management overview

DR/KHALID AL-HARBY 1

MANAGEMENT OVERVIEWDYSLIPIDEMIA

DR / KHALID AL –HARBY

FAMILY MEDICINE CONSULTANT

MBBS, ABFM, SBFM


Prevalence in Saudi Arabiaal –Nuaim AR 1997

The prevalence of HC, 5.2-6.2 mmol/l was 9% and 11% for all male and female (above 15 y.)respect.

The prevalence of HC, > 6.2 mmol/l was 7% and 8% for male and female (>15y.) respectively

The prevalence of HC, 5.2-6.2 for subjects aged 40-59 y. was 14% and 10% for male and female respectively

The prevalence of HC > 5.2 increase with BMI


Al – Awali PHC 1422A pilot study on male adult diabetic patients

High Cholesterol level Pie Chart

no

yes

34.8%

65.2%


Al – Awali PHC 1422A pilot study on male adult diabetic patient

High TG level Pie Chart

no

yes

30.4%

69.6%


Screening

National Cholesterol Education Program (NCEP):• Random TC and HDL for all adult > or = 20 years• Every 5 years U.S.Preventive Task Force:• Men 36-65 y. and women 45-65y. Every 5 years• TC


Recommended algorithm for adults

Measure total chol. And HDL chol.

High: > or = 240 mg/dlBorderline high: 200-239 mg/dl

Desirable: < 200 mg/dl

HDL < 35 mg /dl or< or = 2 risk factors

HDL > or = 35 mg /dlAnd < 2 risk factors

HDL < 35mg/dl

HDL > or= 35 mg /dl

Offer advice on risk

offer adviceon risk

Measure fasting cholesterol and calculate LDL



No evidence of CHD Evidence of CHD

DesirableLDL

Borderline LDL

130-159

High LDL <or=160

Offer advice

>2 R.F <or 2 R.F Clinical evaluat.

Diet

<optimal LDL <100 mg/dl

Optimal LDL >or = 100mg/dl

Offer instru-ctions on dietand activity

Clinical evaluation

Diet therapy

retestretest



LDL > or = 190mg/dl and < 2 R.F

LDL > or = 160 mg/dland > or = 2 R.F

LDL > 100 Mg/dl

Consider drug therapy


NCEP for cholesterol levels

Risk category (mg/dl)LIPID

Desirable Borderline High

Total cholesterol < 200 200-239 >or=240HDL cholesterol > 60 --- < 35LDL cholesterol < 130 130-159 > or= 160 Triglycerides < 200 200-400 400-1000


Friedewald Formula

LDL cholesterol = total cholesterol – HDL cholesterol + 0.16 TG

It is valid for estimating LDL cholesterol if the TG level is < 400 mg /dl and if the individual does not have familial dysbetalipoproteinemia


General Treatment Guidelines

Status Initiation level (mg/dl) Goal level (mg/dl)

No CHD and < 2 risk factorsDiet > or = 160 < 160Drugs > or = 190 < 160No CHD and > or = risk factorsDiet > or = 130 < 130Drugs > or = 160 < 130CHDDiet > 100 < or = 100Drugs > or = 130 < or = 100


The efficacy of primary prevention

AFCAPS/TexCAPS< RCT> (1998): 6605 men and women with average total cholesterol levels (mean 228mg/dl) and low HDL cholesterol (mean 40 mg/dl for women and 36 mg/dl for men), Lovastatin 20 or 40 mg /d reduced cardiovascular event by 37%


The efficacy of secondary prevention

A. Scandinavian Simvastatin Survival Study (1994):• Decrease in cardiac mortality of 42%, and decrease in

all-cause mortality of 30%• In 4444 pt.s with CHD over 5.4 yearsB. Cholesterol and Recurrent Event (CARE) (1996):• Decrease in coronary events of 24% with 5y. On

Pravastatin 40mg/d, decrease in need for PTCA of 23% ,and decrease in need for CABG of 26%

• In 4000 post MI with mean TC of 209 and LDL of 139


4444 with mild high chol.

Simvastatin, placebo

5.4 years

Reduce T.Chol, LDL ,risk of major CAD

Increase 6 y. survival

Secondary

Preventiontrial


4000 post MI

Pravastatin, placebo

5 y.

Reduce C events, needFor PTCA, CABG

Secondary

Preventiontrial


post CHD with high chol.

Pravastatin, placebo

1y .

5.2 / 1000 live saved

Secondary

Preventiontrial

LIPID


The efficacy of secondary prevention

C. The AVERT trial (1999):• 341 patient with stable CAD, LDL > or = 115 mg/dl and

TG < or = 500mg/dl• Randomized to either aggressive lowering of LDL with

atrovastatin (80mg/d), or PTCA and usual care• The atrovastatin group had a reduced but not statistically

significant rate of ischemic events(13.4% vs. 10.1%)• This reassures that drugs are safe and as good as PTCA

for pt.s with stable CAD


341 for PTCA

177 PTCA, 164 LIPITOR

18 MONTHS

LIPITOR reduces ischemia

& need for PTCA

Secondary

Preventiontrial


The role of dietary intervention

A. Oslo Study Group (1981): established the recommendation of dietary intervention

and smoking cessation to improve lipid profilesB. Physician Health Study:• Men who ate fish (including shellfish) at least once a

week had a 52% reduction of sudden cardiac death compared with those who consumed fish < once/month

• Data did not find an inverse association between fish consumption and the rate of MI


Comparison of step I and II diets

Recommended intake

Nutrient Step I Step II

Total fat < 30 % of total caloriesSaturated fat 8% - 10% of total calories < 7% of total caloriesPolyunsaturated fat up to 10 % of total calories Monounsaturated fat up to 15 % of total calories Cholesterol < 300 mg/dl < 200 mg/dlCarbohydrates 50% - 60% of total caloriesProtein 10 % - 20 % of total caloriesCalories to achieve and maintain desired weight


Sources of dietary Fatty Acids

Cholesterol :

egg yolk, organ meats (liver, sweetbreads, brain), animal meats (beef, pork, lamb), butter

Saturated Fatty Acids:

animal fat (beef, pork), whole dairy products (milk, cream, ice cream, cheese), palm oil, coconut oil


Sources of dietary Fatty Acids

Polyunsaturated Fatty Acids:

safflower oil, sunflower oil, soybean oil, corn oil Monounsaturated Fatty Acids:

olive oil, canola oil


Diet therapy guidelines

Step I Diet Monitor at 4-6 W,3 Months

Patient with CHD

Goal not achieved Step II Diet

Monitor at 4-6 W ,3 Months

Goal achieved

Goal not achievedDrug therapy

Goal achieved

Monitor 4 times in 1st year, then 2 / year


Lipid-modifying drugs

Drug class initial dosage maximum dosage monthly cost(S.R) LDL HDL VLDL S.Es

HMG COA reductase inhibitors elevated LFTAtrovastatin 10 mg / d 80 mg / d 210- 783 GI upsetCerivastatin 0.3 mg / d 0.3 mg / d 150 myalgia/myosi.Fluvastatin 20 mg / d 40 mg bid 142- 281Lovastatin 20 mg / d 40 mg bid 262- 941Pravastatin 20 mg / d 40 mg / d 243- 398Simvastatin 10 mg /d 40 mg /d 221- 735

Bile acid sequestrants drug interactionsCholestyramine 4 gm bid 20 gm (divided) 93- 686 GI upsetColestipol 5 gm / d 30 gm (divided) 108- 1233 dec. absorption of vit A,E,K


Lipid-modifying drugs

Drug class initial dosage maximum dosage monthly cost(S.R) LDL HDL VLDL S.Es

Niacin flushing/pruritus 50 – 100 mg bid 3 gm (divide) 6 – 187 rash/ GI upset gout exacerbation hyperglycemia elevated LFT

Fibric acid derivatives pruritus/rashGemfibrozil 300 mg bid 600 mg bid 40 – 303 GI upsetFenofibrate 67 mg / d 201 mg / d 75 – 228 myositis ( micronized) cholelithiasis


Probucol Mechanism of action: not fully understood It lowers LDL by 10-20% but also lowers HDL (neutral

effect on total/HDL cholesterol ratio) Dose: 500 mg BID S.E: GI upset C.I: prolonged QT interval or H/O ventricular

dysrhythmia Limited benefit on lipid profile but can be used as an anti-

oxidant


ERT

INCREASES:1) HDL2) TG

DECREASES:1) LDL

2) LIPOPROTEIN (a)


ERT Recommended by NCEP II expert panel to all

postmenopausal women with lipid disorder (but this is controversial: no support by clinical trials)

Meta-analysis of observational studies: 44% RR in primary prevention of CHD risk by ERT

The postmenopausal Estrogen/Progestin international (PEPI) trial (1995): combined HRT had a less desirable effect on HDL cholesterol than ERT alone


ERT The Heart and Estrogen/Progestin replacement (HERS)

1998 <RCT> for secondary prevention : 2763 postmenopausal women with CHD, combined HRT or placebo, 4 years, no significance difference in the rate of non-fatal MI & CHD mortality between the groups despite significant improvement in LDL, HDL, TG, in the treatment group

For primary prevention: will be evaluated by the ongoing Women’s Health Initiative clinical trial (27500 women over 9 years) will be reported in 2005


2763 postmenop. + CHD

Combined HRT & placebo

4 years

HRT improved lipid but not CHDIncrease S.E

Secondary

Preventiontrial


Other drugs

1) Raloxifen : non steroidal benzothiopene that inhibits the growth of Estrogen receptor-dependent mammary tumors

o It also lowers serum T.chol and LDL chol. o RCT of 601 postmenopausal women over 2

years: dose-dependent reduction of T. chol (9.7%) & LDL chol. (14.1%) in treatment group (Raloxifen 150 mg/ day)


Other drugs

2) D –thyroxin: lower LDL chol. 10 –15 % by enhancing its clearance from circulation , BUT : mild hyperthyroidism, cardiac S.Es

3) Neomycin : lower LDL by 10-15% by decreasing its intestinal absorption BUT: alter normal flora, ototoxicity, renal insufficiency

4) Olestra : non absorbable sucrose polyester fat substitute that interfere with chol. absorption, FDA approved as food not as a drug


Other drugs

5) Sitostanol-ester margarine: o A pine tree extract Stanolo RAISIO group (1995) in Finland <RCT> studied

153 non-obese subjects with mild dyslipidemia (TC > 216, TG > 265) : after 1 year – 10.2% reduction in TC, 14.1% reduction in LDL in treatment group


Combination therapy To achieve a synergistic effect Usually used in severe cases but can be used in less severe

cases by using low doses of 2 agents rather than a high dose of single agent ( less toxicity, cost advantage)

The ideal regimen is bile acid sequestant + statin ( 50% reduction in LDL, good tolerability (bile acid seq. should be taken 1 h. prior to statin)

Statin and fibric acid derivative should not be combined (increase risk of myositis)


Patient Education

One study demonstrated that only approximately 50% of patients who were prescribed a lipid lowering drug were taking it 1 year later

Another study: 20-30 % of women given HRT never started on them, and only 40 % of those who started on HRT were still compliant with the regimen 1 year later


875 healthy postmenop.

Placebo, ERT, 3 HRT regimens

3 years

ERT should be used if no uterus, CEE with

Cyclic MP if uterus +

Primary

Preventiontrial


Controversies and future considerations

(hypertriglyceridemia) Large studies initially linked high TG levels with

CHD, but it was associated with low HDL!!

( it might be due to the low HDL ) Until intervention data are available, TG– lowering

agents should be reserved for patients with TG levels > or = 400 mg/dl and other cardiac disease


Controversies and future considerationssmall, Dense LDL and the Atherogenic Dyslipidemic syndrome

Pattern ALDL-ILDL-II

Pattern B)Small, dense(

LDL-IIILDL-IV

)H (TG)L (HDL

)B (TC

Type II DM, HTN, central obesity, procoagulant state

ADS-: Dominant dyslipidemia

In patient with CHD and familial combined type ? Risk factor for development of type II DM

(similar lipid profile) Standard screening with total chol. And HDL

Chol. Is not adequate for those with ADS“normal lipid profile”

Treatment : combination

Syndrome X metabolic syndrome

LDL subclass


Controversies and future considerationshyperpobetalipoproteinemia (Hyperapo B)

Apolipoprotein B is the component of LDL that serves as the ligand for its receptor

Hyperapo B : increased apo B levels in the absence of hyperlipidemia

It is found in hypertriglyceridemia Analysis of some clinical trials has recognized that apo B

is a strong predictor of CHD risk Prospective studies are needed to determine if apo B is a

better predictor of CHD risk than the current lipid measurements


Controversies and future considerations Lipoprotein (a)

Contains LDL + apoprotein (a) Is considered an independent RF for premature CHD, but

its importance appears to lessen with advancing age Levels of Lp (a) are genetically determined (common in

African-American), but external factors may account for up to 10% of the variation in concentration

No trials to support the view that lowering Lp (a) levels reduces CHD risk


Controversies and future considerations Diabetes Mellitus

CHD is the principal cause of death in DM pt. Subgroup analysis of secondary prevention trials of

statin therapy: decreased LDL in DM is beneficial Unanswered Qs: 1) Should LDL goal of < 100 mg/dl in DM with CHD be

further lowered?2) How aggressively to treat pt.s with DM and no CHD? At present NCEP II recommends : 1) a target LDL of

130mg/dl for primary prevention and < 100 for secondary 2) 200 and 150 for TG


Controversies and future considerations Cerebrovascular disease

Similar RF as CHD except for dyslipidemia No large trials look to CVA as an endpoint Secondary analysis of data from the CARE and the 4S

trials : significant reduction in stroke among pt.s treated with statins

A systemic review of 16 trials using statin therapy: 25% reduction in all forms of stroke when total –chol. And LDL chol. were reduced 22% and 30% respectively


Controversies and future considerations Alcohol

It increases HDL and TG Studies have shown that alcohol in moderation (2-6

drinks/wk) leads to 34-53% reduction in CHD When heavy drinkers (> 2 drinks /d) were compared with

the light drinkers, they had 51% increase in all-cause mortality

Helsinki Heart study: the beneficial effect of moderate alcohol consumption may be restricted to tobacco smokers onlyوسلم: : عليه الله صلى قال الله رسول يا بها نستشفي قالوا

( دواء( ليست و داء انها


Controversies and future considerations Nutritional supplement

A. Fruits and vegetables: epidemiological data showed lower prevalence of CHD in populations with a higher intake of fruits and vegetables

B. Antioxidant vitamins (vit. C&E): o Widespread belief: decrease risk of CHD (based on

the belief that LDL oxidation reduce CHD risk)o GISSI-Prevenzione trial(1999): a RCT on secondary

prevention, randomized 1324 pt. with recent MI to one of 3 groups (Omega-3-PUFAs, vit E, or both)


Controversies and future considerations Nutritional supplement

after 42 months : (1) significant reduction of non-fatal MI + all-cause deaths + stroke in Omega-3 PUFAs group (2) neutral effect of Vit.E supplement

o HOPE study 2000: no effect of vit. E on cardiovascular events in subjects with CAD or DM over 4.5 years

C. Folic acid & vit.B6:o Widespread belief: dec. CHD risk by dec. high

homocystein levels (another Atherogenic factors)o Have yet to be proven by large clinical trials


1324 post MI on MDT diet

Ở- PUVA, Vit E, both

1y .

5.7 / 1000 live saved

Secondary

Preventiontrial


1062 infant

540 dietary counseling, 522 control

5 y.

Reduce T.Chol ,Reduce LDL

In boys only!!!

primaryPreventiontrial


1232 healthy men .With high chol.

Dietary intervention &smoking cessation

5 y.

Improve lipid, reduce CHD morb&mortality

Even after 3 y .

primary

Preventiontrial


9297 at risk for CAD

Ramipril , placebo

5 y.

Reduce rate of death,MI, stroke

Primary

Preventiontrial


4081 asymptomatic Dyslipidemeic men

2051 gemfibrozil, 2030 placebo

Same death rate

Increase HDL, reduce LDL, TChol, TG

primary

Preventiontrial


16608 healthy postmenop withIntact uterus

Combined HRT, placebo

Planed 8.5 y .(stopped at 5 y).

Risks exceed benefits

primaryPreventiontrial


DM vs. control

20 years

Increases 2-3 x Risk of clinical

Atherosclerotic diseases

Same in both sexes

Cohort

study


6605 with average chol.

Lovastatin vs. diet + placebo

5.2 y.

Reduce incidence1st major

CAD

primary

Preventiontrial

management overview

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