By: David Tran, Mercer University, 2013 Pharm.D. CandidatePrececptor: Dr. Ali Rahimi

Morbidity and Mortality Associated with Dyslipidemia

DyslipidemiaAn imbalance of any or all lipid

concentrations in the plasma, including hyperlipidemia, hypertriglyceridemia, and hypercholesterolemia

Puts you at risk of developing heart disease which is the leading cause of death in the United States (~620,000 deaths in 2008)

People of all ages and backgrounds can have high cholesterol

CDC Statistics71 million American adults (33.5%) have high LDL1 out of every 3 adults with high LDL cholesterol

has the condition under controlLess than half of adults with high LDL cholesterol

get treatmentPeople with high total cholesterol have

approximately twice the risk of heart disease as people with optimal levels. A desirable level is lower than 200 mg/dL

The average total cholesterol level for adult Americans is about 200 mg/dL, which is borderline high risk

Hyperlipidemia by Ethnicity (LDL >130 mg/dL)

Race or Ethnic Background

Men (%) Women (%)

Non-hispanic Blacks

34.4 27.7

Mexican Americans

41.9 31.6

Non-hispanic Whites

30.5 32.0

All 32.5 31.0

Lipid GoalsTotal Cholesterol

LDL Triglycerides

HDL

•Desirable <200 mg/dL

•Borderline high200 – 239 mg/dL

• High>240 mg/dL

•Optimal

<100 mg/dL

•Near optimal 100 – 129 mg/dL

• Borderline high130 – 159 mg/dL

• High>160 mg/dL

•Normal <150 mg/dL

•Borderline high150 – 199 mg/dL

•High200 – 499 mg/dL

•Very high>500 mg/dL

•Low<40 mg/dL

•High>60 mg/dL

NCEP/ATP III Recommendations Recommend all adults ≥ 20 years old have

a fasting lipid panel obtained every 5 years

LDL is the primary target

TG should be targeted first if TG are >500 mg/dL

Once LDL goal is achieved, attention should be focused on other parameters (non-HDL cholesterol)

Risk Factors

Age: male >45; female >55Family history: premature CHD in 1st degree

relativeMale <55; female <65

Current cigarette smokingHTN (>140/90 mmHg or on antihypertensive

medications)Low HDL (<40 mg/dL)Abdominal obesity

CHD and CHD Risk EquivalentsEstablished CHDMyocardial ischemiaMICoronary angioplasty

and/or stent placement

CABGPrior unstable angina

CHD Risk EquivalentsCAD

Stroke historyTIACarotid stenosis >50%

Peripheral Artery Disease

Abdominal Aortic Aneurysm

Diabetes Mellitus

Dyslipidemia and Coronary Risk

Continuous, graded relationship between serum total plasma cholesterol concentration and coronary risk

Meta-analysis of 38 primary and secondary prevention trials found that for every 10% reduction in serum cholesterol, CHD mortality would be reduced by 15% and total mortality risk by 11%

High LDL levels associated with an increased incidence of CHD in a large number of studies

Framingham Heart Study found that the risk of myocardial infarction increases by about 25% for every 5 mg/dL decrement below median values

Meta-analysis of prospective population-based studies evaluating the association between serum triglyceride concentration and incidence of cardiovascular disease showed significant risk ratios

Lipid Research Clinics Program found that differences of 30 mg/dL in non-HDL corresponded to 19% and 11% increases in mortality in men and women, respectively

LDL Target GoalsCategory LDL goal LDL goal to

initiate TLCLDL goal to consider drug therapy

CHD or CHD risk equivalents (10 year risk >20%)

<100 mg/dL >100 mg/dL >130 mg/dL

2 or more risk factors (10 year risk 10-20%)

<130 mg/dL >130 mg/dL >130 mg/dL

2 or more risk factors (10 year risk <10%)

<130 mg/dL >130 mg/dL >160 mg/dL

0-1 risk factors <160 mg/dL >160 mg/dL >190 mg/dL

Lipid Synthesis

Lipid Components

LipoproteinsApo-B48 is required for the formation of the

chylomicron and secretion for general circulation

Apo-B100 is required for VLDL assemblyLipoprotein lipase (LPL)- forms free fatty acids

that can be used for energy in the periphery. Also, responsible for the formation of remnants which is taken up by the liver for breakdown into cholesterol

Apo-C2 is responsible for activating LPLApo-E binds to LDL-related protein receptors for

lipids to be taken up into the liver to be broken down into cholesterol and phospholipids

Apolipoprotein BActs as a ligand for LDL receptors in various

cells throughout the body to deliver cholesterolHigh levels of ApoB can lead to plaques that

cause atherosclerosis which can thereby lead to heart disease

ApoB is a marker for CHD riskThe AMORIS study found that measurement of

ApoB improved the prediction of fatal MI at all levels of total cholesterol, LDL, and triglycerides

In multivariate analysis, the concentration of ApoB was more highly significant than LDL in determining outcomes and added predictive power to LDL cholesterol

Apolipoprotein EServes as a transporter of lipoproteins, fat-

soluble vitamins, and cholesterol Variant alleles of ApoE are genetic risk

factors for Alzheimer diseaseDefects in ApoE result in familial

hyperlipidemia which is characterized by increased plasma cholesterol and triglycerides

Cardiovascular biomarker with a positive dose-response association with ischemic stroke

Heart Protection Study

Randomized, placebo-controlled trial of effects of simvastatin and antioxidant vitamins on morbidity and mortality

>20,536 men and women 40–80 yr at increased risk of CHD due to prior disease with total cholesterol >135 mg/dL

Simvastatin 40 mg daily vs placeboDuration of greater than 5 years

Heart Protection StudyPrimary endpoint

The effect of simvastatin on total and cause-specific mortality

Secondary endpointsTreatment effect on CHD morbidity and

mortality in special patient populationsTreatment effect on incidence of cancer,

strokes, major vascular procedures, and other conditions requiring hospitalization

Treatment effect on cause-specific mortality and cancers during longer-term follow-up

Heart Protection Study: Vascular Events by Baseline Disease

Baseline Disease

Simvastatin 40 mg daily (n= 10269)

Placebo (n= 10267)

Previous MI 999 (23.5%) 1250 (29.4%)

Other CHD (non-MI)

460 (18.9%) 591 (24.2%)

No prior CHD•CVD•PVD•Diabetes

574 (16.1%) 172 (18.7%) 327 (24.7%) 276 (13.8%)

744 (20.8%) 212 (23.6%) 420 (30.5%) 367 (18.6%)

All patients 2033 (19.8%) 2585 (25.2%)

Heart Protection Study: Vascular Event by LDL

LDL (mg/dL) Simvastatin 40 mg daily (n=10269)

Placebo (n= 10267)

<100 285 360

100-130 670 881

>130 1087 1365

All patients 2033 2585

References CDC.

Vital signs: prevalence, treatment, and control of high levels of low-density lipoprotein cholesterol. United States, 1999–2002 and 2005–2008. MMWR. 2011;60(4):109–14.

Khan et al. Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke: Systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals. International Journal of Epidemiology. 2013 Apr;42(2):475-492.

MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002 Jul 6;360(9326):7-22.

National Institute of Health. Morbidity and Mortality: 2012 Chart Book on Cardiovascular, Lung, and Blood Diseases. Online. 4/16/2013. http://www.nhlbi.nih.gov/resources/docs/2012_ChartBook.pdf

Pereira, Telmo. Dyslipidemia- From Prevention to Treatment: Dyslipidemia and Cardiovascular Risk: Lipid Ratios as Risk Factors for Cardiovascular Disease. Pgs 279-298.

Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation. 2012;125(1):e2–220.

Uptodate. Screening Guidelines for Dyslipidemia. Online. 4/10/2013. http://www.uptodate.com/contents/screening-guidelines-for-dyslipidemia?topidKey=PC%