Consulting Physician & Cardiologist Critical Care Physician

HON. PHYSICIAN:

Saifee HospitalSir H. N. HospitalMotiben Dalvi Hospital

Lipids GuidelinesLipids Guidelines

The food that we eat is mixture of CarbohydratesProteinsFats (LIPIDS)FibresVitamins, minerals, etc

LIPIDSLipids are a heterogenous group of water –insoluble ( hydrophobic ) organicmolecules .

Lipids areMajor source of energy

Other function .Fat soluble vitamins have regulatory or

coenzyme function. Prostaglandin & steroid hormones

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.

The bowel has limited capacity for the uptake of cholesterol approximately 1500mg/ day,

but the uptake of the TG is unlimited .

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.

LIPID PROFILE

Total CholesterolTriglycerideHigh Density LipoproteinLow Density LipoproteinVery Low Density LipoproteinChylomicronsVarious Ratios

What is a Lipoprotein?

Protein

Lipo (Lipid)

++

Lipoprotein is a macro-molecular complex in blood carrying protected

lipids

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

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)

APOLIPOPROTEINSStabilize the Lipoprotein Structure.

Important regulatory function in LIPOPROTEIN metabolism.

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

Why is the study of Lipid important ?

C V D

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

When should we start examining Lipid profile ?

Adults > 20years of age & then every 05 years

Test children with a family history of premature CHD at age 2 years.

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

Primary PreventionPrimary prevention aims to prevent new

onset CHD

Primary PreventionandRisk Factor assessment

Categories of Risk FactorsMajor, independent risk factorsLife-habit risk factorsEmerging risk factors

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)

Life-Habit Risk FactorsObesity (BMI 30)Physical inactivityAtherogenic diet

Emerging Risk FactorsLipoprotein (a)HomocysteineProthrombotic factorsProinflammatory factorsImpaired fasting glucose Subclinical atherosclerosis

Diabetes

In ATP III, diabetes is regarded as a CHD risk equivalent.

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

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%

ATP III Lipid and

Lipoprotein Classification LDL Cholesterol (mg/dL)

<100 Optimal100–129 Near optimal/above

optimal130–159 Borderline high160–189 High190 Very high

ATP III Lipid and Lipoprotein Classification (continued)

HDL Cholesterol (mg/dL)

<40 Low60 High

ATP III Lipid and Lipoprotein Classification (continued)

Total Cholesterol (mg/dL)

<200 Desirable200–239 Borderline high240 High

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)

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

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

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

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

Exercise

Safety

Aerobic exercise> 20 minutes per activityAt least 3 days per week

Promotes weight loss and HDL

Smoking Cessation

Can lower oxidative stress

Reversal of endothelial dysfunction

HDL

Weight LossIncreases HDL

Improves glycemic control

Reduces blood pressure

DRUG THERAPY

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.

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

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.

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

• 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

Statin Adverse EffectsStatin Adverse Effects

• Major toxicities:

Hepatic transaminases

Myalgias

Rhabdomyolysis

• Selected minor adverse effects:

Dyspepsia/heartburn

Headache

Taste disturbances

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

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).

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

-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

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

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

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.

2nd Goal2nd Goal….. TG

…... Non HDL Cholesterol

Total Chol. = LDL + VLDL + HDL

Non HDL Chol =Total Chol – HDL = LDL + VLDL

Non HDL Cholesterol GoalNon HDL Chol Goal =

30 mg above LDL Goal

T GDiseases associated with High TG:

Type 2 diabetes mellitus, Chronic renal failure, nephritic syndrome, Hypothyroidism, should be looked for and treated.

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

T GTreatment options:1. Increasing dose of statin 2. Add Fibrate (Finofibrate is preferable)3. Add Nicotinic acid

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

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)

3rd GoalLow HDL-C (<40 mg/dL) is considered a

tertiary goal

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)

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

Medication that Raise HDLNiacinStatinsFIbratesEstrogen for womenAlpha blockersCETP inhibitorHDL mimetic or artificial HDLAPO A Milano

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%

HDLNiacin is drug of choice

It raises blood glucose level, but still can be used in diabetics with good control

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)

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

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.

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)

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

Bile Acid SequestrantsDrug Dose

Range

Cholestyramine 4–16 gColestipol 5–20 gColesevelam 2.6–3.8 g

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.

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

• 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

Omega 3 fatty acidsThe AHA recommends 2 to 4 g/day of

eicosapentaenoic acid plus docosahexaenoic acid

Herbs/Natural ProductsHerbs/Natural Products

• Garlic• Fish Oils• Red Yeast Rice• Dietary Fiber• Oat Bran• Plant Sterols• Guggul• CoEnzyme Q10