cholesterol Treatment

8/8/2019 cholesterol Treatment

1/47


2/47

The Present Survival with CAD

Time 0


3/47

Hospital Mortality Post MI

0

5

10

15

20

25

1970 1990 1995

25% 11% 8%


4/47

Follow-up 132 Grafts at 10 Years


5/47

Is This the Best We Can Do?

10 Years Later


6/47

Treatment Goals

in CAD Patients Identify and TreatUnstable Life-ThreateningCoronary Lesions

Antithrombotic Rx Prevent VentricularDilation with ACE Rx

Lower LDL

the More the BetterAfter Lifestyle

smoking

obesity


7/47

Dietary, Exercise & Lifestyle

Modifications

Factors affecting therapyof hyperlipidemia

Modifiable risk factors

Hypertension

Cigarette smoking

Diabetes mellitus

Obesity

Alcohol intake

Other factors

Family history of coronaryheart disease or peripheral

vascular disease

Personal history of early onsetcoronary heart disease

Male sex


8/47

Passive smoking

The incidence of heart disease

among women with smokinghusbands was 14.9 times higherthan that of women with nonsmoking husbands.


9/47

Nutritional Management

of Hypercholesterolemia


10/47

Obesity

Not an independent factor

Strong association with otherrisk factors:

increased blood pressure diabetes

hypercholesterolemia


11/47

Body weight deserves adeliberate attention in any

effort to reducecardiovascular risk.

R l i f B d M I d


12/47

Relation of Body Mass Index,(BMI) to Relative Mortality Risk

BMI Risk Odds

Ratio20 - 30 Desirable 1.0

2530 Mild 1.0 - 1.25

3040 Moderate 1.252.5

40 High > 2.5


13/47

Body Weight

Restoration of normal body weight is mostimportant.

Several studies have shown that decreasing bodyweight decreases the plasma lipids regardless ofthe design of the diet:

decreases LDL Chol decreases TG Increases HDL Chol


14/47

NUTRIENT

AVERAGE

NORTH

AMERICAN

DIET

STEP ONE

DIET

STEP TWO

DIET

MONO

DIET

TOTAL FAT

(% total calories) 35-40%


15/47

CCCC recommendations:Intervention by dietary modification plus exercise

Goals for dietary intervention:

Dietary component % of caloric intakefat < 30%saturated fatty acids < 10%

polyunsaturates < 10%protein 10-15%

In Addition:


16/47

Strategies

Most families have 10-15 recipes thatconstitute their daily diet

It is often more efficient to modify orreplace individual meals, taking into

account: preparation time cost

taste


17/47


18/47

Strategies

Reduction of the major and obvious

sources of saturated fatty acid andcholesterol.

Substitute rather than delete.

F


19/47

FAT Saturated fat: Increases total Chol and LDL C Monounsaturated fat: neutral Polyunsaturated fat: decreases total Choland LDL C

Subtracting a certain amount ofsaturated fat has the same effect asadding twice that amount of

polyunsaturated fat. Animal and vegetable fats do not makea complete distinction:

butter, coconut oil: Increase Chol corn oil, whale oil: decrease Chol


20/47

Replace fat in the diet by carbohydrate.

Carbohydrate has less calories than fat.

Increase fiber gradually


21/47

Increase fish intake to two to three90 g servings per week.

Avoid fish oil supplements.

M i P t ti l f Di t Ch t


22/47

Maximum Potential of Dietary Changes toReduce Serum Cholesterol

Dietary Change in Serum Cholesterol

(%)

saturated fat

from 14 to 7% of total calories

15

polyunsaturated fat

from 7 to 10% of total calories

5

cholesterol

from 500 to 250 mg/day

7

fibre (especially soluble)

from 20 to 40 mg/day

8

Total maximum potential effect of dietary

changes:

35%

verage effect of dietary changes:

1.1 1.4 mmol/L decrease in serum cholesterol level

D M d f


23/47

Dietary Modification

Hepatic over productionis a major cause ofincreased plasma lipids

Reduce excess dietary fat& excess caloric load &this will reduce hepaticproduction & reduce

obesity hypertension

diabetes

Chylomicron

Remnant VLDL

Remnant(IDL)

LDL

LPL

HPLHPL

HDL3

LCAT

HDL2

LPL

Intestine

Liver


24/47

Diet modification remains aprincipal therapy for people with

elevated blood lipid levels.


25/47

Lower LDL the More the Better

SUGGESTED APPROACH BASED ON LIPID


26/47

SUGGESTED APPROACH BASED ON LIPIDLEVELS AND RISK FACTORS (RF)

LIPIDPROFILE

if total Chol

DIETTHERAPY

if LDL Chol

DIET, and thenMEDICATION

if LDL Chol GOAL

< 35 yr., no RF > 6.2 > 4.1 > 5.7 4.1

> 35 yr., no RF > 6.2 > 4.1 > 4.9 4.1

> 2 Risk Factors > 5.2 > 3.4 > 4.1 3.4

With CHD > 0 > 2.5 > 3.4 2.6


27/47


28/47

+ DRUGS

Li id l i t


29/47

Lipid-lowering agents

1.HMG-CoA reductase inhibitors: Inhibit hepaticcholesterol production

2.Bile acid resins: Bind cholesterol in gut

3.Fibric acid derivatives: cholesterol excretion inbile

4.Probucol: LDL-C breakdown and may inhibitLDL-C oxidation

5.Nicotinic acid: production of VLDL-C

Mechanism of action of Bile Acid Sequestrants


30/47

Mechanism of action of Bile Acid Sequestrants

LDLLDL

LDL

Resins

IIMG CoA

Cholesterol

Bile Acids

IIMG CoA

Cholesterol

Bile Acids

Bile acid Sequestrants in


31/47

Ser

umConcentration(mmol/l)

% Change

8.9

6.87.2

5.0

1.1 1.21.4 1.5

Diet

only

Diet +

Cholestyramine (16g/day)Total CholesterolLDL-CholesterolHDL-Cholesterol

Triglyceride

- 23 - 30.5 + 9.1 + 7.0

Bile acid Sequestrants inPrimary Hypercholesterolaemia

HMG C A R d t I hibit


32/47

HMG CoA Reductase Inhibitors

Ratelimitingcontrol of

cholesterolsynthesis(secretedin lipoproteins)

HMG COAMevastatin

(compactin)

Lovastatin

(mevinolin)

Simvastatin

(Synvinolin)

PrevastatinCS 514,

SQ 31000

Fluvastatin(Fluindostatin,

SRI 62320)

(Lactone form) (Lactone form) (Lactone form)

Statins are pharmacologic targets toReduce hepatic productionPeripheral catabolism

T tm nt f h p h l t l mi


33/47

8

6

4

2

0 4 8 12 16 20 24Weeks on treatment

Cholesterol(mmol/l)

Total LDL HDL

Effect of statin treatment (20 mg/day) on total, LDL and HDLcholesterol concentrations (means +- s.e.m., n=10) in patients

with high plasma cholesterol.

Treatment of hypercholesterolemia


34/47

HMG-CoA Reductase InhibitorsContraindications Active liver disease

Pregnancy and lactation

Hypersensitivity

Relative Contraindications Childhood Concurrent use of cyclosporine, erythromycin, (fibrates, niacin)

Side effects Serum transaminases

CK

Myopathies

Abdominal pain, diarrhea, constipation

Headaches

P i P ti T i l


35/47

Primary Prevention Trials

Trials of DietLA Veterans StudyOslo Primary Prevention Study

Multiple Risk Factor Intervention Trial (MRFIT)

Trials of DrugsWHO Cooperative Trial of Clofibrate

Lipid Research ClinicsCoronary Primary Prevention Trial (LRC-CPPT)

Helsinki Heart Study

OSLO P im P ti T i l


36/47

OSLO Primary Prevention Trial

325

300

275

0 1 2 3 4 5

TC(m

g/dl)

Years

Treatment Group N = 604 Controls N = 628

OSLO P i P ti T i l


37/47

OSLO Primary Prevention TrialNumber of episodes Change Relativ

to ControlsCoronary 19 - 47.2%Heart Disease 36*

All Cardiovascular 22 - 43.6%

Disease 39*

Sudden 3 - 72.7%Death 11

Total CVD Death 8 - 46.7%(inc. Stroke) 15

Total 16 - 33.3%Deaths 24

Treatment Group N = 604 Controls N = 628 * P < 0.05

C nclusi ns fr m Primar


38/47

Conclusions from PrimaryPrevention Studies

1) Elevated blood cholesterol is amajor risk factor for CHD

2) Primary preventative measures cangreatly reduce CHD risk

3) A 1% reduction of blood cholesterolreduces CHD risk by 2%

Atherosclerosis CAN be Reversed


39/47

athero

Atherosclerosis CANbe Reversed

Regression only Progression only Lipid effects

Definite lesion changes in the FATS trial according to the three treatmentgroups. The numbers in the horizontal bars on the graph represent

percentage of patients. The numbers in the squares on the right representthe lipid and lipoprotein changes in each of the corresponding treatment

groups.

Global change score

P = 0.005

-7% 5% 15%

-46% 15% -9%

-32% 43% -29%

LDL HDL TG

-40 -20 0 20 40

Niacin + Colestipol39 25

21Lovastatin + Colestipol32

11 46Conventional

Examples of regression FATS


40/47

Examples of regression - FATSLAD OMB RCA OMB LCx

Mean % Stemosis 100% 39% 48% 69% 44%

Mean % Stemosis 28% 18% 30% 37% 30%

Baseline

After

2.5 years

OBJECTIVES


41/47

OBJECTIVES

Randomised trial of cholesterol lowering in 4444patients with coronary heart disease: TheScandinavian Simvastatin Study (4S)

Lancet 344, 1994

To investigate whether long-term simvastatin

therapy reduces total mortality and coronaryevents in post-MI and angina patients with serumtotal cholesterol levels of 5.5 to 8.0 mmol/L (212-309 mg/dl)

Simvastatin and Platelet Dysfunction


42/47

Simvastatin and Platelet Dysfunction8

6

4

2

0

70

60

50

40

30

20

10

0

B 1 4 8 12 B 1 4 8 12 B 1 4 8 12B 1 4 8 12

mean + SD

* P < 0.01

TAC ADP pM PLATELET TXB2 ng/108 pits

**

* * **

*

Decrease in Ischemia


43/47

Decrease in IschemiaWith Decrease in LDL

Episodesofischemia/48hours

24

17

15

10

5

0

24

17

15

10

5

0Baseline 6 months Baseline 6 months

Placebo

(n = 20)

Treatment

(n = 20)

MAJOR CORONARY EVENTS


44/47


Proportion

(%)ofpatie

ntswithou

tevents

Coronary death and nonfatal MI

Years since randomization

100

90

80

70

01 2 3 4 5 6

Simvastatin

Placebo

P < 0.0000134%

Risk reduction

Women and older patients


45/47

Women and older patientsBACKGROUND

CHD is the chief cause of death in women

More than 75 percent of deaths from CHD occur in

individuals older than age 65

Few clinical trials have focused on therapeuticintervention in women and the elderly

Subgroups of both women and the elderly (> 60years) were included in the ScandinavianSimvastatin Survival Study

Women


46/47

Women


Coronary death and nonfatal MI

Numberofpatients

35%Risk reduction

P = 0.01

100

75

50

25

0

91

59

Placebo Simvastatin


47/47

CAD: TherapeuticStrategies for the 2000s

Antiatherogenic Antithrombogenic

Angiogenic

Obesity and Diet

cholesterol Treatment

Documents

Transcript of cholesterol Treatment