Lipid Guidelines - Dr. Ajay Kantharia

Consulting Physician & Cardiologist Critical Care Physician HON. PHYSICIAN : Saifee Hospital Sir H. N. Hospital Motiben Dalvi Hospital Lipids Guidelines

The food that we eat is mixture of Carbohydrates Proteins Fats (LIPIDS) Fibres Vitamins, minerals, etc

LIPIDS Lipids are a heterogenous group of water –insoluble ( hydrophobic ) organic molecules .

Lipids are Major 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 the brush border membrane of the intestinal mucosal cells. From the intestinal mucosal cells they are transported to the lymph >> thoracic duct into the circulation.

LIPID PROFILE Total Cholesterol Triglyceride High Density Lipoprotein Low Density Lipoprotein Very Low Density Lipoprotein Chylomicrons Various 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 Lipo proteins -Harper’s Biochemistry (2000),p 268 For utilization and storage in tissues,it is converted 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)

APOLIPOPROTEINS Stabilize the Lipoprotein Structure. Important regulatory function in LIPOPROTEIN metabolism.

Which Lipoproteins have which Apolipoproteins ? -Harper’s Biochemistry (2000),p 270 Apolipoprotein Lipoprotein Apo A-I/II/IV HDL,Chylo Apo C-I/II/III VLDL,HDL,Chylo Apo D HDL Apo 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,IDL Apo 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 CVA A Family History of CHD or PVD (especially before age 55 years or hyperlipidemia) Hypertension Diabetes mellitus Physical stigmata of hyperlipidermia Obesity (BMI > 28) Chronic Renal Disease Smoking 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 Testing Every 5 years from age 20 – 25 years to 60-70 years according to overall risk. Borderline cases – vary from 1 to 5 years For patients on treatment with Diet – Initially every 3 months then every 6 -12 months For patients on medication – initially every 6 – 8 weeks then every 3-6 months

Primary Prevention Primary prevention aims to prevent new onset CHD

Primary Prevention and Risk Factor assessment

Categories of Risk Factors Major, independent risk factors Life-habit risk factors Emerging risk factors

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

Life-Habit Risk Factors Obesity (BMI  30) Physical inactivity Atherogenic diet

Emerging Risk Factors Lipoprotein (a) Homocysteine Prothrombotic factors Proinflammatory factors Impaired fasting glucose Subclinical atherosclerosis

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

CHD Risk Equivalents Risk for major coronary events equal to that in established CHD 10-year risk for hard CHD >20% Hard CHD = myocardial infarction + coronary death

CHD Risk Equivalents Other clinical forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease) Diabetes Multiple risk factors that confer a 10-year risk for CHD >20%

ATP III Lipid and Lipoprotein Classification LDL Cholesterol (mg/dL) <100 Optimal 100–129 Near optimal/above optimal 130–159 Borderline high 160–189 High  190 Very high

ATP III Lipid and Lipoprotein Classification (continued) HDL Cholesterol (mg/dL) <40 Low  60 High

ATP III Lipid and Lipoprotein Classification (continued) Total Cholesterol (mg/dL) <200 Desirable 200–239 Borderline high  240 High

LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in Different Risk Categories Risk Category LDL Goal (mg/dL) LDL Level at Which to Initiate Therapeutic Lifestyle Changes (TLC) (mg/dL) LDL Level at Which to Consider Drug Therapy (mg/dL) CHD or CHD Risk Equivalents (10-year risk >20%) <100  100  130 (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 13 th 2004 NCEP ATP III update, high risk patient needs to achieve LDL-C<70 mg/dL Risk 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 Diet Reduced 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 Changes Nutrient Composition of TLC Diet Nutrient Recommended Intake Saturated fat Less than 7% of total calories Polyunsaturated fat Up to 10% of total calories Monounsaturated fat Up to 20% of total calories Total fat 25–35% of total calories Carbohydrate 50–60% of total calories Fiber 20–30 grams per day Protein Approximately 15% of total calories Cholesterol Less than 200 mg/day Total 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 activity At least 3 days per week Promotes weight loss and  HDL

Smoking Cessation Can lower oxidative stress Reversal of endothelial dysfunction  HDL

Weight Loss Increases HDL Improves glycemic control Reduces blood pressure

Drug Therapy The 5 most common clinical situations in which drug therapy is needed are elevated LDL-C; high levels of TGs (200 to 500 mg/dL) despite attainment of LDL-C goals; low HDL-C; diabetic dyslipidemia; and very high TGs and/or chylomicronemia syndrome.

Cholesterol-Lowering Drug Therapy HMG CoA Reductase Inhibitors Lovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin Rosuvastatin Cholesterol Absorption Inhibitors Ezetimibe Fibrates Gemfibrozil Micronized Fenofibrate Clofibrate Bile Acid Sequestrants Cholestyramine Colestipol Colesevelam Niacin

Statins Statins 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 Inhibitors 1.) LDL Uptake Cholesterol 2.) Synthesis HMG CoA Bile Acids Cholesterol HMG CoA Bile 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 - Dosing

Statin Adverse Effects Major toxicities:  Hepatic transaminases Myalgias Rhabdomyolysis Selected minor adverse effects: Dyspepsia/heartburn Headache Taste disturbances

Monitoring of Lipid Lowering Therapy 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 Myotoxicity 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 Effects -70 -60 -50 -40 -30 -20 -10 0 10 40 20 80 10 10 20 20 20 20 80 40 40 40 40 1 5 20 Atorvastatin Simvastatin Pravastatin Lovastatin Fluvastatin Rosuvastatin 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

Comparative HDL Effects -4 -2 0 2 4 6 8 10 12 Atorva Simva Prava Lova Rosuva 10 20 40 40 40 40 20 20 20 20 10 10 40 80 80 Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160 & CURVES Study. Am J Cardiol 1998;81:582-7. 10

Comparative TG Effects -35 -30 -25 -20 -15 -10 -5 0 5 10 40 20 80 10 10 20 20 20 20 80 40 40 40 40 Atorvastatin Simvastatin Pravastatin Lovastatin Rosuvaastatin Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160 & CURVES Study. Am J Cardiol 1998;81:582-7. 10

Drug 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

2 nd Goal 2 nd 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.

2 nd Goal 2 nd Goal….. TG … ... Non HDL Cholesterol Total Chol. = LDL + VLDL + HDL Non HDL Chol = Total Chol – HDL = LDL + VLDL

Non HDL Cholesterol Goal Non HDL Chol Goal = 30 mg above LDL Goal

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

Fibrates 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 Precautions 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)

3 rd Goal Low HDL-C (<40 mg/dL) is considered a tertiary goal

Major causes of Low HDL Heredity (40% to 60%) Elevated triglycerides Physical inactivity Cigarette smoking Diets rich in refined carbohydrates & trans – fats Certain B.P. medication (diuretics – B blockers)

Life style factors that Raise HDL Physical activity Weight loss Diet high in mono unsaturated fats eg. Lean meat, Avocado, nuts, olive oil Fish oil containing omega – 3 fatty acids Smoking cessation Small amounts of alcohol

Medication that Raise HDL Niacin Statins FIbrates Estrogen for women Alpha blockers CETP inhibitor HDL mimetic or artificial HDL APO 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%

HDL Niacin is drug of choice It raises blood glucose level, but still can be used in diabetics with good control

Niacin 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 - 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 - 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 Drugs Gastrointestinal-active medication such as a bile acid–binding sequestrant (the resins cholestyramine and colestipol, or colesevelam, a nonabsorbable polymer) Cholesterol-absorption inhibitor (e.g., ezetimibe)

Bile Acid Sequestrants 1.) LDL Uptake Cholesterol 2.) Synthesis HMG CoA Bile Acids Cholesterol HMG CoA Bile Acids Intestines Intestines

Bile Acid Sequestrants Drug Dose Range Cholestyramine 4–16 g Colestipol 5–20 g Colesevelam 2.6–3.8 g

Ezetimibe Ezetimibe 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 acids The AHA recommends 2 to 4 g/day of eicosapentaenoic acid plus docosahexaenoic acid

Herbs/Natural Products Garlic Fish Oils Red Yeast Rice Dietary Fiber Oat Bran Plant Sterols Guggul CoEnzyme Q10

Lipid Guidelines - Dr. Ajay Kantharia

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