DYSLIPIDEMIA

Gambar. VLDL

Lipoproteins transport water-insoluble triglycerides and cholesterol through the bloodstream, and all lipoproteins have a structure similar to that shown for very low density lipoproteins (VLDLs). Triglyceride and cholesteryl ester are isolated within a bipolar layer of phospholipids and apolipoproteins. Most lipoproteins contain several apolipoproteins; VLDL contains apolipoproteins B-100, C-I, C-II, C-III, and E. LDL, which transports most of the cholesterol found in blood, contains only apo B-100.

Calculation of LDL cholesterol

LDL cholesterol is usually calculated rather than measured. The formula used is: LDL cholesterol = Total cholesterol (TG/5 + HDL cholesterol) This formula is accurate unless triglycerides are < 400 mg/dL, LDL cholesterol can also be measured directly.

Role of HDL in Atherosclerosis

HDL cholesterol, is anti-atherogenic; reverse cholesterol transport, that removes excess cholesterol from cells.

Low HDL cholesterol has been shown to increase the risk of CHD.
For every 5 mg/dL decrement in HDL, there is a 25% increased risk of myocardial infarction (MI). High levels of HDL cholesterol shown to be cardioprotective. The new National Cholesterol Education Program guidelines list an HDL cholesterol < 40 mg/dL as a risk factor for CHD.

Coronary Heart Disease Risk Based On LDL-C / HDL-C Gender

Men

Risk
One-half averge Average 2X Average 3X Average One-half averge Average 2X Average 3X Average

LDL-C/ HDL-C
1,00 3,55 6,25 7,99 1,47 3,22 5,03 6,14

Women

Framingham Heart Study

Physical Manifestations of Hyperlipidemia

1.

2. 3.

Xanthelasma: irregularly shaped, slightly raised, yellowishwhite lesions on the upper or lower eyelids that are cholesterol deposits in the skin. Tendinous xanthomas: deposits of cholesterol in the tendons. Eruptive xanthomas: deposits of cholesterol on the trunk and extensor surfaces of the extremities; they appear as painless papules with yellow centers and are seen in patients with severe hypertri-glyceridemia.

Physical Manifestations of Hyperlipidemia

Cond

4- Lipemia retinalis: change in color of the blood vessels in the retina from red to pink or white; This occurs when serum triglyceride levels exceed 1000mg/dL 5- Arcus cornealis: whitish ring seen around the cornea caused by lipid deposits in the periphery of the cornea.

Effect of Lifestyle Modification

Diet Decreased saturated fat (decrease LDL) Replacing saturated and trans unsaturated fats with unhydrogenated monounsaturated or polyunsaturated fats Recommended diet Dietary cholesterol <200 mg/d; total fat <30%; saturated fat <7% CHO (whole grains, fruits,veggies) 50-60% total calories Dietary fiber 20-30 g/d Protein 10-25 g/day Plant stanols/sterols 2 grams/day Effect of LDL lowering should be evident in 6-12 months Elevated BMI associated with decreased dietary response Referral to dietitian helpful

Exercise In a prospective study of 111 sedentary men and women with dyslipidemia randomized to different levels of exercise, decrease in VLDL TG and increase in LDL size observed. Increase in HDL and size and largest effect on LDL seen with high amount high intensity exercise Mechanisms of benefit: reduction in CETP, elevation in LCAT, reduced hepatic lipase and elevated LPL activity Possible effect on LDL particle size Moderate intensity exercise (3-4 mi/hr) for 30 minutes on most days of the week

Diet Supplements
Fish Oil (source of omega-3 polyunsaturated fatty acids) Salmon, flaxseed, canola oil, soybean oil and nuts At high doses > 6 grams/day reduces TG by inhibition of VLDL-TG synthesis and apolipoprotein B Possibly decreases small LDL (by inhibiting CETP) Several studies have shown lower risk of coronary events 2 servings of fish/week recommended?? Pharmacologic use restricted to refractory hypertriglyceridemia Number of undesirable side effects (mainly GI) Soy Source of phytoestrogens inhibiting LDL oxidation 25-50 grams/day reduce LDL by 4-8% Effectiveness in postmenopausal women is questionable Garlic Mixed results of clinical trials In combination with fish oil and large doses (900-7.2 grams/d), decreases in LDL observed Cholesterol-lowering Margarines Benecol and Take Control containing plant sterols and stanols Inhibit cholesterol absorption but also promote hepatic cholesterol synthesis 10-20% reduction in LDL and TC however no outcome studies AHA recommends use only in hypercholesterolemia pts or those with a cardiac event requiring LDL treatment Other agents include soluble fiber, nuts (esp. walnuts), green tea Overall a combination diet with multiple cholesterol-lowering agents causes much more significant LDL reductions

Measurement of Lipoproteins
Lipoprotein analysis 12-14 hours fasting TC and HDL-C can be measured fasting or non-fasting LDL-Cholesterol = Total cholesterol VLDL (1/5 TG)-HDL Validity depends on TG <400 mg/dL Measured directly if patients have profound hypertrig Errors in TC, HDL, and TG can affect values Non-HDL cholesterol= TC HDL-C All cholesterol in atherogenic lipoproteins incl LDL, Lipoprotein a, IDL, VLDL Acute phase response (i.e. MI, surgical trauma or infection) Can reduce levels of TC, HDL, LDL, apo A+B through impairment of hepatic lipoprotein production and metabolism Raise Lpa and TG Lipoprotein analysis should be done as outpatient one month after event

Screening Recommendations
Adult Treatment Panel III (NCEP) Fasting lipid profile at least once q 5 years for all persons 20 y.o. or older If non-fasting obtained and TC >200 or HDL <40, f/u panel recommended If no known CHD and serum LDL <160 (0-1 risk factors) or LDL <130 (2 or more risk factors) then re-screen in 5 years Borderline high cholesterol and <2 risk factors, re-screen in 1-2 years

Metabolic Syndrome
ATP III criteria: (3 or more)
Abdominal obesity (waist circumference >40 inches in men or >35 in women) Hypertriglyceridemia (TG>150 mg/dL) Low HDL <40 men; <50 women SBP >130 or DBP >85 Fasting glucose >110 mg/dL

Increased risk of DM and cardiovascular disease although there has been some controversy in the literature
Kuopio Ischemic Heart Disease Risk Factor Study: 1209 Finnish men (42-60 y.o.) without CVD, cancer or DM at baseline followed for 11.4 years. Results showed that CVD and all-cause mortality are increased in men with MS even in absence of CVD or DM at baseline

Dyslipidemia is atherogenic with low HDL, elevated TG, and small dense LDL Treatment Recommendations:
Weight reduction and exercise LDL goal is same as in patient w/o MS If LDL goal reached, then focus on TG if >200? Calculate non-HDL and goal is 30 above LDL goal Fibrates and nicotinic acid are good choices for elevated TG

1ry prevention trials to lowering cholesterol

1- AFCAPS/Text-CAPS showed that lovastatin decreased the risk of first acute major coronary event in men and women with: Average total cholesterol and, Average LDL cholesterol levels and, Below-average HDL cholesterol levels

1ry prevention trials to lowering cholesterol Contd

2- WOSCOPS showed that treatment with pravastatin : Reduced The incidence of MI and : Reduced death from cardiovascular causes in men with: - moderately high total cholesterol and - moderately LDL cholesterol level

2ndry prevention trials to lowering cholesterol

1- The Scandinavian Simvastatin Survival Study (48) randomized patients : With known CHD and moderately high cholesterol

to simvastatin versus placebo and found:

30% decrease in overall death and, 42% decrease in cardiovascular death. 2. The Cholesterol and Recurrent Events (CARE) study randomized patients with known CHD and average cholesterol levels to pravastatin versus placebo and found 24% decrease in risk of coronary event.

2ndry prevention trials to lowering cholesterol Contd

3. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study randomized patients with known CHD and broad range of cholesterol levels to pravastatin versus placebo and found 24% decrease in risk of coronary events.

Goals of lipid-lowering therapy

The National Cholesterol Education Program (NCEP)/Adult Treatment Panel (ATP) III in 2001 came out with its third report on the treatment of high blood cholesterol in adults (NCEP III). 2. This report focuses on LDL cholesterol as the primary goal of therapy and lists different LDL cholesterol goals based on an individual's risk factors. 0 or 1 risk factor: LDL cholesterol goal < 160 mg/dL > 2 risk factors: LDL cholesterol goal < 130 mg/dL Known CHD or CHD equivalents: LDL cholesterol goal < 100 mg/dL
1.

Cardiac risk factors

Cigarette smoking. Hypertension defined as a blood pressure (BP) = 140/90 mmHg or taking an antihypertensive medication. Low HDL cholesterol ( 40 mg/dL) Family history of premature CHD: - Age < 55 years in male first-degree relative - Age < 65 years in female first-degree relation Age: - 45 years in men - 55 years in women

What are CHD risk equivalents?

Certain patients have diseases = a coronary event. These diseases include: Diabetes Aortic aneurysm Symptomatic carotid artery disease Peripheral vascular disease Stroke Multiple risk factors

Are high triglycerides dangerous?

Triglyceride > 500 mg/dL risk of developing acute pancreatitis. It is not completely clear if high triglycerides are an independent risk factor for CHD. High triglycerides associated with low HDL and insulin resistance. Those with a very high triglycerides (> 500 mg/dL) should have triglyceride lowering as the primary goal of therapy. After the triglyceride level has decreased to < 500, the focus of treatment can be changed to LDL cholesterol goals.

Factors elevate triglycerides

Decreased insulin sensitivity (obesity, type II diabetes) Physical inactivity Hypothyroidism Cigarette smoking Alcohol Diseases: nephrotic syndrome, Cushing's syndrome Medications: estrogens, corticosteroids, retinoids, beta-blockers, cyclosporine, tamoxifen, diuretics Genetic disorders: familial combined hyperlipidemia, familial hyper-triglyceridemia

What can be done to lower cholesterol?

Therapeutic lifestyle changes (TLC) are recommended for all patients with high cholesterol. Pharmacologic therapy is used when TLC cannot lower cholesterol sufficiently.

What are therapeutic lifestyle changes?

1. Diet : a. Saturated fat: < 7% of total daily calories b. Monounsaturated fat: < 20% of total daily calories c. Total fat: 25-35% of total daily calories d. Total cholesterol: < 200 mg/day e. Carbohydrates: 50-60% of total daily calories f. Protein: about 15% of total daily calories g. Soluble fiber intake: 10-25 g/day

2. Weight loss 3. Increased physical activity

How does physical activity affect lipids?

Aerobic exercise: increases HDL cholesterol levels and decreases triglyceride levels. If exercise results in weight loss, LDL also decrease. However, the effect of exercise on LDL cholesterol is highly variable

Drugs Therapy for High Levels of LDL

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, known as "statins," are considered first-line therapy for treating high LDL cholesterol. HMG CoA, a substrate for cholesterol, and competitively inhibit the rate-limiting step in cholesterol synthesis.

Drugs Therapy for High Levels of LDL

Contd
The

statins currently on the market include atorvastatin , fluvastatin, lovastatin, pravastatin and simvastatin . Atorvastatin is the most potent, and fluvastatin is the least potent. If patients cannot take statins, other options include bile acid sequestrants or nicotinic acids.

Potential Side effects of Statins

Elevation AST, ALT, can occur and need to be monitored. If levels reach above two times normal, the dose needs to be decreased or the medicine discontinued. AST, ALT should be checked after 6 weeks of start of statin, then every 6 months Fewer than 1 % of patients taking statins will have an elevation in transaminases high enough to necessitate discontinuing the drug. Myopathy can occur, with elevations of creatinine phosphokinase (CPK).

Potential Side effects of Statins Contd

Patients who complain of muscle pain should have their CPK level checked, and, if elevated, the medicine should be discontinued. Myopathy is more common when statins are combined with fibrates or other drugs that inhibit or compete for the cytochrome enzyme (e.g., cyclosporine, macrolide antibiotics). Other more common side effects include gastrointestinal symptoms and muscle aches.

Effective Drugs in Treating High Triglyceride Levels

Fibric acid derivatives: increase fatty acid oxidation in liver and muscle, decreasing VLDL production. They can also increase the metabolic clearance rate of VLDL. These drugs can lower triglycerides from 20-50% and increase HDL cholesterol < 15%. Nicotinic acid (niacin): inhibits VLDL production in the liver. It lowers triglycerides by 20-50%. HMG CoA reductase inhibitors (statins) have a lesser effect, achieving a < 35% reduction in triglycerides.

Potential side effects of fibrates

Nausea,

abdominal
myopathy.

pain,

There is an increased risk of myopathy when fibrates are combined with statins

Potential side effects of nicotinic acid

With crystalline niacin, flushing occurs in> 90% of patients. This can be reduced by taking an aspirin about 30 minutes beforehand or by using NiaSpan, a relatively safe extendedrelease preparation of nicotinic acid. Nicotinic acid also can elevate blood glucose and uric acid and, Rarely, produces severe hepatotoxicity.