (%)

86

88

0.62**

Compliance with schedule (%)

98 95 0.76**

Insulin dose Units/day Units/kg

76.8 0.9

100.4

1.1

0.003* 0.001*

Glycosylated hemoglobin (%)

Initial 8.6 8.9 0.55*

Final 8.1 6.5 0.006*

Change - 0.6 - 3.0 < 0.001*

Efficacy of monitoring of preprandial versus postprandial bloodglucose monitoring in women with gestational diabetes

* By Student‘s t-test, ** By the Mann-Whitney-U-test deVeciana et al. NEJM 1995

Impact of Impact of qualityquality of of metabolicmetabolic controlcontrol on on CesareanCesarean sectionsection

and and neonatalneonatal outcomesoutcomes byby preprandialpreprandial and postprandial and postprandial

controlcontrol

Variable Preprandial Monitoring

(n=33)

Postprandial Monitoring

(n=33)

p-value

Cesarean section Total For CPD

13 12

8 4

0.29** 0.04**

Birth weight (g) 3848 3469 0.01*

Large for gestational age 14 4 0.01**

Birth weight > 4000g 12 3 0.01**

Small for gestational age 0 1 1.00**

Shoulder dystocia 6 1 0.10**

Neonatal hypoglycemia 7 1 0.05** Hyperbilirubinemia 4 3 1.00**

Transient tachypnea 2 2 1.00**

Apgar score at 5 min ≤≤≤≤ 7 3 1 0.61**

Stillbirth*** 1 0 1.00**

* By Student‘s t-test; ** By Fisher‘s exact test (two tailed)

*** One unexplained stillbirth at 21 weeks, the autopsy was normal

deVecianadeVeciana et al. NEJM 1995et al. NEJM 1995

Prandial insulin substitution with insulin lispro or

insulin lispro mid mixture vs. Basal therapy with

insulin glargine: A randomized controlled trial in

patients with type 2 diabetes beginning insulin therapy

Kazda C, Hülstrunk H, Helsberg K, Langer F, Forst T, Hanefeld M

Journ Diab and Ist Compl 20 (2006) 145-152

Definition of Therapeutic Goal

• Goal for Insulin Lispro / Lispro MidMix: 2h

pp PG: < 10mmol/l

• Insulin Glargine: FPG < 7mmol/l

• Therapy guided by SMBG

Self measured blood glucose profiles

after 3 months and 6 months

100

120

140

160

180

200

220

Fasting 2h pp pre

lunch

2h pp pre

dinner

2h pp bedtime 3:00

Uhr

mg

/d

l

Lispro Lispro Midmix Glargine

100

120

140

160

180

200

220

Fasting 2h pp pre

lunch

2h pp pre

dinner

2h pp bedtime 3:00

Uhr

mg

/d

l

Lispro Lispro Midmix Glargine

C. Kazda et al. / Journ Diab and Its Compl 20 (2006) 145-152

HbA1c

6

6,5

7

7,5

8

8,5

%

Lispro Lispro

MidMix

Glargine

HbA1c-values at baseline and after 24 weeks

Baseline

Endpoint

* **

*,**: p<0.001 versus Glargine

C. Kazda et al. / Journ Diab and Its Compl 20 (2006) 145-152

Dosage of insulin treatment

0.43 ± 0.230.58 ± 0.280.5 ± 0.24Insulin dosage

[I.E./kgBW/24h]

37.45 ±

22.853.04 ± 24.81

47.23 ±

23.81

Insulin dosage

[I.E./24h]

GlargineLispro

MidMixLisproMean ±SD

C. Kazda et al. / Journ Diab and Its Compl 20 (2006) 145-152

Postmeal blood glucose monitoring is

essential for good diabetes control

Examination Schedule

Morning

get upBreakfast Lunch Dinner

30‘ pre-meal monitoring for insulin dosage adjustment

monitoring 2 hours after meal

By extrapolation

A normalisation of postprandial glucose

excursion is a powerful tool to improve

endothelial dysfunction, protect unstable

plaques and prevent cardiovascular

complications.