Prevenzione delle complicanze

1
VI CONGRESSO NAZIONALE SOCIETÀ ITALIANA PER LA
PREVENZIONE CARDIOVASCOLARE
GENOVA 28 Febbraio / 1 Marzo 2008
Prevenzione delle complicanze cardiovascolari nei
soggetti con alterazioni glicemiche Roberto
Miccoli Dipartimento di Endocrinologia e
Metabolismo Università di Pisa rmiccoli_at_immr.med.u
nipi.it - www.diab.it
Task Force SIPREC - Documento Programmatico
2
Changes in ranking for 15 leading cause of death,
2002 and 2030
Mathers C.D. PLOS medicine 3 2011-2030, 2006.
3
Diabetes and hyperglycemia a global
problem

• Excess global mortality attributable to DM has
  been estimated to be 2.9 million deaths, i.e 5.2
  of all deaths.1
• Diabetes causes considerable morbidity.2
• WHO predicts 366 million people worldwide will
  have diabetes by 2030.3

• One in five (21) deaths from ischaemic heart
  disease and one in eight (13) from stroke
  worldwide are attributable to higher-than-optimum
  blood glucose.
• Deaths from cardiovascular disease, including
  those attributable to higher-than-optimum blood
  glucose, generally occurred at younger ages in
  low-and-middle-income countries.4

1. Roglic et al. Diabetes Care 2004 2.
International Diabetes Federation. Available at
http//www.idf.org/home 3. Wild et al. Diabetes
Care. 4. Danaei G et al Lancet, 2006 3681651
4
Natural History of Type 2 Diabetes
Obesity - IGR - Diabetes - Uncontrolled
Hyperglycemia
350
Postmeal glucose
300
250
Fasting glucose
Glucose (mg/dL)
200
150
100
50
250
Insulin resistance
200
Relative Function ()
150
100
Insulin level
50
?-cell failure
0
-10
-5
0
5
10
15
20
25
30
IGRimpaired glucose regulation
Years of Diabetes
5
Prevalence of Abnormal Glucose Regulation
categories DECODE Study (N. 29.108)
Abnormal Glucose Regulation
19

• According to WHO criteria
• NGT, FPG lt110 2hPG lt140
• IFG, FPG gt110lt125
  
• IGT, FPGlt110 2hPG 140-199
• DM, FPG126 or 2hPG200

DECODE Study Group. BMJ. 1998317371-375.
6
Pathogenesis of type 2 diabetes
Genetic predisposition

• Environmental
• factors
• food plentiful
• - exercise optional

Obesity
Insulin Resistance
Normal ß-cells
ß-cells defect
insulin
IGR
gt65
T2DM
NGT
RN Bergman. Harmony and Discord in the
Orchestration of Glucose Metabolism - Banting
Lecture. ADA 2006.
7
TCF7L2 gene polymorphisms and progression to
Diabetes
? TCF7L2
CC
CT
TT
2.5
2.03
2.0
1.55
1.36
1.5
1
1
1
1.0
0.5
0
DPP Study
Go-DARTS Study
Florez JC, et al., N Engl J Med 355 241-250,
2006 Kimber CH, et al., Diabetologia 50
1186-1191, 2007
8
Annual incidence and relative risk of diabetes in
people with various categories of dysglycemia

• People with IGT were 0.33 times as likely to be
• normoglycemic after 1 year compared to people
  with NGT

• The absolute annual incidence of diabetes in
  individuals with various categories of IFG or IGT
  varied from 5 to 10.

Gerstein HC, et al., Diabetes Research and
Clinical Practice 78305312, 2007
9
Who should be screened and with what methods and
frequency to prevent/delay the adverse
consequences of IFG/IGT?

• Screening for IFG/ IGT is fundamentally no
  different from screening for diabetes.
• The same risk factors associated with diabetes
  are, not surprisingly, associated with IFG/IGT.
• At present, FPG and 2-h OGTT are the tests of
  choice to identify all states of hyperglycemia.
• IFG or IGT should be re-tested annually.

Nathan G, Diabetes Care 78305312, 2007
10
Natural History of Type 2 Diabetes
Obesity - IGR - Diabetes - Uncontrolled
Hyperglycemia
350
Postmeal glucose
300
250
Fasting glucose
Glucose (mg/dL)
200
150
100
50
250
Insulin resistance
200
Relative Function ()
150
100
Insulin level
50
?-cell failure
0
-10
-5
0
5
10
15
20
25
30
IGRimpaired glucose regulation
Years of Diabetes
11
Natural History of Type 2 Diabetes
Obesity - IGR - Diabetes - Uncontrolled
Hyperglycemia
350
Postmeal glucose
300
250
Fasting glucose
Glucose (mg/dL)
200
150
100
50
250
Insulin resistance
200
Relative Function ()
150
100
Insulin level
50
?-cell failure
0
-10
-5
0
5
10
15
20
25
30
IGRimpaired glucose regulation
Years of Diabetes
12
Third Report of theNCEP Expert Panel on
Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults (Adult Treatment
Panel III)
Diabetes as CHD risk equivalent
ATP III Final Report, Circulation 106 3163-3223,
2002
13
Myocardial infarction and microvascular endpoints
incidence by mean HbA1c concentration
80 60 40 20 0
MI Microvascular end points
Adjusted incidence per 1000 person-years ()
5 6 7 8
9 10 11
Updated mean HbA1c concentration ()
Adjusted for age, sex, and ethnic group. White
men age 50 to 54 y at diagnosis mean duration of
diagnosis of 10 y.
Error bars 95 CI
Stratton IM, et al. BMJ 321405412, 2000 (UKPDS
35).
14
Hyperglycemia and cardiovascular diseaseA
historical perspectives
15
Glucose as a risk factor for cardiovascular
morbidity
Results of a meta-analysis of published data from
20 studies of 95.783 individuals followed for
12.4 years
3
3
2.5
2.5
2
2
Relative risk
1.5
1.5
1
1
7
4
5
6
8
8
10
12
9
6
4
2h glucose (mmol/l)
Fasting glucose (mmol/l)
Fasting glucose of 110mg/l RR 1.33 (1.06 to
1.67) Postprandial glucose of 140/l RR
1.58 (1.06 to 1.67)
Coutinho M, Diabetes Care 22233-40, 1999
16
Elevated Risk of CVD Prior to Clinical Diagnosis
of Type 2 Diabetes. The NHS
Relative Risk
Nondiabetic throughout the study
Prior to diagnosis of diabetes
After diagnosis of diabetes
Diabetic at baseline
New diabetes diagnosed at follow-up
Hu FB, et al. Diabetes Care 251129-1134, 2002
17
Risk of Cardiovascular and All-Cause Mortality in
Individuals With Diabetes Mellitus, Impaired
Fasting Glucose, and Impaired Glucose
Tolerance The Australian Diabetes, Obesity, and
Lifestyle Study (AusDiab)
Barr ELM, et al. Circulation 116 151-15, 2007
18
The Australian Diabetes, Obesity, and Lifestyle
Study (AusDiab)
CLINICAL PERSPECTIVE

• Persons with known diabetes mellitus had a
  mortality risk that was more than 2 times greater
  than for those with normal glucose tolerance
• Those with impaired glucose tolerance and
  impaired fasting glucose had a 50 to 60 greater
  mortality risk
• 65 of all cardiovascular disease deaths in the
  entire population occurred in people who had
  known diabetes mellitus, newly diagnosed diabetes
  mellitus, impaired fasting glucose, or impaired
  glucose tolerance at baseline

Barr ELM, et al. Circulation 116 151-157, 2007
19
In asymptomatic population, which indicator of
glycemia is most important?
PPG? The highest glucose level
FPG? The lowest glucose level
HbA1c? The
long-term average glycemic exposure glucose level
20
Association of Mealtime Glucose Spikesand Risk
of CVD and Mortality
1. DECODE Study Group. Lancet. 1999 2. Shaw JE
et al. Diabetologia. 1999 3. Tominaga M et al.
Diabetes Care. 1999
4. Balkau B et al.
Diabetes Care. 1998 5. Hanefeld M et al.
Diabetologia. 1996 6. Barrett-Connor E et al.
Diabetes Care. 1998
21
Association of Hemoglobin A1c with
Cardiovascular Disease and Mortality in
AdultsThe EPIC study
MEN n. 4462

• P 0.001 for linear trend across hemoglobin A1c
  categories for all end points.
• Age-adjusted relative risks were determined by
  using logistic regression models.

WOMEN n. 5770
Adapted from Khaw KT. Ann Intern Med.141413-420,
2004
22
Glucose tolerance is negatively associated with
circulating progenitor cell levels
90
80
70

60
CD34KDR cells
50
40
30
20
10
0
CTRL
IGT
IFG
DM
Kruskall- Wallis p0.002
Fadini GP et al., Diabetologia, 50 2156-2163,
2007
23
Hyperglycemia activates multiple mechanisms that
mediate vascular damage
Glucose
Polyol Pathway
Hexosamine Pathway
AGE Formation
Oxidative Stress
Cellular Dysfunction
ROS
ROS
Cell Damage
Vascular Damage
Brownlee M. Nature, 414 814-820, 2001
24
Coronary artery disease and dysglycemia share a
number of risk factros
Insulin Resistance
Pre-Diabetes
Metabolic Syndrome (MetS)
(75 MetS)
Type 2 Diabetes (86 MetS)
Cardiovascular Disease
Grundy SM, J Am Coll Cardiol 471093100, 2006
25
Dysglycemia and cardiovascular disease have
pathogenetic mechanisms in common
26
1-Year mortality in diabetic and nondiabetic
subjects after first MI
Out Hosp
Hosp-28d
28d-1y
5.5
11.0
7.6
3.0
Mortality
7.5
2.2
20.0
7,9
28.6
22.1
11.9
10.9
Diabetic
Non-diabetic
Diabetic
Non-diabetic
Men
Women
Miettinen H, Diabetes Care 21 69-75, 1998
27
Normal glucose regulation is less common than
abnormal glucose regulation in patients with CHD

Normal
IFG
IGT
Diabetes

100
58
51
14
22
80
32
32
60
5
4
40
49
42
20
0
Acute admission (n. 2107)
Elective admission (n. 2854)
Bartnik M, Eur Heart J, 25 1880-1890, 2004
28
Time to the first major cardiovascular event
Kaplan-Meier curves
Normal
Abnormal
first occurrence of a non-fatal stroke,
non-fatal re-infarction, severe heart failure
necessitating hospitalisation or cardiovascular
death.
Bartnik M, Eur Heart J, 25 1880-1890, 2004
29
Plasma glucose concentration and vascular risks
Relative Risk
1.0
Plasma Glucose
30
Environment and lifestyle in Type 2 Diabetes
intervention trials
Da Qing
Finnish DPSG
DPP
IMPAIRED GLUCOSE TOLERANCE
-58
-58
-39
-35
-32
Pan XR et al, Diabetes Care 20 537-544, 1997
Tuomilehto J et al, N Engl J Med 344 1343-1350,
2001 Diabetes
Prevention Program Research Group, N Engl J Med
346 393-403, 2002
31
Changes in selected variables in the Finnish
Diabetes Prevention Study







Tuomilehto J. N Engl J Med 3441343-350, 2001
32
Early intervention and reduction of
cardiometabolic risk factors or CVD events
Lifestyle
Non-thiazolidinediones
Thiazolidinediones

DREAM1
STOP-NIDDM
DPP
DPP
FHSG
IDPP
IDPP
TRIPOD
XENDOS
DPS
Da Qing
DPP
Rosiglitazone
Troglitazone
Gliclazide
Met
Met lifestyle
Acarbose
Orlistat lifestyle
Met
0
26
25
28
31
Reduced rate of Increase o IMT 49 RR reduction
composite CVD
37
42
50
Reduced rate of Increase o IMT
58
58
62
No increase in Incident hypertension
Reduction in blood pressure
75
33
Time to act
Present Future (?)
Past
Cosi è, (se vi pare) L.Pirandello - 1917
Il fu Mattia Pascal L.Pirandello - 1903
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Proactive management
35
Documento programmatico
epidemiologia delle alterazioni cardiometaboliche
pratica clinica quotidiana
realtà clinica italiana
Obiettivi
pratica clinica quotidiana
percorsi clinico-terapeutici condivisi
diffondere messaggi
Prevenzione delle complicanze cardiovascolari nei
soggetti con alterazioni glicemiche - Task Force
SIPREC
36
Documento programmatico

• Coordinatori S. Del Prato (Pisa), M. Volpe
  (Roma)
• Aspetti fisiopatologici e clinici delle
  complicanze cardiovascolari nei pazienti con
  disglicemia
• M.G. Modena
• Disglicemia cosa sono le disglicemie e perché
  rappresentano un importante problema
  cardiometabolico?
• R. Miccoli (Pisa)
• La diagnostica cardiologica nei pazienti con
  disglicemia
• M. Chiariello (Napoli)
• Rischio di eventi cardiovascolari nei pazienti
  con diabete o sindrome metabolica
• P. Verdecchia (Perugia)
• Dati epidemiologici italiani
• D. Vanuzzo (Udine)
• Screening nei soggetti con disglicemia

Prevenzione delle complicanze cardiovascolari nei
soggetti con alterazioni glicemiche - Task Force
SIPREC
37
Documento programmatico
Planning
Prevenzione delle complicanze cardiovascolari nei
soggetti con alterazioni glicemiche - Task Force
SIPREC
38
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