CardioMetabolic Foru

Diabetes and the

Metabolic Syndrome:
New Strategies for
Preventing Death and
Disability
Paris, May 1821, 2005

Companion slide set

1. Continuing burden
of type 2 diabetes and
cardiovascular disease

Number of people with

diabetes world wide (millions)

Global diabetes epidemic

72%
increase

Year
International Diabetes Federation

% Increase in diabetes
cases from 20012025

Developing countries will bear

the burden of the diabetes
epidemic

a
t
a
t
ia
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or
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C
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A
W
id
& eric
Eu
Oc
Am
M
S m
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A

International Diabetes Federation

Disproportionate burden of
diabetes
in some ethnic groups
Women

Prevalence (%)

Prevalence (%)

Men

DiabetesIFG / IGT Normomellitus

glycaemia

DiabetesIFG / IGT Normomellitus

glycaemia

Hispanic (n=212)Non-Hispanic white (n=233)

Lindeman RD et al. Diabetes Care 1998;21:959-66

Poor prognosis associated with a

diagnosis of diabetes in the
NHANES I cohort
Age 4554
at baseline

Age 5564
at baseline

% Survival

Age 2544
at baseline

Duration of follow-up (years)

Diabetes

No diabetes

Gu K et al. Diabetes Care 1998;21:1138-45

Type 2 diabetes confers the same

adverse prognosis as a prior
myocardial infarction
% Surviving

100

80
No diabetes, no MI
Diabetes, no MI

60

No diabetes, with prior MI

Diabetes, with prior MI

40
0

4
6
Years of follow-up

Haffner SM et al. NEJM 1998;339:229-34

Age-standardised mortality
per 100,000 person-years

Sources of excess mortality in

diabetes
NHANES I cohort

Death from
Gu K et al. Diabetes Care 1998;21:1138-45

Cardiovascular risk factors in

type 2 diabetes
Dyslipidaemia

Hypertension
Diabetic

CHD deaths/
1000 patient-years

Non-diabetic

Obesity

Serum cholesterol
(mmol/L)

SBP (mmHg)

BMI (kg/m2)

Adlerberth AM et al. Diabetes Care 1998;21:539-45

Eschwege E. Diabetes Metab 2003;29:6S19-27

Risk factors for coronary artery

disease

Stepwise selection of major risk factors for 280

coronary
artery disease events in 2,693 UKPDS patients
Potentially
p
followedmodifiable
for 10 years

LDL cholesterol
HDL cholesterol
HbA1C

<0.0001
0.0001
0.0022

Systolic blood pressure

0.0065
Smoking
0.056

Age and gender were also significant risk

factors but not
body mass index, fasting plasma insulin,
waist/hip ratio or microalbuminuria

UKPDS 23. BMJ 1998;316:823-8

2. The metabolic
syndrome, type 2 diabetes
and cardiovascular risk

Defining the metabolic

syndrome
WHOa

EGIRb

NCEPc

IDFd

Insulin
resistance
&/or FPG

Insulin
resistance
(hyperinsulinae
mia)

FPG

Central
obesity

Plus 2 or more of

Central
obesity

Central obesity

Central
obesity

FPGe

BP

BP

BP

BPe,f

TG,
HDL-C

TG, HDL-Cf

TG

TGf

World Health Organisation; bEuropean Group for the study of

Microalbumi
HDL-C
HDL-Cf
Insulin
resistance;
c
nuria
National
Cholesterol Education Program; dInternational
Diabetes Federation
Diabetes
Metab 2003;29:6S19-27; International Diabetes Federation
e
or diagnosis of diabetes or hypertension as applicable;

Age-related prevalence of the

metabolic syndrome according to
WHO and EGIR

World Health
Organisation
(WHO)

European Group for

the Study of Insulin
Resistance (EGIR)

Balkau B et al. Diabetes Metab 2002;28:364-76

Eschwege E. Diabetes Metab 2003;29:6S19-27

Age-related prevalence of the

metabolic syndrome (NCEP/ATP
III)

al Health and Nutrition Examination Survey 19992000

Ford ES et al. Diabetes Care 2004;27:2444-9

Changes over time in the

prevalence of components of the
metabolic syndrome
Women

Age-adjusted
prevalence (%)

Men

Abdo TG HDL BP
obesity

Abdo TG HDL BP
obesity

NHANES III (19881994, n=6436)

NHANES 19992000 (n=1677)
Revised NCEP/ATP III definition
Ford ES et al. Diabetes Care 2004;27:2444-9

Cumulative hazard (%)

The metabolic syndrome confers

a high
risk of cardiovascular disease

Coronary heart disease Cardiovascular disease

10

10
Relative risk
3.77
(95% CI 1.74 to 8.17)

Relative risk
3.55
(95% CI 1.96 to 6.43)

MS

MS

No MS

0
0

No MS

0
12

Years of follow-up

12

Lakka HM et al. JAMA 2002;288:2709-16

Insulin resistance and adverse

cardiovascular outcomes (1)
Incidence/1000 patient-years

Prospective cohort study in Malm, Sweden (n=4748)

RR 2.18
(95% CI 1.82 to 3.87)
RR 1.62
(95% CI 1.03 to 2.55)

(+) Insulin resistance

() Insulin resistance
Hedblad B et al. Diabet Med 2002;19:470-5

Insulin resistance and adverse

cardiovascular outcomes (2)
5-year CV event rate (%)

Five-year follow-up of the placebo group

(n=2283) of
the Veterans
RR 1.62 Administration HDL
RR 1.43
(95%CI
1.28 to 2.06)
Intervention
Trial (VA-HIT)
(95%CI 1.03 to 1.98)

(+) Insulin resistance

() Insulin resistance
Robins SJ et al. Diabetes Care 2003;26:1513-7

Prevalence of the metabolic

syndrome according to
glycaemic status
%

Subjects aged 3570 years

Isomaa B et al Diabetes Care 2001;24:683-9

The metabolic syndrome is a risk

factor for coronary heart disease
Prevalence of CHD (%)

Prevalence of CHD in relation to glycaemic

control
and the presence of the metabolic syndrome
RR=2.23
p<0.001

RR=1.73
p=0.04

RR=1.82
p=0.06

WHO criteria for metabolic syndrome

Isomaa et al. Diabetes Care 2001;24:683-9

Metabolic syndrome, component

cardiovascular risk factors and
prognosis
Botnia Study

Relative risk of
CHD

Metabolic
syndrome

2.96

<0.001

Dyslipidaemia

1.73

<0.001

Hypertension

1.57

0.002

Insulin resistance

1.53

0.01

Obesity

1.44

0.07

Microalbuminuria

0.94

0.77

Adjusted for age and gender. The WHO definition of metabolic syn
Insulin resistance = highest quartile of HOMA insulin resistance.
Isomaa et al. Diabetes Care 2001;24:683-9

Development of diabetic
dyslipidaemia
in the setting of insulin
Insulin
1. Failure
of insulin to
resistance
X

suppress lipolysis in
insulin resistance

TG

Lip

TG
Chol

is
s
Chol
oly

TG

3. VLDL-C
Cho
l
Loaded with TG

2. FFA in
portal circulation
increases TG synthesis

TG in systemic
circulation

Small,
dense
LDL-C

4. CETP loads
TG HDL with T
Chol

Lipolysis
TG
Chol
5. Small, dense HDL-C

is rapidly cleared

low HDL-C

Krauss RM. Diabetes Care 2004;27:1496-1504

Diabetic dyslipidaemia: low HDLcholesterol and elevated

triglycerides
Lipid profiles and hyperinsulinaemia in
newly diagnosed type 2 diabetic patients

HDL-C (mmol/L)
Triglycerides
(mmol/L)
LDL-C (mmol/L)
Total-C (mmol/L)
Fasting insulin
(mU/L)

Type 2
diabetes
(n=133)

Control
(n=144)

1.07

1.34

<0.05

2.41

1.60

<0.05

4.49
6.43

4.17
6.7

NS
NS

24.8

15.4

0.003

Niskanen L et al. Diabetes Care 1998;21:1861-9

Age-adjusted CHD mortality

per 10,000 patient-years

Low HDL-cholesterol predicts

coronary mortality irrespective of
total cholesterol
HDL-C <0.9 mmol/L (35 mg/dL)

RR* 1.22
(1.01-1.46)

HDL-C >0.9 mmol/L (35 mg/dL)

RR* 1.25
(0.98-1.60)

Total-C <5.2 mmol/L

(200 mg/dL) (n=4051)

Total-C >5.2 mmol/L

(200 mg/dL) (n=4535)

*Relative risk adjusted for age, blood

Goldbourt U et al. Arterioscler
pressure, smoking and diabetes
Thromb Vasc Biol

Greater outcome benefits from

increasing
HDL-cholesterol in type 2 diabetic
No diabetes (p=0.07)
subjects
Combined
Diabetes (p=0.004)

endpoint

No diabetes (p=0.09)
Diabetes (p=0.17)

Nonfatal MI

No diabetes (p=0.8
Diabetes (p=0.02)

CHD death

No diabetes (p=0
Diabetes (p=0.46

Stroke
Favours active treatment
0.2

0.6

1.0

1.4

Hazard ratio (95% CI)

Rubins HB et al. Arch Intern Med 2002;162:2597-604

Correcting LDL-cholesterol only

partially normalises the risk of a
cardiovascular event

Effects on primary endpoints in major statin trials

% Overall risk
Kastelein JJP. Eur Heart J (Suppl) 2005 (in press)

Prognostic importance of small,

dense LDL
LDL peak diameter
p=0.002

LDL particle size distribution

p<0.001

%
p<0.001
p<0.001

<255

255260

>260

Remained free of ischaemic heart disease (n=1926)

Developed ischaemic heart disease (n=108)
St-Pierre AC. Circulation 2001;104:2295-9

3. Diabetes,
atherothrombosis
and the vascular wall

Anatomy of the atherosclerotic

plaque
Vulnerable Plaque
Large lipid core with
thin fibrous cap,
macrophages
interacting with
thrombus

Stable Plaque

Reduced lipid core with

thick fibrous cap
reinforced with increased
smooth muscle cells
Thrombus
Lumen
Endothelium

Smooth
muscle cell
Lipid rich core
Thin
fibrous cap

Platelets

Macrophage

Thick
fibrous cap

Endothelial function and

fibrinolysis
Cytokines, insulinActivated
platelets
Proinsulin
Plasmin
High glucose
Glycation
Modified
LDL/VLDL
PAI-1
tPA

Plasminogen
tPA

Fibrin
deposits

Damage to the vascular

endothelium is an early event in
diabetogenesis
Odds ratio (95% CI) for
developing diabetes

3.0 (1.08.6

0.044

4.4 (1.513.0)

0.006

10.4 (2.740.0)

0.001

tPA activitya
PAI-1 activityb
tPA antigenb

tPA antigen (adjusted

6.5 (1.333.0)
for CV risk factors)b

0.024

1st quartile vs. quartiles 24

b
4th quartile vs. quartiles 13
a

Eliasson MC et al. Cardiovasc Diabetol 2003,2:19

Insulin resistance and impaired

fibrinolysis
AGE
products

Hyperinsulina
emia

Hyperglycae
mia
INSULIN
RESISTANCE
Hyperten
sion
Smoki
ng

Triglyceri
de
Cholest
erol

PAI1
tPA
Factor
VII
Factor
Fibrino
XII
gen
Grant PJ. Diabetes Metab 2003;29:6S44-52

Fibrinolysis
Clotting
stimulus

Thrombin
Factor XIII

Fibri
n
Cross-linked
fibrin

tPA
Plasminoge
n

Fibrinog
en

+
-

Plasmin

PAI-1

Fibrin
degradation
products

Grant PJ. Diabetes Metab 2003;29:6S44-52

PAI-1 antigen (ng/mL)

Impaired fibrinolysis in type 2

diabetes: plasminogen activator
inhibitor-1 (PAI-1)
p<0.0
01*

Normal
(n=693)
*Adjusted for age, gender

IGT
(n=348)

Type 2
diabetes
(n=510)

Festa A et al. Arterioscler Thromb Vasc Biol

Atherosclerosis and inflammatory

markers in the Rotterdam study
svCAM-1
sICAM-1
Interleukin-6
C-reactive protein

Odds ratio (3rd vs. 1st tertile) for presence of carotid plaque
(determined using a scoring system)
Odds ratios adjusted for
age, gender, smoking, BMI and diabetes
van der Meer IM et al. Arterioscler Thromb Vasc Biol 2002;22:838-42

Inflammation and characteristics

of the atherosclerotic plaque (1)

% Plaques with evidence of inflammation

Moreno PR et al. Circulation 2002;105:2504-11

Inflammation and characteristics

of the atherosclerotic plaque (2)

p=NS

% of plaques

mm2

Thickness
Medial inflammation (n=101)
No medial inflammation (n=324)
p=0.014; 0.0001
IEL: internal elastic lamina
Moreno PR et al. Circulation 2002;105:2504-11

Elevated C-reactive protein in

diabetes

SBP (mmHg)
HDL-C (mmol/L)
Triglycerides
(mmol/L)
LDL-C (mmol/L)
Carotid IMT (mm)

Serum CRP
(mg/L)

Controls
(n=197)

Newly
diagnosed
diabetes
(n=24)

Known
diabetes
(n=50)

118
1.3

141
1. 1

137
1.2

1.2

1.7

1.7

3.9
0.85

3.6
0.93

3.5
1.00

1.0

2.7

2.2

IMT: intima-media thickness; CRP: C-reactive protein

Sigurdardottir V et al. Diabetes Care 2004;27:880-4

Inflammation as a predictor of
diabetes: the Atherosclerosis
Risk
in
Communities
Study
Model 1
Model 2
Interleukin-6
C-reactive protein
Orosomucoid
Sialic acid

0
1
2
3
0
1
2
3
4
5
Adjusted hazard ratio (95% CI) Adjusted hazard ratio (95% CI)

1. Adjusted for age, centre, gender, ethnicity,

2. As left, plus BMI, waist-hip
family diabetes history, hypertension ratio, fasting glucose and in
Duncan BB et al. Diabetes 2003;52:1799-805

Conclusions
There remains a substantial burden of
cardiovascular disease, despite general
improvements in outcomes in recent decades
The coming global epidemic of type 2 diabetes
will exacerbate this situation
The metabolic syndrome and type 2 diabetes
continue to drive adverse cardiovascular
outcomes
Elevated levels of PAI-1 and chronic, low-grade
inflammation contribute importantly to
atherosclerotic changes within the vascular wall

CardioMetabolic Foru
Diabetes and the
Metabolic Syndrome:
New Strategies for
Preventing Death and
Disability
Paris, May 1821, 2005

Management of glycaemia
and cardiovascular risk
with metformin

1. Antihyperglycaemic
efficacy of metformin

Therapeutic actions of metformin:

correcting the pathophysiology of
type 2 diabetes
Pancreas

Impaired
insulin secretion

Increased
glucose
production

Hyperglycaemia

Liver

Decreased
glucose
uptake
Muscle

Metformin

Dose-relationship of
antihyperglycaemic actions of
metformin
Metformin dose

p<0.001 vs. placebo

Garber AJ. Am J Med 1997;102:49

Antihyperglycaemic efficacy and

insulin-sparing action of
metformin
p<0.01

pmol/L

% units

p<0.05

1C

Baseline

3 months of metformin

DeFronzo RA et al. Clin Endocrinol Metab 1991;73:1294-301

Comparative efficacy of
metformin:
meta-analysis of 11 studies
HbA1C

10 -12.5% -12.5%
9

Fasting glucose
Postprandial glucos

10

-14%

-19%

15

mmol/L

%
8

10

7
Metformin SU
(n=148) (n=159)

SU: sulfonylurea

-44.5% -44.5%

mmol/L

20

5
Metformin SU
(n=148) (n=159)
Baseline

Metformin SU
(n=214) (n=213)

Final

Campbell IW et al. Diabetes Metab Rev 1995;11 (Suppl 1):S57-62

Blood glucose control in the

UK Prospective Diabetes Study
9

FPG

HbA1C

10
Median HbA1c (%)

Median FPG (mmol/L)

11

9
8
7
6
5

2
4
6
8
10
Time from randomisation (y)
Metformin
Diet

8
7

6
5

2
4
6
8
10
Time from randomisation (
Glibenclamide
Insulin

UKPDS 34. Lancet 1998;352:

Choice of agents in current use

Glipizide
Gliclazide
Glimepiride
Glibenclamide

TZDs

Sulfonylureas

Metformin

Acarbose
Miglitol
Voglibose

-glucosidase
inhibitors

Meglitinides
Rosiglitazone
Pioglitazone

Repaglinide
Nateglinide

Efficacy of co-administered
combinations based on metformin
HbA1C (%)
Base

Mean
change

Metformin +
glibenclamide1

8.8

1.7

Metformin +
glimepiride2

6.5

-0.7

Metformin +
repaglinide3

8.5

-1.4

Metformin +
pioglitazone4

9.8

-0.6

Metformin +

2
DeFronzo RA et al. N Engl J 5Med 1995;333:541-9;
Charpentier
G et al. Diabet
8.8
-0.8
rosiglitazone
Med 2001;16:
828-34; 3Moses R et al. Diabetes Care 1999;22:119-24; 4Einhorn
D et al. Clin Ther 2000;22:1395-409;
Metformin +
1

2. Improvements in
cardiovascular risk
factors with
metformin

Effects of metformin on insulin

sensitivity
Non-oxidative
glucose metabolism

15
*

30
20
10

25
g/kg/min

40

Glucose
oxidation
g/kg/min

mmol/kg/min

Whole-body
glucose disposal

1
5
5

20
15
10
5

Plac

Met

Before treatment

Plac

Met

Plac

Met

1 month placebo or metformin

*p<0.05 vs. placebo

Gianarelli R et al. Diabetes Metab 2003;29:6

Effects of metformin on
glycaemia and lipids: data from a
meta-analysis
Mean change with
metformin (95%
CI)

HbA1C (%)

-0.74 (-0.84 to -0.65)

<0.0000
1

Triglycerides
(mmol/L)

-0.13 (-0.21 to -0.04)

0.003

Total cholesterol
(mmol/L)

-0.26 (-0.34 to -0.18)

<0.0001

LDL-cholesterol
(mmol/L)

-0.22 (-0.31 to -0.13)

<0.0000
1

HDL-cholesterol
(mmol/L)

0.01 (-0.02 to -0.03)

0.50

Wulffele MG et al. J Intern Med 2004;256:1-14

10-year risk (%)

Cardiovascular risk engines

underestimate the cardiovascular
benefits of metformin

Wulffele MG et al. J Intern Med 2004;256:1-14;

UK Prospective diabetes Study (UKPDS) risk engine;
Prospective Cardiovascular Mnster study (PROCAM) risk calculator

Metformin and body weight

regulation

Meta-analysis: net difference (+) 4 kg

for sulfonylureas

**

***

***

***

***
*

el
l
p
b

C
am

B
oy
d

an

n
H
er
m

an

H
er
m

N
ou
ry

J
ku
tt
y

C
ol
li

er

s
R
ai
n

la
rk
e

**

*p<0.05 **p<0.01 ***p<0.001

Campbell IW & Howlett HCS. Diabetes Metab Rev 1995;11:S57-62

Metformin-induced alterations in
body composition
Selective loss of visceral fat
Change from % Decrease

baseline from baseline value

Weight (kg)

- 3.3

4%

0.006

Body mass index (kg/m2)

- 1.2

4%

0.006

Total body fat (L)

- 2.8

9%

0.014

Total subcutaneous fat (L)

- 2.1

7%

0.025

1.2
Abdominal subcutaneous fat -(L)

11%

0.013

- 0.6

15%

0.01

No change

NS

Visceral fat (L)

Lean body mass

Data are means. Duration of treatment: 6

months
Kurukulasuriya R et al. Diabetes

% Increase in forearm blood flow

Endothelial function in diet-failed

type 2 diabetic patients before
and after metformin
500

Endothelium-dependent
(acetylcholine)

500

Endothelium-independent
(verapamil)

p<0.05

p=NS

400

400

300

300

200

200

100

100

0
Placebo Metformin
(n=15)
(n=29)
Baseline

Placebo Metformin
(n=29)
(n=15)
12 weeks
Mather KJ et al. JACC 2001;37:1344-50

Effects of metformin on levels of

PAI-1

PAI-1 (AU/mL)

p=0.001

Nagi DK, Yudkin JS. Diabetes Care 1993;16:621-9

Fibrinolysis in type 2 diabetic

patients treated with metformin
HbA1C

-0.5
***
***

Placebo (n=23)

80

0
ng/mL

% of baseline value

% units

0.5

-1.5

tPA antigen

120

1.0

-1.0

PAI-1

40

-2

**
***

-4

Metformin 3000 mg/day (n

Metformin 1500 mg/day (n=25)

*p<0.05, **p<0.01, ***p<0.001 vs. placebo

Grant PJ. Diabetes Care 1996;19:64-6

Factor XIII activity (units/mL)

Factor XIII activity in type 2

diabetic patients following
metformin treatment

Placebo

Metformin
1500 mg/day

*p=0.01 vs placebo

*
Metformi
n
3000
mg/day

Standeven KF et al. Diabetes 2002;51:189-97

Mean change from baseline

in Factor VII antigen (%)

Factor VII levels in type 2 diabetic

patients following metformin
treatment

Placebo

Metformin
1500 mg/day

Metformin
3000 mg/day

Grant PJ. Thromb Haemost 1998;80:209-10

Other antiatherogenic actions of

metformin
Action

Potential effect

Oxidation

Apoptosis, oxidative
damage
Inflammation,
oxidative
stress/apoptosis

Advanced glycation
end-products

Endothelial adhesion
Atherogenesis
molecules
Monocytes
Atherogenesis
macrophages
Kurukulasuriya
R et al.by
Diabetes 1999;48
Suppl:A315; Beisswenger P et al.
Lipid uptake
Atherogenesis
Diabetes Metab 2003;29:6S95-103; Pavlovi D et al. Diabetes Obes Metab
macrophages
2000;2:251-6; Mamputu JC et al. Diabetes Metab 2003;29:6S71-6.

3. Improved
cardiovascular
outcomes with
metformin

Intensive glycaemic management

with
metformin
in the UKPDS
4209 patients in
the main UKPDS
analysis
1704 overweight
patients from 15
UKPDS centres

2505
nonoverweight
patients

Conventional
management
with diet
(n=411)

Intensive
Intensive
management
management
with
with
metformin
sulfonylurea or
(n=342)
insulin
(n=951)
UKPDS 34. Lancet
1998;352:854-65

Clinical outcomes in the UKPDS

Metformin
Sulfonylurea / Insulin
Intensive (n=342) Intensive (n=951)
Change in risk* P value
Change in risk*P value
42%
Diabetes-related deaths

0.017

20%

0.19

36%

0.011

8%

0.49

32%
Any DM-related endpoint

0.0023

7%

0.46

Myocardial infarction 39%

0.01

21%

0.11

41%

0.13

14%

0.60

All-cause mortality

Stroke

*Compared with conventional, diet-based therapy

(overweight group)
UKPDS 34. Lancet 1998;352:854-65

Metformin and cardiovascular

outcomes in
the PRESTO trial: design of the
analysis
revention of REStenosis
with Tranilast and its Outcom
Double-blind, randomised, placebo-controlled
trial of tranilast after percutaneous
intervention for myocardial ischaemia
(N=11,484)
Primary endpoint: major cardiovascular
events
combined incidence of MI, death and
revascularisation for ischaemia

25% of the PRESTO population had diabetes at

baseline
Effect on outcomes in the diabetic subpopulation metformin was analysed
retrospectively (metformin vs. non-insulin
sensitiser therapy)
Kao J et al. Am J Cardiol 2004;93:1347-50

Metformin and outcomes in

PRESTO:
patient characteristics at
baseline
Metformin
(n=887)

Non-insulin
sensitiser
(n=1110)

63

61

Women/men (%/%)

30/70

30/70

Dyslipidaemia (%)

62

65

Hypertension (%)

74

77

Coronary artery
disease

51

60

History of MI (%)

40

40

Mean age (y)

Kao J et al. Am J Cardiol 2004;93:1347-50

PRESTO: improved outcomes

with metformin
Odds ratios for adverse clinical outcomes for
metformin vs. non-insulin sensitiser therapy
Any clinical event (p=0.005)
Myocardial infarction (p=0.002)
Death (p=0.007)
Ischaemia-driven
revascularisation (p=NS)
Favours
metformin Adjusted odds ratio (95% CI)
Kao J et al. Am J Cardiol 2004;93:1347-50

Role of metformin postmyocardial infarction

*

*p=0.003
Follow-up 3 years
Sgambato S et al. Clin Ter 1980;94:77-85

Effects of metformin treatment on

the
symptoms
cardiovascular
Angina + GTN of
tablets
Myocardial ischaemia
(n=42)disease (n=102)
% Patients

100

83%

50

70%

0
Baseline

6 months of
metformin

Montaguti U et al. Res Clin Forums 1979;1:95-103

20

15

**
*
Metformin

10

Placebo

5
0

Treatments crossed over

Peripheral arterial blood

flow (mL/100 mL/min)

Effects of metformin treatment on

peripheral arterial blood flow

Placebo

Metformin

**

Duration of treatment (months)

*p<0.05, **p<0.001 vs. baseline
Sirtori CR et al. J Cardiovasc Pharmacol 1984;6:914-23

Cardioprotection with metformin

vs. other pharmacologic
cardiovascular interventions
Lipid-lowering
a
c
b

h
Antihypertensive
Antidiabetic
j
s
e
r

% Reduction in risk
(primary CV endpoint)

d
l
i
n
e
i
e lf
n
i
e
in
i
l
z
k
g
t
t
n
n
t
i
i
u
ri an loc
ta ta bro bra
s
p
m
i
p
s
n
s
or r i
od ala art a-b
va va mfi ofi
f
l
t
o
e En
n
s et
m ra e
e
i
F
e
o
G
S
P
B
F
M SU
L

4S; bCARE; cVA-HIT; dDAIS; eHOT; fHOPE; gLIFE; hBIP;

i
UKPDS 34; jUKPDS 33
a

Libby P. Diabetes Metab 2003;29:6S117-20; Libby P, Plutzky J. Circulation

4. New indications and

recommendations for
the use of metformin

Management of paediatric
type 2 diabetes
Goal is to control glycaemia to reduce risk of
complications
Lifestyle intervention as first therapy
diet and exercise may not be effective long term

Oral antidiabetic therapy

children are not small adults: children and adults
may respond differently to treatment
lack of well-designed clinical trials in children
only metformin has been well studied in
paediatric subjects

Metformin improves glycaemia

in type 2 diabetic adolescents
3.6 mmol/L

1.2%
(p<0.001)

HbA1C (%)

FPG (mmol/L)

(p<0.001)

Baseline

Last double-blind
measurement

Jones KL et al. Diabetes Care 2002;25:8994

Metformin and lipid profiles in

paediatric
type 2 diabetes
Metformin

Placebo

Base Mean

Base Mean

Total cholesterol4.5

0.25

4.9

+0.01

0.043

LDL-cholesterol 2.6

-0.11

2.9

+0.1

0.053

HDL-cholesterol 1.1

-0.1

1.1

-0.04

NS

-0.04

2.3

0.0

NS

Triglycerides

1.7

Significance values are vs. placebo

NS: not significant
Jones KL et al. Diabetes Care 2002; 25: 8994

Indications for Glucophage in

paediatric type 2 diabetes in
Europe
Indicated for use in paediatric patients
with
type 2 diabetes
as monotherapy
in combination with insulin
Glucophage 500 mg tablets can be
used in paediatric patients aged 10
years or older
The maximum recommended daily
dose in this population is 2000 mg
Glucophage Prescribing Information (Europe)

Indications for Glucophage in

paediatric type 2 diabetes in the
USA
Indicated for use in type 2
diabetic patients
10 years of age or older
May be used in combination with
a sulfonylurea or insulin in type
2 diabetic patients aged 17
years of age or older
The maximum recommended
for
daily dose
of Glucophage
Glucophage
Prescribing Information
(USA);
American
Association.
Diabetes Care
paediatric
useDiabetes
is 2000
mg

Rationale for metformin in the

management of PCOS
Insulin resistance and hyperinsulinaemia are
key
endocrine defects in PCOS
Metformin addresses insulin resistance as its
primary mechanism of action
Metformin is insulin sparing and reduces
hyperinsulinaemia
Metformin does not increase body weight
Metformin does not induce hypoglycaemia
Decades of therapeutic use in type 2
diabetes

Baselin
e
p=0.057a

Insulin sensitivity
(M/I ratio, mmol/kg.min/mU/mL)

Fasting insulin (mU/mL)

Effect of metformin on insulin

sensitivity in patients with
PCOS
6 months
p=0.024a

Difference between groups (ANOVA)

Moghetti P et al. J Clin Endocrinol Metab 2000; 85: 139-46

Effects of metformin on ovulation

and pregnancy rates in women
with PCOS

Metformin
vs. placebo

Odds ratio for

p
metformin
Ovulation rates(95% CI) 3.9 (2.3 to
6.7)

<0.00001

Pregnancy rates
2.8 (0.9 to
9.0)
0.09
Metformin + Ovulation
rates
4.4 (2.4 to
clomifene vs. 8.2)
<0.00001
clomifene
Pregnancy rates
4.4 (2.0 to
alone
9.9)
0.0003
Lord JM et al. The Cochrane Library, Issue 3, 2003;
Lord JM et al. BMJ 2003;327:951-3

New guidelines support the use

of
metformin in clomifene-resistant
Anovulatory women
PCOSwith polycystic
ovary syndrome who have not responded
to clomifene citrate and who have a body
mass index of more than 25 should be
offered metformin combined with
clomifene citrate because this increases
ovulation and
rates.
NICEpregnancy
Guideline CG11
Fertility 2004
Metformin should be considered in most
women with PCOS as initial therapy,
particularly when they are overweight or
obese. Metformin improves many
metabolic abnormalities in PCOS and may
improve menstrual cyclicity and the
potential for
pregnancy.
AACE
Position statement 2004

5. Metformin and
diabetes prevention

The Diabetes Prevention Program

(USA)
3234 subjects with IGT

R
Metformin

Placebo

+ standard lifestyle
counselling

+ Standard
lifestyle
counselling

Double-blind

Intensive
lifestyle
counselling

Open

s Prevention Program Research Group. N Engl J Med 2002;346:393-403

 Risk vs. standard

lifestyle (%)

Diabetes Prevention Program:

metformin vs. intensive lifestyle
intervention

-31%*

-58%*

p<0.001 vs. *baseline, metformin

s Prevention Program Research Group. N Engl J Med 2002;346:393-403

Subgroup analyses in the

Diabetes Prevention Program
Reduction in diabetes risk
versus placebo (%)

Age (y)
44 59 60

>
25
45

FPG (mmol/L)
3
.
5

.1
6
<

.0
7
1
.
6

BMI (kg/m2)

0
5
3
3
<
< 35

>
22
30

Intensive lifestyle intervention

Metformin

s Prevention Program Research Group. N Engl J Med 2002;346:393-403

Other major diabetes prevention

studies in subjects with impaired
glucose tolerance (IGT)
Study

Diabetes Prevention study

522
(Finland)1
STOP-NIDDM
(international)2

Int. lifestyle 58%

1429 Acarbose

DaQing study (China)3 577

XENDOS

EvaluationsDiabetes risk
reductionsa

694b

Diet
Exercise
Diet +
exercise

25%
31%
46%
42%
45%

c
Orlistat
c
vs. control or placebo; sub-group with IGT; combined with
b

intensive lifestyle intervention

Tuomilehto J et al NEJM 2001;344:1343-50; 2Chiasson JL et al Lancet

2002;359:2072-7; 3Pan X et al Diabetes Care 1997; 20:537-44;

6. Safety and
tolerability of
metformin

Tolerability of metformin
Main tolerability issue is in the
gastrointestinal tract1
Treatment discontinuation in <5% of
patients1
Impact can often be minimised

take with meals

start with low dose
cautious titration
dose reduction if necessary

Prolonged-release metformin
(Glucophage XR) may improve
tolerability where available2
1. Scarpello JHB. Br J Diabetes Vasc Dis 2001;1:28-36;
2. Howlett H et al. Br J Diabetes Vasc Dis 2004;4273-7

Dose-relationship of
gastrointestinal
side-effects with metformin

% Patients

Frequency of GI side-effects
Discontinuations for GI side-effec

Metformin dose
(mg/day)

Garber AJ. Am J Med 1997;102:491-7

GI tolerability with Glucophage

XR and immediate-release
metformin

% Patients

pective chart review of the first year of metformin tre

p=0.0414

IR: immediate release

p=0.0169

Switching from immediaterelease metformin to

Glucophage XR: GI side-effects
e and after a switch from immediate-release (IR) metf
to Glucophage XR in a retrospective chart review

% Patients

p=0.0006

IR: immediate release

p=0.0084

Laying to rest the issue of

metformin-related lactic acidosis
The Comparative Outcomes Study of Metformin
Intervention versus Conventional (COSMIC)
Approach
Randomised (4:1), open-label, activecomparator, parallel-group, 1-year trial
in type 2 diabetic patients sub-optimally
controlled on diet or sulfonylurea
Metformin (n=7227) vs. other usual
care (n=1505)
Primary endpoint: serious adverse
events, death, hospitalisation
95% confidence of detecting events
occurring at a rate of 5/10,000 patientyears of metformin treatment

Cryer DR et al. Diabetes Care 2005; 28: 539-543

No lactic acidosis with metformin

in the COSMIC Approach study
Odds ratios (95% CI)
Metformin
(n=7227)

Usual care
(n=1505)

All-cause mortality:

1.1 (0.9 to
1.4)

1.3 (0.82.0)

0.59
6

All-cause
hospitalisations:

9.4 (8.8 to
10.1)

10.4 (8.9 to
12.1)

0.22
9

Hospitalisations or
mortality for lactic
acidosis

No lactic acidosis was observed

Hospitalisations for
other metabolic
0.9 (0.7 to 1.2)
causes

0.9 (0.5 to
1.6)

1.000

Cryer DR et al. Diabetes Care 2005; 28: 539-543

Mean plasma lactate (mmol/L)

COSMIC lactate sub-study

p=0.137

Bars are SD
Cryer DR et al. Diabetes Care 2005; 28: 539-543

Systematic review of lactic

acidosis in patients receiving
metformin or other therapies
Independent systematic review 1 based
on a Cochrane analysis of 194 trials 2

>1 month of metformin (monotherapy or

combination)
36,893 patient-years on metformin
30,109 patient-years on other antidiabetic
agents

No lactic acidosis occurred

Probable upper limit for the true
incidence of lactic acidosis was similar
between treatments
8.1/100,000 patient-years for metformin
9.9/100,000
for other
1.
Salpeter SR etpatient-years
al. Arch Intern Med
2003;163:2594-2602
2. Salpetertreatments
S et al. Cochrane Database Syst Rev 2003 2:CD002967

Conclusions: metformin
As effective as other oral antidiabetic
treatments
Can be combined with any other
antidiabetic agent
Improves classical CV risk factors, with
other insulin-dependent/independent antiatherogenic mechanisms
Unique improvement in cardiovascular
outcomes comparable with cardiovascular
medications
Well tolerated and safe (no greater risk of
lactic acidosis than other antidiabetic
treatments)

CardioMetabolic Foru
Diabetes and the
Metabolic Syndrome:
New Strategies for
Preventing Death and
Disability
Paris, May 1821, 2005

Optimising glycaemic
control as diabetes
progresses

1. The need for more

effective blood
glucose control

Median HbA1C (%)

UKPDS: long-term efficacy of

monotherapies
UKPDS
Diet
Su
Metformin
Insulin

Time from randomisation (years)

UKPDS Group. Lancet 1998; 352:854

Limited duration of glucoselowering efficacy of antidiabetic

monotherapy
Data from overweight patients

Duration of follow-up
Turner RC et al. JAMA 1999;281:2005-2

Dual defect of type 2 diabetes:

treating a moving target
In
su
l

Insulin
-cell
Type 2
ia
Resistance DiabetesDysfunction em
a
in

Ac
t io

r
e
yp
-cell Failure
H

yc
l
g

Insulin
Concentration

Insulin
Resistance
Euglycaemia
Normal

IGT obesity Diagnosis of Progression of

type 2 diabetes type 2 diabetes
DeFronzo R et al. Diabetes Care 1992;15:318-68

Combination therapy and the dual

endocrine defect of type 2
diabetes
Insulin
resistance
Metformin + insulin secretagogue
1
Metformin + TZD
Metformin + AGI
Sulfonylurea + TZD
Sulfonylurea + AGI
TZDs + AGI

-cell
deficiency

Sulfonylurea or meglitinide
TZD: thiazolidinedione
AGI: -glucosidase inhibitor
1

Efficacy of combination
therapies
Metformin +
antidiabetic agent

Net change
in HbA1C

Glibenclamide (10-20 mg)a

-1.8%

Repaglinide (1.5-12 mg)b

-1.1%

Glimepiride (2-6 mg)c

-0.8%

Rosiglitazone (8 mg)d

-1.2%

Acarbose (300 mg)e

-0.8%

DeFronzo RA et al. N Engl J Med 1995;333:541-9; bMoses R et al,

Diabetes Care 1999;22:119-24; cCharpentier G et al, Diabet Med
2001;16:828-34; dFonseca V et al, JAMA 2000;283:1695-702;

2. The need for more

effective blood
glucose control and
reduced risk of
complications

Burden of type 2 diabetes

Years of follow-up

Complications
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1

Heart attacks
Stroke
Retinopathy

27 patients
10 patients
23 patients

Premature mortality
Diabetes deaths28 patients
Life expectancy5-7 years

100 patients - age 55 UKPDS 33.

Lancet 1998;352:837-53
Panzram G et al. Diabetologia 1987;30:123-31

Oral antidiabetic agents and

clinical outcomes
Agent

Outcome data Year

Metformin
Glibenclamide
Gliclazide
Glimepiride
Glipizide
Repaglinide
Nateglinide
Rosiglitazone
Pioglitazone
a

IGT subjects

Yes
Yes
No
No
No
No
No
No
No

1998
1998
2007

2007
2008
2005

Study
UKPDS
UKPDS
ADVANCE
NAVIGATORa
RECORD
PROACTIVE

UKPDS clinical outcomes for

metformin and glibenclamide
Clinical endpoints

Metformin Glibenclamide
riska

riska p

Any DM-related complication

32% 0.0023 18% 0.018
Diabetes-related death 42% 0.017

8% 0.59

All-cause death

36% 0.011

9% 0.43

Myocardial infarction

39% 0.01

22% 0.056

Microvascular complications
29% 0.19

34% 0.017

Retinal photocoagulation
31% 0.17

37% 0.008

Compared with conventional diet-based therapy

Metformin was evaluated in overweight patients
a

UKPDS 33. Lancet 1998;352:

UKPDS 34. Lancet 1998;352:

Complementary effects of
metformin and glibenclamide
Insulin
-cell
Type 2
Resistance Diabetes Dysfunction
Metformin
Glibenclamide

Metabolic
Syndrome
Macrovascular
Complications

Hyperglycaemia
Microvascular
Complications

Adherence to prescribed
medication

atients meeting medication goals

Days of drug exposure
Adherence Index > 90%
40
30
20

31

p<0.01
365

34

13

10
0

Su
Met Met + Su
alone
alone co-admin.
(n=1329)(n=531)(n=1060)

No. of days

% Adherence

p<0.01

310

300

302
266

255
200

Su
Met Met + Su
alone
alone co-admin.
(n=1329)(n=531)(n=1060)

Morris AD et al. Diabetes 2000;49 (Suppl 1): A76

Fixed-dose combinations

1. Metformin + glibenclamide (Gluco

- PK and extensive clinical data

2. Metformin + rosiglitazone (Avand

- PK data only

3. Metformin + glipizide (Metaglip)

- PK and limited clinical databas
Dailey GE. Expert Opin Pharmacother 2003;4:1417-30
Bailey CJ, Day C. Int J Clin Pract 2004;58:867-76
Goldstein BJ et al. Clin Ther 2003;25:890-903

Adherence rate (%)

Improved compliance with

Glucovance vs. metformin and
glibenclamide co-administered
p<0.001

Glucovance
(n=105)

Met + glib
co-administered
(n=1815)

Melikian C et al. Clin Ther 2002;24:460-7

Glucovance tablet technology:

engineered to optimise drug
delivery

<6 mm 710 mm 1120 mm >20 mm

25%
Metformin
soluble
matrix

50%

75%
Glibenclamid
e particle
range

Howlett H et al. Curr Med Res Opin 2003;19:218-25

Glibenclamide plasma
concentrations (ng/mL)

Glucovance compared with

metformin
and glibenclamide coEarlier glibenclamide
absorption with similar PK
administered
overall
Glucovance Co-administered metformin and
glibenclamide tablets

70
60
50
40
30
20
10
0

BreakfastLunch

8am

2pm

Dinner
8pm

2am

8am

Time of day

Howlett H et al. Curr Med Res Opin 2003;19:218-25

3. Glucovance:
efficacy in
type 2 diabetes

Study in patients hyperglycaemic

despite diet and exercise therapy

Patients
with HbA1C
>7% and
<12%
despite diet
and
exercise

Glucovance 250 mg/1.25 mg

(n=158)a
Glucovance 500 mg/2.5 mg
(n=162)
Metformin 500 mg (n=159)
Glibenclamide 2.5 mg (n=160)
Placebo (n=161)
Double-blind treatment 20 weeks

Glucovance 250/1.25 mg is the recommended tablet strength

for initiation of therapy in this population
Garber A et al. Diabetes Obes Metab 2002;4:201-8

HbA1C response in patients

hyperglycaemic despite diet and
exercise therapy
Glucovance

HbA1c (%)

250/1.25
500/2.5
Metformin
Glibenclamide Placebo
-0.21

-0.5

-1.0
-1.03
-1.5

-2.0

-1.48

-1.24

-1.53

*
Mean daily dosages (mg):
*

Metformin 568

840

1324

Glibenclamide
2.8

4.2

5.4

*p<0.001 vs. placebo

p<0.02 vs. monotherapy

Garber A et al. Diabetes Obes Metab 2002;4:201-8

Superior effects on fasting and

postprandial insulin vs.
glibenclamide

Mean changes from baseline in 806 diet-failed

patients

Placebo
Glucovance

Mean
Fasting 2-h PPI 2-h PPI
met/glib insulin (mIU/m excursio
dosages (mIU/mL
L)
ns
(mg/day)
)
(mIU/mL)

1.4

0.9

-0.2

568/2.8

3.8

29.7

25.3

840/4.2

4.9

250/1.25 mg
500/2.5 mg

Glibenclamide
2.5
mg PPI: postprandial
5.4 insulin 7.2
*p<0.05;

25.0
15.1

18.9

7.4

Garber A et al. Diabetes Obes Metab 2002;4:201-8

Durability of HbA1C response to

Glucovance in patients previously
hyperglycaemic on diet and exercise
52-week open-label study
11

Direct enrolment - baseline FPG > 240 mg/dL

Delayed enrolment - post double-blind (DB) stu

HbA 1c
(%)

Baseline Week 13 Week 26 Week 39 Week 52

Direct
n162
=
Post DB n
498
=

160
486

146
468

141
449

129
412

Garber A et al. Clin Ther 2002;24:1401-13

Double-blind randomised study

in patients previously receiving
metformin
Glucovance 500 mg/2.5
mg (n=101)a

Patients with
FPG >7
mmol/L (126
mg/dL)
despite
metformin
>1500
mg/day
a

Glucovance 500 mg/5

mg (n=103)
Metformin 500 mg (n=104)

Glibenclamide 5 mg (n=103)
Double-blind treatment 16 weeks

Glucovance 500/2.5 mg is the recommended tablet strength

for initiation of therapy in this population
Marre M et al. Diabet Med 2002;1

Mean change in
HbA1C (%)

Efficacy in patients
hyperglycaemic despite prior
treatment with metformin

1660 mg
13.4 mg

1170/11.7 mg

*p<0.001

1225/6.1 mg

Marre M et al. Diabet Med 2002;1

Proportion of patients achieving

HbA1C < 7%: post-metformin
study
75% more patients

% Patients

80
70
60
50
40
30
20
10
0

GlibenclamideMetformin 500/2.5 mg

500/5 mg

Glucovance
Marre M et al. Diabet Med

Glucovance vs. metformin +

rosiglitazone:
study design
24-week, double-blind trial
Inadequate glycaemic control (HbA1C >7% and
12%) on
1500 mg/day metformin for at least 8 weeks
Primary outcome: HbA1C change at week 24
318 patients
randomised
Glucovance
500/2.5 mg bid
n=160

Metformin 500 mg +
rosiglitazone 4 mg
n=158

Doses could be increased during the first 20 weeks if mean daily

glucose 126 mg/dL. Max Glucovance dose: 2000/10 mg
Max met/rosi dose: 2000 mg/4 mg bid

Garber A et al. Diabetes 2003;52 (Suppl 1): A119

Glucovance is more effective than

two
insulin sensitisers co-administered
Double-blind, randomised, parallel-group study

Mean change from

baseline in HbA1C (%)

All patients

Glucovance
Rosi
+ met
(n=160) (n=158)

Patients with HbA1C >9%

+ met
GlucovanceRosi
(n=40)
(n=45)

-1.0

-1.0
-1.1

-2.0

-3.0

-1.5

-1.4
-2.0

-0.4%
p<0.001

-2.4
-3.0

-1.0%

Garber A et al. Diabetes 2003;52 (Suppl. 1):A119

Efficacy in patients
hyperglycaemic despite prior
treatment with a sulfonylurea
Glucovance 500 mg/2.5
mg (n=160)a

HbA1C>7.4% &
FPG>7.0
mmol/L
(126mg/dL)
despite >halfmaximal doses
of a
sulfonylurea
a

Glucovance 500 mg/5

mg (n=162)
Metformin 500 mg (n=153)

Glibenclamide 5 mg (n=164)
Double-blind treatment 16 weeks

Glucovance 500/2.5 mg is the recommended tablet strength

for initiation of therapy in this population
Blonde L et al. Diabetes Obes Metab 2002;4:368-75

Mean change in HbA1C (%)

Efficacy in patients
hyperglycaemic despite prior
treatment with a sulfonylurea

Glucovance Glucovance
Metformin Glibenclamide
500/2.5 mg
500/5 mg
0.8
(n=153)
(n=164)
(n=160)
(n=162)
0.4
0.0

-0.4
-0.8
-1.2
-1.6

1.9%
p<0.001

1.7%
p<0.001

1.9% p<0.001
1.7% p<0.001

Blonde L et al. Diabetes Obes Metab 2002;4:368-75

Durability of HbA1C response to

Glucovance in patients previously treated
with sulfonylurea monotherapy

HbA1C (%)

10

9.4

7.9

7.9

7.6

7.4

39

52

4
Baseline

13

26

Weeks of open-label
therapy
Blonde L et al. Int J Clin Pract 2004;58:820-6

Study in patients hyperglycaemic

despite oral combination therapy
Retrospective chart review at 4 US
clinics
HbA1

HbA1C

Co-administration

Combination

Metformin (< 2000

mg/day) + Glibenclamide
(< 20 mg/day)
-6

-5

-4

-3

-2

-1

Glucovance tablets
(2000/< 20 mg/day)

-1

-2

-3

-4

Months

Months

-5

Last
Rx

Switch
Duckworth W et al. JMCP 2003;9:256-262

Switching from metformin +

glibenclamide
co-administered to Glucovance:
HbA
1C
All patients
Base HbA >8% (n=37)
1C

10

10

Mean HbA1C (%)

Mean HbA1C (%)

(n=72)
-0.6%
p<0.01

9
8
7

-1.3%
p<0.001

9
8
7
6

6
GlucovanceMet + SU
co-administered

Glib (mg/day)
17
Met (mg/day)

*p<0.01;
p<0.05
1624

15
1750

Glucovance
Met + SU

co-administered

17*

15

1607

1743

Duckworth W et al. JMCP 2003;9:256-262

Triple oral therapy

The benefits of adding rosiglitazone
to patients inadequately controlled on
Glucovance

Dailey G et al. Am J Med 2004;116:223-9

Evaluation of Glucovance
plus rosiglitazone: study
design
Enrolment: patients on monotherapy or combination
therapy
with HbA1C >7%
2- to 12-week lead-in: Glucovance titrated to
1500/7.5 mg/day
Randomisation: 365 patients with HbA1C >7% and 10%
Glucovance
+ placebo (n=184)

Glucovance
+ rosiglitazone (n=181)

Primary outcome: HbA1C change from

baseline at week 24
Dailey G et al. Am J Med 2004;116: 223-9

Intensification of therapy
beyond Glucovance: effects on
HbA1C
8.5

HbA1C (%)

8.2%
8.0

1.0%
p<0.001

7.5
7.2%
7.0

Glucovance + placebo (n=178)

Glucovance + rosiglitazone (n=177)

6.5
0

12

16

20

24

Weeks
Dailey GE et al. Am J Med 2004;116:2239

4. Tolerability of
Glucovance

Glucovance in patient subgroups

Patients with hyperglycaemia despite

Diet/exercisea Metforminb Sulfonylureab
HbA1Cc Hypod

HbA1CcHypo

HbA1CcHypo

HbA1C < 8%

-0.9

24.7

-0.5

10.5

-0.6

12.5

HbA1C > 8%

-2.0

3.5

-2.2

11.6

-1.7

7.4

Age < 65
years

-1.5

13.4

-1.1

14.7

-1.5

7.8

13.0

-1.3

3.0

-1.5

9.7

Age > 65
years

-1.5
-1.7

10.4

-1.3

6.7

-1.6

9.4

7.5
14.5
-1.4
-1.2 12.7
-1.5
BMI < 28
Data
for
2 patients receiving Glucovance a250/1.25; b500/2.5; c
kg/m
d
% units; % patients

BMI > 28
2

Garber A et al. Diabetes Obes Metab 2003;5:171-9

Withdrawals for hypoglycaemia

from four double-blind,
randomised studies
% Patients
patients

Glibenclamide

Glucovance
Previous Rx

Diet & exercise (1) 2

Diet & exercise (2) 2

Metformin

Sulfonylurea

250/1.25 500/2.5 500/5 2.5 mg or 5 mg

2.5 mg in post-diet studies, 5 mg in post-monotherapy studies

Davidson J & Scheen AJ. Drug Saf 2004;27:1205-16

Discontinuations for all-cause

side-effects
in double-blind, randomised
studies
% Patients
patients
% patients
Glucovance

Previous Rx 250/1.25500/2.5 500/5

Diet & exercise14

11

Diet & exercise24

Metformin3

Sulfonylurea4

3
3

7
3

Met

Glib

500 mg2.5 or 5 mg
6

2.5 mg in post-diet studies, 5 mg in post-monotherapy studies

Davidson J & Scheen AJ. Drug Saf 2004;27:1205-16

Changes in body weight from

double-blind, randomised studies
Mean changes from baseline
Glucovance

Met

Glib

Previous RxPlacebo
250/1.25500/2.5500/5500 mg
2.5 or 5 mg
Diet & exercise0.7
(1)

1.4

1.9

NA

0.6

1.7

Diet & exercise (2)

1.6

1.1

2.0

Metformin

NA

NA

0.6

1.0

1.8

0.9

Sulfonylurea

NA

NA

0.8

0.5

2.8

0.4

2.5 mg in post-diet studies, 5 mg in post-monotherapy studies

Davidson J & Scheen AJ. Drug Saf 2004;27:1205-16

5. Therapeutic
mechanisms of
Glucovance

Glucovance mechanism of action

study: hypothesis and aims
Hypothesis:
Treatment with metformin/glibenclamide tablets
will be associated with improvements in -cell
function in an early type 2 diabetic population

Primary objective:
Percentage change from baseline in the secondphase insulin response

Secondary objective:
Percentage change from baseline in the firstphase insulin response

Bruce S et al. Diabetologia 2004;47 (Suppl 1):A14

Evaluating the therapeutic

mechanism of Glucovance:
study design
Double-blind, randomised, multicentre,
parallelgroup, clinical trial
Type 2 DM < 5
years duration
and HbA1C
>6.7% and
9.5% on diet
and exercise

Glucovance 250/1.25 mg

Metformin 500 mg
Glibenclamide 2.5 mg

Double-blind treatment 20 weeks

Bruce S et al. Diabetologia 2004;47 (Suppl 1):A14

Glucovance mechanism of
action study: procedures
5 h oral glucose tolerance test (Day -1 &
Week 20)
Hyperglycemic clamp (Day -2 and Week 20)
overnight insulin infusion (Mokan Schema) to
obtain euglycaemia (4.45.0 mmol/L [80-90
mg/dL]) by early morning.
initial glucose bolus to raise plasma glucose to
10.6 mmol/L
(190 mg/dL) with continuous infusion to maintain
for 3 hours

Definitions:
1st phase insulin: sum of insulin values during
the first Bruce S et al. Diabetologia 2004;47 (Suppl 1):A14

Glucovance mechanism of
action study: population at
baseline
Glucova Metform
nce
in
(n=18)
(n=15)
Age (years)
Male/Female (%)
BMI (kg/m2)

49 (12)

48 (9)

51 (8)

39/61

47/53

29/71

32.9 (4.8)

Diabetes duration
(y)
HbA1c (%)

2.6 (1.3)

33.1
(6.5)

36.2 (3.8)

2.7 (2.2)

2.4 (1.6)

8.1 (1.50) 7.7 (1.0)

8.0 (1.3)

Means (SD) except where stated

Fasting insulin
(IU/mL)

Glibencla
mide
(n=17)

12.7 (7.9)

18.0
(11.1)

16.3 (8.3)

Bruce S et al. Diabetologia 2004;47 (Suppl 1):A14

Glucovance mechanism of
action study: effects on indices of
glycaemia
FPG

mmol/L

% Units

HbA1C

Mean final dose

Glucovance 250/1.25 mg tablets (n=17) 708/3.5
mg
Metformin
500 mg tablets (n=14) 1500 mg

Glibenclamide 2.5 mg tablets (n=15)6.6

mg
Bruce S et al. Diabetologia 2004;47 (Suppl 1):A14

Glucovance mechanism of action

study: secondphase insulin
response
Means and 95% CI
Mean % change in
second-phase insulin

125

100

75
50
25

+93%
+36%

+46%

GlucovanceMetforminGlibenclamide
*p<0.05 week 20 vs. baseline
Bruce S et al. Diabetologia 2004;47 (Suppl 1):A14

Glucovance mechanism of
action study:
firstphase
insulin
response
Means
and 95%
CI
Mean % change in
first-phase insulin

70
60

50
40
30
20
10
0
-10

+35%

+15%

+19
%

Glucovance MetforminGlibenclamide

*p<0.05 Week 20 vs. baseline

Bruce S et al. Diabetologia 2004;47 (Suppl 1):A14

Glucovance mechanism of
action study: absorption of
glibenclamide
60
Glucovance
Plasma glibenclamide
concentration (ng/mL)

40

Glibenclamide

20

0
0

6
120
0
Time
(min)

180

Bruce S et al. Diabetologia 2004;47 (Suppl 1):A14

Conclusions: therapeutic
mechanisms of Glucovance
Treatment with Glucovance improved:
glycaemia (HbA1C)
indices of -cell function (1st and 2nd phase
insulin responses)

Resolution of glucotoxicity led to

improvement in -cell function in all
treatment groups
An additional improvement in the 1st and
2nd phase insulin response was seen with
Glucovance, as seen in randomised trials
This may be due to earlier absorption of
glibenclamide from Glucovance, or to a
Bruce
S et al.
Diabetologia
2004;47 (Suppl
synergistic
effect
from
a partnership
with1):A14

6. The place of
Glucovance in the
management of
type 2 diabetes

Glucovance: major indications

Patients inadequately controlled
on diet

Primary diet failures

Patients inadequately controlled

on monotherapy

Post-metformin monotherapy
Post-sulfonylurea monotherapy

Patients inadequately controlled

on combination therapy

nce SmPC. Registration conditions may vary from country to country

Initiating therapy with

Glucovance
Initiate therapy with a low dosage and
gradually increase the dose based on efficacy
and tolerability
Diet-failed patients
start with one tablet per day of 250 mg/1.25 mg

Replacement of monotherapy
start with one tablet per day of 500 mg/2.5 mg

Replacement of metformin + sulfonylurea coadministered

start with 12 tablets per day of 500 mg/2.5 mg

Contraindications as for metformin +

nce SmPC. Registration conditions may vary from country to country

Optimising therapy with

Glucovance
Adjust dosage by one tablet every 12
weeks
guided by the therapeutic response
Glucovance 500 mg/5 mg is available for
patients needing further intensification

Maximum dose is 46 tablets daily, with

meals
maximum glibenclamide dose = 20 mg
Divide dosages of more than one tablet
per day between breakfast and evening
meals

Registration
and noon if
TID dosing
nce SmPC.
conditions
may vary from country to country

Glucovance summary
Effective on hyperglycaemia despite diet and
exercise or antidiabetic monotherapy,
including clinically important patient
subgroups
More effective than co-administered
combinations
metformin + sulfonylurea
metformin + rosiglitazone
Well tolerated, with minimal effect on body
weight
A practical solution to the compliance
burden