심장질환의 고위험군이란 ?

뇌졸중 심근경색

위험인자

Hypercholesterolemia Hypertension Diabetes Mellitus Smoking Others

10 20 30 40 50 60 70 80

연령

(세)

증상

(+)

증상

(-)

동맥경화의정도

심장질환의 고위험군이란 ?

• 심혈관 질환자 – 특히 급성관동맥증후군

• 당뇨 환자

• 동맥경화성 혈관 질환자

• 매우 심한 정도의 위험인자를 가진 경우

• 많은 위험인자를 가진 경우 ; 3개 이상의 위험인 자를 가진 경우

• 중등도의 위험을 가지고 있으면서 대사성증후군 또는 높은 CRP 수치등을 가진 경우 (optional)

Elderly People are the Major Target for Risk Reduction to Prevent Atherosclerotic Disease

한 기 훈

울산대학교 의과대학 심장내과학교실

• Cigarette smoking

• Hypertension

(blood pressure

≥

140/90 mmHg or on antihypertensive medication)

• Low HDL cholesterol

(< 40 mg/dL)

†

• Family history of premature CHD

(CHD in male first-degree relative < 55 years

; CHD in female first-degree relative < 65 years)

• Age (men ≥ 45 years; women ≥ 55 years)

*Diabetes is regarded as a coronary heart disease (CHD) risk equivalent.

†HDL cholesterol≥ 60 mg/dL counts as a “negative” risk factor; its pres ence removes 1 risk factor from the total count.

Major Risk Factors That Modify LDL Goals * (Exclusive of LDL Cholesterol)

NCEP-III Guideline ^European Guideline

Distribution of Absolute Risk* of CHD Within 10 Years European Populations

Men Women

<10% 46% 82%

10-20% 38% 16%

20-40% 15% 2%

>40% <1% 0%

* Framingham - Anderson function

Absolute Risk

⁺

of >20% of CHD Within 10 Year s by Age and Sex European Populations

Years Men Women

25-34 35-44 45-54 55-64 65-74 25-74

0%

1%

11%

34%

68%

20%

0%

<1%

<1%

3.5%

6.4%

1.6%

+

Framingham - Anderson function

Points 10-Yr-Risk %

한국성인의 총 콜레스테롤 분포

0 2 4 6 8 10 12 14

<130 140- 160- 180- 200- 220- 240- 260-

남자 여자

%

mg/dl

Men = 7.9%

Women=9.6%

자료: 보건복지부. 1998년 국민건강영양조사 자료

연령군별 고지혈증 유병률

0 5 10 15 20 25

30-39 40-49 50-59 60-69 70이상

남자 여자 전체

자료: 보건복지부. 2001년 국민건강영양조사자료

중간요약 (1)

• 고위험군은 주로 (남성) 고령자에게 많이 발견된다.

• 우리나라에서도 고지혈증은 주로 고령에 서 많이 발견된다.

얼마나 낮추어야 하는가 ? : LDL-C Goal

• Very High Risk ; 70 – 100 mg/dl

• High Risk ; 100 mg/dl

• Intermediate Risk ; 130 mg/dl

Distribution of LDL-C Levels in Patients With 2 or More CHD Risk Factors Distribution of LDL

Distribution of LDL- -C Levels in Patients C Levels in Patients With 2 or More CHD Risk Factors With 2 or More CHD Risk Factors

No. of US Adults (millions) No. of No. of US Adults US Adults (millions) (millions)

LDL-C Level, mg/dL (mmol/L) LDL-C Level, mg/dL (mmol/L)

<60

<60--129129 (1.6 (1.6--3.3)3.3)

130 130--159159 (3.4 (3.4--4.1)4.1)

160 160--300300 (4.1 (4.1--7.8)7.8)

NHANES III phase II (1988 NHANES III phase II (1988--1994) data.1994) data.

Adapted from Jacobson TA et al.

Adapted from Jacobson TA et al. Arch Intern MedArch Intern Med. 2000;160:1361. 2000;160:1361--1369.1369.

Mean LDL-C:

139.5 mg/dL (3.6 mmol/L) Mean LDL-C:

139.5 mg/dL (3.6 mmol/L) 0

0 1 1 2 2 3 3 44 5 5

P40

S20

R10

A20

S40

LDL - 30 %

LDL - 45 %

Mt.Goal

A10

스타틴의 용량조절

THREE-STEP TITRATION

10 20 30 40 50 60

% Reduction in LDL Cholesterol 0

-6% -6%

Simvastatin 10 mg

_mg²⁰ _mg⁴⁰ _mg⁸⁰

-6%

Effect of Statin Therapy on LDL-C Levels: “The Rule of 6”

스타틴의 고용량에서의 주의점

• Myopathy 의 발생이 높은 집단을 이해 !

• 고령 (주로 80세 이상)

• 몸집이 작은 사람

• 당뇨성 신증등 다기관의 질병

• 약물병용

• 알코올 의존 경향

ONE-STEP COADMINISTRATION THREE-STEP TITRATION

10 20 30 40 50 60

% Reduction in

LDL-C

0

Statin 10 mg 20 mg

40 mg

80 mg

Statin 10 mg + Ezetimibe 10 mg

새로운 LDL 강하방법 ; Ezetimibe

Rosuva Atorva Simva / EZ Simva Lova / Prava TC LDL-C

5 10 20 22 27

10 20 40 27 34

10 20 40 80 32 41

20 40 10 / 10 80 37 48

40 80 42 55

Dose (mg) of agent % Reduction

Roberts WC. Am J Cardiol. 1997;80:106-107.

Stein E et al. J Cardiovasc Pharmacol Therapeut. 1997;2:7-16.

Rule of 5s & 7s

용량에 따른 LDL 강하효과

S. Int. Rinse S. Int. Wall

L. Int. Rinse L. Int. Wall

Stomach Liver

Pancreas Adrenal

Kidney Lung

Heart Spleen

Teste Serum 0

60 50 40 30 20 10

% IV dose

0.3 mg/kg, 3-hr post-dosing, n=4/group

Tissue

Localization of IV-Dosed

¹²⁵

I-Gluc-Ezetimibe

(SCH 61209) in Normal Rats

중간요약 (2)

• EZ는 장에서의 콜레스테롤 흡수를 선택적 으로 저해한다.

• EZ는 주로 장관에만 분포하기 때문에, 기 타 조직에 미치는 효과가 거의 없다.

Daily Dose of Ezetimibe (mg)

0 5 10 20 40

From Baseline to Endpoint Mean (±S.E.M.) Percent Change in LDL-C -20%

-15%

-10%

-5%

0%

5%

Placebo

Ezetimibe

Results from three Phase II Clinical Therapy Trials

Relationship Between Dose of Ezetimibe and

% Change in Plasma LDL-C EZ + Simvastatin Study: Efficacy on LDL-C

Mean % Change

10 mg EZ 10 mg

+ Simva

10 mg 20 mg 40 mg 80 mg

Simvastatin

* p<0.01 combination therapy versus statin alone

Davidson M et al. ACC 2002: Abstract.

Davidson M et al. ACC 2002: Abstract.

-46 -45

-27*

-36* -38*

-60 -50 -40 -30 -20 -10 0

EZ + Statin Studies: Efficacy on TG

Pooled Results

* p<0.01 combination therapy versus statin alone

Atorvastatin Pravastatin

Simvastatin Lovastatin

Median % Change

*

*

*

*

Davidson M et al. ACC 2002: Abstract.

Ballantyne C et al. ACC 2002: Abstract.

Melani L et al. WCC 2002: Abstract.

Lipka L et al. WCC 2002: Abstract.

-24 -14

-20 -12

-33 -21

-29 -25

-40 -30 -20 -10 0

Statins only + EZ 10 mg/d

Atorvastatin Pravastatin

Simvastatin Lovastatin

4

7 7

4

9* 9**

8

7*

0 2 4 6 8 10

Mean % Change

* p<0.01 combination therapy versus statin alone

** p=0.03 combination therapy versus statin alone

Ezetrol + Statin Studies: Efficacy on HDL-C

Pooled Results

Davidson M et al. ACC 2002: Abstract.

Ballantyne C et al. ACC 2002: Abstract.

Melani L et al. WCC 2002: Abstract.

Lipka L et al. WCC 2002: Abstract.

Statins only

+ EZ 10 mg/d

Pooled Safety of Ezetimibe (EZ)

Results from three Phase III Pooled Monotherapy Trials

No. of Patients (%) Placebo Ezetimibe

( n=431 ) ( n=1288 )

Adverse events

285 (66) 802 (62)

Gastrointestinal 93 (22) 230 (18)

DC 2° AE

11 (2.6) 51 (4)

Liver function tests (≥3 x ULN)

ALT 2 (<1) 7 (<1)

AST 3 (<1) 6 (<1)

GGT 10 (2) 20 (2)

Total bilirubin 0 0

ALP 0 0

Creatine kinase (CK) elevations

5-10 x ULN 0 8 (<1)

≥10 x ULN 1 (<1) 3 (<1)

Ezetimibe in KOREANS

Wk - 4 0 4 8 12 14 Eze10mg + Simva10mg (n = 55 pts)

Simva10mg (n = 55 pts) Placebo run-in

& diet

Figure 2. Plot of LS Mean Percent Change from Baseline in LDL-C over Time: Modified Intention-to-Treat Approach

-60 -40 -20 0

Baseline Week 4 Week 8 Week 12 Week

Percent Change from Baseline i LDL-C

Simvastatin Ezetimibe + Simvastatin

Ezetimibe in KOREANS ; good effects !

• Ezetimibe와 statin의 병용으로 콜레스테 롤의 흡수와 생합성을 저해시킬 수 있다.

• Ezetimibe의 추가투여로 LDL 수치를 추가 로 20% 감소시킬 수 있다.

• Ezetimibe와 statin의 병용으로 부작용의 증가를 경험하지 않고도 LDL 의 목표치에 도달할 수 있다 (80% 이상)

중간요약 (3)

Strategies for LDL reduction in elderly people

• Dose titration according to the target goal

; 30 % or less = lower dose, or less potent statins

; 30 % or more = higher dose, or potent statins / low dose statin + Ezetimbe

; 50 % or more = tolerble dose of statin + Ezetimibe

Final Summary

• Many elderly people are under high risk.

• Ezetimibe-Boned Medication

; Evidence-Based Medicine for safe LDL reduction