Clinical Lipidology

Question 1

What is the structure of lipoproteins?

Answer 1

1. Macromolecular structures that carry various lipids and proteins in plasma 2. Particle core consists of a mix of triglycerides (TG) and Cholesteryl Ester 3. Covered by a monolayer of amphipathic (both hydrophobic and hydrophilic) phospholipids and smaller amounts of free cholesterol 4. Apolipoproteins on surface perform different functions and give unique identity

Question 2

What is the composition of lipoproteins?

Answer 2

Concentrations of cholesterol and triglycerides will very between the lipoproteins which impacts relative size and density

Question 3

Explain Apolipoprotein B (ApoB)?

Answer 3

1. Mediates the interaction between LDL and the arterial wall 2. Component of all lipoprotein particles considered atherogenic a. Low Density Lipoprotein (LDL) b. Intermediate Density Lipoprotein (IDL) c. Very Low Density Lipoprotein (VLDL) d. Chylomicron Remnants e. Lipoprotein (a) aka Lp(a) 3. One molecule of ApoB is on each particle; therefore an ApoB measurement can be used to assess the number of atherogenic particles (e.g., LDL particle number). However, the amount of cholesterol on each particle is variable. Thus ApoB is superior to the LDL-C value for estimating the plasma concentration of LDL particles

Question 4

Explain Apolipoprotein A1?

Answer 4

1. Major apolipoprotein of High Density Lipoprotein (HDL) a. Involved in Reverse Cholesterol Transport b. Considered protective or antiatherogenic

Question 5

Explain Role of Lipoproteins in the Development of Atheroma

Answer 5

A. Retention of ApoB containing lipoproteins is critical to the early stages of atheroma formatioin 1. ApoB lipoprotein particles enter the intima and are retained, 2. Retained lipoprotein particles are likely modified (e.g. oxidized) 3. Monocytes are attracted to the artery wall. 4. Monocytes enter and turn into macrophages. 5. Macrophages ingest lipids and become foam cells. 6. Other immune cells enter. 7. Immune cells are activated. 8. Inflammatory cytokinies, chemokines, proteases, and free radicals cause further tissue damage. 9. Process-of-retention and response-to-retention eventually lead to atheroma formation B. Lower levels of circulating ApoB lipoproteins lower the probability of inflammatory response to retention.

Question 6

What are triglycerides? what are they used for? are they atherogenic? Associated with what changes that are risk factors for atherosclerosis?

Answer 6

A. Essential energy source for the body B. Comprised of 3 fatty acids attached to a glycerol backbone. C. Debated whether triglycerides themselves are atherogenic D. Clearly associated with a number of metabolic or physiologic changes that are risk factors for atherosclerosis 1. Increased VLDL cholesterol rich remnants 2. Low HDL-C 3. Small, dense LDL 4. Increased chylomicron remnants 5. Coagulation changes

Question 7

What are the triglyceride risk categories? Risk of CAD?

Answer 7

E. Triglyceride Risk categories 1. Normal < 150 mg/dl 2. Borderline high 150-199 mg/dl 3. High 200-499 mg/dl 4. Very high > 500 mg/dl F. Relative risk of CAD is linear at even levels between 50 mg/dl to 150 mg/dl

Question 8

What is the role of HDL cholesterol?

Answer 8

Role of HDL Cholesterol A. Low HDL-C is a strong independent predictor of CHD B. The lower the HDL-C level the higher the risk for atherosclerosis and CHD C. HDL cholesterol tends to be low when triglycerides are high

Question 9

What is the significance of non-HDL cholesterol?

Answer 9

A. Represents a reasonable surrogate marker of ApoB B. Inexpensive – just a simple calculation: Total cholesterol minus HDL cholesterol C. Encompasses all known and potential atherogenic lipid particles D. Correlates closely with obesity and especially visceral adiposity E. Stronger predictor of cardiovascular death than LDL-C F. Recommended as a secondary target for persons with TG > 200 mg/dl G. Non-HDL-C goal is 30 mg/dl higher than LDL-C goal

Question 10

What are the treatment guidelines for hyperlipidemia?

Answer 10

A. LDL-C is a traditional primary target of lipid-lowering therapy 1. Multiple lines of evidence (animal studies, epidemiology, genetic forms of hypercholesterolemia, and controlled clinical trials indicate a strong causal relationship between elevated LDL-C and CAD (coronary artery disease) 2. Both National and International Guidelines list LDL-C as the primary modifiable lipid risk factor: a. Optimal LDL-C defined as less than 100 mg/dl b. More intensive LDL targets are recommended for patients with all forms of clinical atherosclerotic disease (CAD, PAD, carotid artery disease) (1) Reduce LDL-C below 70 mg/dl (2) Reduce Non-HDL to below 100 mg/dl (3) Recent meta-analysis suggests LOWEST IS BEST with a 22% event reduction per each 40 mg/dl LDL reduction with further benefit as low as 20 mg/dl B. Non-HDL is increasing mentioned in Guidelines as a preferred or at least a secondary target of therapy Emerging risk factors (e.g. homocysteine, lipoprotein(a) and hs-CRP) 1. Can help guide intensity of risk reduction therapy 2. Do not categorically alter LDL-C goals

Question 11

Explain dietary cholesterol and CAD?

Answer 11

1. Complicated issue a. Not everyone is a “responder” to high cholesterol feeding b. Diets high in saturated fat often have high cholesterol 2. Studies have shown atherogenic role for elevated dietary cholesterol independent of serum cholesterol change 3. Two prospective cohort studies do not show increased risk from egg consumption in healthy individuals a. Consumption of up to 1 egg/day okay for most b. Not significant impact on risk of CHD or stroke c. Exception: Diabetics who have increased risk

Question 12

What should be the focus of diet therapy? why?

Answer 12

LDL-C should be primary focus of dietary therapy 1. High LDL-C initiate atherogenesis 2. High LDL-C promote it at every stage 3. LDL-C lowering therapy reduces CAD risk a. At highest risk, lowers total/CHD deaths b. Even in late stages of atherogenesis 4. Populations devoid of elevated LDL a. Low prevalence of CHD even though other risk factors are common b. Japanese in 7 Countries Study with 9%

Question 13

Explain the Mediterranean diet?

Answer 13

Mediterranean Diet 1. Components of Mediterranean diet that benefit endothelial function a. Antioxidant-rich foods (1) Vegetables (2) Fruits (3) Vegetable and fruit derivatives (eg, vinegar) b. Omega-3-rich oils (1) Canola oil (2) Fish oil 2. Lyon Diet Heart Study a. Included many dietary changes in a ”Mediterranean style diet” (1) Specifically increased n-3 fatty acids in diet (2) More fish (3) More dietary fiber (4) More monounsaturated fatty acids (olive oil – highest MUFA; canola) (5) Low in saturated fatty acids (6) Low in saturated fat, cholesterol (7) Less meat, butter, cream (8) Not more alcohol b. Compared to AHA Step 1 diet c. Demonstrated significant improvement in survival with the experimental diet that occurred early and was not explained by lipid changes in the two groups

Question 14

What do trans-fats do in large amounts? Sources of dietary trans fats?

Answer 14

1. When consumed in high amounts a. Increased LDL-C b. Decreased HDL-C 2. Major Sources of Dietary TFA a. Baked goods (cookies, donuts, biscuits, pies) b. Snack foods (crackers, chips) c. Stick margarine, shortening (fries, fried foods) 3. Nurses’ Health Study a. Large scale observational study b. Demonstrated linear relationship between TFA intake and risk of CHD

Question 15

Explain carbs: simple, complex?

Answer 15

1. Simple carbohydrates a. White, refined and processed carbs contain very little fiber and are enriched b. Increases insulin resistance, insulin levels, blood sugar, triglycerides, body fat c. High Glycemic Index diets are associated with increased risk of CAD 2. Moderating sugar intake a. Use less added sugar b. Limit soft drinks, sugary cereals, candy c. Choose fresh fruits or those canned in water or juice 3. Complex carbohydrates a. Sources (1) Grains, especially whole grains (2) Legumes (3) Vegetables 4. Viscous Fiber a. Sources (1) Oats, barley (2) Pectin-rich fruits and vegetables b. Lipid lowering benefits beyond those achieved by reductions in total and saturated fat alone c. Trials have demonstrated decreased risk of CAD with increased fiber intake

Question 16

What do plant sterols/stanols do? Negative aspects?

Answer 16

1. Mechanism: reduce cholesterol absorption by up to 65% 2. Efficacy a. Can lower LDL-C by 10-15% b. LDL-C lowering may be better in older adults c. No fat malabsorption d. Effect is additive to statins 3. Negative Aspects a. Expense b. Preference – some don’t like to use margarine c. Decrease in carotenoids in some studies (1) Adjust by adding increased fruits, veggies in diet

Question 17

Explain Fish and Fish oil use?

Answer 17

1. DART Trial (Two meals of fish/wk) a. Death and recurrent MI lower earlier in trial b. 25% used fish oil capsules if couldn’t eat fish c. Decreased total mortality by 29% 2. Seattle Case-Control Study of Sudden Death Survivors 3. GISSI Prevenzione Trial a. 1000 mg Fish Oil Capsules (875 EPA+DHA) b. Re-analysis shows early effect on sudden death (45% reduction) 4. Summary of Recommendations for Omega-3 Fatty Acid Intake a. Patients without documented CHD (1) Eat a variety of preferably oily fish at least twice a week. (2) Include flaxseed, canola and soybean oils, and walnuts b. Patients with documented CHD (1) Consume 1 gram of EPA+DHA per day (a) 2-3 oz salmon, sardines, mackerel per day (b) Low potency supplement (3 g/d) (c) High potency supplement (Omacor - 1 capsule daily) c. Patients needing triglyceride lowering (1) Two to four grams of EPA+DHA per day

Question 18

Nuts and chronic heart disease?

Answer 18

1. Nurses’ Health Study a. Significantly lowered CHD risk for those who ate > 5 oz. of nuts per month 2. Indo-Mediterranean Diet a. Significant reduction in fatal and non-fatal MI or sudden cardiac death

Question 19

Vitamins and Chronic heart disease? Recommendations?

Answer 19

1. Trials have failed to demonstrate consistent or significant effect of any single vitamin or combination of vitamins on the incidence of CHD 2. Recommended for pregnant women, alcohol consumers, or the elderly 3. Will provide higher intakes of folic acid and B vitamins a. May reduce homocysteine levels

Question 20

Alcohol and chronic heart disease?

Answer 20

1. Increases HDL in a dose-dependent manner 2. Increasing amounts lead to increasing total mortality 3. No difference between red and white wine in studies

Question 21

Mechanism of statins?

Answer 21

a. Blocks synthesis of cholesterol b. May have additional pleiotrophic benefits (1) Improves endothelial function (2) Atherosclerotic plaque stabilization (3) Inhibition of LDL-C oxidation (4) Reduces inflammation (hs-CRP) (5) Platelet inhibition and antithrombosis

Question 22

Efficacy of statins?

Answer 22

a. Most potent LDL-C lowering drug (decreases LDL-C 20%-60% depending on product and dose) b. Lowers triglycerides 10%-40% c. Increases HDL-C 3%-15%

Question 23

Side effects of statins?

Answer 23

a. Generally well tolerated b. At high doses may elevate LFTs (1%-2%) c. Myopathy (1) Myalgia – Muscle aches, soreness, or weakness (2) Myopathy – Myalgia with CK level >10,000 U/L (3) Rhabdomyolysis – An acute, potentially fatal disease of skeletal muscle that entails destruction of skeletal muscle as evidenced by myoglobinemia and myoglobinuria (a) Rare event (b) Risk factors include age, combination therapy, and CYP 450 drug interactions d. Only rare cases of toxicity e. No increases in total or non-CHD mortality

Question 24

Are statins effective? What is the rule of 6’s for statins?

Answer 24

4. Multiple major statin trials demonstrated significant reduction in coronary events 5. The Rule of 6’s a. Greatest LDL percentage reduction occurs with initial dose of statin b. Doubling of statin dose results in only an additional 6% reduction in LDL

Question 25

2013 ACC/AHA Cholesterol Guidelines define four major statin benefit groups what are they?

Answer 25

2013 ACC/AHA Cholesterol Guidelines define four major statin benefit groups a. Through a rigorous process based on evidence from randomized controlled trials (RCTs) and systemic reviews, four groups of individuals were identified for whom a reduction in atherosclerotic cardiovascular disease (ASCVD) events could be demonstrated with high-intensity statin therapy (1) Individuals with clinical ASCVD (acute coronary syndromes, or a history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin. (2) Primary elevations of LDL-C cholesterol (LDL-C) ≥190 mg/dl (3) Individuals 40-75 years of age with diabetes, and LDL-C 70-189 mg/dl without clinical ASCVD (4) Individuals without clinical ASCVD or diabetes, who are 40-75 years of age with LDL-C 70-189 mg/dl, and have an estimated 10-year ASCVD risk of 7.5% or higher

Question 26

what is high intensity statin therapy defined as? which patients should receive ASCVD?

Answer 26

c. High-intensity statin therapy is defined as a daily dose that lowers LDL-C by ≥50% and moderate-intensity by 30% to <50%. All patients with ASCVD should receive high-intensity statin therapy; or if not a candidate for high-intensity, should receive moderate- intensity statin therapy.

Question 27

explain the drug use in high, mid, and low intensity statin use?

Answer 27

Question 28

Explain the mechanism of action, efficacy and side effects of Ezetimibe?

Answer 28

1. Mechanism of action a. Selectively inhibits the intestinal absorption of cholesterol
2. Efficacy a. Reduces LDL 18%-20% in monotherapy b. Decreases triglycerides 8%-10% c. Raises HDL-C 1%
3. Side Effects a. Similar to that reported with placebo b. Should not effect liver function studies c. Isolated reports of myalgias or myositis

Question 29

What is the formulation of Ezetimibe?

Answer 29

a. Only one agent available by prescription (Zetia)
b. Only one dose (10mg/d)

Question 30

Combination therapy with a statin?

Answer 30

1. Statin with Ezetimibe a. Adding Ezetimibe to starting dose of statin results in the same LDL-C lowering as the maximal dose of statin in monotherapy

Question 31

Explain resins? may do what?

Answer 31

1. Nonsystemic
2. Reduces plasma LDL by decreasing absorption of bile acids which are the precursors of endogenous cholesterol
3. 16%-20% LDL-C reduction alone or in combination with statins
4. Colesevelam a. Pill form of resin b. Tolerability relatively good c. High pill burden may decrease compliance and reduce effectiveness
5. May paradoxically increase triglycerides

Question 32

Explain nicotinic acid mechanism, efficacy, and side effects?

Answer 32

1. Mechanism of action not fully understood
2. Efficacy a. Best drug for raising HDL-C b. Can reduce triglycerides c. Modestly lowers LDL-C
3. Side effects, including flushing, may limit use a. Niaspan better tolerated than over-the-counter niacin b. Flushing may be minimized by taking a regular-strength aspirin of ibuprofen about 30 minutes before taking Niaspan c. Take at bedtime with a low-fat snack d. Avoid spicy foods and hot or alcoholic beverages

Question 33

Explain the mechanism of action, efficacy, side effects and formulation of fibrates?

Answer 33

1. Mechanism of action a. Increases peripheral lipolysis b. Decreases hepatic TG production
2. Efficacy a. Decreases TG 20%-50% b. Increase HDL 6%-15% c. Variable effect on LDL
3. Side Effects a. GI upset b. Cholelithiasis c. Myositis d. Abnormal LFTs
4. Formulations
   a. Fenofibrate (1) Once daily dosing (2) Better absorption (3) Better LDL reductions than Gemfibrozil (4) Safer when used with statins in combination therapy
   b. Gemfibrozil (1) Available in a generic form (a) Less expensive (2) Needs to be taken twice daily (30 min before meals) (3) More frequent myopathy when combined with statins

Question 34

Explain PCSK9 Inhibitors (proprotein convertase subtilisin-kexin type 9 inhibitor) mechanism of action, efficacy, formulations, side effects?

Answer 34

1. Mechanism of Action a. LDL receptors are normally recycled back to the surface of the liver once they deposit their lipid in the hepatocyte for degradation b. PCSK9 is a regulatory protein that is secreted by the liver that irreversibly binds the LDL particle to the LDL receptor. c. The PCSK9 bound LDL receptor cannot escape from the lysosome and is degraded along with the LDL particle; thus the receptor is destroyed and cannot recycle back to the liver surface. d. PCSK9 inhibitors are human monoclonal antibody therapies that bind to PCSK9 when it is secreted and neutralizes it, so that it does not interfere with the recycling of the LDL receptor.
2. Efficacy a. Dramatic reductions in LDL-C of 45-70% which occur in addition to that already achieved with statin and non-statin therapy. b. ApoB reductions of 45% c. Non-HDL reductions of near 50% d. Median triglyceride reductions of approximately 12-20% e. Increase in HDL of 4-8% f. Reduction in Lp(a) of 27%
3. Formulations a. Evolocumab (Repatha – Amgen) b. Alirocumab (Praluent – Regeneron)
4. Adverse reactions a. Similar to placebo b. Rare localized injection site reactions and possible hypersensitivity c. Possibility of neutralizing antibodies – although none yet discovered with evolocumab therapy
5. Large clinical trials demonstrated significant reduction in coronary events with both available agents