Italiana di Dal rischio al danno cardio e cerebrovascolare ... danno CV Palermo 20… · Dal rischio al danno cardio e cerebrovascolare (il valore dell’epidemiologia clinica) Giorgio

Dal rischio al danno cardio e cerebrovascolare(il valore dell’epidemiologia clinica)

Giorgio Sesti

Università “Magna Graecia” di Catanzaro

DIABETE MELLITO - SINDROME CLINICA COMPLESSA

Diapositiva preparata da Giorgio Sesti e

ceduta alla Società Italiana di D

iabetologia.

Per avere una versione originale si prega di scrivere a [email protected]

http://www.google.it/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=9L8Q0_nuyozWDM&tbnid=19HgPzghiIqGRM:&ved=0CAUQjRw&url=http://www.cuscatanzaro.it/cus_cz_new_004.htm&ei=ek3lUbivAcTHOcnfgaAD&bvm=bv.48705608,d.bGE&psig=AFQjCNH4dnnNkPytmwFdqC4wmyqAFGUp1A&ust=1374068251595580


Il Prof Giorgio Sesti dichiara di aver ricevuto negli ultimi due anni

compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o

Diagnostiche:

Novo Nordisk, MSD, Boehringer‐Ingelheim, Lilly, Janssen,

AstraZeneca, Novartis e Takeda per attività di Relatore ad eventi.

Novo Nordisk, Intarcia, Boehringer‐Ingelheim, Lilly, MSD, Servier,

AstraZeneca e Janssen per attività di Consulenza.

Potenziali conflitti di interesse



iabetologia.


CVD mortality rate among people with and without diabetes:the National Health Interview Survey (NHIS) (242,383 adults >18 years)

0

2

4

6

8

10

1997-1998 1999-2000 2001-2002 2003-2004

De

ath

s/1

00

0 p

ers

on

-ye

ars

NHIS Sample Periods

Gregg et al., Diabetes Care 35: 1252—1257, 2012

*Rate difference between 1997/1998 and 2003/2004, –4.0; P < 0.001 for trend

*

With diabetes

Without diabetes



iabetologia.


1. Strength (effect size)

2. Consistency (reproducibility)

3. Specificity

4. Temporality

5. Biological gradient

6. Plausibility

7. Coherence

8. Experiment

9. Analogy

Bradford Hill A Proceedings of the Royal Society of Medicine 58: 295–300, 1965

The Bradford Hill criteria



iabetologia.


1. Strength (effect size): A small association does not mean that there is not a

causal effect, though the larger the association, the more likely that it is

causal.


3. Specificity

4. Temporality


6. Plausibility

7. Coherence

8. Experiment

9. Analogy





iabetologia.


WOMENMEN

Survival Post-MI in Diabetic and Nondiabetic Men and Women: Minnesota Heart Survey

Sprafka JM et al. Diabetes Care 14:537-543, 1991

100

80

60

40

0

Su

rviv

al

(%)

Months Post-MI

No diabetes

n=228

n=1628

Months Post-MI

0 20 40 60

Diabetes

100

80

60

40

0

80 0 20 40 60 80

Diabetes

No diabetes

n=156

n=568



iabetologia.


Hazard ratios (HRs) for coronary heart disease and ischaemic stroke by baseline fasting blood glucose concentration: a cohort study in 1,921,260 individuals in England

Dinesh Shah A et al. Lancet Diabetes Endocrinol 3: 105–13, 2015



iabetologia.



2. Consistency (reproducibility): Consistent findings observed by different

persons in different places with different samples strengthens the likelihood

of an effect.

3. Specificity

4. Temporality


6. Plausibility

7. Coherence

8. Experiment

9. Analogy





iabetologia.


P<0.001 for prior MI vs. no prior MI and for diabetes vs. no diabetes

7-Year Incidence of Fatal and Nonfatal MI

0

10

20

30

40

50

4%

19%

45%

Prior MI

Nondiabetic Diabetic(n=1,373) (n=1,059)

No Prior MI Prior MINo Prior MI

20%

Haffner SM, et al. N Eng J Med 339:229-234, 1998



iabetologia.


0

0,05

0,1

0,15

0,2

0,25

Eve

nt

rate

Months

6 9 153 18 2112

RR=2.88 (2.37-3.49)

24

RR=1.99 (1.52-2.60)

RR=1.71 (1.44-2.04)

RR=1.00

Diabetes/CVD (n=1,148)

No Diabetes/CVD (n=3,503)

Diabetes/No CVD (n=569)

No Diabetes/No CVD (n=2,796)

Organization to Assess Strategies for Ischemic Syndromes (OASIS) Study Mortality by Diabetes and CVD Status

Malmberg K, et al. Circulation 102:1014-1019, 2000



iabetologia.


Schramm et al. Circulation 117:1945-54, 2008

Cardiovascular mortality in relation to diabetes mellitus and a prior MI:A Danish Population Study of 3.3 Million People



iabetologia.




3. Specificity: The more specific an association between a factor and an effect

is, the bigger the probability of a causal relationship.

4. Temporality


6. Plausibility

7. Coherence

8. Experiment

9. Analogy





iabetologia.


UKPDS 35 - Fatal and Non-Fatal Myocardial Infarction

Stratton IM, et al. UKPDS 35. BMJ 321: 405-412, 2000

14% decrease per 1% decrement in HbA1c

P<0.0001

0 .5

1

5

0 5 6 7 8 9 10 11

Updated mean HbA1c

Ha

za

rd r

ati

o



iabetologia.


UKPDS 35 - Fatal and Non-Fatal Stroke

0.5

1

5

0 5 6 7 8 9 1 0 1 1


P=0.035

Updated mean HbA1c

Ha

za

rd r

ati

o




iabetologia.


UKPDS 35 - Amputation or Death from Peripheral Vascular Disease

0 .1

1

1 0

2 0

0 5 6 7 8 9 1 0 1 1


P<0.0001

Updated mean HbA1c

Ha

za

rd r

ati

o




iabetologia.


UKPDS 35 - Heart Failure

0 .5

1

5

0 5 6 7 8 9 1 0 1 1


P =0.016

Updated mean HbA1c

Ha

za

rd r

ati

o




iabetologia.


Association of type 2 diabetes with 12 CVD in patients aged ≥30 years: a cohort study in 1,9 millions individuals

HRs for different initial presentations of CVD associated with T2DM, adjusted for age, sex, BMI, deprivation, HDL cholesterol, total cholesterol, systolic blood pressure, smoking status, and statin and antihypertensive drug

Dinesh Shah A et al. Lancet Diabetes Endocrinol 3: 105–13, 2015



iabetologia.




3. Specificity

4. Temporality: The effect has to occur after the cause


6. Plausibility

7. Coherence

8. Experiment

9. Analogy





iabetologia.


DCCT-EDIC: intensive treatment significantly reduces and maintains HbA1cH

bA

1c

(%)

Year

DCCT

11

10

9

8

7

6

09

ConventionalIntensive

1 2 3 4 5 6 7 8 1 2 3 4 5 6 7DCCT end EDIC

Conventional group encouraged to switch to

intensive treatment

N Engl J Med 353:2643-2653, 2005

HbA1c=7.4 vs. 9.1; P<0.01

HbA1c = 9.1 vs.9.1

HbA1c = 7.9 vs.7.8



iabetologia.


N Engl J Med 353:2643-2653, 2005

DCCT-EDIC: intensive treatment is associated with a 42% reduction in risk of CVD as compared with conventional treatment

(P = 0.02)



iabetologia.




3. Specificity

4. Temporality

5. Biological gradient: Greater exposure should generally lead to greater

incidence of the effect.

6. Plausibility

7. Coherence

8. Experiment

9. Analogy





iabetologia.


0,891

1,45

2,37

2,91

0

1

2

3

P value for trend <0.001

Selvin E. et al. N Engl J Med 362:800-11, 2010

Ha

za

rdra

tio

for

co

ron

ary

he

art

dis

ea

se

Hazard Ratios for coronary heart disease in the Atherosclerosis Risk in Communities (ARIC) population during the 15-Year study period according to HbA1c category at

baseline

Model was adjusted for age, sex, and race

<5.0% 5.0 to <5.5% 5.5 to <6.0% 6.0 to <6.5% ≥6.5%(reference)



iabetologia.


Relative Risk of mortality in a population of 25.364 subjects without known diabetes according to fasting plasma glucose and 2h post-OGTT (DECODE)

Adjusted for age, center, sex, cholesterol, BMI, SBP, smoking

<110 110–125 >126

>200

140–199

<140

Fasting plasma glucose (mg/dl)

2.5

2.0

1.5

1.0

0.5

0.0

Ha

za

rds r

ati

o

DECODE Study Group. Lancet 354: 617-621, 1999



iabetologia.


50

70

90

110

130

150

170

190

210

230

250

0 30 60 90 120

NGT 1h-low

NGT 1h-high

Isolated IFG

IGT

Time (min)

Pla

sm

a g

luco

se

co

nce

ntr

ati

on

(mg

/d

l)

x

Fiorentino TV et al. J Clin Endocrinol Metab100:3744-3751, 2015

Plasma glucose levels during OGTT in subjects with NGT 1h-low, NGT 1h-high, isolated IFG and IGT



iabetologia.




IMT is increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl

IMT

(mm

)

NGT1-h PG<155

(n=231)

P=0.006

NGT1-h PG>155

(n=89)

IGT(n=80)

Succurro E. et al. Atherosclerosis 207 : 245–249, 2009

P=0.03



iabetologia.




Left ventricular mass is increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl - the CATAMERI study

LV

MI

(g/m

2)

NGT1-h PG<155

(n=356)

P<0.002

P=0.002

NGT1-h PG>155

(n=158)

IGT(n=168)

Sciacqua A. et al. Diabetes Care 34:1406–1411, 2011



iabetologia.




2h PG <140 and 1-h PG<155

(n=1112)

2h PG <140 1-h PG>155

(n=449)

2h PG 140-199 and1-h PG>155

(n=301)

2h PG 140-199 and1-h PG<155

(n=83)

P values refer to results after analyses with adjustment for sex, age, smoking, BMI, systolic and diastolic blood pressure and fasting blood glucose

HR

(9

5%

CI)

Bergman M et al. Diabet. Med. 2016

Total mortality is increased in subjects with 1-h PG >155 mg/dl as compared with individuals with 1-h PG<155 mg/dl - the Israel Study of Glucose

Intolerance, Obesity and Hypertension (n= 1942)

(1.12 to 1.56)

(1.20 to 2.15)

(1.54 to 2.23)



iabetologia.




3. Specificity

4. Temporality


6. Plausibility: A plausible mechanism between cause and effect is helpful

7. Coherence

8. Experiment

9. Analogy





iabetologia.


Hyperglycemia

AdvancedGlycation

End Products(AGE)

PolyolPathway

DAGPKC NF-kBHexosamine

Pathway

Vascular damage

NAD(P)H oxidases

ER stress



iabetologia.




3. Specificity

4. Temporality


6. Plausibility

7. Coherence: Coherence between epidemiological and laboratory findings

increases the likelihood of an effect

8. Experiment

9. Analogy





iabetologia.


Increased glucose metabolism through the hexosamine pathwayenhances intracellular O-linked glycosylation

glucose

glucose-6-P

fruttose-6-P

triose phosphate

Glycolysis

O2-

NAD+

NADPH

mitochondria

glucosamine-6-P

UDPGlcNAc

GFAT

glugln

O-linked

glycosylation

gln

(GFAT)glutamine:fructose-6-phosphate

amidotransferaseAzaserine

GAPDH



iabetologia.


O-GlcNacylation is increased in carotid plaques from diabeticsubjects

Federici M et al, Circulation 2002

%o

fO

-Glc

Na

cyla

tio

n

imm

un

ore

acti

vit

y

0

10

20

30

40

50

diabetic nondiabetic

***

Diabetic Nondiabetic

Federici M et al. Circulation 106:466-472, 2002



iabetologia.


Effects of high glucose and glucosamine on eNOS phosphorylation and activity in HCAEC

- + - + - + 0

50

100

150

200

250

300

Insulin

**

Ctrl HG GLNe

NO

S a

cti

vit

y%

of

co

ntr

ol

eNOS pSer1177

Insulin

eN

OS

pS

er1

17

7/e

NO

S

Ctrl HG GLN- + - + - +

0

10

20

Federici M et al. Circulation 106:466-472, 2002



iabetologia.




3. Specificity

4. Temporality


6. Plausibility

7. Coherence

8. Experiment: Occasionally it is possible to appeal to experimental evidence.

9. Analogy





iabetologia.


Glucosamine induces ER stress and promotes the activation of pro-inflammatory, pro-thrombotic, and pro-apoptotic pathways in HUVECs time-dependently

BIP= Binding immunoglobulin protein (chaperone)CHOP=C/EBP homologous protein (promoter of ER stress-mediated apoptosis)IRE1α=inositol-requiring enzyme (cleaves X-box binding protein 1 (XBP-1) mRNAactivate cell death and inflammatory pathways)PARP=Poli-ADP-ribose polymerase (caspase substrate) Jan= Jun N-terminal kinase (pro-inflammatory and pro-apoptotic kinase)

Fiorentino TV et al. Cardiovasc Res. 107:295-306, 2015



iabetologia.




Glucosamine induces the expression of pro-coagulant factors and promotes the synthesis and release of pro-inflammatory cytokines in HUVECs




iabetologia.




Glucosamine promotes pro-apoptotic pathways in HUVECs


PARP=Poli-ADP-ribose polymerase (caspase substrate)



iabetologia.






3. Specificity

4. Temporality


6. Plausibility

7. Coherence

8. Experiment

9. Analogy: The effect of similar factors may be considered.





iabetologia.


Stamler J, et al. Diabetes Care 16:434-44, 1993

0

20

40

60

Number of Risk Factors

None One Two All Three

Ag

e A

dju

ste

d C

V D

ea

th R

ate

Pe

r 1

0,0

00

Pe

rso

n Y

ea

rs

80

100

120

140

MULTIPLE RISK FACTOR INTERVENTION TRIAL (MRFIT)Type 2 Diabetes is a CV Risk Factor Additive Effects of Hypertension,

Hypercholesterolemia, and Smoking

Stamler J, et al. Diabetes Care 16:434-444, 1993

Nondiabetic (n=342,815)

Diabetic (n=5,163)



iabetologia.


Hazard ratio for CHD Mortality in US Adults from the NHANES II (n=6255; 13.3 years follow-up)

Malik S. et al. Circulation 110:1245-1250, 2004

1

2,1

2,87

5,02

6,8

11,3

0,0

2,0

4,0

6,0

8,0

10,0

12,0

P<0.04

No MetS 1-2 MetSMetS

no DMMetSw/DM

pre-existingCVD

pre-existingCVD and DM

P<0.003

P<0.0001

P<0.0001

P<0.0001



iabetologia.


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Italiana di Dal rischio al danno cardio e cerebrovascolare ... danno CV Palermo 20… · Dal rischio al danno cardio e cerebrovascolare (il valore dell’epidemiologia clinica) Giorgio