Lipid Guidelines - Dr. Ajay Kantharia
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Consulting Physician & Cardiologist Critical Care Physician
HON. PHYSICIAN:
Saifee HospitalSir H. N. HospitalMotiben Dalvi Hospital
Lipids GuidelinesLipids Guidelines
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The food that we eat is mixture of CarbohydratesProteinsFats (LIPIDS)FibresVitamins, minerals, etc
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LIPIDSLipids are a heterogenous group of water –insoluble ( hydrophobic ) organicmolecules .
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Lipids areMajor source of energy
Other function .Fat soluble vitamins have regulatory or
coenzyme function. Prostaglandin & steroid hormones
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An adult ingests about 60-150 gm of lipids / day.90% is Triglycerides (TG)
The remaining 10% is cholesterol , cholesteryl esters , phospholipids and unesterified (free ) fatty acids.
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The bowel has limited capacity for the uptake of cholesterol approximately 1500mg/ day,
but the uptake of the TG is unlimited .
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The various lipids are emulsified, degraded, mixed by and with various digestive juices & enzymes so that it can be absorbed.
The primary site of lipid absorption is thebrush border membrane of the intestinalmucosal cells.
From the intestinal mucosal cells they are
transported to the lymph >> thoracic duct into
the circulation.
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LIPID PROFILE
Total CholesterolTriglycerideHigh Density LipoproteinLow Density LipoproteinVery Low Density LipoproteinChylomicronsVarious Ratios
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What is a Lipoprotein?
Protein
Lipo (Lipid)
++
Lipoprotein is a macro-molecular complex in blood carrying protected
lipids
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Why are lipoproteins formed?
Cholesterol is insoluble in water
To transport it thro’ blood (92% water) it is combined with Protein to make
Watersoluble Lipoproteins
-Harper’s Biochemistry(2000),p 268
For utilization and storage in tissues,it isconverted to water-insoluble
Cholesterol ‘Ester’
-Krause’s (2000),Food,Nutrition and Diet Therapy, p 62
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What is a Apolipoprotein?
-Harper’s Biochemistry(2000),p 270
Apo = ‘Derived from’Apolipoprotein is the name given to
‘Protein’ part of Lipoprotein(ie,Protein derived from Lipoprotein)
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APOLIPOPROTEINSStabilize the Lipoprotein Structure.
Important regulatory function in LIPOPROTEIN metabolism.
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Which Lipoproteins havewhich Apolipoproteins?
-Harper’s Biochemistry(2000),p 270
Apolipoprotein Lipoprotein Apo A-I/II/IV HDL,Chylo
Apo C-I/II/III VLDL,HDL,ChyloApo D HDLApo E VLDL,LDL,HDL,Chylo
B-100 has the longest amino acidchain(4536) B-48 means 48 % of B 100
Apo B-100 LDL,VLDL,IDLApo B-48 Chylo
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Why is the study of Lipid important ?
C V D
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WHOM TO TEST ?A personal history of CHD, peripheral
vascular disease or CVAA Family History of CHD or PVD
(especially before age 55 years or hyperlipidemia)
HypertensionDiabetes mellitusPhysical stigmata of hyperlipidermiaObesity (BMI > 28)Chronic Renal DiseaseSmoking habits
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When should we start examining Lipid profile ?
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Adults > 20years of age & then every 05 years
Test children with a family history of premature CHD at age 2 years.
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Frequency of TestingEvery 5 years from age 20 – 25 years to 60-
70 years according to overall risk. Borderline cases – vary from 1 to 5 yearsFor patients on treatment with Diet – Initially
every 3 months then every 6 -12 monthsFor patients on medication – initially every 6
– 8 weeks then every 3-6 months
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Primary PreventionPrimary prevention aims to prevent new
onset CHD
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Primary PreventionandRisk Factor assessment
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Categories of Risk FactorsMajor, independent risk factorsLife-habit risk factorsEmerging risk factors
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Major Risk Factors (Exclusive of LDL Cholesterol) That Modify LDL GoalsCigarette 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 yearsCHD in female first degree relative <65 years
Age (men 45 years; women 55 years)
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Life-Habit Risk FactorsObesity (BMI 30)Physical inactivityAtherogenic diet
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Emerging Risk FactorsLipoprotein (a)HomocysteineProthrombotic factorsProinflammatory factorsImpaired fasting glucose Subclinical atherosclerosis
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Diabetes
In ATP III, diabetes is regarded as a CHD risk equivalent.
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CHD Risk EquivalentsRisk for major coronary events equal to that
in established CHD10-year risk for hard CHD >20%
Hard CHD = myocardial infarction + coronary death
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CHD Risk EquivalentsOther clinical forms of atherosclerotic
disease (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease)
DiabetesMultiple risk factors that confer a 10-year
risk for CHD >20%
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ATP III Lipid and
Lipoprotein Classification LDL Cholesterol (mg/dL)
<100 Optimal100–129 Near optimal/above
optimal130–159 Borderline high160–189 High190 Very high
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ATP III Lipid and Lipoprotein Classification (continued)
HDL Cholesterol (mg/dL)
<40 Low60 High
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ATP III Lipid and Lipoprotein Classification (continued)
Total Cholesterol (mg/dL)
<200 Desirable200–239 Borderline high240 High
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LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC)and Drug Therapy in Different Risk Categories
Risk CategoryLDL Goal(mg/dL)
LDL Level at Which to Initiate
Therapeutic Lifestyle Changes
(TLC) (mg/dL)
LDL Level at Which
to ConsiderDrug Therapy
(mg/dL)
CHD or CHD Risk Equivalents(10-year risk
>20%)
<100 100130
(100–129: drug optional)
2+ Risk Factors (10-year risk
20%)<130 130
10-year risk 10–20%: 130
10-year risk <10%: 160
0–1 Risk Factor <160 160
190 (160–189: LDL-lowering drug
optional)
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And –the latest
As per July 13th 2004 NCEP ATP III update, high risk patient needs to achieve LDL-C<70
mg/dLRisk LDL goal
mg/dL(NCEP ATP III)1
LDL goal (Recommendations for
modifications to footnote ATP III)2
CHD
(10 yr risk>20%)
< 100 < 70
2+ RF
-10 yr risk 10-20%
-10 yr risk < 10%
< 130
< 130
< 100
Unchanged
0-1 RF < 160 Unchanged
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Therapeutic Lifestyle Changes in LDL-Lowering Therapy
Major Features
TLC DietReduced intake of cholesterol-raising
nutrients Saturated fats <7% of total calories Dietary cholesterol <200 mg per day
LDL-lowering therapeutic options Plant stanols/sterols (2 g per day) Viscous (soluble) fiber (10–25 g per day)
Weight reduction Increased physical activity
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Therapeutic Lifestyle ChangesNutrient Composition of TLC Diet
Nutrient Recommended IntakeSaturated fat Less than 7% of total caloriesPolyunsaturated fat Up to 10% of total caloriesMonounsaturated fat Up to 20% of total caloriesTotal fat 25–35% of total caloriesCarbohydrate 50–60% of total caloriesFiber 20–30 grams per dayProtein Approximately 15% of total caloriesCholesterol Less than 200 mg/dayTotal calories (energy) Balance energy intake and
expenditure to maintain desirable body weight /prevent weight gain
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Other Dietary Considerations
Limit trans fatty acids
Proven dietary components to lower cholesterol:Plant stanols/sterols (2 g/day)Soluble fiber (10-25 g/day)
Questionable role of alcohol
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Exercise
Safety
Aerobic exercise> 20 minutes per activityAt least 3 days per week
Promotes weight loss and HDL
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Smoking Cessation
Can lower oxidative stress
Reversal of endothelial dysfunction
HDL
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Weight LossIncreases HDL
Improves glycemic control
Reduces blood pressure
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DRUG THERAPY
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Drug TherapyThe 5 most common clinical situations inwhich drug therapy is needed are (1) elevated LDL-C; (2) high levels of TGs (200 to 500 mg/dL)
despite attainment of LDL-C goals; (3) low HDL-C; (4) diabetic dyslipidemia; and (5) very high TGs and/or chylomicronemia
syndrome.
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Cholesterol-Lowering Drug Cholesterol-Lowering Drug TherapyTherapy
HMG CoA Reductase HMG CoA Reductase InhibitorsInhibitors
• Lovastatin• Pravastatin• Simvastatin• Fluvastatin• Atorvastatin• Rosuvastatin
Cholesterol Absorption
Inhibitors• Ezetimibe
FibratesFibrates• Gemfibrozil• Micronized Fenofibrate• Clofibrate
Bile Acid SequestrantsBile Acid Sequestrants• Cholestyramine• Colestipol• Colesevelam
NiacinNiacin
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StatinsStatins are the most potent agents for
lowering LDL-C. These agents work by competitively inhibiting the rate-limiting step
of cholesterol synthesis and upregulating LDL receptors in the liver.
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HMG CoA Reductase HMG CoA Reductase InhibitorsInhibitors
1.) LDL 1.) LDL UptakeUptake
CholesterolCholesterol
2.) Synthesis2.) Synthesis
HMG CoAHMG CoA
Bile AcidsBile Acids
CholesterolCholesterol
HMG CoAHMG CoA
Bile AcidsBile Acids
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• Start with lower dose and increase as needed (according to LDL)– Pick dose appropriate to LDL-lowering needed
• Doses should be given in the evening or at bedtime (Atorva and Rosuva can be given any time).
• May need to decrease dose occasionally– Adding potentially interacting drug– Profound drop in LDL
Statins - DosingStatins - Dosing
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Statin Adverse EffectsStatin Adverse Effects
• Major toxicities:
Hepatic transaminases
Myalgias
Rhabdomyolysis
• Selected minor adverse effects:
Dyspepsia/heartburn
Headache
Taste disturbances
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Monitoring of Lipid Lowering Monitoring of Lipid Lowering TherapyTherapy
• Lipid Profiles– Before initiation and at 6-12 weeks until stable– Every 6 months thereafter
• Hepatic Transaminases– Baseline and every 6-12 weeks until stable– Every 6 months thereafter
• Creatine Kinase (CK)– Only as needed
• Glucose, Uric Acid
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Signs and Symptoms of Signs and Symptoms of MyotoxicityMyotoxicity
• Symptoms consist primarily of gradually decreased muscle strength and localized or generalized muscle weakness.
• Symptoms can occur within days or may not occur for years after starting therapy.
• Symptoms involving other organ systems (such as fatigue, shortness of breath, decreased urine output, dark-colored/turbid urine).
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Comparative LDL EffectsComparative LDL Effects
-70
-60
-50
-40
-30
-20
-10
0
10
40
20
80
10
10
20
20
20
20
80
40
40
40
401
5
20
AtorvastatinAtorvastatin SimvastatinSimvastatin PravastatinPravastatin LovastatinLovastatin FluvastatinFluvastatin RosuvastatinRosuvastatin
Am J Cardiol 1998;81:582-7. Am J Cardiol 2001;88:504-8. J Int Med Res 2000;28:47-68. Clin Cardiol 2000;23:39-46.
80
80
80
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-4
-2
0
2
4
6
8
10
12
Atorva Simva Prava Lova Rosuva
10102020
4040
4040
4040
4040
20202020
2020
2020
1010
1010
4040
8080
8080
Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160 & CURVES Study.Am J Cardiol 1998;81:582-7.
Comparative HDL Effects
1010
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Comparative TG EffectsComparative TG Effects
-35
-30
-25
-20
-15
-10
-5
0
5
1010
4040
2020
8080
1010
1010
2020
2020
20202020
80804040
4040
4040
4040
AtorvastatinAtorvastatin SimvastatinSimvastatin PravastatinPravastatin LovastatinLovastatin RosuvaastatinRosuvaastatin
Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160 & CURVES Study. Am J Cardiol 1998;81:582-7.
1010
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Drug InteractionsDrug Interactions
• Pharmacodynamic– Risk of hepatotoxicity and/or myalgias or myopathy
when combined with fibrates or niacin
• Pharmacokinetic absorption with bile acid sequestrants– Inhibition or induction of CYP-based metabolism– Inhibition of CYP activity
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2nd Goal 2nd Goal after LDL C is TG control:A TG level >150 mg/dL is considered
elevated. After correcting LDL- C, TG should be less than 150mg%.
For patients with mildly elevated TG values (150 to 199 mg/dL), Diet and exercise may be adequate.
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2nd Goal2nd Goal….. TG
…... Non HDL Cholesterol
Total Chol. = LDL + VLDL + HDL
Non HDL Chol =Total Chol – HDL = LDL + VLDL
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Non HDL Cholesterol GoalNon HDL Chol Goal =
30 mg above LDL Goal
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T GDiseases associated with High TG:
Type 2 diabetes mellitus, Chronic renal failure, nephritic syndrome, Hypothyroidism, should be looked for and treated.
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T G Drugs that elevate TGs, such as
corticosteroid therapy, estrogen therapy,retinoid therapy, or high doses of beta-blockers, should be stopped or substituted
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T GTreatment options:1. Increasing dose of statin 2. Add Fibrate (Finofibrate is preferable)3. Add Nicotinic acid
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FibratesFibrates
• Mechanism of action– Inhibition of cholesterol synthesis– Decreased TG synthesis– Inhibition of lipolysis in adipose tissue– Decreased production of VLDL / clearance– Increased plasma and hepatic LPL activity
• Effect on lipids TC, LDL, HDL, TG
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Fibrates - Dosing and Fibrates - Dosing and PrecautionsPrecautions
• Dosing– Gemfibrozil: 600mg BID– Micronized Fenofibrate: 67mg QD; to 67-201mg
QD– Clofibrate: 2g daily in divided doses
• Adverse effects– Nausea, diarrhea, cholelithiasis, phototoxicity
• Drug interactions– Increased risk of hepatotoxicity and/or myalgias
with concurrent statins and/or niacin– Protein binding displacement (e.g., warfarin)
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3rd GoalLow HDL-C (<40 mg/dL) is considered a
tertiary goal
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Major causes of Low HDL
Heredity (40% to 60%)Elevated triglyceridesPhysical inactivityCigarette smokingDiets rich in refined carbohydrates & trans –
fatsCertain B.P. medication (diuretics – B
blockers)
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Life style factors that Raise HDLPhysical activityWeight lossDiet high in mono unsaturated fats eg. Lean
meat, Avocado, nuts, olive oil Fish oil containing omega – 3 fatty acidsSmoking cessationSmall amounts of alcohol
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Medication that Raise HDLNiacinStatinsFIbratesEstrogen for womenAlpha blockersCETP inhibitorHDL mimetic or artificial HDLAPO A Milano
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Common medications that increases levels of HDL and its subclasses
Medication
HDL HDL2 HDL3 Apo AI
Statins +5 to 10% +5 + 30% -5 to +5% -5 to +5%
Fibrates+10 to 15%
-5% +5 to +30 -5 to +5
Niacin+25 to 50%
+50 to 200%
-5 to +5%+5 to +30%
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HDLNiacin is drug of choice
It raises blood glucose level, but still can be used in diabetics with good control
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NiacinNiacin
• Mechanism of action– Inhibition of free fatty acid release from adipose
tissue– Inhibition of cAMP accumulation– Inhibition of VLDL and LDL synthesis– Increased LPL activity
• Effects on lipids TC, LDL, HDL, TG– Conversion of LDL phenotypic pattern B into
pattern A– Lowers Lp(a)
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Niacin - DosingNiacin - Dosing
• Immediate release– 100mg TID; by 100mg TID every week as
tolerated– Goal = 500-1000mg TID
• Sustained release– 375mg QD; gradually as needed– Goal = 500-2000mg QD
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Niacin - PrecautionsNiacin - Precautions
• Adverse effects– Flushing, pruritis, headache, fatigue (PG-mediated? --
ASA)– Gastritis, abdominal pain, aggravation of PUD,
hepatotoxicity– Impaired glucose control, uric acid concentrations
• Drug interactions– Alcohol: risk of hepatotoxicity– Statins, fibrates: risk of hepatotoxicity and/or
myalgias
Contra-Indication –H/o gout,peptic ulcer ds., liver ds.
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Other DrugsGastrointestinal-active medication such as a
bile acid–binding sequestrant (theresins cholestyramine and colestipol, or colesevelam, a nonabsorbable polymer)
Cholesterol-absorption inhibitor (e.g., ezetimibe)
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Bile Acid SequestrantsBile Acid Sequestrants
1.) LDL 1.) LDL UptakeUptake
CholesterolCholesterol
2.) Synthesis2.) Synthesis
HMG CoAHMG CoA
Bile AcidsBile Acids
CholesterolCholesterol
HMG CoAHMG CoA
Bile AcidsBile Acids
Intestines Intestines
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Bile Acid SequestrantsDrug Dose
Range
Cholestyramine 4–16 gColestipol 5–20 gColesevelam 2.6–3.8 g
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EzetimibeEzetimibe is a cholesterol-absorption
inhibitor. It lowers LDL-C by about 20%, lowers TGs,
and raises HDL-C slightly. 10 mg/day, and it can be taken at any time of
the day.
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Ezetimibe: A New Cholesterol Absorption Inhibitor
First of a new class of drugs with unique mechanism of action Targets intestinal absorption of dietary and
biliary cholesterol Inhibits absorption of dietary and biliary
cholesterol Reduces plasma LDL-C
Adapted from Leitersdorf E Eur Heart J Suppl 2001;3(suppl E):E17-E23; Miettinen TA Int J Clin Pract 2001;55:710-716; Stein E Eur Heart J Suppl 2001;3(suppl E):E11-E16.
• In co-administration therapy with statins– Inhibits cholesterol absorption in the intestine and
biosynthesis in the liver (dual inhibition)– Achieves lipid reductions greater than those with statins
alone
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• Is useful as monotherapy for patients intolerant or
nonresponsive to statins or enhanced benefits in
addition to statins
• Favorable safety and tolerability profile shown in
clinical trials
– similar to placebo
– similar to statin alone, in coadministration
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Omega 3 fatty acidsThe AHA recommends 2 to 4 g/day of
eicosapentaenoic acid plus docosahexaenoic acid
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Herbs/Natural ProductsHerbs/Natural Products
• Garlic• Fish Oils• Red Yeast Rice• Dietary Fiber• Oat Bran• Plant Sterols• Guggul• CoEnzyme Q10