VASCULAR PROBLEMS in

patients with DIABETES

MELLITUS

PROF dr BAMBANG IRAWAN

INTERNIST KARDIOLOGIST
FK UGM
Risk Factors for Cardiovascular Disease

Modifiable Non-modifiable
Smoking Personal history
Dyslipidaemia of CVD
Raised LDL-C Family history
Low HDL-C of CVD
Raised triglycerides Age
Raised blood pressure Gender
Diabetes mellitus
Obesity
Dietary factors
Thrombogenic factors
Lack of exercise
Excess alcohol consumption

Pyrl K et al. Eur Heart J 1994;15:13001331.

 The Metabolic Syndrome and
Associated CVD Risk Factors

Hypertension

Abdominal obesity
Atherosclerosis
Hyperinsulinaemia
Insulin
Diabetes
Resistance
Hypercoagulability
Endothelial
Dyslipidaemia Dysfunction
high TGs
small dense LDL
low HDL-C

Deedwania PC. Am J Med 1998;105(1A);1S3S.

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

LDL-C BP Risk factors Diabetes Smoking Heart failure

Oxidative stress

Endothelial dysfunction

NO Local mediators Tissue ACE-Ang II

Endothelium Growth factors Proteolysis

PAI-1 VCAM
matrix
ICAM cytokines

Thrombosis Inflammation Vasoconstriction Vascular lesion Plaque rupture

and remodelling

Clinical endpoints

NO Nitric oxide
Gibbons GH, Dzau VJ. N Engl J Med 1994;330;14311438.
 Arterial wall:
structure and function
Vascular endothelium modification
in atherosclerosis
Plaque formation
1 Fatty streak
Plaque formation
2 Fibrous cap
Plaque formation
3 Lipid core
 Characteristics of the
stable atherosclerotic plaque
Fibrous cap
(VSMCs and matrix) Intimal VSMCs
Endothelial (repair phenotype)
cells

Lipid core

Adventitia

Medial VSMCs
(contractile phenotype)
The vulnerable atherosclerotic plaque

Lipid core

Adventitia
 Plaque rupture
The main releasing factors
The Grip of Angina
From plaque to thrombosis, key event:
plaque rupture
 Severity of Coronary Artery Stenosis
Prior to Acute MI
68%
60

MI
Patients 40
(%)
20 18%
14%

0
<50% 50%70% >70%
% Stenosis
Data constructed from 4 individual trials in approximately 200 MI patients
Falk E et al. Circulation. 1995;92:657-671. 10
 Atherosclerosis Timeline
Complicated
Foam Fatty Intermediate Fibrous Lesion/
Cells Streak Lesion Atheroma Plaque Rupture

Endothelial Dysfunction
From First From Third From Fourth
Decade Decade Decade

Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 10A):23S-27S.

CRE027/Jul07-Jul08/TEP | RTD Master Slide 2nd Semester
 NCEP ATP III Guidelines

Initiate TLC* Drug therapy LDL-C

Patients with if LDL-C considered if LDL-C treatment
goal

01 risk factors 160 mg/dL 190 mg/dL <160 mg/dL

(160189
mg/dL: drug
optional)

10-yr risk 1020%:

2 risk factors 130 mg/dL <130 mg/dL
130 mg/dL
(10-year risk 20%)
10-yr risk <10%:
160 mg/dL

CHD and CHD risk 130 mg/dL

100 mg/dL <100 mg/dL
equivalents (100129
(10-year risk >20%) mg/dL: drug
optional)
100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L; 190 mg/dL = 5 mmol/L

* TLC: therapeutic lifestyle changes

Adapted from NCEP, Adult Treatment Panel III. JAMA 2001;285:24862497.

 NCEP ATP III: LDL-C Goals

CHD or 2 risk < 2 risk

CHD risk factors factors
equivalents

190 - goal
160
LDL-C level

mg/dL

160 - goal
130
mg/dL

130 - goal
100
mg/dL

100 -

100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L

Adapted from NCEP, Adult Treatment Panel III, 2001. JAMA 2001:285;24862497.
 NCEP ATP III: LDL-C Goals
(2004 proposed modifications)
Moderately Moderate Lower
High Risk High Risk Risk Risk
CHD or CHD risk 2 risk 2 risk < 2 risk
equivalents factors factors factors
190 - (10-yr risk (10-yr risk (10-yr risk goal
>20%) 1020%) <10%) 160
mg/dL

160 - goal goal

LDL-C level

130 130
mg/dL mg/dL

130 - goal
or
100 optional
mg/dL
100
mg/dL*

100 -
or
optional
Existing LDL-C goals

70 Proposed LDL-C goals

mg/dL*

70 -
*Therapeutic option
70 mg/dL =1.8 mmol/L; 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L;
160 mg/dL = 4.1 mmol/L
Grundy SM et al. Circulation 2004;110:227239.
 Main Effects of Statins

Effects on lipids:
Reduce LDL-C, TC and TG
Increase HDL-C

Pleiotropic effects:
Improve or restore endothelial function
Enhance the stability of atherosclerotic plaques
Decrease oxidative stress
Decrease vascular inflammation
Anti-thrombotic effects

Takemoto M, Liao JK. Arterioscler Thromb Vasc Biol 2001;21:17121719.

 Mechanism of Action of Statins:
Cholesterol Synthesis Pathway
acetyl CoA
HMG-CoA synthase
HMG-CoA
HMG-CoA reductase X Statins
mevalonic acid

mevalonate pyrophosphate

isopentenyl pyrophosphate

geranyl pyrophosphate

ubiquinones farnesyl pyrophosphate dolichols

Squalene synthase
squalene

cholesterol
 Pharmacokinetics of Statins

Statin Metabolised Protein Lipophilic Half-

by CYP450 binding life (h)
(%)

rosuvastatin minimal ~90% No ~19

atorvastatin Yes >98% Yes ~15
simvastatin Yes 958% Yes ~3
pravastatin No ~50% No ~2
fluvastatin Yes >98% intermediate* ~3

* intermediate between hydrophilic and lipophilic

Horsmans Y. Eur Heart J Supplements 1999;1(Suppl T):T712, Vaughan CJ et al. J Am

Coll Cardiol 2000;35:110. Rosuvastatin data from Core Data Sheet.
 Diabetes Mellitus

One of the most common non-communicable

diseases

Fourth leading cause of death in most developed

countries

More than 194 million people with diabetes

worldwide

Incidence of diabetes is increasing estimated to

rise to 333 million by 2025
To more than double in Africa, the Eastern Mediterranean
and Middle East, and South-East Asia

To rise by 50% in North America, 20% in Europe, 85% in

South and Central Americas and 75% in the Western
Pacific

International Diabetes Federation website.

 Types of Diabetes Mellitus

Type 1 diabetes (insulin-dependent diabetes)

mainly in childhood/early adult life
1020% of cases

Type 2 diabetes (non-insulin-dependent diabetes)

usually develops in the middle-age/elderly
incidence increasing at a younger age
8090% of cases

At least 50% of all people with diabetes are unaware

of their condition

International Diabetes Federation website.

 The Chronic Complications of
Diabetes Mellitus (US)
Macrovascular complications:
Cardiovascular disease
Leading cause of diabetes related deaths (increases
mortality and stroke by 2 to 4 times)
Microvascular complications:
Retinopathy
Leading cause of adult blindness
Nephropathy
Accounts for 44% of new cases of ESRD
Neuropathy
6070% of patients with diabetes have nervous
system damage

ESRD end-stage renal disease

National Diabetes Statistics US 2000.
Typical Lipid Profile in Patients with Diabetes
Compared with No Diabetes (1): UKPDS
Women
6 Women 4 p<0.001
(232) (154)

5.8 3.8 Men

(224) (147)
Men
5.6 3.6
(216) (139)

5.4 3.4
(208) (131)

5.2 no no 3.2 no no
(201) DM DM DM DM (124) DM DM DM DM

5 3
(116)
(193) Total cholesterol mmol/L (mg/dL) LDL-C mmol/L (mg/dL)

DM diabetes mellitus
UKPDS. Diabetes Care 1997;20:16831687.
Typical Lipid Profile in Patients with Diabetes
Compared with No Diabetes (2): UKPDS

1.6 2
(62) Women (177) Men Women
p<0.001 p<0.001
p<0.001
1.8
(159)
1.4
(54) 1.6
(142)
Men
1.4
p<0.02
1.2 (124)
(46)
no no
DM
1.2
no (106)
DM no DM DM
DM DM DM
DM
1 1
(39) HDL-C mmol/L (mg/dL) (89) Triglycerides (mmol/L)

DM diabetes mellitus
UKPDS. Diabetes Care 1997;20:16831687.
 Combination of Risk Factors Increases
Risk of MI: PROCAM

120
Incidence of MI/1000 pts

100

80

60

40

20

0
Prevalence (%): 54.9 22.9 2.6 2.3 9.4 8.0

Assmann G, Schulte H. Am Heart J 1988;116:17131724.

 Patients with Diabetes at Similar Risk to
No Diabetes with MI: East West Study

p<0.001
50
7-year incidence of CV events (%)

40

30 p<0.001
No prior MI
MI
20

10
ns

n=1304 n=69 n=890 n=169

0
No diabetes Diabetes
(n=1373) (n=1059)

Haffner SM et al. N Engl J Med 1998;339:229234.

 Survival Post-MI in Men and Women
With and Without Diabetes
Diabetes
No diabetes

100 Men 100 Women

90 90

Survival, %
80 80
Survival, %

n=1628 n=568
70 70

60 60

50 50

40 40 n=156
n=228

0 10 20 30 40 50 60 0 10 20 30 40 50 60
Months Post-MI Months Post-MI

Sprafka JM et al. Diabetes Care 1991;14:537543.

 ADA Recommendations for Lipid
Goals in Patients With Diabetes

LDL-C <100 mg/dL (2.6 mmol/L)

or a reduction of 30-40%

<70 mg/dL (1.8 mmol/L)#

HDL-C* >40 mg/dL (1.15 mmol/L)

TG <150 mg/dL (1.7 mmol/L)

*For women, HDL value should be increased by 10 mg/dL

#An optional goal for high-risk patients with diabetes and overt CVD

ADA. Diabetes Care 2005;28(suppl 1):S4S36.

Primary Prevention Treatment with Statins Reduce
Major Coronary Events in Patients with Diabetes:
CARDS
15
placebo (n=1410)
Major coronary events (%)

atorvastatin (n=1428)

10

37%
RRR
5
p=0.001

0
0 1 2 3 4 4.75 Years

Placebo 1410 1351 1306 1022 651 305

Atorva 1428 1392 1361 1074 694 328

RRR relative risk reduction

Colhoun HM et al. Lancet 2004;364:685696.
 Improving Lipid Profile with Fibrates
Reduces CVD Risk in Diabetes
Diabetes
Study Fibrate pts (n) Clinical Outcomes

Helsinki Heart Gemfibrozil 135 68% risk reduction in MI or

Study1* sudden cardiac death (ns)

70% reduction in definite

SENDCAP2 * Bezafibrate 164
CHD events (p=0.01)

32% risk reduction for

VA-HIT3* Gemfibrozil 769 composite endpoint (p=0.004)

DAIS4 Fenofibrate 418 23% reduction in combined

cardiac endpoints (ns)

* Post hoc subgroup analysis.

1. Koskinen et al. Diabetes Care 1992;15:820825. 2. Elkeles et al. Diabetes Care 1998;21(4):641648.
3. Rubins et al. Arch Int Med 2002;162:25972604. 4. DAIS Investigators. Lancet 2001;357:905910.
 Summary
Atherosclerosis is associated with CVD, which is a
major cause of death in developed countries
Dyslipidaemia, in particular elevated LDL-C and low
HDL-C, is associated with increased risk for CVD
Large statin trials have shown that the lower the level
of LDL-C achieved the greater the reduction in CV
events
Diabetes is a risk factor for CVD, which is the leading
cause of death amongst people with diabetes
Dyslipidaemia is associated with diabetes and the
metabolic syndrome
Guidelines recommend lipid levels to reduce the
morbidity and mortality caused by dyslipidaemia, and
proposed recommendations suggest even more
stringent levels for the future