Metabolic Problems and

Vascular Disease
Sarwono Waspadji
Jakarta Diabetes & Lipid Center
Division of Endocrinology & Metabolism,
Department of Medicine, School of Medicine
University of Indonesia, Jakarta

Vascular disease and its pathogenesis

Risk factors for vascular disease
Metabolic syndrome vs. Cardiometabolic risk
Mechanism of the development of
vascular disease in Diabetes Mellitus,
Dyslipidemia, Hypertension and Obesity
Overall management of Diabetes Mellitus
Overall management of Dyslipidemia, Hypertension
and Obesity
Conclusion

Vascular Complications

Microangiopathy

Macroangiopathy

Retinopathy

Brain

Blindness

Stroke

Cardiomyopathy

Nephropathy

Heart

Coronary Diseases

Kidney

failiure

Perpheral
Artery Disease
Neuropathy

Pathogenesis of
Microvascular Lesion

Normal

Microvascular

Atherosclerotic Plaque,
Formation, and Rupture
Increased
lipid levels
Endothelial
dysfunction

Plaque
rupture and
thrombosis
Monocyte
migration

Plaque
formation

LDL oxidation
Macrophage
differentiation and
inflammation
Foam cell
formation

The Potensial Mechanisms for

the Pathogenesis of Chronic DM Vascular
Complications

Aldose reductase pathway,

Pleiotropic Protein Kinase C pathway,
Glucosamine biosynthesis pathway,
Production of advanced glycation species,
Cytoplasmic oxidative stress,

with pathobiologic process involving:

inflammation,
procoagulant state
renin angiotensin system.
PPAR

Vascular disease and its pathogenesis

Risk factors for vascular disease
Metabolic syndrome vs. Cardiometabolic risk
Mechanism of the development of
vascular disease in Diabetes Mellitus,
Dyslipidemia, Hypertension and Obesity
Overall management of Diabetes Mellitus
Overall management of Dyslipidemia, Hypertension
and Obesity
Conclusion

The Progression from CV Risk Factors to

Endothelial Injury and Clinical Events
LDL-C

Smoking
Diabetes
Heart failure

Risk Factors

BP

Oxidative stress
Endothelial
Dysfunction
NO

PAI-1

Local mediators

VCAM

Tissue ACE-Ang II

Endothelium

ICAM, cytokines
Thrombosis

Inflammation Vasoconstriction

Growth
factors matrix
Vascular Lesion
and Remodelling

Proteolysis

Plaque Rupture

Vascular Complications
NO = nitric oxide

Adapted
Adapted from
from Gibbons
Gibbons GH,
GH, Dzau
Dzau VJ.
VJ. N
N Engl
Engl JJ Med
Med .. 1994;330;14318.
1994;330;14318.

Genetic Susceptability

cardio-vascular deaths globally -

Metabolic factors
12/23/16
12/23/16
12/23/16
12/23/16
12/23/16
12/23/16
12/23/16
12/23/16
12/23/16
12/23/16

Attributable deaths due to selected risk

factors (000)

Slide 15
Source: WHO 2011. Global Atlas
on CVD prevention and Control 1-164

Type 2 diabetes increases the

risk of CVD
Any CVD event

Stroke
Intermittent claudication

Cardiac failure

CHD

MI

Males with DM
Females with DM

Angina pectoris
Sudden death

N/A

Coronary mortality

3
4
5
2
6
Age-adjusted risk ratio
(1 = risk for individuals without diabetes)
1

< 0.1;

p < 0.05;

p < 0.01;

Adapted from Kannel WB et al. Am Heart J. 1990; 120: 6726.

p < 0.001

Vascular disease and its pathogenesis

Risk factors for vascular disease
Metabolic syndrome vs. Cardiometabolic risk
Mechanism of the development of
vascular disease in Diabetes Mellitus,
Dyslipidemia, Hypertension and Obesity
Overall management of Diabetes Mellitus
Overall management of Dyslipidemia, ypertension
and Obesity
Conclusion

Defining the Metabolic Syndrome

WHOa

EGIRb

NCEPc

IDFd

Insulin resistance
&/or FPG

Insulin resistance
(hyperinsulinaemia)

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

HDL-C

HDL-Cf

Microalbuminuria

World Health Organisation; bEuropean Group for the study of Insulin

resistance;
c
National Cholesterol Education Program; dInternational Diabetes
Federation
a

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

Ele Ferrannini. CONTROVERSY IN CLINICAL ENDOCRINOLOGY

Metabolic Syndrome: A Solution in Search of a Problem. The Journal of Clinical Endocrinology & Metabolism
92(2):396398
Printed in U.S.A. Copyright 2007 by The Endocrine Society

Comparison of the Two Approaches to

the Metabolic Syndrome
Pathophysiological

Clinico-epidemiological

Term
Insulin resistance syndrome
Metabolic syndrome
Purpose Provide a conceptual framework
Predict CVD based on
for understanding clustering of presence of risk factor
risk factors and other adverse cluster
clinical conditions
Clinical Goals Alert physicians that patients 1. Make clinical
diagnoses
with insulin resistance are
2. Risk-stratify patients
at risk for multiple adverse
3. Guide treatment
clinical conditions decisions
Seeks Strict
No
Yes
Clinical Definition?
Available Definitions AACE
WHO,NCEP ATPIII, IDF
Advocates
Endocrinologists
Lipidologists,
Cardiologists
Research Tools
Basic science,
Population-based studies
clinical research laboratories

The Metabolic (Insulin Resistance)

Syndrome: A network of atherogenic
factors
Genetic and
Environmental
factors

Hyperglycaemia/IG
T

Obesity

Dyslipidaemia
Hypertension
Insulin resistance

Endothelial
dysfunction/
Microalbuminuria
Hypofibrinolysis

Insulin resistance is linked to a

range of CVD risk factors

Inflammation

Atheroscleros
Adapted from McFarlane S et al. J Clinis
Endocrinol Metab .2001; 86: 7138.

Kesepakatan Para Pakar (2009)

Kumpulan berbagai faktor risiko,
yang memberikan peningkatan risiko
untuk terjadinya kelainan metabolik
dan kardiovaskular

Cardio-metabolic Risk
Diagnosis criteria ? Belum sepakat

Patients With
Major Cardiovascular Event (%)

Impact of Gluco-metabolic Characteristics

on Risk of Major CV Events in TNT
(All Patients)
Characteristic absent Characteristic present
HR=1.33

Low
HDL-C

HR=1.30

HR=1.24

HR=1.18

HR=1.48

Fasting Body-mass
TriglyceridesHypertension
glucose
index 250 mg/dL
100 mg/dL 28 kg/m2

Deedwania for TNT. Lancet. 2006;368:919-928(A).

Cardio Vascular Disease in patients

with T2DM
Primary composite
endpoint* (%)

Conclusion
The intensified intervention
aimed at multiple risk
factors reduces the risk of
cardiovascular and
microvascular events by
about 50 %

60
50
40
30

Conventional
treatment
P = 0.007
Intensive treatment

20
10
0

12

24

36

48

60

72

84

96

44
61

41
59

13
19

Follow-up (months)
Number at
risk

80
80

72
78

70
74

63
71

59
66

50
63

Conventional
Intensive
* Composite endpoint = CV death and amputation
(with either therapy), and relative risk for organ damage
Gaede P et al. N Engl J Med. 2003; 348: 3839
(with intensive therapy)

Potential anti-atherogenic Effects of

Thiazolidinediones
Traditional Risk
Factors

Decrease of HbA1c, FPG,

PRS
Lowering of Systolic BP

Non-traditional Risk
Factors

Reduction of vascular
Inflammation
Lowering of CRP, IL-6, NFkB,
Increase of HDL-Cholesterol
Antiplatelet Effects: sCD40L, PSelectin
sICAM, sVCAM, MCP-1, MMP-9
Decrease of Triglycerides
Improvement of Fibrinolysis
Decrease of Lp (a)
lowering of PAI-1
Improvement of Endothelial
Decrease of small-dense
Dysfunction
lowering of ADMA
LDL-Particles
Neovascularisation & Neoangiogenesi
Increase of endothelial progenitor c
(EPC)

Vascular disease and its pathogenesis

Risk factors for vascular disease
Metabolic syndrome vs. Cardiometabolic risk
Mechanism of the development of
vascular disease in Diabetes Mellitus,
Dyslipidemia, Hypertension and Obesity
Overall management of Diabetes Mellitus
Overall management of Dyslipidemia, Hypertension
and Obesity
Conclusion

Micro- and Macroangiopathy

is related to the toxicity of glucose

itself
First tissues affected by intracellular
hyperglycemia are those without
glucose transport regulation by insulin
(retina, endothelial cells, neurons...)

Hyperglysolia

Biochemical Pathways of Hyperglycemic Damage

Nonenzymatic
glycation
Pentose
shunt
HK/GK

Glucose

R-5P

GlcN-6P

Hexosamine
pathway

GFAT

G-6P

F-6P

GAPDH

GA-3P

AR

Sorbitol
SD

DHAP

Polyol
pathway

DAG

Fructose

Oxidative
stress

PKC

Glycolysis

Pyruvate
DAG de novo
synthesis

Effect of Hyperglycemia
Sorbitol
pathway

DAG-PKC
pathway

Hexosamine
pathway

AGE
pathway

Oxidative stress
Increase
Increase of procoagulant proteins
proteins
Extracellular
Extracellular coagulant
Increase
Increase of
of ::

matrix
matrix
Collagen
Collagen
Fibronectin
Fibronectin

von
von Willebrandt
Willebrandt
factor
factor
tissue
tissue factor
factor

Decrease
Decrease of
of
proliferation,
proliferation,
migration,
migration,
and
and
fibrinolytic
fibrinolytic
potential
potential

Vascular complications

Increase
Increase of
apoptosis
apoptosis

Stehouwer CDA et al. 200

Dyslipidemia
Increased
Increased postprandial
postprandial TGRL
TGRL (Chylomicron
(Chylomicron and
and VLDL)
VLDL)

Small dense LDL

HDL Cholesterol

Enhance oxidative stress

Impair endothelial function

Hypertension
Decreased availability of NO

Vasoconstriction
Decreased glomerular filtration
Impaired tubuloglomerular feed-back
Decreased medullary blood flow
Impaired pressure natriuresis
Progressive proteinuria

Obesity
Visceral
Visceral obesity,
obesity, hypertension,
hypertension, dyslipidemia,
dyslipidemia, insulin
insulin
resistance
resistance

TNF-a, Leptin, PAI-1

Endothelial dysfunction

Atherothrombosis and microangiopathy

Vascular disease and its pathogenesis

Risk factors for vascular disease
Metabolic syndrome vs. Cardiometabolic risk
Mechanism of the development of
vascular disease in Diabetes Mellitus,
Dyslipidemia, Hypertension and Obesity
Overall management of Diabetes Mellitus
Overall management of Dyslipidemia, Hypertension
and Obesity
Conclusion

Natural History of Disease

Progression

Aggressive treatment of established cardiovascular risk factors

Macrovascular
complications
Microvascular
complications

Aggressive glycemic control

-cell function

Insulin
resistance
Blood
glucose

10

Prevention
IGT/IF
G of IGT
Prevention

0
Diagnosis

Treatment

10

Years

Type 2
diabetes

Prevention of progression of IGT to Type 2 DM

Adapted from Bergenstal RM, et al. Diabetes mellitus, carbohydrate metabolism and lipid disorders. In
Endocrinology. 4th ed. 2001.

Strategies for Reduction of Diabetic

Complications
Prevention of impaired glucose tolerance
Prevention of progression of IGT to type 2
diabetes
Aggressive glycemic control
Aggressive treatment of established
cardiovascular risk factors

The Cornerstones of
DM Management Medical Nutrition
Therapy

1. Education

Medications

Lifestyle
Modification

2. Medical Nutrition
Therapy
An essential component of any
comprehensive
diabetes mellitus management program
3. Physical Activity
4. Pharmacological Intervention

Algoritme Pengelolaan DM tipe-2 Tanpa

Dekompensasi
Diagnosis
DM

Tahap-I

Tahap-II

Tahap-III

GHS

GHS
+
monoterapi
Catatan:
1. GHS = gaya hidup
sehat
2. Dinayatakan gagal
bila terapi selama
2-3 bulan pada
tiap tahap tidak
mencapai target
terapi HbA1c <7%
3. Bila tidak ada
pemeriksaan
HbA1c dapat
dipergunakan
pemeriksaan
glukosa darah
Rata-2 hasil
pemeriksaan
beberapa kali
gukosa darah
sehari yang

GHS
+
Kombinasi 2
OHO
Jalur pilihan
alternatif, bila:
-tidak terdapat insulin
-penyandang betulbetul menolak insulin
-kendali glukosa belum
optimal

GSH
+
Kombinasi 3
OHO

GHS
+
Kombinasi 2
OHO
+
Basal insulin
Insulin intensif
(Basal-plus
atau
Basal-bolus)

CHD with intensive glucose-lowering vs.

standard treatment
Intensive treatment/
standard treatment

Weight of
study size

Odds ratio
(95% CI)

Odds ratio
(95% CI)

Participants

Events

UKPDS

3071/1549

426/259

8.6%

0.75 (0.541.04)

PROactive*

2605/2633

164/202

20.2%

0.81 (0.651.00)

ADVANCE

5571/5569

310/337

36.5%

0.92 (0.781.07)

892/899

77/90

9.0%

0.85 (0.621.17)

5128/5123

205/248

25.7%

0.82 (0.680.99)

17267/15773

1182/1136

100%

VADT
ACCORD
Overall

0.85 (0.770.93)

0.6 0.81.01.21.41.6
Intensive
Standard
treatment
* Included non-fatal myocardial infarction
and death fromtreatment
all-cardiac
mortality
better
better
Ray KK et al. Lancet. 2009;373:176572

Early and Intensive Glycemic Control

Delays Diabetes Complication

Diabetes Care. 2012;35(6):1364-79

Individualized Treatment based on several criteria to control

blood glucose

Slide 44

Inzucci SE, et al. Diabetologia. 2012

Diabetes Care. 2012;35(6):1364-79

AACE Comprehensive Diabetes Management Algorithm. Endocrine Practice. 2013;10(2):331

CE Comprehensive Diabetes Management Algorithm. Endocrine Practice. 2013;10(2):332

Vascular disease and its pathogenesis

Risk factors for vascular disease
Metabolic syndrome vs. Cardiometabolic risk
Mechanism of the development of
vascular disease in Diabetes Mellitus,
Dyslipidemia, Hypertension and Obesity
Overall management of Diabetes Mellitus
Overall management of Dyslipidemia, Hypertension
and Obesity
Conclusion

A Model of Steps in
Therapeutic Lifestyle Changes (TLC)
Visit I

Visit 2
6 wks

Begin Lifestyle
Therapies
Emphasize
reduction in

saturated fat &

cholesterol
Encourage

moderate physical
activity

Consider referral

to dietitian

6 wks

Evaluate LDL
response
If LDL goal not
achieved,
intensify
LDL-Lowering
Tx
Reinforce
reduction
in saturated fat and
cholesterol
Consider adding
plant stanols/sterols
Increase fiber intake
Consider referral to
a dietitian

Visit 3
Q 4-6 mo
Evaluate LDL
response
If LDL goal not
achieved,
consider
adding Drug Tx
Initiate Tx for
Metabolic
Syndrome
Intensify weight
management &
physical activity
Consider referral
to a dietitian

Visit N
Monitor
Adherence
to TLC

Diabetic Dyslipidemia
In the Management of Diabetic dyslipidemia,
DM = CHD risk equivalent
TLC is the basis of lipid management in DM
Always intensively treat non-lipid risk factors
Target LDL-C < 100 mg/dL
In general start with LDL lowering (statin)
Consider fibrate or low dose nicotinic acid if
Non HDL-C > 130 mg/dL

Factors that Favor a Decision to Reduce

LDL-C levels to 70 mg/dL (Very High Risk)
The Presence of Established CHD PLUS
1. Multiple major risk factors (especially DM)
2. Severe and poorly controlled risk factors
(especially cigarrete smoking)
3. Multiple risk factors of Metabolic Syndrome
especially High TG> 200 mg/dL
plus non-HDL-C > 130 mg/dL
with Low HDL-C (40 mg/dL)
4. Pts with Acute Coronary Syndrome

Grundy SM, et al. Circulation 2004;110:227-3

Algorithm for Treatment of

Hypertension
Lifestyle Modifications
Not at Goal Blood Pressure (<140/90 mmHg)
(<130/80 mmHg for those with diabetes or chronic kidney
disease)
Initial Drug Choices

Without
Compelling
Indications

With Compelling
Indications

Stage 1 Hypertension

Stage 2 Hypertension

(SBP 140159 or DBP 9099

mmHg)
Thiazide-type diuretics for most.

(SBP >160 or DBP >100 mmHg)

2-drug combination for most
(usually thiazide-type diuretic
and
ACEI, or ARB, or BB, or CCB)

May consider ACEI, ARB, BB,

CCB,
or combination.

Not at Goal
Blood Pressure
Optimize dosages or add additional drugs
until goal blood pressure is achieved.
Consider consultation with hypertension
specialist.

Drug(s) for the compelling

indications
Other antihypertensive drugs
(diuretics, ACEI, ARB, BB, CCB)
as needed.

orhytm for Treatment of Hypertension in Diabe

Syst. 130 - 139
Diast. 80 - 89

Syst. > 140

Diast. > 90

Lifestyle
Modification
months, inadequate response
Lifestyle +ACE Inhibitor Beta Blocker Diuretic
modification

Alpha Blocker

AIIRA

1-2 months, target not achieved

Increase Dose
other antihypert.

Change to other antihypert.

Add

Add other antihypertensive

(second, third, etc., (one of them should be
diuretic) or macroalb./clinical nephropathy present, use
If microalbuminuria,
ACE inhib, or AIIRA or Non Dihydropyridine Ca. Antag.

Algorithm for Management of Obesity

Assesment of Obesity and Its Risks
Initiate: Behaviour modification
Diet therapy
Physical activity
3 - 6 months

No Weight Loss
(< 6 Kg), BMI >27

Continued weight loss

( > 6 Kg )

Initiate drug therapy

Continue diet and exercise

3 - 6 months

Reassess if no weight loss and BMI >27

consider more intensive drug therapy, VLCD
Bariatric Surgery

Potential Benefits of
Moderate
(5-10%)
Weight
Subcutaneous
AdiposeLoss
Tissue
5-10%
weight loss
~30% Visceral
adipose tissue loss
(diet, physical
activity,
pharmacotherapy)

Visceral
Adipose Tissue

Blood Pressure

Deteriorated

Lipid

Improved

Insulinprofile
sensitivity Improved
Impaired

Insulinaemia, Glycaemia
Susceptibility to thrombosis

Inflammation markers

Abdominally
Reduced Obesity
Obese (high waist HighRisk of Coronary Heart DiseaseLow (low waist measurement)
measurement)

Desprs JP, BMJ 2001;322:716-20

Vascular disease and its pathogenesis

Risk factors for vascular disease
Metabolic syndrome vs. Cardiometabolic risk
Mechanism of the development of
vascular disease in Diabetes Mellitus,
Dyslipidemia, Hypertension and Obesity
Overall management of Diabetes Mellitus
Overall management of Dyslipidemia, Hypertension
and Obesity
Conclusion

Pada Pengelolaan Penyakit Vaskular

Strategi Pencegahan Primer Sangat Penting

Perubahan Gaya Hidup Ke arah Pola Hidup Sehat Sangat Penting

Pola Hidup Sehat juga penting untuk strategi pencegahan:
Diabetes Melitus
Dislipidemia
Hipertensi
Kegemukan
Komponen lain Resistensi Insulin

Problem
Metabolik

Tindakan aktif sudah harus dikerjakan, tidak hanya

dalam tingkat wacana saja
Pengelolaan berbagai faktor risiko harus dikerjakan sekali
gus
Depkes dapat mengkoordinasi pelaksanaan program
pencegahan dalam tingkat nasional Tingkat Primer
Bekerja sama dengan institusi dan profesi terkait

Thank Yo

tur Nuwun