Lipid Lowering Agents

Question 1

What is the highest risk factor for a first MI?

Answer 1

Question 2

What form of cholesterol leads to athersclerosis?

Answer 2

Oxidized LDL

Question 3

Where is cholesterol mostly stored within the blood as its transported?

Answer 3

Lipoproteins

Question 4

What is the highest indicator for risk of coronary heart disease?

Answer 4

LDL-Cholesterol

Question 5

Statin mechanism

Answer 5

Statins can inhibit the production of cholesterol by inhibiting HMG-CoA (rate limiting step of cholesterol production) in the liver

1. Cholesterol biosynthesis - The liver creates extra LDL receptors on the outside of it’s membrane in order to bring more LDL out of the plasma, that brings LDL levels down
2. Geranylgeranyl-PP (GGPP) - inhibit the synthesis of other important isoprenoid intermediates such as GGPP. These GGPP’s (Rho Rock) are also important in cancer develoment.
3. Anti-cancer effect? Prevents metastasis

Question 6

How are Statin’s classified?

Answer 6

Estimate risk of athersclerotic disease in the next 10 years, and if risk is in a certain range or history of stroke/CAD

Question 7

Every 1% of LDL reduction is 1% reduction of what?

Answer 7

Coronary heart disease

Question 8

Side effect of Statins?

Answer 8

1. Statin associated muscle symptoms (SAMS): Myalgias, cramps, myopathy, clinical rhabdomyolysis (<1%)
2. Immune related (sensitivity) is extremely rare
3. Diabetes - Increases the risk of new onset diabetes (accelerates insulin resistance diabetes)

Goal is to start high dose, and titrate down based on how they can tolerate it

Question 9

Ezetimide

Answer 9

MOA: Works on the absorption of cholesterol, blocks NPC1L1 transporter that lowers LDL indirectly

INDICATIONS: Usually added on to a statin if needed because LDL is still high, very well tolerated and not a lot of side effects

Question 10

Nicotinic Acid

Answer 10

• *MOA**: 1. Lowers localization of free fatty acids (can’t produce triglycerides -> vLDL -> LDL)
  2. Raises HDL

SIDE EFFECTS: Poorly tolerated, itchy, flushing, etc.

Question 11

Bile Acid Sequestrants

Answer 11

MOA: Bind to bile, and prevents it from going back to the liver. So the liver makes more LDL receptors in attempt to get more, lowering LDL in the process.

SIDE EFFECTS: Designed to stay in the gut, so a lot of GI issues (constipation, diarrhea, bloating, etc.)

CONTRAINDICATIONS: If triglycerides are too high (>400mg/dl) than you can’t use these. A rebound increase in serum triglyceride concentrations occur. Relative contraindication >200mg/dl

Question 12

Fibrates

Answer 12

MOA: Inhibit lipoprotein lipase and work on lowering triglycerides and increasing HDL

INDICATIONS: People with high triglycerides

SIDE EFFECTS: GI related, gallstones with chronic use
Fenofibrate is okay to use with statin; Gemifibrozil contraindicated with statin that increases the risk of rhabdomyolysis

Question 13

PCSK-9 Mutations

Answer 13

Extracellular PCSK9 binds to LDL receptors, and promotes internalization and degradation in hepatocytes. If you didn’t have PCSK9, then you would have increased levels of LDL receptors that take up cholesterol in the blood

$$$$$$$$$ (Injections are about 10-20K/year)

Gain of function would decrease LDL receptors, and increase LDL-C
Familial hypercholesterolemia phenotype

PCSK9 Loss of function increases LDL receptors, and decrease LDL-C
Protected from CV disease