Lipid Lowering Drugs

Question 1

HMG-CoA Inhibitors: Mechanism of Action

Answer 1

Inhibits HMG-CoA, the rate-limiting enzyme in the biosynthesis of LDL cholesterol in liver
Inhibition of LDL synthesis results in increased recycling of the LDL receptor (LDLR)
Increased LDLR enhances hepatic clearance of LDL and dramatically lowers serum LDL levels (some preparations also increase in HDL)

Question 2

HMG CoA Reductase Inhibitors

Answer 2

Lovastatin (Mevacor®)
Pravastatin (Pravacol®)
Simvastatin (Zocor®)
Fluvastatin (Lescol®/Lescol XL®)
Atorvasatin (Lipitor®)
Rosuvastatin (Crestor®)
Pitavastatin(Livalo®, Pitava®)

Question 3

Side Effects of HMG CoA Inhibitors

Answer 3

Hepatotoxicity:

• Mild elevation of LFT’s occurs approximately 2 % of time
• Severe hepatoxicity is rare and usually reversible with cessation of drug

Muscle Injury :

• Myositis is most common side-effect from depletion of mitochondrial ubiquinone
• Rhabdomyolysis is rare, but most serious complication and risk is increased when combined with other medications

Question 4

Drug Interactions with Statins

Answer 4

Cyclosporine
*Fibric Acid derivatives
Macrolide antibiotics
Ketoconazole

Increased risk with drugs metabolized via cytochrome P450 system

Question 5

PKSC9 Inhibitors Available

Answer 5

Alirocumab (Praulent®) produce a 47-61% reduction in LDL
Evolocumab (Repatha®) produce a 61-73% reduction in LDL
No CV outcomes yet
Only approved for those with FH

Question 6

Inhibitors of Cholesterol Absorption

Answer 6

Ezetimide

Ezetimibe Blocks Internalization of the NPC1L1/LDL Complex to decrease LDL absorption

Inhibits LDL absorption in the intestine
Results in decreased delivery of cholesterol to the liver, reduction in hepatic cholesterol stores and promoting increased plasma clearance of LDL

Question 7

Effectiveness of Ezetimide

Answer 7

Lowers LDL by 10-15 %
Lowers ApoB by 11-16%
Much more effective in combination with a Statin or Fibrate
**It possesses independent CV protection + additional cardioprotective effects when used in combination with statins
Are useful in avoiding higher doses of statins in patients with statin intolerance which helps achieve target LDL levels

Question 8

Side Effect of Ezetimide

Answer 8

Requires activation by liver and infrequently associated with elevated liver functions

Question 9

Mechanism of Action of Fibrates

Answer 9

PPAR-α Agonists

PPAR-α receptors are expressed in liver, adipose, heart and muscle which in turn inhibit lipolysis and stimulates HDL synthesis

Stimulates Lipoprotein Lipase activity
Reduces VLDL synthesis and lowers serum TG’s
Increase HDL levels by stimulating Apo A-I and Apo A-II synthesis

Question 10

Fibrates Available

Answer 10

Gemfibrozil (Lopid® & Trilipix®)
Trilipix® is a slow-release formulation of gemfibrozil
**Finofibrate (Tricor®) - safest to use with statins
Bezafibrate(Bezalip®)
Ciprofibrate(Modalim®)

Question 11

Side-Effects of the Fibrates

Answer 11

Myositis: rare when used as single agent

• Occurs more commonly when used in combination with high-dose “statins”
• Fenofibrate in combination with “statin” reportedly has a lower risk (Ticor)

Interferes with the clearance of warfarin & results in prolonged Pro Times/INR

GI upset (most common side-effect)

Question 12

Bile Acid Sequestrants: Mechanism of Action

Answer 12

Bind to bile salts and sequesters them in intestine resulting in inhibition of their entero-hepatic recirculation

Bile salts are made from cholesterol, so this drug depletes liver cholesterol thus lower LDL from circulation

Most effective when combined with a Statin which enhances statin-effect by an additional 8-10 %

Question 13

Bile Acid Compounds Available

Answer 13

Cholecystyramine (Questran®)
Cholestipol (Cholestid®)
Colesveleman (Welchol®)

Question 14

Side-Effects of Bile Acid Sequestrants

Answer 14

Abdominal bloating, cramps, and gas
Elevated LFT’s
Impaired absorption of fat soluble vitamins and many medications (these must be taken an 1 hr before or 2 hr after the sequestrants)

Question 15

Nicotinic Acid: Mechanism of Action

Answer 15

Receptor-mediated inhibition of lipolysis in adipocytes
Inhibition of HDL catabolism

Inhibit lipolysis
Reduction in hepatic TG’s and VLDL production, therefore lowering LDL
Increases LDL uptake by liver increasing peripheral HDL levels
Inhibits transfer of VLDL to HDL resulting in higher levels of HDL
Lowers Lp(a) and PAI-1 levels which decrease plasma fibrinogen levels & procoagulant state

Question 16

Effectiveness of Nicotinic Acid

Answer 16

No CV protective effect when taken with statins – only time use is patient that cannot take statins with low HDL and high TG

Question 17

Nicotinic Acid Preparations

Answer 17

Immediate Release Preparations: must be taken 3-4 times per day and most likely to cause side-effects!

Sustained Release Preparations
Niacor®
Niaspan®
Slow-Niacin®

Question 18

Cholesteryl ester transfer protein (CETP) Inhibitors

Answer 18

CETP is a plasma protein that facilitates the transport of cholesterol esters and TG’s from VLDL and LDL and attaches to HDL decreasing HDL concentrations
Pharmacologic inhibition of this enzyme results in much higher circulating HDL levels

Increases uptake of fat off HDL so HDL can get back into circulation

Question 19

Clinical Effects of CETP Inhibitors

Answer 19

40% decrease in LDL from baseline with 138% increase in HDL

Compounds have not passed clinical trials
The first med caused worsening CV effects, and the other two are still in testing

Question 20

Main Mechanism Targeted by Lipid Lowering Medications

Answer 20

In the hepatocyte, acetyl-CoA becomes HMG CoA reductase, which then binds LDL and makes cholesterol. Cholesterol can then make VLDL, bile acids, or be transferred to the intestine for elimination