Endothelial dysfunction

Atherosclerosis is a diffuse process

Usually several unstable AS plaques

The main purpose of hypolipidemic therapy

is stabilisation of vulnerable

atherosclerotic plaques

Statins stabilize

AS plaques:

• Reduction of lipid

core

• Increase fibrous cap

• Reduction

of inflammatory response

Lipoproteins

-IDL

Function of LDL-receptors

Increased amount of free cholesterol (CH) in the cells leads to down-regulation of LDL-receptors

and to a reduced endogenous cholesterol synthesis and low free CH content in the cells leads to

up-regulation of LDL-receptors and increased endogenous cholesterol synthesis in cells.

VLDLIDLLDL

HDL

Anti-

atherogenic

LP particles

Atherogenic

LP particles

LP(a)

CH

CH

CHCHCHCHCHCH

CH

TG

chylomicron

Risk of acute

pancreatitis

Lipoprotein particles: risk of atherossclerosis and pancreatitis

Exogennous factors increasing

cholesterol levels

• Increased intake of CH and saturated

fats-decreased number and function of

LDL receptors - decreased uptake of

IDL a LDL

• Increased caloric intake – overweight -

increase of VLDL- IDL and LDL

Triglycerides, HDL-C and risk of

CHD

The Emerging Risk Factors Collaboration. JAMA 2009;302:1993-2000

Small dense LDL (LDL III) – the most

atherogenic subpopulation of LDL

Atherogenic lipoprotein phenotype: LDL III, HDL-C , TG , LDL-C

risk of CHD 2-7x. Increase of LDL III from TG>1.5 mmol/l.

Insulin resistance

HDL

Symp. activity

Hypertension

Uric acid

Microalbuminuria

Triglycerides

Postprandial

lipemia

SD LDL

PAI-I

fibrinogen

InflammationIL-6, TNF alfa, CRP,

fibrinogen, PAI-1, ICAM-1

Resistin

Adiponectin

leptin

Endothelial

dysfunction

Insulin resistance

Hyperinsulinemia

IFG, IGT,DM2FFA

FFA

CV diseases

Criteria for Clinical Identification of the

Metabolic Syndrome According to ATP III

1. triglycerides 1.7 mmol/l

2. HDL-C <1.0 mmol/l for men or

<1.3 mmol/l for women

3. waist circumference >102 cm for

men or 88 cm for women

4. blood pressure 130/ 85 mm

5. fasting glucose 5.6mmol/l

3 of 5 required for diagnosis

Metabolic syndrome

KV risk

2-3x

T2DM

7-8x

Causes of hypertriglyceridemia

• Genetic disorders of

triglyceride

metabolism

• Type 2 diabetes

mellitus

• Type 1 diabetes

mellitus

• Renal insuficiency

• Excess total caloric

intake (obesity)

• Excess carbohydrate

intake

• Excess ethanol intake

• Beta-adrenergic

blocking agents

HDL

Antioxidant and

antinflammatory

effects

Reverse

cholesterol

transport

Removes

CH from the

vessel wall

↓AS plaques

Stabilizes

AS plaques,

inhibits

plaque rupture

Prevents LDL

from oxidative

modification

↓ expression of

adhesive

molecules,

antithrombotic

effects

Antiatherogenic effects of HDL

Causes of reduced HDL-C

• Cigaret smoking

• Obesity

• Lack of exercise

• Insulin resistance

• Genetic factorsPrimary hypoalfalipoproteinemia

• Androgenic related

steroids

• Beta adrenergic

blocking agents

Clasification of hyperlipidemias

• Hypercholesterolemia

• Combined hyperlipidemia

• Hypertriglyceridemia

- Primary

- Secondary

Causes of secondary DLP

• Hypothyroidism

• Diabetes mellitus:

-Type 1 DM in case

of bad glucose control

-Type 2 DM in all

cases – IR

• Nephrotic syndrome

• Chronic renal failure

• Cholestasis

• Alcohol induced

• Drugs:

progetins

anabolic steroids

Common genetic hyperlipidemias

Familial hypercholesterolemia

Familial defective apo B 100

Polygenic hypercholesterolemia

Familial combined hyperlipidemia

Familial hypertriglyceridemia

Familial hyperchylomicronemia

Routine lipoprotein profile

Total cholesterol (TC)

Triglyceride

HDL-C

LDL-cholesterol (LDL-C)

calculated :

LDL-C=TC-(TG/2.2+HDL-c)

directly measured

nonHDL-C TC - HDL-C

Apolipoprotein B

VLDLIDLLDL

HDL

HDLLDL IDL VLDL

Non-HDL-C = cholesterol content of all atherogenic LP particles

(Non-HDL-C = total cholesterol – HDL-C)

ApoB concentration → number of all atherogenic LP particles

apoA-I apoB-100

Anti-

atherogenic

LP particles

Atherogenic

LP particles

LP(a)

LP(a)

Figure 2.

A

B

CH

CH

CHCHCHCHCHCH

In subjects with prevalence of cholesterol-depleted sd LDL,

LDL-C underestimates the number of LDL particles most

CH

apoB

CH

CH

B. Prevalence of sd LDL

CH

CH

CH

A. Prevalence of large buoyant LDL

CH

CH

CH

CHCH

CH

CHCH

CHlbLDL lbLDL

apoB

sdLDL

sdLDL

lbLDL

LDL-C = 3 mmol/l LDL-C = 3 mmol/l

Evaluation of cardiovascular risk

We evaluate the absolute risk of

cardiovascular mortality in the

next 10 years

according to SCORE system

Accumulation of risk factors increases

global risk of CHD mortality

Framingham Study

SCORE system –Systematic

Coronary Risk Evaluation

Patients with very high and

high riskVery high risk:

• patients with CVD (secondary prevention)

• diabetic patients (DM2, DM 1 with MAB) (both

with or without AS manifestations)

• chronic kidney disease (CKD)-eGFR<30ml/min

• SCORE risk > 10%

High risk:

• with very high individual risk factors (BP, LDL-C)

• SCORE > 5% and < 10%

• CKD - eGFR<60 and ≥30 ml/min

Tabulky: www.escardio.org/guidelines; elektron. verze: www.heartscore.org

Modification of risk after inclusion of HDL-C

W

O

M

E

N

LDL-C goals Class Level

Very high risk:

KVD, DM2,

DM 1 with MAB

CKD 3-5

SCORE risk ≥ 10%

LDL-C < 1.8

and/or

≥ 50% ↓LDL-C

When it is not

possible to reach

goal

I A

High risk:

SCORE risk ≥5 a <10% or

markedly elevated indiviadual

risk factors

LDL-C < 2.5IIa A

Moderate risk:

SCORE risk ≥ 1 a < 5%LDL-C < 3.0

IIa C

ESC/EAS guidelines 2011

Non-HDL-C goal

is 0.8 mmol/L higher than LDL-C goal

for appropriate risk category.

Apo B goal

for high risk category is <1.0 g/L,

for very high risk <0.8 g/L

Markers of increased coronary risk:

HDL-cholesterol < 1 mmol/l (M)

< 1.2 mmol/l (F)

Triglyceride > 1.7 mmol/l (M/F)

These values may shift the subject to the

higher risk category → earlier and more

aggressive pharmacotherapy.

Choice of drugs for hypolipidemic therapy

Type of dyslipidemia

Hypercholesterolemia

• familial hypercholesterolemia

• familial def. apo B-100

• polygennic hypercholesterolemia

• familial combined hyperlipidemia (phenotype IIa)

Therapy

1. statins

2. sequestrants – in children and women in reprod. age

3. ezetimibe

3. combined therapy

- statin + ezetimibe

- statin + sequestrant

Choice of drugs for hypolipidemic therapy

Type of dyslipidemia

Combined hyperlipidemia

• familial combined hyperlipidemia

• type 3 - familial dysbetalipoproteinemia

• familial hypertriglyceridemia

Therapy

1. Statins - TG< 5-10 mmol/L

Combination therapy

- statin + fibrate

- statin + omega-3 fatty acids

Choice of drugs for hypolipidemic therapy

Type of dyslipidemia

Hypertriglyceridemia > 10 mmol/l

(TG 5-10 mmol/l)

• familial hypertriglyceridemia

• familial hyperchylomicronemia

Therapy

1. fibrate

2. n- 3 fatty acids

Combined therapy:

statin + fibrate

combination with

n-3 fatty acids

LDLReceptor

Statins – mechanism of action

Acetate

LDL 20-60%

HMG-CoAReductase

Cholesterol

STATINS ON OUR MARKET

• Atorvastatin (Sortis®)…………10 – 80 mg

• Simvastatin (Zocor®)………… 10 – 80 mg

• Lovastatin (Mevacor®)..…….. 20 – 80 mg

• Fluvastatin (Lescol®)..………. 20 – 80 mg

• Rosuvastatin (Crestor®).……. 10 – 40 mg

Side effects of HMG-CoA reductase inhibitors

- liver test elevation ( AST, ALT)

- myopathy (increase of CPK, myalgia)

- rhabdomyolysis – rare, most common in cases of interaction with other drugs

(cyclosporin, fibrate – gemfibrozil, not fenofibrate, macrolide ATB –clarithromycin, erytromycin,

systemic antifungal drugs –ketoconazole, itraconazole)

Symptoms of rhabdomyolysis:

Muscle weakness and tenderness

Elevation of CPK and myoglobin, myoglobinuria

Acute renal failure

Drug interactions of statins.Metabolism in liver: cytochrome P 450

Substráty

(metabolizované

izoenzymy

CYP450)

Inhibitory

izoenzymů

CYP450

Zvýšená

koncentrace

substrátu

potenciál

pro

nežádoucí

účinek léku

3A4

2C9

2D6

1A2

ostatní

Játra:

enzymy

CYP450

De Swarte. JAllergy Clin Immunol. 1984

Borda et al. JAMA. 1968

Substrates

(metabolized by

izoenzymes

CYP450)

Inhibitors of

izoenzymes

CYP450

Increased

concentration

of substrate

potential

for

side effect

of drug

2C9

3A4

2D6

1A2

others

Liver:

enzymesCYP450

De Swarte. JAllergy Clin Immunol. 1984

Borda et al. JAMA. 1968

Bile acid sequestrants

usual dose

• cholestyramine

Questran light 8 – 16 g

Vasocan S, P 8 – 16 g

• colestipol

Colestid 10 – 20 g

● colesevelam

Side effects of bile acid sequestrants

• Gastrointestinal

- constipation

- epigastric fullness and distress

- abdominal discomfort

• Metabolic

- rise in serum triglycerides

Ezetimibe: cholesterol absorption inhibitor

Ezetimibe localizes in the brush border of small-intestinal enterocytes and reduces the

uptake of dietary and biliary cholesterol into these cells. In this way, cholesterol

delivery to the liver is decreased, secondarily inducing the synthesis of LDL-C receptors.

The net result is the increased removal of LDL-C from the plasma.

Duodenum

Jejunum

Ileum

Colon

Biliary CHtransport

andabsorption

Fecalexcretion

(1200mg/d)

Dietary cholesterol(400 mg/d)

Absorption~50%

Chylomicron

apoB48

liver

Biliary

cholesterol

(2000 mg/d)

Biliary and dietary cholesterol

Dual cholesterol inhibition.

Duodenum

Jejunum

Ileum

CM

apoB48

liver

CM remnantapoB48

VLDLapoB100

EzetimibeX

LDLapoB100

XStatin

Colon

1-step

3-steptitration

Statin + ezetimibe vs statin titration

Lowest dose of statin 1. 2. 3.

Lowest dose of statin

15–18%

dose dabbling

+ ezetimibe

5–6% 5–6% 5–6%

Bays H et al. Expert Opin Pharmacother 2003;4:779-790.

% decrease LDL-C

Drugs influencing triglyceride levels

FIBRATES usual dose

• bezafibrate 400 – 600 mg

(Regadrin B)

• ciprofibrate micronized 100 mg

(Lipanor)

• fenofibrate 200 – 300 mg

(Lipanthyl 100)

• fenofibrate micronized, NT 200 mg

(Lipanthyl 200M, Lipanthyl 267 267 mg

Lipanthyl Supra) 160 mg

• gemfibrozil 800 – 1200 mg

(Gevilon)

SIDE EFFECTS OF FIBRATES

- Cholelithiasis

- Myopathy

- Abdominal discomfort

- Liver test elevation

NICOTINIC ACID

TG, LDL-C,HDL-C, Lp(a) – (20% all)

bad compliance for flush and GIT discomfort

extended release nicotinic acid

NIASPAN®

less side effects, better compliance but negative results

of AIM-HIGH study

Niaspan + laropiprant

less flush but negative results of HPS 2-THRIVE study

New therapies in development

• CETP inhibitors (anacetrapib, evacetrapib)

• Anti sense oligonukleotide apoB (mipomersen)

• MTP inhibitor (lomitapid)

• Drugs influencing HDL composition and function

• Anti LP-PLA2 – darapladib

• Antiinflammatory drugs – metotrexat, anti IL-1ß

• PCSK9 inhibitors

Non-pharmocological procedures:

treatment of severe hypercholesterolemia

- LDL-apheresis

- Liver transplantation

Pathophysiology of familial hypercholesterolemia

Arcus lipoides corneae

Xanthelasma palpebrarum

Tendon xanthomas

Tendon xanthomas

Tendon

xanthomas

Tendon xanthomas

Tendon xanthomas

Tuberose xanthoma

Tuberose xanthoma

0 0

125,0

48,4

8,4 4,5 2,6 1,1

0

20

40

60

80

100

120

140

0 - 19 20 - 39 40 - 59 60 - 79

ženy

muži

Atherosclerosis 142 (1999): 105 - 112

Rel

ati

vn

í ri

zik

oMortality from CHD in heterozygotes of FH.

Simon Broome Register Group.

věk

Relative risk of mortality from CHD in

heterozygotes of FH (men + women):

84,3

5,31,2 3,6

17,5

3,3 2,1 2,5

0

20

40

60

80

100

0 - 19 20 - 39 40 - 59 60 - 79 0 - 79

1992 - 95

1980 - 91

Reduction of RR in age

cathegory 20 - 59 yr

from 8 to 3,7

Atherosclerosis 142 (1999): 105 - 112

Rel

ati

ve

risk

věk

Eruptive xanthoma in severe hypertriglyceridemia

Very high triglycerides – risk of pancreatitis