Module 12: Drugs to Lower Blood Cholesterol & Triglycerides

Question 1

When does coronary heart disease occur?

Answer 1

Coronary heart disease occurs when coronary blood circulation fails to adequately supply the heart with blood

Question 2

What primarily causes coronary heart disease?

• How does it occur?
• What does it cause?

Answer 2

Coronary heart disease is primarily caused by atherosclerosis
- Atherosclerosis occurs when plaque builds up on the walls of the arteries - This causes the artery to narrow and results in decreased blood flow to the heart

Question 3

What is the risk of developing coronary heart disease?

- Who is at risk?

Answer 3

The risk of developing coronary heart disease is directly related to the levels of cholesterol in the blood
- Therefore people with high blood cholesterol are at risk of developing coronary heart disease

Question 4

Why is cholesterol important?

- What is it an essential component of?

Answer 4

Cholesterol is an important molecule that supports many physiological roles.
- It is an essential component of cell membranes, a precursor of steroid hormones (i.e. testosterone and estrogen) and a precursor of bile salts

Question 5

How do we obtain cholesterol?

- Where is it synthesized?

Answer 5

We obtain cholesterol through dietary sources (exogenous cholesterol) or through synthesis (endogenous cholesterol) which occurs primarily in the liver
- Approximately 80% of the cholesterol in the body is synthesized by the liver, whereas 20% is obtained from dietary sources

Question 6

T/F
Although cholesterol is an essential molecule for the reasons described above, high blood levels are linked to atherosclerosis and heart disease.

Answer 6

True

Question 7

What is the basic structure of lipoproteins?

- Outer layer vs. Core

Answer 7

The outer hydrophilic shell is made up of phospholipids
- This allows lipoproteins to be soluble in plasma

In contrast, the core is composed of lipophilic cholesterol and triglycerides.

Question 8

What is the primary function of lipoproteins?

- What do they require to be soluble in blood?

Answer 8

The primary function of lipoproteins is to transport cholesterol and triglycerides in the blood
- Since cholesterol and triglycerides are lipophilic, they require lipoproteins in order to be soluble in the blood.

Question 9

Where are apolipoproteins embedded?

- What is the function (3)?

Answer 9

All lipoproteins also have apolipoproteins embedded in the phospholipid shell. Apolipoproteins have three functions:

1. Allow recognition by cells which may bind and ingest lipoproteins.
2. Activate enzymes that metabolize lipoproteins.
3. Increase the structural stability of lipoproteins.

Question 10

What do lipoproteins containing apolipoprotein A-I vs. B-100 transport?

Answer 10

Lipoproteins that contain apolipoprotein A-I transport cholesterol from non-hepatic tissue back to the liver.

Lipoproteins that contain apolipoprotein B-100 transport cholesterol to non-hepatic tissue.

Question 11

Where do low density lipoproteins deliver cholesterol to?

Answer 11

LDL’s deliver cholesterol to non-hepatic tissue.

Question 12

Structure of LDL’s?

Answer 12

Have a cholesterol rich core and account for 60 – 70% of the cholesterol in blood.

LDL particles contain one apolipoprotein B-100 molecule, which allows them to bind to cells and transfer their lipid (mostly cholesterol) to cells

Question 13

T/F

There is no clear link between LDL cholesterol and development of atherosclerosis.

Answer 13

False
There IS a clear link between LDL cholesterol and development of atherosclerosis
- The higher the blood LDL level, the greater the risk of developing coronary heart disease

Question 14

What does reducing blood LDL levels do in relation to artherosclerosis?

Answer 14

Reducing blood LDL levels halts or even reverses atherosclerosis and has been proven to decrease death from coronary heart disease.

Question 15

What is LDL often referred to as?

Answer 15

Because of the role it plays in coronary heart disease, LDL cholesterol is often referred to as “bad cholesterol”

Question 16

Where do high density lipoproteins deliver cholesterol to?

- What does it promote?

Answer 16

HDL’s deliver cholesterol from non-hepatic tissue back to the liver.
- Therefore, HDL’s promote cholesterol removal from the blood.

Question 17

Structure of HDL’s

Answer 17

Similar to LDL, HDL’s have cholesterol as their main core lipid and account for 20 – 30% of total blood cholesterol

HDL particles may contain multiple apolipoproteins including A-I, A-II and A-IV
- The A-I apolipoprotein is believed to mediate the beneficial effects of HDL cholesterol.

Question 18

What is the effect of HDL on coronary health disease?

Answer 18

The effect of HDL on coronary heart disease is opposite to that of LDL.
- Therefore, elevated HDL decreases the risk of coronary heart disease.

Question 19

What is HDL often referred to?

Answer 19

Since HDL cholesterol protects against atherosclerosis, it is often referred to as “good cholesterol”.

Question 20

What do LDL’s promote?

- Describe the steps (7):

Answer 20

LDL’s promote the initiation of atherosclerosis.

Steps:

1. Atherosclerosis is initiated when LDL’s move from the blood into the sub-endothelial space of the arterial epithelium.
   - In the sub-endothelial space LDL’s may become oxidized, a crucial step in the initiation of atherosclerosis.
2. Oxidation of LDL cholesterol causes recruitment of monocytes (a type of immune cell) to the sub-endothelial space.
3. Monocytes are then converted to macrophages.
   - Macrophages are another type of immune cell that are capable of “ingesting” foreign material.
4. Macrophages then take up oxidized LDL
   - During this process they become larger and vacuolated
   - In this form they are referred to as foam cells.
5. As more foam cells accumulate beneath the epithelium, a fatty streak appears
6. This is followed by platelet adhesion, smooth muscle migration and collagen synthesis.
7. The end result is an atherosclerotic lesion characterized by a lipid core and a tough fibrous plaque.

Question 21

T/F
Although LDL cholesterol plays a critical role in the development of atherosclerosis, it is important to note that atherosclerosis is PRIMARILY an inflammatory process

Answer 21

True
- LDL penetration of the arterial wall can be thought of as causing a mild injury to the arterial endothelium. It is the subsequent inflammatory response (i.e. monocyte/macrophage infiltration) that that mediates the development of atherosclerosis.

Question 22

Who is cholesterol screening generally recommended for?

- What about regardless of age (6)?

Answer 22

In Canada cholesterol screening is recommended for all males over the age 40 and all females over the age of 50 or females that are post-menopausal.

Other:

• have diabetes
• have heart disease or a family history of heart disease
• have hypertension
• have central obesity: a waist circumference greater than 102 cm (40 inches) for men and 88 cm (35 inches) for women
• smoke or have recently stopped smoking
• have inflammatory (i.e. arthritis, lupus) or renal disease

Question 23

How is cardiovascular risk assessed?

• What does is use?
• What does it represent?

Answer 23

The most commonly used form of cardiovascular risk assessment is called the Framingham Risk Score (abbreviated FRS)
- The Framingham Risk Score uses gender, age, total blood cholesterol, smoking status, HDL cholesterol and systolic blood pressure in a formula to calculate a risk score

The risk score represents the patient’s 10 year risk of developing coronary heart disease
- Patients with a Framingham 10 year risk score greater than 20% are considered high risk, between 10-19% are considered moderate risk and a score below 10% is considered low risk

Question 24

T/F
It is important to note the Framingham score has been shown to overestimate risk in youth, women and patients with metabolic syndrome.

Answer 24

False
- It is important to note the Framingham score has been shown to UNDERESTIMATE risk in youth, women and patients with metabolic syndrome.

Question 25

What is metabolic syndrome?

Answer 25

Is a combination of medical disorders that cause increased risk of coronary heart disease and type II diabetes.

Question 26

Metabolic syndrome is diagnosed when patients have three or more of (5):

Answer 26

1. Central obesity – Waist circumference > 102 cm (40 inches) for men or 88 cm (35 inches) for women 2. Elevated triglycerides – Blood triglycerides > 1.7 mmol/L 3. Low HDL cholesterol - HDL cholesterol < 1.03 mmol/L in men or 1.29 mmol/L in women. 4. Hyperglycemia – Fasting blood glucose > 5.6 mmol/L. 5. Hypertension – Blood pressure > 135/85 mmHg

Question 27

How is metabolic syndrome treated?

Answer 27

Treatment of metabolic syndrome is targeted at decreasing the risk for coronary heart disease and type II diabetes.

Question 28

Estimates suggest that ___ in four Canadians have metabolic syndrome

Answer 28

One

Question 29

What are 4 types of non-drug treatment of LDL cholesterol?

Answer 29

1) Diet – Modification of diet is targeted towards decreasing LDL cholesterol and establishing a healthy body weight. - Dietary recommendations suggest intake of less than 200 mg/day of total cholesterol and intake of saturated fats of 7% or less of total calories. - Further recommendations suggest the intake of soluble fiber of 10 – 25 grams/day and plant stanols and sterols of 2 grams/day. 2. Weight Control – Obesity is one of the leading causes of heart disease in Canada and the USA. - In most people this is a modifiable risk factor. Weight loss by dietary modification and exercise lowers LDL cholesterol and decreases the risk of coronary heart disease. 3. Exercise – More and more Canadians are living sedentary lifestyles making the need for regular exercise greater than ever. - Cardiovascular exercise has many benefits which include decreasing LDL cholesterol, elevating HDL cholesterol along with decreasing insulin resistance and blood pressure. - Recommendations suggest that all people should exercise for between 30-60 minutes per day. 4. Cigarette Smoking – Smoking cigarettes decreases HDL cholesterol and increases LDL cholesterol therefore increasing risk of coronary heart disease. - Smoking has been called the “leading preventable cause of death and disease” and is an especially important risk factor in younger (under 50) men and women. - All patients should be counselled to quit smoking.

Question 30

T/F | Drug therapy IS the first line treatment for elevated LDL cholesterol

Answer 30

False Drug therapy is NOT the first line treatment for elevated LDL cholesterol - The primary treatment for high LDL cholesterol is lifestyle changes including modification to diet, weight, exercise plan and smoking status.

Question 31

When is drug treatment initiated to treat elevated drug lipids?

Answer 31

When target cholesterol levels are not achieved by lifestyle changes, drug treatment is initiated.

Question 32

Classes of drugs used to treat elevated blood lipids include:

Answer 32

1. Statins 2. Bile Acid Sequestrants 3. Nicotinic Acid 4. Cholesterol Absorption Inhibitors 5. Fibric Acid Derivatives

Question 33

What is a statin?

Answer 33

HMG-CoA Reductase Inhibitors

Question 34

Statins: Cholesterol Synthesis - Occurs where? - Pathway? - When is it greatest?

Answer 34

Approximately 80% of total body cholesterol is synthesized in the liver. Hepatic cholesterol synthesis occurs in what is known as the mevalonic acid pathway: 1) In this pathway, acetyl CoA (from the citric acid cycle) is converted to 3-hydroxy-3-methylglutaryl CoA (HMG CoA). 2) HMG CoA is then enzymatically converted to mevalonic acid by the enzyme HMG CoA Reductase. 3) After several other enzymatic steps, cholesterol is formed. 4) Conversion of HMG CoA into mevalonic acid is the rate-limiting step in cholesterol synthesis. Cholesterol synthesis is greatest during the night.

Question 35

Statins: Mechanisms of Action - What do they decrease? - What does the mechanism cause? - Net effect?

Answer 35

Statins decrease the hepatic synthesis of cholesterol by inhibiting the enzyme HMG CoA reductase, the rate-limiting step of cholesterol synthesis. Through complicated mechanisms (beyond the scope of this course), inhibition of HMG CoA reductase causes an upregulation of hepatic LDL receptors. - This allows the liver to remove more cholesterol from blood. The net effect is a decrease in LDL cholesterol blood levels.

Question 36

What are the three benefits of statins?

Answer 36

1. ↓LDL cholesterol 2. ↑HDL cholesterol 3. ↓ Triglycerides

Question 37

Statins: Primary Prevention Studies - Target? - Prevents? - Decrease incidence of?

Answer 37

- Primary prevention is targeted at preventing the development of cardiovascular disease. - Statins are effective in the primary prevention of coronary heart disease. - Multiple recent studies have shown that statins decrease the incidence of coronary events (i.e. heart attack and stroke) even in low risk patients with no history of coronary heart disease.

Question 38

Statins: Secondary Prevention Studies - Aim? - Prevents?

Answer 38

Secondary prevention aims to prevent the recurrence of cardiovascular events. - For example, preventing a patient who has had a heart attack from having another heart attack. Statins are effective drugs for preventing recurrent cardiovascular events in higher risk patients.

Question 39

T/F Due to their remarkable ability to prevent the onset and progression of cardiovascular disease, statins are among the highest prescribed drugs in the world

Answer 39

True - In fact, atorvastatin (Lipitor) is the highest prescribed drug in Canada and the USA, while rosuvastatin (Crestor) is the 4th highest prescribed drug in Canada.