DIABETES COMO FACTOR DE DIABETES COMO FACTOR DE RIESGO CARDIOVASCULARRIESGO CARDIOVASCULAR

DR. LEOCADIO G. MUÑOZ DR. LEOCADIO G. MUÑOZ BELTRANBELTRAN

Lumen

Media:

Smooth muscle cell

Matrix proteins

Internal elastic membrane

Endothelium

Intima:

External elastic membrane

Normal Arterial WallNormal Arterial Wall

Risk Factors for Cardiovascular Risk Factors for Cardiovascular DiseaseDisease

ModifiableModifiable– SmokingSmoking– DyslipidaemiaDyslipidaemia

Raised LDL-CRaised LDL-C

Low HDL-CLow HDL-C

Raised triglyceridesRaised triglycerides

– Raised blood pressureRaised blood pressure– Diabetes mellitusDiabetes mellitus– ObesityObesity– Dietary factorsDietary factors– Thrombogenic factorsThrombogenic factors– Lack of exerciseLack of exercise– Excess alcohol consumptionExcess alcohol consumption

Non-modifiableNon-modifiable– Personal history Personal history

of CVDof CVD– Family history Family history

of CVDof CVD

– Age Age – GenderGender

Pyörälä K et al. Eur Heart J 1994;15:1300–1331.

The Progression from CV Risk Factors to The Progression from CV Risk Factors to Endothelial Injury and Clinical EventsEndothelial Injury and Clinical Events

Risk factors

Oxidative stress

Endothelial dysfunction

NO Local mediators Tissue ACE-Ang II

PAI-1 VCAM

ICAM cytokines

Endothelium Growth factors matrix

Proteolysis

LDL-C BP Heart failureSmokingDiabetes

Vasoconstriction Vascular lesion and remodelling

Plaque ruptureInflammationThrombosis

Clinical endpoints

NO Nitric oxideGibbons GH, Dzau VJ. N Engl J Med 1994;330;1431-1438.

Historical Model of AtherogenesisHistorical Model of Atherogenesis

healthy subclinical symptomatic

Threshold

Decades Years-Months Months-Days

Plaque

Intima

MediaLumen

• Stable angina• Stable plaques with narrowing• Simple diagnostic (ECG, angiography)• Rare MI• Easy to treat

Antischkow N. Beitr Path Anat Allg Path 1913;56:379-404.

New ParadigmNew Paradigm

healthy subclinical symptomatic

Threshold

Decades Years-Months Months-Days

Intima

Media

PlaquePlaque

Thrombus

Lumen

• Unstable angina• Unstable plaque no narrowing• Difficult to diagnose (IVUS, MRI)• Frequent MI with sudden death• Easy to prevent

Upregulation of endothelialadhesion molecules

Increased endothelial permeability

Migration of leucocytes into the artery wall

Leucocyte adhesion

Lipoprotein infiltration

Endothelial Dysfunction in AtherosclerosisEndothelial Dysfunction in Atherosclerosis

Formation of foam cells

Adherence and entry of leucocytes

Activation of T cells

Migration of smooth muscle cells

Adherence and aggregation of platelets

Fatty Streak Formation in Fatty Streak Formation in AtherosclerosisAtherosclerosis

Formation of the fibrous cap

Accumulation ofmacrophages

Formation ofnecrotic core

Formation of the Complicated Formation of the Complicated Atherosclerotic PlaqueAtherosclerotic Plaque

Haemorrhage from plaque microvessels

Rupture of the fibrous cap

Thinning of thefibrous cap

The Unstable Atherosclerotic PlaqueThe Unstable Atherosclerotic Plaque

Intraluminal thrombus

Intraplaque thrombus

Lipid pool

Atherosclerotic Plaque Rupture and Atherosclerotic Plaque Rupture and Thrombus FormationThrombus Formation

Libby P. Circulation 1995;91:2844-2850.

The Vulnerable Atherosclerotic PlaqueThe Vulnerable Atherosclerotic Plaque

Manifestaciones clinicas de Manifestaciones clinicas de la Aterosclerosisla Aterosclerosis

Enfermadad Arterial CoronariaEnfermadad Arterial Coronaria– Angina de pecho, infarto del miocardio, muerte Angina de pecho, infarto del miocardio, muerte

subita cardiacasubita cardiaca

Enfermedad Cerebrovascular Enfermedad Cerebrovascular – Isquemia Cerebral Transitoria, strokeIsquemia Cerebral Transitoria, stroke

Enfermedad vascular PerifericaEnfermedad vascular Periferica– Claudicacion intermitente, gangrenaClaudicacion intermitente, gangrena

Diabetes MellitusDiabetes MellitusOne of the most common non-communicable One of the most common non-communicable diseasesdiseases

Fourth leading cause of death in most developed Fourth leading cause of death in most developed countriescountries

More than 194 million people with diabetes More than 194 million people with diabetes worldwideworldwide

Incidence of diabetes is increasing – estimated to Incidence of diabetes is increasing – estimated to rise to 333 million by 2025rise to 333 million by 2025

– To more than double in Africa, the Eastern Mediterranean To more than double in Africa, the Eastern Mediterranean and Middle East, and South-East Asiaand Middle East, and South-East Asia

– To rise by 50% in North America, To rise by 50% in North America, 20% in Europe, 20% in Europe, 85% in 85% in South and Central Americas and 75% in the Western PacificSouth and Central Americas and 75% in the Western Pacific

: International Diabetes Federation website

The Chronic Complications of The Chronic Complications of Diabetes Mellitus (US)Diabetes Mellitus (US)

Macrovascular complications:Macrovascular complications:

Cardiovascular diseaseCardiovascular disease– Leading cause of diabetes related deaths (increases Leading cause of diabetes related deaths (increases

mortality and stroke by 2 to 4 times)mortality and stroke by 2 to 4 times)

Microvascular complications:Microvascular complications:

Retinopathy Retinopathy – Leading cause of adult blindnessLeading cause of adult blindness

NephropathyNephropathy– Accounts for 44% of new cases of ESRD Accounts for 44% of new cases of ESRD

NeuropathyNeuropathy– 60-70% of patients with diabetes have nervous system 60-70% of patients with diabetes have nervous system

damagedamage National Diabetes Statistics US 2000

PROCAM: Combination of Risk Factors PROCAM: Combination of Risk Factors Increases Risk of MIIncreases Risk of MI

0

20

40

60

80

100

120

In

cid

en

ce

of

MI/

10

00

pts

None

Hyper

tensi

on

only

Diabe

tes on

ly

Hyper

tens

+

diabe

tes

Dyslip

idae

mia

Dyslip

idae

mia

+

hyper

tens

+/-

diab

etes

Prevalence (%): 54.9 22.9 2.6 2.3 9.4 8.0

Assmann G, Schulte H. Am Heart J 1988;116:1713-1724.

East West Study: Patients with DiabetesEast West Study: Patients with Diabetesat Similar Risk to No Diabetes with MIat Similar Risk to No Diabetes with MI

0

10

20

30

40

50

7-y

ea

r in

cid

en

ce

ra

te o

f M

I (

%)

No prior MIMI

p<0.001

p<0.001

No diabetes (n=1373)

Diabetes (n=1059)

Haffner SM et al. N Engl J Med 1998;339:229-234.

ns

HPS: Percent of Patients with Major Vascular HPS: Percent of Patients with Major Vascular EventsEvents** by Prior Disease in Placebo Group by Prior Disease in Placebo Group

* CHD, stroke, revascularization

0

10

20

30

40

DM Alone CHD Alone CHD + DM

Prior Disease

Perc

en

t d

evelo

pin

g 1

st

majo

r vasc

ula

r even

t

Collins R et al. Diab Care 2003;361:2005-2016.

PARIS: CHD Mortality Increases with PARIS: CHD Mortality Increases with Increased Impaired Glucose ToleranceIncreased Impaired Glucose Tolerance

0

1

2

3

4

5

CH

D m

ort

ali

ty r

ate

/1

00

0

G<140 mg/dL

IGT G≥200 mg/dL

Newly diagnosed diabetes

Known diabetes

p<0.001

n=6055 n=690 n=158 n=135

Eschwege E et al. Horm Metab Res 1995;17(Suppl):41-46.

G - glucose

Pyörälä K et al. Diabetes Care 1997;20:614-620.

4S: CHD Event Reduction in 4S: CHD Event Reduction in Patients with DiabetesPatients with Diabetes

0

2

4

6

8

10

12

14

16

18

VALUE: incidencia de nuevos casos de diabetes

23% de reducción

del riesgo

con valsartan

p < 0.0001

13.1%

16.4%

Regímenes basados en amlodipino(n = 5,168)

Ap

ari

ció

n d

e n

ue

vo

s c

as

os

de

dia

be

tes

(%

de

pa

cie

nte

s e

n e

l g

rup

o d

e

tra

tam

ien

to)

Regímenes basados en valsartan(n = 5,254)

Julius S et al. Lancet. 2204; 363: 2022-31.

Sistema renina angiotensina

Nuevos casos de diabetes

ALLHAT Officers and Collaborators. JAMA. 2002; 288: 2998-3007. Yusuf S et al. JAMA. 2001; 286: 1882-85.Dahlof B et al. Lancet. 2002; 359: 995-1003. Lithell H et al. J Hipertensión. 2003; 21: 875-86.

Fármaco

LisinoprilRamiprilLosartan

CandesartanValsartan

Comparador

ClortalidonaConvencional

AtenololConvencional

Amlodipino

Reducción

43%33%25%19%23%

Protocolo

ALLHATHOPELIFE

SCOPEVALUE

Efecto Metabólico del Comparador

----+

Statins Reduce CVD Risk in Statins Reduce CVD Risk in Patients with DiabetesPatients with Diabetes

37% (p<0.001)

25 (p=0.05)

55 (p=0.002)

19 (ns)

22 (p<0.0001)

na

23 (p<0.001)

32 (p<0.001)

25 (p<0.001)

24 (p<0.0001)

40%

28%

36%

25%*0.9 mmol/L(35 mg/dL)

Primary prevention

CARDS1 (atorvastatin; n=1428)

Secondary prevention

CARE2 (pravastatin; n=586)

4S3 (simvastatin; n=202)

LIPID4 (pravastatin; n=1,077)

HPS5 (simvastatin; n=5963)

% CVD risk reduction (diabetes)

% CVD risk reduction (overall)

LDL-C lowering

Study

* value for overall group