Transcript C H

Age-standardized prevalence of raised total cholesterol
in adults aged 25+ years, by WHO Region and
World Bank income group, comparable estimates
EMR - Eastern Mediterranean, SEAR - South East Asia, WPR - Western Pacific
WHO, 2008
Facts
•
In 2008, the global prevalence of raised total cholesterol among adults was 39%
(37% for males and 40% for females). Globally, mean total cholesterol changed little
between 1980 and 2008, falling by less than 0.1 mmol/L per decade in men and
women (59). The prevalence of elevated total cholesterol was highest in the WHO
European Region (54% for both sexes), followed by the WHO Region of the Americas
(48% for both sexes). The WHO African Region and the WHO South-East Asia
Region showed the lowest percentages (23% and 30% respectively).
•
The prevalence of raised total cholesterol increased noticeably according to the
income level of the country.
•
In low-income countries, around a quarter of adults had raised total cholesterol, in
lower-middleincome countries this rose to around a third of the population for both
sexes.
•
In high-income countries, over 50% of adults had raised total cholesterol; more than
double the level of the low-income countries.
• Czech republic:
- more than 37,5 % of inhabitants older
than 40 have total plasma cholesterol
above 6.2 mmol/L
Atherogenic lipoproteins
– produced by liver
TG
CH
TG
CH
apoB
VLDL
CH
apoB
IDL
CH
apoB
LDL
apoB
sd LDL
transport CH to tissues
Antiatherogenic lipopoteins
- trapped by liver
CH
apoA-I
HDL
transport CH from tissues
Atherogenic potential of LDL & HDL
3
2,5
2
25
1,5
1
0,5
0
45
65
85
220
160
LDL cholesterol (mg/dL)
100
We can: to decrease LDL-C
 intake cholesterol in diet
 resorption in our GIT
 synthesis of CH in liver and tissues
 catabolism of CH in liver
We cannot: to increase HDL
 synthesis of HDL - ?
 degradation of HDL - ?
• statins
• fibrates
• resins
• nicotinic acid
• ezetimib
Zdroje cholesterolu
Statins
STATINS
•
most mammalian cells can produce cholesterol
•
cholesterol biosynthesis is a complex process involving more than 30 enzymes
•
early attempts to reduce cholesterol biosynthesis were disastrous ‒ triparanol,
which inhibits a late step in the pathway, was introduced into clinical use in the
mid-1960s, but was withdrawn from the market shortly after because of the
development of cataracts and various cutaneous adverse effects. These
side effects were attributable to tissue accumulation of desmosterol, the
substrate for the inhibited enzyme.
•
HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA) is the rate-limiting
enzyme in the cholesterol biosynthetic pathway
STATINS
•
In the 1970s, the Japanese microbiologist Akira Endo first discovered natural
products with a powerful inhibitory effect on HMG-CoA reductase, including
ML236B (compactin) in a fermentation broth of Penicillium citrinum. Although
no HMG-CoA reductase inhibitor has been shown to have useful antimicrobial
activity, the possibility that an agent that inhibited the rate-limiting step in the
cholesterol biosynthesis pathway could have useful lipid-lowering properties
was quickly appreciated by Endo and others.
•
In the rabbit, monkey, and dog, compactin was shown to lower plasma
cholesterol.
•
The prototype compound compactin was developed by Sankyo, and was
shown to be highly effective in reducing concentrations of total and LDL
cholesterol in the plasma of patients with heterozygous familial
hypercholesterolaemia.
•
In 1978, Alberts, Chen and others at Merck Research Laboratories found a
potent inhibitor of HMG-CoA reductase in a fermentation broth of Aspergillus
terreus ‒ they named their discovery mevinolin and later named officially as
lovastatin.
Hargreaves et al., 2005
STATINS
• inhibition of 3-hydroxy-3-methyl-glutaryl-coenzymA
reductase
• depl. of CH in liver -LDL receptors - uptake LDL ch.
• AS plaques stabilization
• decreased total mortality
• I: isolated hypercholesterolaemia, comb. dyslipidaemia
• ADRs: increased liver enzymes, myopathy,
rhabdomyolysis
• lovastatin, simvastatin, pravastatin, fluvastatin,
atorvastatin, rosuvastatin, (cerivastatin)
The effect of statins on lipids
5
0
HDL-C
LDLC5
change (%)
-5
-10
-20
-25
-35
+0‒
12%
-5‒
30%
-15
-30
TG
-20 ‒
55%
Extralipid effects of statins
• effect on vessels: NO, PGE2 & PGI2, improved ED - (
vasospastic activity)
• effect on AS plaque: inhibition of oxidation of LDL-C,
plaque stabilization
• effect on the activity of inflammation:  activity of cytokines
(CRP, TNF-, IL-1, IL-6,…)
• antithrombotic effect:  activation of thrombocytes,
fibrinolysis potentiation (NO, PGE2 & PGI2,  PAI-1)
STATINS
 simvastatin & lovastatin
- intermediately effective, shorter eff.
- metab. via CYP 3A4
 fluvastatin & pravastatin
- low risk of D-D interactions, flu metabolized via CYP2C9
 atorvastatin
-highly effective, even on high TG, low toxicity
- metabolized via CYP3A4 & P-gp
 rosuvastatin & pitavastatin
- most effective, not substrates for CYP
Vývoj statinů
I. generace
O
HO
O
O
O
O
O
H3C
H
H3C
H
H3C CH3
CH3
H3C
Lovastatin
2. generace
O
H
CH3
O
H 3C H
Simvastatin
CO2 Na
OH
OH
F
F
CO2 Na
OH
O
H
CH3
HO
HO
HO
HO
O
HO
N
Pravastatin
CO2 Ca ++
3. generace
HO
CO 2 Na
OH
F
N
N
CH3 O
Fluvastatin
Atorvastatin
Cholstat®
cerivastatin
FK profiles of statins
ROSUVASTATIN
ATORVASTATIN
SIMVASTATIN
FLUVASTATIN
NO
NO
Y
NO
Y
NO
NO
Y
important
metabolites
NO
Y
Y
NO
elimination
dual ren./hepat.
hepatal
dual
ren./hepat.
dual
ren./hepat.
hydrophilicity
Y
NO
NO
NO
hepatoselect.
Y
Y
Y
Y
biol. availability
20%
14%
<5%
21%
half-life (hrs)
19
14
1,9
2,7
metab. CYP3A4
CYP2C9
decrease of LDL-C in (%)
STATINS – influence on LDL-C
0
rosuvastatin
1 10 20 40
atorvastatin
10 20 40 80
simvastatin
10 20 40 80 mg
-20
-40
-60
1. Prescribing Information for CRESTOR. AstraZeneca, Wilmington, DE. 2. Data on file, DA-CRS-02.3. Jones et al. Am J Cardiol. 2003;93:152-160.
STATINs – influence on HDL-C
increase of HDL-C (%)
10
8
6
4
2
0
1 10 20 40
rosuvastatin
10 20 40 80
atorvastatin
10 20 40 80 mg
simvastatin
Jones et al. Am J Cardiol. 2003;93:152-160.
STATINs ‒ influence on mortality
& morbidity (sec. prophylaxis)
%
4S
HPS
LIPID
CARE
0
-20
-40
total mortality
CV mortality
-60
MI
stroke
Inhibition of CH resorption
phytosterols
ezetimib
Ezetimib
inhibition of a specific transportation system, NPC1L1 (Niemann-Pick
C1-like 1 protein) on the surface of enterocytes
The effects of ezetimib in
monotherapy (12 wks)
average change in
LDL (%)
+5
+4.3
ezetimib ezetimib
0.25 mg
1 mg
(n=47)
(n=49)
ezetimib ezetimib
5 mg
10 mg
(n=49)
(n=46)
0
placebo
(n=52)
-10
9.9*
-12.6*
-16.4*
-20
-18.7*
* P<0.05 vs placebo
Bays H et al. Clini Ther 2001 Aug: 23 (8);1209-30
The effects of ezetimib in
combination with atorvastatin
average change in LDL (%)
atorva10 mg
ezetimib
+atorva10 mg
atorva80 mg
-´53*
-54
ezetimib
+atorva80 mg
0
-10
-20
-30
-37
-40
-16
-50
-60
-7
-61*
* P<0.01 combination versus statin
Ballantyne, Circulation
Inhibitors of bile acids
resorption
pryskyřice
RESINS
• blocked reabsorption of BA in intestine
•  conversion of CH into BA -  LDL rec.
• synergism with statins
• ADRs: constipation, flatulency, nausea, vomiting
• cholestyramine (low tolerance, interactions with
absorption of concomitantly administered drugs)
• colesevelam (better tolerance, low risk of
interactions)
Increase levels of HDL
pryskyřice
FIBRATES
• derivatives of fibric acid
• stimulation of PPAR-alpha, thus  expression of genes
for apolipoproteins A-I, A-II a C-III, lipoprotein lipase
(LPL), and thus decrease of VLDL (rich on TAG) and
increase of HDL
• I: hyperTAGemia, low HDL, combined dyslipidemia
• ADRs: cholelithiasis, GIT (nausea, diarrhea),
rhabdomyolysis
• fenofibrat, ciprofibrat
FIBRATES: sec. prevention, DM)
%20
FIELD
BIP
VA-HIT
ACCORD
0
-20
*
* *
total mortality
-40
CV mortality
MI
-60
stroke
Nicotinic acid
nicotinic acid (niacin)
- lipolysis inhibition in adipose tissue -  synthesis
of VLDL, LDL
I: combined dyslipidaemia
fix. combination with laropiprant (anta PGD2 –
flushes reduction)
The influence of niacin on lipidogram
HDL-C
10
5
change (%)
0
LDLC5
-5
-10
-15
-20
TG
+
12%
-13%
-25
-30
-32%
"...it may one day be possible
for many people to have their
steak and live to enjoy it too"
•
Michael Brown and
Joseph Goldstein - The
Nobel Prize in
Physiology or Medicine
1985for their
discoveries concerning
the regulation of
cholesterol
metabolism (1985)