1

Pharmacological Effects

of Statins

2

OverviewOverview• Lipids and Lipoproteins

• Pharmacology of Statins

• How Do we Choose a Statin?How Do we Choose a Statin?

3

Lipids and LipoproteinsLipids and Lipoproteins

4

LipidsLipids

TriglyceridesTriglycerides• Source: sugars,

alcohol• Essential energy

source• Energy storage

CholesterolCholesterol• Source: fats, dietary

cholesterol• Bile acid formation• Hormone synthesis• Cell membrane

component

5

Lipids vs. LipoproteinsLipids vs. Lipoproteins

• Lipids need to get to site of action for use– Not water soluble not readily carried by

bloodstream

• Special transport “vehicle” necessary for delivery of lipids to tissues for use

• Lipoprotein = Proteins + TG +

Cholesterol + Phospholipids

6

Structure of Lipoproteins

Free cholesterol

PhospholipidTriglyceride

Cholesteryl esterApolipoprotein

7

ApolipoproteinsApolipoproteins

• Protein components of lipoproteins• Several functions

– Structural stability– Receptor binding (function as ligands in lipoprotein-

receptor interactions)– Regulate enzyme activity

• lecithin cholesterol acyltransferase (LCAT)• lipoprotein lipase (LPL)• hepatic triglyceride lipase (HTGL)

• Concentrations may related to CHD risk• Possible site of genetic variation

8

ChylomicronsChylomicrons• Formed in intestines

• Metabolized via LPL (lipoprotein lipase; a triglyceride hydrolase) into remnants which are taken-up by liver

• Primary function is transport of exogenous fatty acids and cholesterol

Major LipoproteinsMajor Lipoproteins

apoB-48apoE

apoA-I, A-IV

apoC-I, C-II, C-III

9

VLDLVLDL• Formed in the liver

• Metabolized by LPL into IDL

• Primary function is TG and cholesterol transport

IDLIDL• Formed via VLDL

• Metabolized by LPL into LDL

• Primary function is TG and cholesterol transport

Major LipoproteinsMajor Lipoproteins

apoB-100

10

LDLLDL• Formed via IDL

• Metabolized by tissue and hepatic uptake

• Function is cholesterol transport

HDLHDL• Formed primarily via

metabolism of chylomicrons and VLDL

• Primary function is reverse cholesterol transport

Major LipoproteinsMajor Lipoproteins

11

Lipoprotein(a); Lp(a)Lipoprotein(a); Lp(a)

SS

LDLLDL

apoB-100

Plasminogen-like domain

apo(a)

12

Exogenous PathwayExogenous PathwayFood particles

Intestines

Free Fatty AcidsFree Fatty Acids

Breakdown of Triglyceride

ChylomicronsChylomicrons

BloodstreamBloodstream

LiverLiver

Chylomicron Chylomicron RemnantsRemnants

Bile AcidsBile Acids

13

Endogenous PathwayEndogenous Pathway

Free Fatty AcidsFree Fatty Acids

Breakdown of Triglyceride

BloodstreamBloodstream

LiverLiver

IDLIDL

VLDLVLDL

LDLLDL

Body TissuesBody Tissues

HDLHDL

14

Possible Causes of Secondary Possible Causes of Secondary DyslipidemiaDyslipidemia

DiseasesDiseases• Diabetes• Hypothyroidism• Nephrotic Syndrome• Obstructive Liver

Disease

DrugsDrugs• Progestins• Corticosteroids• Anabolic steroids -blockers• Thiazide diuretics• Cyclosporin• Sulfonylureas• Isotretinoin• Alcohol

Benefit of Lowering Cholesterol

Adapted from Gould AL et al. Circulation 1998;97:946–952

Meta-analysis of 38 primary and secondary prevention trials,with more than 98,000 patients in total

Mortality in CHD, p=0.012

Total mortality, p=0.04

Cholesterol reduction (%)

Mo

rtal

ity

(lo

g o

dd

s ra

tio

)

0 4 8 12 16 20 24 28 32–1.0

–0.8

–0.6

–0.4

–0.2

0.0

16

Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk

Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm

1% decreasein LDL-C reduces

CHD risk by1%

1% increasein HDL-C reduces

CHD risk by3%

17

Managements of Dyslipidaemia

• Therapeutic lifestyle change (TLC)

• Lipid-lowing agents

18

降血脂藥物 全民健康保險藥品給付規定 (劃線部分為 93/9/1後適用）

血脂異常之

起步治療準則 血脂濃度 ≧ 2個危險因子 (如附註二)

TC/HDL-C>5 或

HDL-C<40mg/dl 治療目標 處方規定

≧ 200mg/dl ˇ × <200mg/dl TC

≧ 240mg/dl × × <240 mg/dl

≧ 130mg/dl ˇ × <130mg/dl LDL-C

≧ 160mg/dl × × <160mg/dl

︵如附註一︶

無心血管疾病患者

三至六個月非藥物治療

有下列情況之一時，應給予

TG ≧ 200mg/dl (需同時合併有TC/HDL-C>5或是HDL-C<40mg/dl)

× ˇ <200mg/dl (87/4/1)

如非藥物治療未達治療目標，得使用降血脂藥物(請附三個月前及本次血脂檢查數據)，接受藥物治療後，應每三至六個月抽血檢查一次，同時請注意副作用產生，如肝功能異常或橫紋肌溶解症等，如已達治療目標，請考慮減量，並持續治療之。

TC ≧ 200mg/dl × × < 160mg/dl (87/7/1) LDL-C ≧ 130mg/dl × × ≦ 100mg/dl (87/7/1)

或糖尿病患者

有心血管疾病

非藥物治療

同時予以

TG ≧ 200mg/dl (需同時合併有 TC/HDL-C>5或是HDL-C<40mg/dl)

× ˇ < 150mg/dl (87/7/1)

接受藥物治療後，應每三至六個月抽血檢查一次，同時請注意副作用產生，如肝功能異常或橫紋肌溶解症等。

血中三酸甘油酯高於 500mg/dl，具有罹患急性胰臟炎危險者，得使用降血脂藥物。

附註一：心血管疾病： (ˇ )需符合此項條件 (一)冠狀動脈粥狀硬化患者 (×)不需符合此項條件

? 有心導管檢查證實(附檢查報告、醫院名稱及日期)。 ? 曾患心肌梗塞有心電圖(附心電圖)或住院證實(附檢查醫院名稱及日期)。 ? 心絞痛病患，有缺氧性心電圖變化或運動試驗陽性反應者(附檢查報告)。

(二)腦血管病變患者 ? 腦梗塞。 ? 腦內出血(不含其他顱內出血)。 ? 陣發性腦缺血患者(TIA)其頸動脈超音波證實有粥腫樣變化併有 70%以上阻塞者。

(三)周邊血管粥狀硬化有缺血性症狀且經血管都卜勒超音波或血管攝影證實者。 附註二：危險因子： ? ? ? ≧高血壓 糖尿病 男性 45 ? ? ≧歲 有早發性冠心病家族史 女性 55歲或停經沒有雌激素療法者 ? 吸菸(因吸菸而符合起步治療準則之個案，如要求藥物治療，應以自費治療)。

19

Cholesterol-Lowering Drug TherapyCholesterol-Lowering Drug TherapyHMG CoA Reductase HMG CoA Reductase

InhibitorsInhibitors• Amlodipine/Atorvastatin• Aspirin/Pravastatin• Atorvastatin• Cerivastatin (2001/8 withdrawal from

market)• Lovastatin• Niacin/Lovastatin• Pitavastatin• Pravastatin• Rosuvastatin• Simvastatin

FibratesFibrates• Gemfibrozil• Micronized

Fenofibrate• Clofibrate

Bile AcidBile Acid SequestrantsSequestrants

• Cholestyramine• Colestipol• Colesevelam

NiacinNiacin

20

B-48

B-100

HMG Reductase

21

22

Effect of Lipid-Modifying Therapies on Lipids

Therapy

Bile acidsequestrants

Nicotinic acid

Fibrates(gemfibrozil)

Probucol

Statins*

* Daily dose of 40 mg of each drug (cerivastatin 0.3 mg)TC–total cholesterolLDL–low density lipoproteinHDL–high density lipoproteinTG–triglyceride.

TC

Down 20%

Down 25%

Down 15%

Down 25%

Down 15–30%

LDL

Down 15–30%

Down 25%

Down 5–15%

Down 10–15%

Down 24–50%

HDL

Up 3–5%

Up 15–30%

Up 20%

Down20–30%

Up 6–12%

TG

Neutral or up

Down 20–50%

Down 20–50%

Neutral

Down 10–29%

Patienttolerability

Poor

Poor toreasonable

Good

Reasonable

Good

(Adapted from Yeshurun 1995, Knopp 1999)

23

Primary PreventionPrimary Prevention• Fewer coronary events• Fewer angiographies,

PTCAs, and CABGs

Secondary PreventionSecondary Prevention• Less lesion progression,

fewer new lesions• Increased lesion

regression• Fewer coronary events• Less cardiac-related

mortality• Less overall mortality

Benefits of TherapyBenefits of Therapy

24

Pharmacology of Statins

25

History

• Isolated from a mold, Penicillium citrinium, and identified as inhibitors of cholesterol biosynthesis in 1976 by Endo et al.

• Brown et al,. (1978) established that statins act by inhibiting HNG-CoA reductase

• Yamamoto et al., first statin studied in human (1984)---compactin (mevastatin)

• Alberts et al., first statin approved (1987) for use in human---lovastain (isolated from Aspergillus terreus)

26

Atorvastatin

Simvastatin

PravastatinB M YB M Y

Fluvastatin

LovastatinCerivastatin

Rosuvastatin

19911987 1993

200019961997 2003

2001/8 withdrawal

History of Statins

27

28

Cholesterol Synthesis Pathway

acetyl CoA

HMG-CoA

mevalonic acid

mevalonate pyrophosphate

isopentenyl pyrophosphate

geranyl pyrophosphate

farnesyl pyrophosphate

squalene

cholesterol

dolicholsubiquinones

HMG-CoA synthase

HMG-CoA reductase

Squalene synthase

X Statins

蛋白質合成

信息傳遞

細胞能量代謝

細胞膜穩定維持

細胞能量代謝

29

Statin Dose-Response CurveStatin Dose-Response Curve

0

10

20

30

40

50

60

70

Increasing Dose

% L

DL

Red

ucti

on

CURVES Study. Am J Cardiol 1998;81:582-7.

30

How do we Choose a Statin?How do we Choose a Statin?Differences among the HMG-CoA Reductase Inhibitors

• Potency (LDL, HDL, TG)

• Clinical efficacy

• Hydrophilic vs Lipophilic

• Pharmacokinetics

• Cost

• Drug Interactions

• Non-lipid effects

31

Comparative LDL EffectsComparative LDL Effects

-70

-60

-50

-40

-30

-20

-10

0

10

40

20

80

10

10

20

20

20

20

80

40

40

40

401

5

20

AtorvastatinAtorvastatin SimvastatinSimvastatin PravastatinPravastatin LovastatinLovastatin FluvastatinFluvastatin RosuvastatinRosuvastatin

Am J Cardiol 1998;81:582-7. Am J Cardiol 2001;88:504-8. J Int Med Res 2000;28:47-68. Clin Cardiol 2000;23:39-46.

80

80

80

32

-4

-2

0

2

4

6

8

10

12

Atorva Simva Prava Lova Fluva Rosuva

10102020

4040

4040

4040

4040

2020

2020

2020

2020

1010

1010

4040

8080

8080

CURVES Study. Am J Cardiol 1998;81:582-7.

Comparative HDL EffectsComparative HDL Effects

1010

2020 4040

33

Comparative TG EffectsComparative TG Effects

-35

-30

-25

-20

-15

-10

-5

0

5

1010

4040

2020

8080

1010

1010

2020

2020

20202020

80804040

40404040

4040

AtorvastatinAtorvastatin SimvastatinSimvastatin PravastatinPravastatin LovastatinLovastatin FluvastatinFluvastatin

CURVES Study. Am J Cardiol 1998;81:582-7.

34

Statins – Therapeutic Ratio

Muscle

Liver

Drug interactions

Therapeutic Effects

Adverse Effects

Cardiovascular protection

Benefit

Risk

35

Statin – Liver Effects

Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

0.0

0.5

1.0

1.5

2.0

2.5

3.0

20 30 40 50 60 70LDL-C reduction (%)

Pers

iste

nt

ALT >

3 ×

ULN

(%

)

Fluvastatin (20–80 mg)

Rosuvastatin (10–40 mg)

Lovastatin (20–80 mg)

Atorvastatin (10–80 mg)

Simvastatin (40–80 mg)

Persistent ALT >3 Persistent ALT >3 ×× ULN: Frequency by LDL-C Reduction ULN: Frequency by LDL-C Reduction

36

Statin - Muscle Effects

Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

Cerivastatin (0.2–0.8 mg)

Rosuvastatin (10–40 mg)

Pravastatin (40–80 mg)

Atorvastatin (10–80 mg)

Simvastatin (40–80 mg)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

20 30 40 50 60 70

LDL-C reduction (%)

CK

>10 ×

ULN

(%

)

CK >10 CK >10 xx ULN: Frequency by LDL-C Reduction ULN: Frequency by LDL-C Reduction

37

Drug InteractionsDrug Interactions

• Pharmacodynamic– Risk of hepatotoxicity and/or myalgias or

myopathy when combined with fibrates or niacin

• Pharmacokinetic absorption with bile acid sequestrants– Inhibition or induction of CYP-based

metabolism– Inhibition of CYP activity

38

Statin MetabolismStatin Metabolism

CYP3A

CYP2C9

Other enzymes/renal

Lovastatin, Lovastatin, Simvastatin, Simvastatin, AtorvastatinAtorvastatin

FluvastatinFluvastatin

PravastatinPravastatin

Active and inactive

metabolites, which are excreted in

urine and/or bileRosuvastatinRosuvastatin

39

Potential Drug Interactions

• Simvastatin

• Atorvastatin

• Lovastatin• Diltiazem

• Clopidogrel

• Amiodarone

• Cimetidine

• Ery/clarithromycin

• Ketoconazole

• Carbamazepine

• Grapefruit juice

• Fluvastatin

• Rosuvastatin• Phenytoin

• Fluconazole

• Warfarin

3A4 2C9

40

CYP3A InteractionsCYP3A Interactions• ALL statins (except fluvastatin and rosuvastatin)

are metabolized at least in part by CYP3A

• CYP3A inhibitors may statin concentrations– Verapamil, diltiazem, Azole antifungals, erythromycin,

nefazodone, fluoxetine, Protease inhibitors

• CYP3A inducers may statin concentrations– Rifampin, phenytoin, phenobarbital, troglitazone

• Statins may also interact with other CYP3A substrates (i.e., cyclosporine)

41

CYP2C9 InteractionsCYP2C9 Interactions

• Fluvastatin is metabolized by CYP2C9 and inhibits CYP2C9 activity

• CYP2C9 inducers (e.g., rifampin) and inhibitors (e.g., amiodarone) may or fluvastatin concentrations, respectively

• Fluvastatin can inhibit CYP2C9 activity, increasing the concentration and effect(s) of other CYP2C9 substrates (e.g., S-warfarin)

Pharmacokinetic properties of Statins

Thomas N. Riley, PhD & Jack DeRuiter, PhD (2004); 陳昭姿 , 當代醫學雜誌 (2005)

Parameter Rosuva Atorva Prava Simva Fluva LovaAbsolute

bioavailability,% 20 14 17 < 5 24 <5

Food effect on bioavailability None 13% 30% None

15-25%

50%

Half-life, h19

( 任何時間服用)

14( 任何時間服用 )

2( 晚上服用 )

2( 晚上服用

)

1( 睡前服用)

3( 晚上服用

)

Hepatic extraction,

% dose90 >70 50 78-87 68 >70

Metabolic enzyme2C9

(10%)3A4 Sulfation 3A4

2C9

(75%)3A4

Protein binding, % 88 >90 50 95 98 95Solubility Hydrophilic Lipophilic Hydrophilic Lipophilic Lipophilic Lipophilic

Elimination, %

Feces

Urine

90

10

98

2

70

20

60

13

90

5

83

10

Pharmacologic properties of Statins

Parameter Rosuva Atorva Prava Simva Fluva Lova

Potency, IC50 5.4 mg 8.2 mg 27.6 mg NA 44.1 mg 11.2 mg

Usual adult dosage (USA)

5-40 mg 10-80 mg 10-80 mg 5-80 mg 20-80 mg 10-80 mg

LDL-C % 45-63 % 39-60 % 22-34 % 26-47 % 22-35 % 21-40 %

HDL-C % 8-14 % 5-9 % 2-12 % 8-16 % 3-7 % 2-9 %

TG % 10-35 % 19-37 % 11-24 % 12-33 % 12-19 % 10-19 %

Comparative efficacy of Statins

LDL-C % TC % Rosuva Atorva Simva Lova Prava Fluva

27 22 -- -- 10 20 20 40

34 27 -- 10 20 40 40 80

41 32 5 20 40 80 80 --

48 37 10 40 80 -- -- --

55 42 20 80 -- -- -- --

63 47 40 -- -- -- -- --

Am J Cardiol 2004; 93(15): 809-811

Cost - Effective of Statins

陳昭姿 , 當代醫學雜誌 (2005) Brown WV et al., Am Heart J. 2002; 144:1036-43.

規格 給付價總膽固醇

降值

LDL-C平均降值

降 LDL-C

1% 費年

達目標值病人比例

達目標值每人年費

Rosuva

10 mg 33.6 元 33% 45.9% 267 元 0.8214956元

20 mg 42.1 元 38% 52.3% 294 元 0.8917266元

Atorva10 mg 33.8 元 27% 36.7% 397 元 0.69

17880元

40 mg 57.0 元 36% 47.8% 306 元 0.8524476元

Prava

10 mg 42.3 元 15% 20.1% 768 元 0.3149804元

20 mg 51.0 元 17% 24.3% 365 元 0.4442307元

40 mg 57.0 元 22% 29.7% 701 元 0.5537827元

Simva

10 mg 42.3 元 20% 28.3% 545 元 0.5130273元

20 mg 44.7 元 26% 35.0% 466 元 0.6325898元

40 mg 59.0 元 28% 38.8% 555 元 0.6632369元

Fluva 80 mg 39.9 元 35% 35%

Lova 20 mg 42.0 元 17% 21% 730 元 ?

46

Thanks for your attention!

47

• Superior LDL-lowering ability

• Combinations with a resin may provide benefit with little risk of additive toxicity

• Some concern about risk of rhabdomyolysis with statin-niacin or statin-fibrate combinations

• Others have found these combinations to be safe

Studied Combinations

Statin + Resin

Statin + Resin + Niacin

Statin + Niacin

Statin + Fibrate

Niacin + Resin

Combination TherapyCombination Therapy

48

• Statins and Endothelial Function

• Statins and Plaque Stability

• Statins and Inflammation

• Statins and Lipoprotein Oxidation

• Statins and Coagulation

Possible Non-Lipid-Lowering Possible Non-Lipid-Lowering Effects of the StatinsEffects of the Statins