Drugs Affecting Lipid Metabolism

Question 0

Which lipoproteins are considered “TG-rich”?

Answer 0

Chylomicrons (CMs), CM remnants, VLDL, IDL

Question 1

For every 30mg/dL lowered LDL, what’s the decreased risk for coronary artery disease?

Answer 1

Every 30mg/dL -> 30% reduction in risk.

Question 2

Primary goal in cholesterol therapy?

Answer 2

Lower LDL.

Decreasing TGs and non-HDL, and increasing HDL are secondary goals.

Question 3

Targets for LDL levels?

Answer 3

It depends.

< 100, or even <70 is good if patient has existing CHD or lots of risk factors.

Question 4

Normal TG levels?

Answer 4

< 150. In chylomicronemia, can be over 1000.

Question 5

Definition of low HDL?

Answer 5

<40 mg/dL… but perhaps the cutoff for women should be higher, as estrogen pushes up HDL.
(anybody noticing a trend in these studies neglecting women?)

Question 6

4 aspects of therapeutic life changes (TLC) for dyslipidemia? What does each affect?

Answer 6

Diet modification (lowers LDL, ...not sure about HDL)
Exercise (increases HDL)
Weight loss (increases HDL)
Avoiding alcohol (lowers LDL)

Question 7

3 classes of drugs used to lower LDL?

Answer 7

Statins
Cholesterol absorption inhibitors
Bile acid sequestrants

Question 8

Review: Mechanism of statins?

Problem with them?

Answer 8

HMG CoA reductase inhibition.

Problem: lots of important things are made from downstream metabolites, such as farnesyl-PP.

Question 9

So statins reduce cholesterol synthesis. What does that have to do with lowering LDL?

Answer 9

If hepatocytes don’t have enough cholesterol (and with a statin, they don’t), they upregulate LDLR to recover the cholesterol from circulating LDL.
Statins have few side effects because they don’t push cholesterol way down… they bring it back to “normal.”

Question 10

What does the rule of 6% with statins refer to?

What total reduction of LDL can be achieved with statins?

Answer 10

After the initial dose, each doubling of a dose of statins tends to reduce LDL by a further 6% (i.e. most of the effect is up front).
Statins can reduce LDL by 31-60%.

Question 11

What have meta-analysis shown to be the reduction in risk of major coronary events for every 40mg/dL reduction in LDL?

Answer 11

22% (probs not important to memorize… but just know that it’s a big effect)

Question 12

2 main adverse effects of statins?

Answer 12

Elevated liver transaminases (usually transient).

Muscle-related problems.

Question 13

Worst muscle problem caused by statins?

Answer 13

Rhabdomyolysis - muscle damage that leads to kidney damage.

Question 14

What do risk factors for statin-induced myopathy have in common?

Answer 14

They increase statin levels.

being old and frail, grapefruit juice, polypharmacy, etc.

Question 15

What’s the MoA of the cholesterol absorption inhibitor Ezetimibe?

Answer 15

Binds to the cholesterol transport NPC1L1, inhibiting cholesterol absorption in the small intestine.
(can be used in combo with statins… but data showing decreased CV events has not yet been produced)

Question 16

What do bile acid sequestrants do? Why does this lower cholesterol?

Answer 16

They cause bile acids to agglomerate, so they can’t be absorbed by the transporter IBAT1 (note that they don’t directly inhibit IBAT1).
If bile acids are excreted in feces, the liver has to shunt more cholesterol to bile acid production.

Question 17

Are BASs effective at lowering LDL?

When are they used?

Answer 17

Yeah… they lower LDL 15-25% in mono or combination therapy.
They’re used to augments statins, or when people are statin-intolerant.

Question 18

3 bile acid sequestrants (BASs)?

Answer 18

Cholestyramine
Colestipol
Colesevelam

Question 19

Adverse effects of BASs? (3 things)

Answer 19

They’re not absorbed, so don’t cause systemic effects.
But they do cause GI side effects: flatulence, nausea, constipation, bloating, heartburn.
Can interfere with drug absorption.
Can raise TGs. (?)

Question 20

If you don’t have functioning LDLR, will statins, CAIs, or BASs lower LDL?

Answer 20

Nope. Their mechanisms rely on the liver upregulating LDLR as a response to their activity.

Question 21

If drugs really aren’t working, how can you get somebody’s LDL down?

Answer 21

Apheresis

Question 22

How can you target PCSK9? (recall PCSK9’s function)

Answer 22

PCSK9 targets the LDLR for destruction.

It’s hard to hit with a small molecule, but anti-PCSK9 antibodies can be given SubQ every 2 weeks.

Question 23

How can apoB production be reduced?

Answer 23

Weekly subQ injection of a anti-sense oligonucleotide (mipomersen).

Question 24

Why would you want to inhibit MTP?

Answer 24

This protein loads TGs onto VLDL. If you inhibit it, there will be less LDL secretion.

Question 25

3 kinds of drugs that increase HDL / decrease TGs?

Answer 25

Fibrates
Omega 3 fatty acids (fish oils)
Nicotinic acids

Question 26

Fibrates MoA?

Does this affect CV outcomes?

Answer 26

Fibrates activate the transcription factor PPAR-alpha.
PPAR alpha leads to increased HDL, decreased VLDL production, increased VLDL clearance, and decreased LDL.

CV outcomes are mixed, but the best results are in people with high TGs.

Question 27

When do we use fibrates today?

Answer 27

In patients with very high TGs (>500) to prevent pancreatitis.
As an adjunct to statins in pts with elevated TGs.

Question 28

Fibrate adverse effects?

Answer 28

Generally well tolerated.
Elevated LFTs.
Myopathy/myopathy.
Some drug interactions…

Question 29

What are the primary omega-3 fatty acids thought to be beneficial?

Answer 29

EPA and DHA

Question 30

Utility of prescribing fish oils?

Answer 30

Outcome data for CV events isn’t really there, but it does reduce TGs (useful to prevent pancreatitis?).

Question 31

How does niacin lower cholesterol?

Answer 31

Reduces free fatty acid flux from adipose, and thus VLDL production.

Question 32

What limits niacin’s use for lowering cholesterol?

Answer 32

It works great at moving lipid levels in all the directions we want (including Lp(a)!)
Niacin causes a very uncomfortable flushing reaction in most of the patients taking it. (laropriprant helps prevent this..)
Hepatotoxicity is also a significant problem.
(making gout and diabetes worse are other concerns)

Question 33

Does CETB inhibition, which raises HDL, reduce bad CV outcomes?

Answer 33

Nope. In one study it made them worse.
(but… one might think that the increased HDL is a compensation to the inhibition of an enzyme necessary for HDL to function… so I don’t think this ends the HDL debate)