earlier is better and combination is better park...cerebrovascular disease prevention effect. we...

Earlier is better and Combination is better

Division of Cardiology, Department of Internal Medicine,

Hanyang University College of Medicine

Cardiovascular center, Hanyang University Guri Hospital

Kyungchun-ro 153, Guri city, Republic of Korea

[email protected]

mailto:[email protected]

Disclosure

The author have no financial conflicts of interest to disclose

concerning the presentation

Dyslipidemia

1. What is Dyslipidemia?

2. Dyslipidemia in Korea

3. Guidelines for Dyslipidemia

01

Limitations of statin monotherapy

1. Low LDL-C Goal Achievement rate

2. Additional need for LDL-C reduction

3. Safety

02

Benefits of adding Ezetimibe

1. LDL-C Lowering Effect

2. Prevention the Risk of CV Events

3. Additional Benefits

03

Dyslipidemia01




5


DyslipidemiaAbnormal amount of lipids in the blood

TG

≥ 150mg/dL

TC

≥ 200mg/dL

LDL-C

≥ 130mg/dL

HDL-C

< 40mg/dL

Cardiovascular risk IncreaseTG = TriglycerideTC = Total CholesterolLDL-C = Low Density Lipoprotein CholesterolHDL-C = High Density Lipoprotein Cholesterol

Ref.> Korean Guidelines for the Management of Dyslipidemia 4th ed. Committee of Clinical Practice Guideline of KSoLA. 2018.

6


Ref.> Dzau V, et al. Am Heart J. 1991;121(4 Pt 1):1244-1263.


1495

2283

3272

4165

5553

6780

8258

9914

11558

0

2000

4000

6000

8000

10000

12000

14000

2002 2004 2006 2008 2010 2012 2014 2016 2018

(X1000person)

Number of People Diagnosed with Dyslipidemia

0 20 40 60 80 100

57.6%

48.1%

Awareness 2016-2018

TreatmentRate 2016-2018

X 7.8

1 out of 5 Korean adults had hypercholesterolemia (2018)

20.7%

Prevalence and Management of Hypercholesterolemia

41.3%Control Rate 2016-2018

Ref.> Dyslipidemia fact sheets in Korea. Korean Society of Lipidology and Atherosclerosis (KSoLA). 2020.


※ Hypertension is defined as systolic/diastolic blood pressure ≥140/90mmHg or taking

Antihypertensive medication

※ Diabetes is defined as fasting plasma glucose ≥126 mg/dl, previously diagnosed, or taking glucose-lowering drugs.

Dyslipidemia in Adults with Hypertension Dyslipidemia in Adults with Diabetes

31.3

56.6

68.3%

0

10

20

30

40

50

60

70

80

36.8

69.2

86.4%

0

20

40

60

80

100

Without hypertensionLDL-C ≥160 mg/dl

With hypertension LDL-C ≥160 mg/dl

With hypertension LDL-C ≥130 mg/dl

(%) (%)

Without diabetesLDL-C ≥160 mg/dl

With diabetesLDL-C ≥160 mg/dl

With diabetesLDL-C ≥100 mg/dl


Treated for Hypertension or Diabetes

Patient Treated for Dyslipidemia (7694 person)

74.2%

Treated for Dyslipidemia alone

25.8%

Dyslipidemia+Hypertension

40.6%

Dyslipidemia+Hypertension+Diabetes

20.7%

Dyslipidemia+Diabetes

11.1%

Treatment for Hypertension and Diabetes Among Persons Treated for Dyslipidemia



Dual therapy

18.6%

Monotherapy

80.3%

Triple therapy

1.1%

Statin+Ezetimibe

72%

Prescriptions of Lipid-Lowering Drugs


Prescription

Pattern


Treatment Algorithm for LDL-C Lowering

Ref.> Mach F, et al. Eur Heart J. 2020;41(1):111-188.


2019 ESC· EAS Guideline

Treatment goals for LDL-C across categories of 10-year risk of fatal CVD (SCORE)




Secondary Prevention in Patients With Clinical ASCVD


2018 AHA/ACC Guideline

Ref.> Grundy SM, et al. Circulation. 2019;139(25):e1082-e1143.

Primary Prevention


2018 AHA/ACC Guideline

Ref.> Grundy SM, et al. Circulation. 2019;139(25):e1082-e1143.

Treatment goals for LDL-C and non-HDL-C in different risk categories


2018 Korea Dyslipidemia Guideline


Risk Categories LDL-C (mg/dL)

Very High risk

High risk

Moderate risk

Low risk

Non – HDL-C (mg/dL)

Diabetes 2)

Coronary artery disease

Atherosclerotic Ischemic Stroke

Transient ischemic attack

Peripheral artery disease

Carotid artery disease1)

Abdominal aortic Aneurysm

Major risk factor 3) ≤1

Major risk factor 3) ≥2

1) In case of significant Carotid artery stenosis (which has been shown to be strongly predisposed to clinical events)2) Target goal can be lowered in patients who have target organ damage or major cardiovascular risk factors.

3) Age (Male ≥ 45y, Female ≥ 55y), family history of premature ASCVD, Hypertension, Smoking, Low HDL-C

Pharmacological Hypercholesterolemia treatment Strategy


2018 Korea Dyslipidemia Guideline


CV risk evaluation

Very High risk

Statin

Moderate risk

LDL-C Goal Reached?

· CAD· Atherosclerotic Ischemic Stroke or

Transient ischemic attack· Peripheral artery disease

· Carotid artery disease· Abdominal aortic Aneurysm· Diabetes

· Major risk factor ≥2

High risk

YES NO

YES

NO

Maintain current therapy

Adverse event evaluation

Maximum tolerableStatin

Very High risk < 70 mg/dLHigh risk < 100mg/dLModerate risk < 130mg/dL

Recommendations for the treatment of Dyslipidemias in DM


3. Guidelines for Dyslipidemia with DM


2019 Korea Diabetes Guideline Treatment of Dyslipidemia in DM

성공모델 sP 내용 넣기1. Serum lipid profile test (TC, HDL-C, TG, LDL-C) should be done once DM diagnosed, and follow up annually. Evaluate treatment response and adherence by testing before and after 4-12 week. [E, I]

2. In DM patients without Cardiovascular disease, LDL-C goal of ‹100 mg/dL recommended. [A, I]

3. In DM patients with Cardiovascular disease, LDL-C goal of ‹70 mg/dL recommended. [A, I]

4. In DM patients with Risk factors such as Albuminuria, CKD(GFR 60 mL/min/ ‹1.73 m2), Target organ damage, Hypertension, smoking, family

history of premature ASCVD , LDL – C goal of ‹70 mg/dL recommended. [B, IIa]

5. Target goals are TG <50 mg/dL , HDL –C > 40 mg/dL(male), >50 mg/dL(female). Promote active lifestyle modification and strict blood glucose control to reach this goal. [C, I]

6. In patients with Dyslipidemia, promote active lifestyle modification. [A, I]

7. In DM patients with Dyslipidemia, Statin should be 1st line therapy. [A, I]

8. Adding Ezetimibe or PCSK9 inhibitors are recommended in DM patients with Cardiovascular disease if the LDL-C goal is not achieved on

maximal tolerated Statin. However, Ezetimibe is favored considering the cost. [B, IIa]

9. Adding Ezetimibe is recommended in DM patients without Cardiovascular disease if the LDL-C goal is not achieved on maximal tolerated

Statin. [C, IIb]Ref.> Treatment Guideline for Diabetes 6th ed. Korean Diabetes Association. 2019.

3. Guidelines for Dyslipidemia with DM

2018 Korea Hypertension Guideline

Treatment of Dyslipidemia in Hypertension

Ref.> Treatment Guideline for Hypertension. The Korean Society of Hypertension. 2018.

3. Guidelines for Dyslipidemia _with Hypertension

10.7.2. Lipid lowering agent treatment

Lipid lowering agents for high risk hypertension patients have significant Cardio-

cerebrovascular disease prevention effect. We cannot present exact number due to the

lack of Korean data. However, significant prevention effect of showing more than 50%

reduction using Statin appeared in study with Hypertension patients of LDL-C

≥130mg/dL without Cardio-cerebrovascular disease. In Hypertension patients with

Coronary artery disease, target goal of LDL-C <70mg/dL is recommended. In

Hypertension patients with history of Stroke, average 133mg/dL LDL-C statin therapy

effect is significant, but there is lack of data on lowering <70mg/dL treatment.

Limitations of statin monotherapy 02



3. Safety

21

DYSIS

Europe and Canada study1

48.2%

CEPHEUS

Pan-Asian study2

50.9%


Ref.> 1. Gitt AK. Eur J Prev Cardiol. 2012;19(2):221-30. 2. Park JE. Eur J Prev Cardiol. 2012;19(4):781-94. 3. Akyea RK, et al. Heart. 2019;105(13):975-981.

Number at risk Optimal response 80802 73747 57766 43543 29881 17588 6922 Sub-Optimal response 84609 76145 57326 41509 27426 15584 6295

22%

LDL-C goal Optimal responders

LDL-C goal Sub-optimal responders

(LDL-C reduction < 40%)

Adjusted HR(95% CI)=1.22(1.19-1.25)

Follow-up(years)

CVD risk

1DYSIS Europe and Canada studyDYSIS: the Dyslipidemia International Study∙ Objective: To assess the prevalence and types of persistent lipid

abnormalities in patients receiving statin therapy.∙ Patients: 11 European countries and 22,063 Canada patients treated with statins∙ Methods: multicenter, epidemiologic cross-sectional study

2CEPHEUS Pan-Asian study CEPHEUS Pan-Asian study: the Centralized Pan-European survey on the Under-treatment of hypercholesterolemia∙ Objective: to determine the proportion of patients on lipid-lowering pharmacological treatment attaining LDL-C goals,

as defined by the NCEP ATP III guidelines ∙ Patients: 8 Asian countries (Korea, Taiwan, Thailand, Indonesia, Philippines, Malaysia, Vietnam, Hongkong, China)∙ Methods: prospective, multinational, cross-sectional study

∙ Objective3 : To assess LDL-C response in patients after initiation of statins, and future risk of CVD.∙ Methods3 : Prospective Cohort study. 165411 patients who treated Statin for CVD primary prevention between 1990y~ 2006y. Analyzed relationship between optimal LDL-C response rate and CVD event(ASCVD,TIA, Peripheral vascular

disease, death by CVD). <40% reduction in baseline LDL-C within 24months was classified as a sub-optimal statin response.

LDL-C goal attainment failure rate by Statin monotherapy

Incidence of CVD according to LDL-C goal attainment3

22


Ref.> 1. Rosenson RS. Expert Opin Emerg Drugs. 2004;9(2):269–279. 2. LaRosa JC, et al. N Engl J Med. 2005;352(14):1425–1435. 3. Pedersen TR, et al. JAMA. 2005;294(19):2437-2445. 4. Nakamura H, et al. Lancet. 2006;368(9542):1155-1163. 5. Gragnano F, et al. Atherosclerosis. 2018; 269:219-228.

Relationship between LDL-C reduction and CV incidence reduction1-

4Relationship between LDL-C Reduction and

Plaque regression5

The earlier is better ?

Intracellular actions of statins in β-cells

The earlier is better ?

28

Asian Race

FemaleGender

Variability Of Metabolizing

Enzymes

Variability of Transporters

Interactions

LactoneForm

Co-morbidites

Increase risk of statin-associated

myotoxicity

HighDose

LipophilicStatin

FattyMeal

AdvancedAge

Gen

etic R

isk Fa

ctors O

fSta

tin M

yop

ath

y

EnvironmentalRisk Factors-Patient Related

En

viro

nm

en

tal

Ris

k F

act

ors

Dru

g R

ela

ted

SAMS(Statin-Associated Muscle Symptoms)

3. Safety

Ref.> Taha DA, et al. Transl Res. 2014;164(2):85-109.

Statin Associated Muscle Symptoms(SAMS): Risk factors

29

Creatine kinase elevations > 10times ULN Alanine amino transferase elevations > 3times ULN

3. Safety

Statin related Major adverse effect

Ref.> Brewer HB Jr. Am J Cardiol. 2003;92(4B):23K-29K.

ULN, upper limit of normal[Study design] to examine the benefit-risk profile of rosuvastatin at doses of 10 to 40 mg, Compared LDL-C reduction effect and Safety data between atorvastatin 10-80 mg, simvastatin 10-80 mg, pravastatin 10-40 mg.

Benefits of adding Ezetimibe03

1. LDL-C lowering effect

2. Prevention the risk of CVD events

3. Additional benefits

AtheromaBlood

LiverIntestine

Bile Acids

FreeChol

Chol

Acetyl CoA

Remnantreceptors

Hepatic Apo B100

Intestinal Apo B48

Cholesterol Pool

CMRCM

VLDL

lDL

LDL

Peripheral Tissues

Intestine : EZETIMIBE

Liver : STATIN

31


Ref.> 1. Shepherd J. Eur Heart J. 2001;3(Suppl E):E2-E5. 2. McTaggart F, et al. Am J Cardiol. 2001;87(5A):28B-32B. 3. Jeu L, et al. Clin Ther. 2003;25(9):2352-2587.

Statin and Ezetimibe: DUAL INHIBITION in cholesterol

32

10 20 30 40 50 60

Reduction in LDL-C(%)

0

Statin 10 mg 20mg 40mg 80mg

-6% -6% -6%

-18%

3-step Statin titration

+ Ezetimibe 10mgStatin 10 mg“1-step”Co-administration


Ref.> Bays H, et al. Expert Opin Pharmacother. 2003;4(5):779-790.

Rule of six

Ref.>. Ouchi Y, et al. Circulation. 2019; 140(12):992-1003.

EWTOPIA 75

2. Prevention the risk of CVD events

16951716

15821617

14181445

12171219

887897

383387

No. at RiskControlEzetimibe

34%

EWTOPIA 75 study ∙ Objective : To evaluate the preventive efficacy of ezetimibe for patients aged ≥ 75years, with elevated LDL-C without history of coronary artery disease∙ Method : prospective, randomnized, open-label, blined end-point evaluation (PROBE design)

3796 Patients aged ≥ 75years, with LDL-C 140mg/dL, without history of CHD were randomly assigned (1:1) to receive ezetimibe(10mg/day) versus usual care with dietary counseling

N Baseline After treatment % change p value

Fasting Blood Glucose (mg/dL) 116 94.0±23.8 94.3±28.4 0.5±14.7 NS

Fasting Insulin (μIU/mL) 102 12.7±17.5 9.4±8.2 -12.8±9.8 P <0.05

HbA1c (%) 35 6.2±1.0 5.9±1.0 -3.4±8.6 P <0.05

hs-CRP (ng/mL) 76 601.8±461.6 485.1 ±366.9 -10.8±36.8 P <0.01

Adiponectin (㎍/mL) 102 10.8±5.9 11.8±6.8 13.4±47.5 P <0.01

34

* hsCRP = High-Sensitive C-Reactive Protein

•Objective : The effects of ezetimibe on clinical benefit of inhibiting intestinal cholesterol absorption, surrogate markers of cholesterol absorption and synthesis, lipid and glucose metabolism, and obesity and inflammation•Subjects : 120 patients with dyslipidemia who had not achieved the LDL-C goal recommended by 2007 JAS(=Japan Atheroscleosis Society) Guideline despite diet/exercise or any statin therapy•Methods : After treated with ezetimibe 10mg/day for 12 weeks, following parameters are monitored

; serum lipid profile(TC, LDL-C, TG, HDL-C), glucose metabolism(fasting blood glucose, fasting insulin, HbA1c) , markers of obesity and inflammation(adiponectin, hsCRP),markers of cholesterol absorption and synthesis, BMI, waist circumference, blood pressure and heart rate

3. Additional benefits

Improvements in levels of glucose metabolism and inflammatory markers

Ref.> Hiramitsu S, et al. J Atheroscler Thromb. 2010;17(1):106-114.

Take-home Messages

• The prevalence of dyslipidemia in South Korea is rising every year and

dyslipidemia is prevalent among HTN or DM patients.

• Guidelines recommends that the higher patient has the risk of CVD, the more

LDL-C levels should be reduced significantly.

• Statin monotherapy is difficult to achieve LDL-C goals and high-dose statin

can cause major adverse effects.

Take-home Messages

• Ezetimibe added to statin therapy showed additional LDL-C lowering effect and

prevention the risk of CVD events

Thank you for your attention !!

earlier is better and combination is better park...cerebrovascular disease prevention effect. we...

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