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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
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%
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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
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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
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Many to work with who need our care and expertise
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