Lipid lowering agents

Question 1

What is the MOA of statins?

Answer 1

Inhibits hepatic HMG-CoA reductase which causes intracellular cholesterol to decrease–> increases LDL-R expression–> increases hepatic uptake of LDL-C–> lowers LDL-C by increased uptake
- Also, by lowering intracellular cholesterol this decreases VLDL and TGs

Question 2

How effective are statins?

Answer 2

VERY effective= first line tx for dyslipidemia
Lowers LDL-C (30-60%), lowers TGs (35-45%), increases HDL-C (5-15%)

Question 3

What are side effects of statins?

Answer 3

Hepatotoxicity, skeletal muscle toxicity (myalgia, myopathy, myositis, rhabdomyolysis)
Note: factors that increase SKM toxicity include higher doses, drugs that lower hepatic uptake or metabolism, low thyroid hormone levels, and low vitamin D levels

Question 4

T/F: We should get baseline LFTs and CK before putting a patient on a statin

Answer 4

True

Question 5

What drug is a cholesterol absorption inhibitor?

Answer 5

Ezetimibe

Question 6

What is the MOA of cholesterol absorption inhibitors (ezetimibe)?

Answer 6

Inhibits intestinal NPC1L1 transporter which decreases absorption of cholesterol and lowers incorporation of cholesterol into chylomicrons–> decreases cholesterol delivery to the liver–> decreases intracellular cholesterol–> increases LDL-R expression–> increases hepatic uptake of LDL-C–> lowers LDL-C
Note: this drug also decreases intracellular cholesterol which increases HMG-CoA reductase which can attenuate LDL-C lowering action

Question 7

How effective are cholesterol absorption inhibitors?

Answer 7

Lowers LDL-C by 18-22%, lowers TGs by <2%, and increases HDL-C by <2%
- Not as effective BUT has minimal adverse effects

Question 8

What drugs are bile acid sequestrants?

Answer 8

Cholestyramine, colestipol, and colesevelam

Question 9

What is the MOA of bile acid sequestrants?

Answer 9

Binds BAs in the intestine–> increases fecal excretion of BAs–> decreases intracellular BAs–> increases BA synthesis–> lowers intracellular cholesterol–> increases LDL-R expression–> increases hepatic uptake of LDL-C–> lowers LDL-C
Note: also lowers intracellular cholesterol which can increase HMG and attenuate LDL lowering action

Question 10

How effective are BA sequestrants?

Answer 10

Lowers LDL-C (15-25%), increases TGs (3-10%), increases HDL-C (<5%)
- Not as effective and actually increases triglycerides

Question 11

What are general adverse effects seen with BA sequestrants?

Answer 11

Normally well tolerated and safe because not absorbed systemically but can have GI effects: bloating, constipation, nausea, and flatulence
Note: can affect GI absorption of other drugs and fat-soluble vitamins

Question 12

What is the MOA of PCSK-9 inhibitors (alirocumab, evolocumab)

Answer 12

Monoclonal antibody to PCSK-9 (a protein released by hepatocytes that binds to LDL-Rs and promotes degradation of them). Leads to increased hepatic LDL-R expression–> increased hepatic uptake of LDL-C–> lowers LDL-C

Question 13

How effective are PCSK-9 inhibitors?

Answer 13

Really effective but have to be given as SC injection (lowers LDL-C by 70%)

Question 14

Nicotinic acid MOA?

Answer 14

Activates niacin receptors (Gi) on fat cells–> lowers HSL–> lowers lipolysis–> decreases release of fatty acids–> lowers hepatic TG synthesis–> decreases VLDL–> lowers LDL-C
Note: it is taken up by the liver and inhibits TG synthesis

Question 15

How effective is niacin?

Answer 15

Lowers LDL-C (20-30%), lowers TGs (35-40%), and increases HDL-C (30-40%)
- Really effective at lowering TGs!!

Question 16

What are adverse effects seen with niacin?

Answer 16

Flushing, itching, dyspepsia, headache (bc increased PGs), hepatotoxicity, hyperglycemia, hyperuricemia

Question 17

T/F: Niacin should be given with statins to reduce skeletal muscle toxicity risk

Answer 17

False, niacin can actually increase the risk of skeletal muscle toxicity if combined with statins

Question 18

What is the MOA of fibrates? (fenofibrate, gemfibrozil)

Answer 18

Activates PPARa receptors which increase LPL–> increases clearance of TG rich VLDL and chylomicrons–> decreases VLDL and may increase LDL-C
Note: has complex effects on apoproteins and increases fatty acid oxidation which leads to decreased hepatic VLDL secretion

Question 19

How effective are fibrates?

Answer 19

LDL-C (variable and may only increase a little), lowers TGs (up to 50%), increases HDL-C (up to 15%)
- Really good at lowering TGs!!

Question 20

What are adverse effects seen with fibrates?

Answer 20

GI (dyspepsia, abdominal pain, diarrhea, constipation, increased risk of gallstone formation, increased risk of skeletal muscle toxicity if combined with statins (esp gemfibrozil)