Metabolic & Endocrine Disease SummitDyslipidemia and Current Guidleines

for Lipid ManagementThursday July 28, 2011

Orlando, FL

Joyce L. Ross, MSN, CRNP, CS, FPCNA, FNLADiplomate Accreditation Council for Clinical Lipidology

Certified Clinical Lipid SpecialistUniversity of Pennsylvania Health System – Retired

Joyce@joycerossnp.com484-614-5027

Current Estimates of the Impact of

CVD and Dyslipidemia in the US

American Heart Association. Heart Disease and Stroke Statistics―2008 Update. Dallas, Texas: American Heart Association; 2008.

• 1 in 2 adults has total cholesterol ≥200 mg/dL

• 1 in 3 adults has CVD

# 1 Killer in US since 1900

Prevalence of Cardiovascular Disease

2002 Heart and Stroke Statistical Update. American Heart Association2002 Heart and Stroke Statistical Update. American Heart Association

Effects 1/5 th of the population

Approximately 40% of all first MI’s are fatal

63% of women/50% of men with CAD had no prior knowledge of disease

Every 29 seconds an American suffers a coronary event

Every 60 seconds an American dies from a coronary event

                                                                              

   

CAD = coronary artery disease.Adapted from Levy D et al. In: Textbook of Cardiovascular Medicine. Philadelphia, Pa: Lippincott-Raven; 1998.

CHD: The Diagnosis Often Comes Too Late

MI or death as initial presentation MI or death as initial presentation of CADof CAD

MenMen 62%62%

WomenWomen 46%46%

00 1010 2020 3030 4040 5050 6060 7070Percentage Percentage of Patientsof Patients

40% are absent because death is the sign and symptoms

Fatigue Poorly localized chest tightness

Fever Chest pressure or aching

Pallor Arm pressure or aching (5 min or <)

Intermittent claudification Dypsnea

Mild angina on exertion Lightheadedness

Confusion Palpitations

CVD costs the nation $274 billion each year,

including health expenditures and lost productivity

2600 people die every single day!!!!!!!!!!!!!

How, What and Why?????

13 million Americans have some form of coronary heart disease

Risk factorsHigh LDL-C levels

Low HDL-C levels

Hypertension

Diabetes Mellitus

Obesity- BMI> or equal 30kg/m2

Smoking

Sedentary Lifestyle

Dyslipidemia

Dyslipidemia is a major risk factor for CHD, the leading cause of death in the United States1

The World Health Organization estimates that dyslipidemia is associated with >50% of global ischemic heart disease cases and >4 million deaths per year2

1. Smith DG. Am J Manag Care. 2007;13:S68-S71. 2. World Health Organization. The World Health Report. 2002;4:47-97.

CHD = coronary heart disease.CHD = coronary heart disease.

Atherosclerosis

Large part of CAD

Plays a tremendous role in mortality, morbidity

Deposition of fat containing plaques that consist of cholesterol and lipids on the innermost layer of the walls of large and medium sized arteries

Progression of atherosclerosis finds its foundation in continued elevation of cholesterol blood levels

Causes of Lipid DisordersPrimary and Secondary Causes Primary are related to genetics Secondary may be related to medical disorders, and

medications, that effect specific parameters of the lipid profile

Metabolic endocrineDiabetesThyroid disease

RenalHepaticdrugs

Ross, J 2005

Focus on Multiple Risk Factors

CHD risk equivalents

DM, PVD, symptomatic carotid disease, AAA, stroke, TIA

Framingham projections of 10-year CHD risk

Identify certain patients with multiple risk factors for more intensive treatment

Multiple metabolic risk factors

metabolic syndrome

NCEP ATP III. JAMA. 2001;285:2486-2497.

National Cholesterol Education Guidelines ATP III

Features of ATP III - Triglycerides

Patients with triglycerides 200 mg/dL LDL cholesterol: primary target of therapy Non-HDL cholesterol: secondary target of therapy

Non HDL-C = total cholesterol – HDL cholesterolExample: TC 270 minus HDL 50 = 220 non-HDL-

C - Should not be higher than 30 points than LDL goal.

- If LDL goal 130, non HDL goal = < 130

NCEP ATP III. JAMA. 2001;285:2486-2497

Recommendation for Screening/Detection (20 years old)

If family history of premature CAD – check lipids at 2 years old

Complete lipoprotein profile

Fasting – 12 hour recommended

Total cholesterol (< 200) LDL (per risk factors) HDL (> 40 men, > 50 women) Triglycerides (<150)

NCEP ATP III. JAMA. 2001;285:2486-2497

Very low-density lipoprotein Made in the liverTG-rich

IDL

No

n-H

DL

-C I

ncl

ud

es

All

Ath

ero

gen

ic A

po

B-

con

tain

ing

Lip

op

rote

ins1,

2

Intermediate-density lipoprotein – VLDL remnantMade from VLDL by TG lipolysisTG and cholesterol-rich

Low-density lipoprotein Made from IDL by TG lipolysisCholesterol-rich High TG increases density and atherogenicity1,2

High-density lipoprotein Removes cholesterol from artery wallOther possible anti-atherogenic effects (eg, anti-inflammatory)3

1. Chapman MJ, Caslake M. Eur Heart J. 2004;(suppl A):A43-A48. 2. Garg R et al. Prev Cardiol. 2005;8:173-177. 3. Gotto AM, Brinton EA. J Am Coll Cardiol. 2004;43:717-724.

VLDL

HDL

Definition of Non-HDL-C

LDL

Non-HDL-C = Total Cholesterol minus HDL-C

Risk AssessmentStep Process

Traditional risk factors Framingham 10 year risk assessment

when appropriate Assess for metabolic syndrome in all

patients

NCEP ATP III. JAMA. 2001;285:2486-2497

Risk Category

CHD and CHD riskequivalents Multiple (2+) risk factors

Zero to one risk factor

LDL Goal (mg/dL)

<100 < 70 *

<130

<160

Three Categories of Risk that Modify LDL-Cholesterol Goals

NCEP ATP III UpdateNCEP ATP III UpdateCirculation 2004, 2004;110:227-239Circulation 2004, 2004;110:227-239

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

Cigarette smokingHypertension (BP 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)

† HDL cholesterol 60 mg/dL counts as a “negative” risk factor; its presence removes one risk factor from the total count.

NCEP ATP III. JAMA. 2001;285:2486-2497

Determination of 10-year CHD RiskFramingham Point Scores For Hard CHD

Event

Step 1

• Calculate traditional risk factors

Step 2

• Determine 10-year CHD risk from table according to point total

Ross, J 2005

Framingham Limitations

No consideration of risk with a first degree relative

60% of people with heart disease have established FH risk

No reflection of true risk for older age women

Representation of younger patients at risk still needs examination

Focus has been on older than 50 years especially men demonstrated age related risk and plaque development Cardiovascular disease leading cause of death in women

AGEAge (years) Male Female 20 - 34 - 9 - 7 35 - 39 - 4 - 3 40 - 44 0 0 45 - 49 3 3 50 - 54 6 6 55 - 59 8 8 60 - 64 10 10 65 - 69 11 12 70 - 74 12 14 75 - 79 13 16

NCEP ATP III. JAMA. 2001;285:2486-2497

Total Cholesterol

TC 20 - 39 y 40 -49 y 50-59 y 60 - 69 y 70 - 79 y mg/dl M F M F M F M F M F < 160 0 0 0 0 0 0 0 0 0 0160 - 190 4 4 3 3 2 2 1 1 0 1200 - 239 7 8 5 6 3 4 1 2 0 1240 - 279 9 11 6 8 4 5 2 3 1 2 280 11 13 8 10 5 7 3 4 1 2

Smoking Status

Nonsmoker 0 0 0 0 0 0 0 0 0 0Smoker 8 9 5 7 3 4 1 2 1 1

NCEP ATP III. JAMA. 2001;285:2486-2497

Blood PressureSystolic Blood Untreated

Treated M F M F

< 120 0 0 0 0

120 - 139 0 1 1 3

140 - 159 1 3 2 5

> 160 2 4 3 6NCEP ATP III. JAMA. 2001;285:2486-2497

HDL - Cholesterol

HDL-cholesterol (mg/dL) M F

> 60 - 1 - 150 - 59 0 040 - 49 1 1< 40 2 2

NCEP ATP III. JAMA. 2001;285:2486-2497

10 - Year CHD Based on Point Count

Male Female Point total 10 year risk (%) Point total 10 year risk (%) < 0 < 1 < 9 < 1 0 1 9 1 1 1 10 1 2 1 11 1 3 1 12 1 4 1 13 2 5 2 14 2 6 2 15 3 7 3 16 4 8 4 17 5 9 5 18 6 10 6 19 8 11 8 20 11 12 10 21 14 13 12 22 17 14 16 23 22 15 20 24 27 16 25 > 25 > 30

> 17 > 30 NCEP ATP III. JAMA. 2001;285:2486-2497

ATP III: Risk Is More Than Elevated LDL-C

Expert Panel. JAMA 2001; Grundy et al. Circulation 2005; 112:2735-52.

MetabolicSyndrome

ElevatedLDL-C

Waist Circumference Low levels of HDL-C Elevated BP Elevated TG Elevated Fasting Glucose

Easily measured variables

ATP III and Metabolic Syndrome

ATP III draws attention to the importance of the metabolic syndrome

Provides a working definition of this syndrome for the first time

Those with metabolic syndrome are at increased risk for development of DM CHD plus increased mortality in general

Ross, J 2005Adapted from NCEP ATP III. JAMA. 2001;285:2486-2497

Diagnosis of metabolic syndrome

Defined as any pathophysiologic dysfunction that results in

a loss of metabolic control of homeostasis in the body

ATP III gives specific criteria for the syndrome but does not go as far as to call it a CAD

equivalent

Components of the syndrome discussed in terms of risk factors and defining

levels

Diagnosis is established when 3 of These risk factors are present

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

> 102 cm (>40 in)>88 cm (>35 in)

Abdominal obesity(Waist circumference)

110 mg/dL Fasting glucose

Blood pressure

<40 mg/dL/ <50 g/dL

130/85 mm/Hg

HDL-C

Men/Women

150 mg/dLTG Men & Women

Defining LevelRisk Factor

0

1

2

3

4CVD*

CHD†

0 1 2 3 4 5

Mo

rta

lity

haz

ard

ra

tio

Number of Metabolic Syndrome Criteria

*Adjusted for age, sex, race or ethnicity, education, smoking status, non–HDL-C, recreational/nonrecreational activity, white blood cell count, alcohol use, prevalent heart disease, and stroke †Similar adjustments except for prevalent stroke

Ford ES. Atherosclerosis 2004;173:309-314

Metabolic Syndrome: Risk of DeathMetabolic Syndrome: Risk of Death

CHD=Coronary heart disease, CVD=Cardiovascular disease

Risk is Proportional to the Number of ATP III Criteria

Role of Insulin Resistance and Compensatory Hyperinsulinemia

Genetics Environment

Insulin Resistance

Hyperinsulinemia

Glucose Uric Acid Dyslipidemia Hemodynamic Hemostatic

Metabolism elevated TG

increased PP Lipemia

decreased HDL

small, dense LDL

LDL Oxidation

Coronary Heart Disease

Decreasedclearance

SympatheticResponseSodium retention &Increased BP

IncreasedPAI I &fibrinogen

IncreasedGlucose Levels =diabetes

American Journal of Epidemiology 2000; 152(10): 897-907Sakkinen PA, Wahl P, Cushman M, et al

What is the pathophysiology of an MI?

(What is the last straw?)Is it the last Donut Pizza Hamburger with cheese French fries ???????????

Bad Luck ?

Poor parental choices?

A series of chemical events?

The Damage from Cholesterol and other factors assert their influence on

the

CONTRIBUTING FACTORS IN VASCULAR DISEASE

lifestylecholesterolHTNgeneticsdiabetesnovel risk factors

Ross, J 2005

EndotheliumEndothelium(Gateway to the Cardiovascular System)(Gateway to the Cardiovascular System)

Largest organ in the bodyLargest organ in the body

Total surface = 6 tennis courtsTotal surface = 6 tennis courts

Total mass = 5 normal heartsTotal mass = 5 normal hearts

Total weight = 1800 GTotal weight = 1800 G

Total # of cell = 1 trillionTotal # of cell = 1 trillion

Living Organ that forms a barrier Living Organ that forms a barrier between between the blood and the tissuesthe blood and the tissues

One layer cell liner of blood vessels

Lies between the lumen of arteries and vascular smooth muscle

Maintaining arterial vascular, tone and structure

Mediation of inflammatory and immune mechanisms

Coagulation (fibrinolysis, retardation of platelet and leukocyte adhesion)

Endothelial Dysfunction

FoamCells

FattyStreak

IntermediateLesion Atheroma

FibrousPlaque

ComplicatedLesion/Rupture

From first decade From third decade From fourth decade

Growth mainly by lipid accumulationSmoothmuscle

& collagen

Thrombosis,hematoma

Non-obstructive plaque

Endothelium

Plaque Cap

Apolipoprotein B (ApoB) LDL Particle Density – Pattern A & B

Serves as an identification protein for specific receptors located on hepatic and peripheral cells

involved in lipoprotein metabolism

Produced in the liver

Useful in patients with borderline LDL cholesterol levels

especially if there is a family history of premature disease

Adapted from Prev Cardio 1999:2:105-114Diagram: Ross J 2005

Atherogenic Changes Associated with Triglycerides

Low HDL-C

Increased VLDL Remnants

Coagulation changes

Increased PAI-1

Increased fibrinogen

Increased Chylomicron Remnants

Small dense LDL particles

HYPERTRIGLYCERIDEMIA

Vascular Biology Working Group

Serum TG Levels: NCEP/ATP III Goals and Cutpoints

ClassificationSerum TG Level

(mg/dL)

Normal <150

Borderline High 150-199

High 200-499

Very High ≥500

Third Report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). NIH Publication No. 02-5215; September 2002.

Elevated Trigyceridescontributing factors

Contributing factors Obesity and overweight Physical inactivity Excess ETOH intake High carbohydrate diets

Genetic disorders FCHL Hyperlipidemia FH Familial

dysbetalipoproteninemia

Several diseases Type 2 DM Chronic renal failure Nephrotic syndrome

Medications Corticosteroids,

estrogens Retinoids Higher doses of beta-

adrenergic blocking agents

Protease inhibitors tomoxifin

Risk of CHD by Triglyceride Level:

The Framingham Heart Study

Castelli WP. Am J Cardiol. 1992;70:3H-9H.

0.0

0.5

1.0

1.5

2.0

2.5

3.0

50 100 150 200 250 300 350 400

Rel

ati

ve

risk

MenWomen

n=5,127

Triglyceride level (mg/dL)

Antioxidative Activity

AntithromboticActivity

Other Antiatherogenic Actions of HDL

ReverseCholesterolTransportCellular

CholesterolEfflux

AntiapoptoticActivity

AntiinflammatoryActivity

HDLAntiinfectious

Activity

Chapman MJ, et al. Curr Med. Res Opin. 2004,20:1253-1268.Assmann G, et al. Annu Rev Med. 2003,53:321-41.

EndothelialRepair

VasodilatoryActivity

Hs CRP - CRP is an acute phase reactant

High levels associated with increased vascular events, MI, CVA

Assay precisely measures low levels of CRP

Inflammation is part of the sequence of events for MI

most studies demonstrate A 3 - 4 fold increased risk associated with the highest quartile compared with the lowest levels

stronger prediction when combined with the lipid panel

shown to be decreased with statin therapy and Niacin

Inflammation in Atherothrombosis: How to Use High-Sensitivity C-Reactive Protein (hsCRP) in Clinical Paul M. Ridker, MD, MPH.Am Heart Hosp J (2004) 2;4 Suppl 1:4-9

Recommendations for Use:hs-CRP in Clinical Practice

Not recommended for routine screening of entire populationIn patients at intermediate risk (10% to 20% CHD risk per 10 years):– hs-CRP may help direct further evaluation and

therapy in primary preventionIn patients with stable coronary disease, acute coronary syndromes:– hs-CRP measurement may be useful as an

independent marker of prognosis for recurrent events

Ross J 2005

The elbow and feet of the ARH patient showing xanthomas at 10 years of age (a,b). Complete regression of xanthomas shown at the age of 23 (c,d).

S. Lind et al., J Int Med 2004; 256: 406-12

Eruptive Xanthomas Before and After Zetia + Statin

TREATMENT OF

ASSIGNED RISK

Use standard guidelines by the appropriate experts in the fieldMany will offer suggestions that include the

other aspects of cardiovascular risk

ALL plans begin with Therapeutic Lifestyle Management (TLC)

Involve the patient

Enhanced communication improves patient adherence, outcomes, and satisfaction

Barrier PA et al. Mayo Clin Proc. 2003;78:211-4.

Patient-centered approach facilitates identification of risk

conditions

Provider-centered approach may lead to missed diagnoses and

poor adherence

Integrative medicine framework

Edelman D et al. J Gen Intern Med. 2006;21:728-34.

Mind-body Mind-body approachesapproaches

PhysicalPhysicalactivityactivity

GroupGroupsessionssessions

IndividualIndividualsessionssessions

Improvedhealth

behaviorsNutritionNutrition HealthHealth

self-educationself-education

Multidimensional, patient-centered, individualized

Effecting Change Change Agents

Educative process The past does not equal the

future The process of pain and

pleasure What do changes mean

to the patient Setting reachable goals Partnering for progress

Contracts Support Change the attitude =

Change in behaviorRoss J 2004Ross J 2004

Therapeutic Lifestyle Interventions

Weight reduction– enhances LDL-C lowering– reduces metabolic syndrome risk factorsIncreased physical activity reduces VLDL levels, raises HDL-C,

lowers LDL-C levels lowers blood pressure reduces insulin resistance Dietary carbohydrate restrictions periodic assessments of dietary changes

Metabolic Syndrome and Subclinical Atherosclerosis

Therapeutic Lifestyle Changes in LDL-Lowering Therapy

Major Features

TLC Diet Reduced intake of cholesterol-raising nutrients

(same as previous Step II Diet)Saturated fats <7% of total caloriesDietary cholesterol <200 mg per day

LDL-lowering therapeutic optionsPlant stanols/sterols (2 g per day)Viscous (soluble) fiber (10–25 g per day)

Weight reduction Increased physical activity

Adapted from NCEP ATP III. JAMA. 2001;285:2486-2497

ObesityChronic, relapsing disease characterized by an excessive accumulation of body fat It is heterogeneousGeneticEnvironmental Metabolic Behavioral

Associated with multiple risk factors that lead to morbidity and mortality

American Heart Association has classified obesity as a chronic illnessmajor, modifiable risk factor for CAD

1. Wing RR, et al. 1. Wing RR, et al. Arch Intern MedArch Intern Med. 1987;147:1749–1753.. 1987;147:1749–1753.2. Goldstein DJ. 2. Goldstein DJ. Int J ObesInt J Obes. 1992;16:397–415.. 1992;16:397–415.3. Thomas PR, ed. 3. Thomas PR, ed. Weighing the Options.Weighing the Options. 1995 1995..

Health Benefits of Weight Loss

Weight loss of 5%–10% in obese individuals with type 2 diabetes, hypertension or dyslipidemia resulted in: Improved glycemic control1

Reduced blood pressure2 Improved lipid profile2

“Several studies demonstrate that small losses...help reduce obesity-related comorbidities and that improvements in these risk factors persist with maintenance of these modest weight losses.”3

— Institute of Medicine

Lifestyle Modification: NHLBI Recommendations

Assess patient readiness and motivate the patient Diet: – 500–1000 kcal/day deficit for loss of 1–2 pounds

per week

– Reducing dietary fat along with calories can help Physical activity goal: – Moderate activity for 30–45 minutes, 3 to 5 times

per week to start, increasing to 30 minutes most

or all days of the week

National Institutes of Health. National Institutes of Health. Obes ResObes Res. 1998;6(suppl 2):51S–209S.. 1998;6(suppl 2):51S–209S.

Risk Reduction Therapy

Risk Behavior % Mortality – 10 years Smoke Cessation 35 – 45 %LDL Reduction to goal 25 – 35 %BP management to goal 10 – 15 %ASA 10 % ACE Inhibitor Use 20 – 30 %Weight Loss 20 %Exercise 20 %

Grundy 9/2000

Problems with Smoking

Reduced HDL

reduces O2 in the blood

constricts arteries

damages the blood vessels

Ross J 2004Ross J 2004

Atherogenic dyslipidemia is an important target of therapy for CV risk management, and commonly occurs in patients with the metabolic syndrome and/or diabetes

A substantial proportion of patients with atherogenic dyslipidemia are not at lipid goals

Guidelines recommend non-HDL-C as a secondary target in patients with atherogenic dyslipidemia, including combination therapy with a fibrate and statin

Atherogenic Dyslipidemia as a Target of Therapy

Features of Patients With the Metabolic Syndrome or Type 2 Diabetes

Characteristic No MS/No DM MS DM

Waist circumference, cm 89 108* 109*

LDL-C, mg/dL 124 129* 122*†

HDL-C, mg/dL 54 40* 44*†

TG, mg/dL 105 214* 220*†

Fasting glucose, mg/dL 93 100* 175*‡

SBP/DBP, mmHg 118/71 134*/77* 134*/71*‡

Prevalent CVD, % 5.2 13.6 26.7

Malik S et al. Diabetes Care. 2005;28:690-693.

* P<0.0001 compared with no MS/no DM; † P<0.01 comparing MS with DM; ‡ P<0.0001 comparing MS with DM.

Atherogenic dyslipidemia is common in patients with metabolic syndrome (MS), including type 2 diabetes (DM)

Lipid Therapy Options for Dyslipidemia

1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497. 2. Zetia® (ezetimibe) [package insert]. Merck/Schering-Plough Pharmaceuticals. North Wales, PA; 2008. 3. Lovaza™ (omega-3-acid ethyl esters) capsules [package insert]. Reliant Pharmaceuticals. Durham, NC; 2007.

Drug Class LDL-C HDL-C TG Key Limitations

Statins1 ↓ 18%–55% ↑ 5%–15% ↓ 7%–30% Myositis, ↑ LFTs

Bile acid sequestrants1 ↓ 15%–30% ↑ 3%–5% No effect or ↑

Upper/lower GI complaints (eg, constipation)

Nicotinic acid1 ↓ 5%–25% ↑ 15%–35% ↓ 20%–50%Flushing, hyperglycemia, hyperuricemia/gout

Fibric acid derivatives1 ↓ 5%–20% ↑ 10%–20% ↓ 20%–50%

Upper GI complaints, myopathy

Cholesterol-absorption inhibitors2

↓ 18% ↑ 1% ↓ 8%↑ LFTs in combination with statins; lack of outcomes data

Omega-3 fatty acids3*

↑ 45% ↑ 9% ↓ 45%↑ LDL-C; lack of outcomes data

* Based on use in patients with very high TG levels (≥500 mg/dL).

Agents that reduce TGs

Lifestyle management Exercise – as powerful

as any medication if applied appropriately

Dietary changesReduction of

carbohydratesReduced amounts

of fruit juice, soda with sugar

Medications Fibrates – Gemfibrozil,

Fenofibrates Niacin (Niaspan) HMG Co reductase

Inhibitors (all) Fish Oil

Medications Fibrates

Drugs of choice for increased VLDL

Safe in combination with statins if renal function normal

Effects on Lipids increase/decrease LDL decrease TGs increase HDL

Fenofibrate (now 4 ) much more efficacious and safer than previous fibrates Fenofibrate decreases

TGs 32 - 53 %, HDL increased by 2 - 26 %

Gemfibrozil decreased TG’s 31 - 35 %, HDL increased by 6 - 10 %

Niacin

Mechanism of action poorly understood

Decreased VLDL production

Niacin Effects decreases LDL, shifts

LDL density gradient to larger, buoyant

increases HDL decreases VLDL, shifts to

more buoyant type

B-3 VitaminFirst used to lower chol. In 1955Agents: IR Niacin SL Niacin Extended release - Niaspan

Effect on Cholesterol decreases TC, TG, increased

HDL, lowers LDL

F i s h O i lused as modifier for lipid profile, specifically triglyceride levels, using various doses daily

can have some GI issues when startingcan titrate up to about 9 grams dailybest taken with food

Need to be cautious with Anticoagulants Coumadin Warfarin

Antiplatelet Drugs ASA NSAIDS Ticlid Plavix

Fish Oil

Potential mechanisms for reduction of

CV Risk Reduce susceptibility of the heart to ventricular arrhythmia Anti-thrombogenic Reduce Triglycerides (fasting & postprandial) Retard growth of atherosclerotic plaque

Reduce adhesion molecule expression Reduce platelet-derived growth factor Anti-inflammatory

Promote nitric oxide induced endothelial relaxation Mildly hypotensive

Recommend combination of EPA & DHA

Etherston et al.Circulation(106):2747 2002

Prescription Fish OilOmacor

EPA/DHA rich fish oil capsule

Was used in the study that encouraged AHA Recommendation to add fish oil to all patients withKnown CAD

One gram capsule cardio protection – 1 grams dailyto reduce TGs – 4 grams daily

Ezetimibe

The first in a new class of lipid-lowering compounds that:

Selectively inhibits the intestinal absorption of cholesterol and related phytosterols

STATINS: Mechanism of Action

Inhibit the rate-limiting enzyme HMG-CoA in cholesterol biosynthesis

The associated decrease in synthesis stimulates production of LDL receptors

Also possible increased removal of VLDL and IDL remnants which accounts for some decrease in triglycerides

Other effects

Current Research theories with

HMG Co-reductase inhibitors

 anti-inflammatory effects

plaque stabilization

decreased thrombus formation

endothelial restoration

NEWSFLASH !!!!!All Statins Are Not Created

EqualHow are they different ?

strength at starting dose

way the body metabolizes it

hydro/lipophilic

Taking a walk on the Cytochrome P450 Pathway

Ross J 2004

Role of CYP450 3A4 in Drug Metabolism

Responsible for converting lipophilic substrates to water-soluble products to facilitate urinary excretion

• High potential for drug-drug interactions, as approximately 50% of drugs are metabolized by this enzyme

• Hydrophilic agents do not require clinically significant metabolism through this pathway

Wilson. Pharmacokinetics: the dynamics of drug absorption, distribution, and elimination. Hardman et al, eds. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 2003:3-30.

Dose Efficacy of Statin-Based Therapies for LDL-C Reduction (%)1

Dose Efficacy in STELLAR1*

Drug 10 mg 20 mg 40 mg 80 mg

CRESTOR® (rosuvastatin calcium) 46 52 55

Lipitor® (atorvastatin calcium) 37 43 48 51

Pravachol® (pravastatin sodium)

20 24 30 *

Zocor® (simvastatin) 28 35 39 46

•VytorinTM (ezetimibe 10 mg/simvastatin)* reduces LDL-C by 46% to 59%2*

•Data derived from the prescribing information for Vytorin

Safety: Looking at the Data From Another Perspective: If You Put 1,000

Patients on Aspirin and a Statin ...

• Aspirin (81 mg) You can expect ~25

(10 - 40) hemorrhagic CVAs annually

You can expect ~135 (70 - 200) major GI bleeds annually

• Statin You can expect 2 cases

of mild rhabdomyolysis annually

No cases of liver failure No deaths

Lauer MS, et al. N Engl J Med 2002:346;1468-1474.Law MR, et al. BMJ 2003:326:1423.

A Lot of fear and mis-perspection taking place, causing our patients not to take statins or not taking enough statin to reach goal

Combination Therapies for Hypertriglyceridemia

• Fibrates & statin therapy• Niacin & statin therapy• Zetia and Statin therapy• Prescription omega-3 fatty acids &

statin

Advicor• First and new combination therapy utilizing Lovastatin

and Niaspan• Helps met ATP III guidelines• Modifies LDL, HDL, TG, and Lp(a)• Once nightly dosing• Data from 748 patients exposed for 1 years and almost

400 for 2 years revealed that it is safe and well tolerated.Elevated LFTs > 3 X ULN occurred in < 1%

at doses of 2000/40 or less

NIASPAN® [package insert]. Miami, Fla: Kos Pharmaceuticals, Inc.; 2003.Morgan JM et al. J Cardiovasc Pharmacol Ther. 1996;1:195-202

Vytorin

• Combination of

Zocor

Zetia

• Enhanced LDL lowering than with just statin therapy

• Cost effective in one product

• Outcome studies not completed

Ross, J 2004

Combination Therapy:Adding Fibrate to a Statin

Better TG and HDL-C

non-HDL-C

PROS

May myositis/ myopathy risk

cost and complexity

LDL particle size

Potential for other drug interactions

CONS apo B

VLDL

Grundy SM. Am J Cardiol. 2005;95:462-468.

Jones PH. Am J Cardiol. 2005;95:120-122.

Combination Therapy• Fibrate and statin monotherapy increase the risk of

myositis or myopathy, and have been associated with rhabdomyolysis.

• Data from observational studies suggest that the risk for rhabdomyolysis is increased when fibrates are co-administered with a statin (with a significantly higher rate observed for gemfibrozil).

• The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes, renal failure, or hypothyroidism.

• WARNING: The combined use of fibrates and HMG-CoA reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination

• The combined use of fibric acid derivatives and HMG-CoA reductase inhibitors has been associated with rhabdomyolysis, markedly elevated creatine kinase (CK) levels and myoglobinuria, leading in a high proportion of cases to acute renal failure

Fibrate Class Labeling Regarding Concomitant Statin Therapy

Number of Reports of Rhabdomyolysis for Fibrate/Statin Therapies (1998 to 2002)

MedicationNo. Cases Reported*

No. Prescriptions Dispensed†

No. Cases reported

per Million Prescriptions

FenofibrateWith cerivastatinWith other statinsFenofibrate total

14 216

100,0003,419,0003,519,000

140 0.58

4.5

GemfibrozilWith cerivastatinWith other statinsGemfibrozil total

533 57590

116,0006,641,0006,757,000

4600 8.6

87

15xincrease

Jones PH, Davidson MH. Am J Cardiol. 2005;95:120-122.

* Food and Drug Administration’s Adverse Event Reporting System (January1, 1998 to March 31, 2002).† Calculated from data from the National Prescription Audit Plus Report, IMS Health (January 1, 1998 to March

31, 2002), and a Verispan, LLC Concomitancy Report (January 1, 1998 to March 31, 2002).

Case Study

60-Year-Old Woman With Type 2 Diabetes and a History

of Chronic Pancreatitis

• Patient profile: 60-year-old woman with well-controlled type 2 diabetes of 3 years’ duration and a history of chronic pancreatitis presents for a new patient examination

• Social history: She smokes 1 pack/day and drinks alcohol moderately

60-Year-Old Woman WithType 2 Diabetes and a History of Chronic Pancreatitis (cont’d)

• Current medications Amlodipine 5 mg Glipizide 10 mg Metformin 1000 mg BID Simvastatin 40 mg

• Physical findings BMI: 36 kg/m2

Waist circumference: 41 in (104 cm) Blood pressure: 141/90 mm Hg

• Lipid profile TC: 250 mg/dL HDL-C: 36 mg/dL LDL-C: 100 mg/dL TG: 570 mg/dL

What is her risk for any CV event

in the next 10 years?1. 2%

2. 8%

3. 17%

4. 22%

5. ≥30%

6. Not necessary to calculate

Age (y)

Points

20-34 -7

35-39 -3

40-44 0

45-49 3

50-54 6

55-59 8

60-64 10

65-69 12

70-74 14

75-79 16

TC Age (y)

(mg/dL) 20-39 40-49 50-59 60-69 70-79

<160 0 0 0 0 0

160-199 4 3 2 1 0

200-239 8 6 4 2 1

240 -279 11 8 5 3 2

280 13 10 7 4 2

Step 2: TC

HDL-C (mg/dL)

60 50-59 40-49 <40

Points-1 0 1 2

Step 3: HDL-C

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486.

Framingham Risk Scoring (Women)

Framingham Risk Scoring (Women) (cont’d)

Systolic BP (mm

Hg)

Points (Untreated

)

Points (Treated

)

<120 0 0

120-129 1 3

130-139 2 4

140-159 3 5

160 4 6

Age (y)

20-39 40-49 50-59 60-69 70-79Nonsmok

er0 0 0 0 0

Smoker 9 7 4 2 1

Points 10-Yr Risk

Points

10-Yr Risk

<9 <1% 14 2%9 1% 15 3%

10 1% 16 4%11 1% 17 5%12 1% 18 6%13 2% 19 8%

20 11%

21 14%

22 17%

23 22%

24 27%

25 30%

87

Step 4: Systolic Blood Pressure Step 4: Systolic Blood Pressure

Step 5: Smoking Status

Step 5: Smoking Status

Step 6: Add up the PointsStep 6: Add up the Points

Step 7: Calculate Risk of CHDStep 7: Calculate Risk of CHD

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486.Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486.

Diagnosis is established when 3 of These risk factors are present

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

> 102 cm (>40 in)>88 cm (>35 in)

Abdominal obesity (Waist circumference)

Special levels now for Asian population

110 mg/dLFasting glucose

Blood pressure

<40 mg/dL/ <50 g/dL

130/85 mm/Hg

HDL-C

Men/Women

150 mg/dL TG Men & Women

Defining LevelRisk Factor

Which of the following would you consider adding to this particular patient's regimen?

1. Fenofibrates

2. Niacin

3. Pravastatin

4. Prescription omega-3 fatty acids

5. Absorption Inhibitor

Treatment Plan• Patient was treated with prescription

omega-3 fatty acids, 4 g daily for 3 months• Continued statin treatment at same dose• Compliant with low-fat diet and lost 10 pounds• Diabetes remained under control• Blood pressure to 134/90 mm Hg• Continue lifestyle management• Stop Smoking• Return for follow up in 3 months• Lipid profile at 3-month follow-up:• TC: 210 mg/dL; HDL: 36 mg/dL; LDL: 103 mg/dL; TG:

355 mg/dL, Non-HDL 174, glucose 118, HbA1c 7.0, renal and liver functions WNLs

3-Month Follow-up

• Patient was continued with prescription omega-3 fatty acids, 4 g daily

• Changed statin to Rosuvastatin 20 mg• No change with diabetic medication• Blood pressure medications unchanged but added ACE • Continue with lifestyle management• Stop Smoking• Lipid profile at 3-month follow-up:

On Return• TC: 140 mg/dL; HDL: 40 mg/dL; LDL: 65 mg/dL; TG: 165 mg/dL,

Non-HDL not necessary since TGs are < 200, glucose 104, HbA1c 6.9, liver and kidney function normal. BP 122/78

91

Take Home Message

• Dyslipidemias are an important CVD risk factor• Patients who are at LDL-C goal with statin therapy

and still have hypertriglyceridemia remain at increased risk for CVD

• Niacin, fibrates, and prescription omega-3 fatty acids are approved agents for lowering TG levels

• Studies have shown that combination therapies using niacin + statin, omega-3 fatty acids + statin, and fibrates + statin are effective at reducing TG levels

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NCEP ATP III Current Guidelines Provide Directionon How to Treat Patients With Dyslipidemia

• The first priority of treatment is to lower LDL-C– The first line of drug therapy to manage LDL-C is statins– In high-risk patients, the LDL-C goal is <100 mg/dL– Optional goal of LDL-C to <70 mg/dL for patients considered to be at

very high risk• If LDL-C at goal but TG ≥200 mg/dL– Non-HDL-C is a second target of therapy– Combining a fibrate or nicotinic acid with an LDL-C-lowering drug can

be considered• TG ≥150 mg/dL defined as borderline high and should be addressed• A specific goal for HDL-C is not specified– HDL-C <40 mg/dL is defined as low– Treatment of low HDL-C should be considered for high-risk patients

We have our work cut out for us

Many to work with who need our care and expertise

ARE YOU UP & READY TO MEET THE CHALLENGE ?