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