2. Age-standardized prevalence of raised total cholesterol in adults aged 25+ years, by WHO Region and World Bank income group, comparable estimates WHO, 2008 EMR - Eastern Mediterranean, SEAR - South East Asia, WPR - Western Pacific

3. 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.

5. Czech republic:Czech republic: - more than 37,5 % of inhabitants older than 40 have total plasma cholesterol above 6.2 mmol/L

6. TG CH apoB TG CH apoB CH apoB CH apoB Atherogenic lipoproteins – produced by liver – produced by liver VLDLIDLLDLsd LDL Antiatherogenic lipopoteins - trapped by liver - trapped by liver CH apoA-I transport CH from tissues HDL transport CH to tissues

7. Atherogenic potential of LDL & HDL LDL cholesterol (mg/dL) HDL- cholesterol (mg/dL)

8. 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

9. We cannot: to increase HDL  synthesis of HDL - ?  degradation of HDL - ?

10. statins fibrates resins nicotinic acid ezetimib

12. Zdroje cholesterolu

13. Statins

14. STATINS most mammalian cells can produce cholesterol cholesterol biosynthesis is a complex process involving more than 30 enzymes riparanol withdrawn cataractscutaneous adverse effects accumulationdesmosterolearly attempts to reduce cholesterol biosynthesis were disastrous ‒ triparanol, which inhibits a late step in the pathway, was introduced into clinical use in the mid-1960s, but was withdrawn from the market shortly after because of the development of cataracts and various cutaneous adverse effects.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 reductaserate-limiting enzymeHMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA) is the rate-limiting enzyme in the cholesterol biosynthetic pathway

15. STATINS compactinIn 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. shown to lower plasma cholesterolIn 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. lovastatinIn 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.

16. Hargreaves et al., 2005

18. 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)

20. The effect of statins on lipids HDL-C 5 0 -5 -10 -15 -20 -25 -30 -35 -20 ‒ 55% 5 - 5 ‒ 30% LDL- C TG change (%) + 0 ‒ 12%

22. effect on vessels:  NO, PGE 2 & PGI 2, 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, PGE 2 & PGI 2,  PAI-1) Extralipid effects of statins

23. 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

24. Vývoj statinů 3 CH HO O H O C H 3 C H 3 3 CH Simvastatin O O HO Pravastatin O H 3 H C HO H 3 CH CO 2 Na O OH HO COCa ++ 2 Atorvastatin OH CHN O N F F N Fluvastatin HO CO 2 Na OH HO CO 2 Na OH F N CH 3 O HO O H H O C H 3 C H 3 3 CH Lovastatin O O I. generace 2. generace 3. generace Cholstat ® cerivastatin

25. FK profiles of statins ROSUVASTATINATORVASTATINSIMVASTATINFLUVASTATIN metab. CYP3A4 CYP2C9 NO Y NO Y NO NOYNOY important metabolites NONOYYNONO elimination dual ren./hepat.hepatal dual ren./hepat. hydrophilicity YNONONONONO hepatoselect. YYYY biol. availability 20%14%<5%21% half-life (hrs) 19141,91,92,7

26. rosuvastatin atorvastatin simvastatin 1 10 20 40 10 20 40 80 10 20 40 80 mg decrease of LDL-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

27. STATINs – influence on HDL-C 1 10 20 40 10 20 40 80 10 20 40 80 mg rosuvastatin atorvastatin simvastatin increase of HDL-C (%) Jones et al. Am J Cardiol. 2003;93:152- 160.

28. STATINs ‒ influence on mortality & morbidity (sec. prophylaxis) 4S HPS LIPID CARE total mortality CV mortality MI stroke %

31. Inhibition of CH resorption phytosterols ezetimib

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

33. average change in LDL (%) placebo ( n=52 ) +5 ezetimib 0.25 mg (n=47) ezetimib 1 mg (n=49) ezetimib 5 mg (n=49) ezetimib 10 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)

34. atorva- 80 mg ezetimib +atorva- +atorva- 80 mg atorva- 10 mg ezetimib+atorva- average change in LDL (%) -16 -7 -37 -54 -61* * P<0.01 combination versus statin Ballantyne, Circulation The effects of ezetimib in combination with atorvastatin -´53*

35. Inhibitors of bile acids resorption pryskyřice

36. 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)

37. Increase levels of HDL pryskyřice

38. 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

39. FIBRATES: sec. prevention, DM) FIELD BIP VA-HIT ACCORD total mortality CV mortality MI stroke % * * *

40. nicotinic acid (niacin) - lipolysis inhibition in adipose tissue -  synthesis of VLDL, LDL I: combined dyslipidaemia fix. combination with laropiprant (anta PGD 2 – flushes reduction) Nicotinic acid

41. The influence of niacin on lipidogram HDL-C 5 0 -5 -10 -15 -20 -25 -30 -13% 5 -32% LDL- C TG change (%) + 12% 10

43. "...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)