Age-standardized prevalence of raised total cholesterol in adults aged 25+ years, by WHO Region and

World Bank income group, comparable estimates

WHO, 2008EMR - Eastern Mediterranean, SEAR - South East Asia, WPR - Western Pacific

FactsFacts

• 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:Czech republic:

- more than 37,5 % of inhabitants older

than 40 have total plasma cholesterol

above 6.2 mmol/L

TGCH

apoB

TGCH

apoB

CH

apoB

CH

apoB

Atherogenic lipoproteinsAtherogenic lipoproteins – – produced by liverproduced by liver

VLDL IDL LDL sd LDL

AntiatAntiathherogenerogenic lipopoteinsic lipopoteins - trapped by liver- trapped by liverCH

apoA-I

transport CH from tissuestransport CH from tissuesHDL

transport CH to tissues

Atherogenic potential of LDL & HDL

0

0,5

1

1,5

2

2,5

3

220 160 100

85

65

45

25

LDL cholesterol (mg/dL)

HDL- choles

terol

(mg/dL)

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

StatinsStatins

STATINSSTATINS

• 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 ‒ triparanolriparanol,

which inhibits a late step in the pathway, was introduced into clinical use in the

mid-1960s, but was withdrawnwithdrawn from the market shortly after because of the

development of cataractscataracts and various cutaneous adverse effectscutaneous adverse effects. These

side effects were attributable to tissue accumulationaccumulation of desmosteroldesmosterol, the

substrate for the inhibited enzyme.

• HMG-CoA reductaseHMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA) is the rate-limiting rate-limiting

enzymeenzyme in the cholesterol biosynthetic pathway

STATINSSTATINS• In the 1970s, the Japanese microbiologist Akira Endo first discovered natural

products with a powerful inhibitory effect on HMG-CoA reductase, including ML236B (compactincompactin) 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 shown to lower plasma cholesterolcholesterol.

• 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 lovastatinlovastatin.

Hargreaves et al., 2005

STATINSSTATINS

• 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

HDL-C5

0

-5

-10

-15

-20

-25

-30

-35-20 ‒ 55%

5

- 5 ‒ 30%

LDL-C

TGch

ange

(%

)

+ 0 ‒ 12%

• 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)

Extralipid effects of statins

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

3CH

HO

OH

O

CH3

CH3

3CH

Simvastatin

O

O

HOPravastatin

O

H3HC

HO

H3CH

CO2Na

O

OH

HOCO Ca++

2

Atorvastatin

OHC

HN

O

N

FF

N

Fluvastatin

HO CO2 Na

OH

HO CO2 NaOH

F

N

CH3 O

HO

OHH

O

CH3

CH3

3CH

Lovastatin

O

OI. generace

2. generace 3. generace

Cholstat®

cerivastatin

FK profiles of statinsROSUVASTATIN ATORVASTATIN SIMVASTATIN FLUVASTATIN

metab. CYP3A4

CYP2C9

NO

NO

Y

NO

Y

NO

NO

Y

important metabolites

NO Y Y NO

elimination dual ren./hepat. hepataldual

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

-60

-40

-20

0

rosuvastatin atorvastatin simvastatin 1 10 20 40 10 20 40 80 10 20 40 80 mg

dec

reas

e of

LD

L-C

in (

%)

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 LDL-C

0

2

4

6

8

10

STATINs – influence on HDL-C

1 10 20 40 10 20 40 80 10 20 40 80 mgrosuvastatin atorvastatin simvastatin

incr

ease

of

HD

L-C

(%

)

Jones et al. Am J Cardiol. 2003;93:152-160.

-60

-40

-20

0

STATINs ‒ influence on mortality & morbidity (sec. prophylaxis)

4S HPS LIPID CARE

total mortality

CV mortality

MI

stroke

%

Inhibition of CH resorptionInhibition of CH resorption

phytosterolsezetimib

EzetimibEzetimib

inhibition of a specific transportation system, NPC1L1 (Niemann-Pick C1-like 1 protein) on the surface of enterocytes

aver

age

chan

ge in

L

DL

(%

)

placebo(n=52)

+5ezetimib 0.25 mg(n=47)

ezetimib

1 mg(n=49)

ezetimib

5 mg(n=49)

ezetimib10 mg(n=46)+4.3

-20

-10

0

-9.9* -12.6*

-16.4*

-18.7*

Bays H et al. Clini Ther 2001 Aug: 23 (8);1209-30 * P<0.05 vs placebo

The effects of ezetimib in monotherapy (12 wks)

-60

-50

-40

-30

-20

-10

0

atorva-atorva-80 mg80 mg

ezetimibezetimib +atorva-+atorva-

80 mg80 mgatorva-atorva-10 mg10 mg

ezetimibezetimib+atorva-+atorva-

10 mg10 mg

aver

age

chan

ge

in L

DL

(%

)

-16

-7

-37

-54

-61** P<0.01 combination versus statin

Ballantyne, Circulation

The effects of ezetimib in combination with atorvastatin

-´53*

Inhibitors of bile acids Inhibitors of bile acids resorptionresorption

pryskyřice

RESINS

• blocked reabsorption of BA in intestine

conversion of CH into BA - LDL rec.

• synergism with statins

• ADRs: constipation, flatulency, nausea, vomiting

• cholestyraminecholestyramine (low tolerance, interactions with absorption

of concomitantly administered drugs)

• colesevelamcolesevelam (better tolerance, low risk of interactions)

Increase levels of HDLIncrease levels of HDL

pryskyřice

FIBRATESFIBRATES

• 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

-60

-40

-20

0

20

FIBRATES: sec. prevention, DM)

FIELD BIP VA-HIT ACCORD

total mortality

CV mortality

MI

stroke

%

* * *

nicotinic acid (niacin)- lipolysis inhibition in adipose tissue - synthesis of VLDL, LDLI: combined dyslipidaemiafix. combination with laropiprant (anta PGD2 – flushes reduction)

Nicotinic acid

The influence of niacin on lipidogram

HDL-C

5

0

-5

-10

-15

-20

-25

-30

-13%

5

-32%

LDL-C

TG

chan

ge (

%) +

12%

10

"...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)