• Hypercholesterolemia (lowering LDL) 

• Hypercholesterolemia 
• Hypertriglyceridemia
• Increasing HDL 

• Although niacin has shown to increase HDL.  This combination has no effect on mortality or morbidity 
• NOT approved by the FDA b/c there was an increased likelihood of myopathy

• Hypertriglyceridemia where VLDL is elevated

• Hypercholesterolemia w/NORMAL triglycerides

But their use is limited b/c of SE

• Block cholesterol absorption in the intestine

• HMG-CoA + HMG-CoA reductase→ mevalonic acid 
• Mevalonic acid → → cholesterol 

HMG-CoA redutase is the rate limiting step for the synthesis of cholesterol 

• Inhibition of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by being a structural analog of HMG-CoA intermediat.  Since HMG-CoA is an essential step in cholesterol synthesis, cholesterol synthesis in the liver decreases
• B/c synthesis decreases, the liver increases LDL receptors to uptake more cholesterol from the plasma, which results in a decrease in cholesterol 

• There is increasing evidence that is stating that mortality and morbidity are being reduced by statins through their anti-inflammatory actions, particularly in the vasculature
• MOA is unclear but does:

• Decreasing cholesterol (particularly LDL)
• If the primary problem is too much cholesterol, these are a good choice of treatment

• Decreases LDL by increasing LDL receptors in the liver 
• Often see a small decrease in triglycerides
• Often see a small increase in HDL cholesterol 

When do you use statins?

Outcome of patients on statins?

• Aggressive therapy in "high risk" populations
• If patient has 2 risks: Goal is to reduce LDL < 70 mg/dL  and without these risk factors the goal is < 130
• 25% reduction in stroke in high risk patients on statins
• NO reduction in brain hemorrhage 

• Hepatic damage in 1-2% (elevated hepatic enzymes) with possiblity of heptatis really low.  So monitor liver enzyme levles 
• Peripheral neuropathaties on discontinuation of the drugs.  This is reversible.
• Myalgia in 1-5% - myopathy in < 1% - rhabdomyolysis is rare. 

               -Monitor for myopathy more carefully when on fibrate because more                         frequent.  

               -Avoid combining with erythromycin, verapamil, diltiazem, grapefruit                               juice. 

• Rhabdomyolysis can cause acute renal failure 
• Lovastatin + simvastatin cross BBB = sleep disturbances 

• HMG-CoA inhibotrs also inhibit Q10 (ubiquinone). This is the most likely cause 

• Pregnancy:  B/c growing fetus requires cholesterol 
• Erythromycin; verapamil, diltiazem, grapefruit juice (avoid these b/c they decrease the metabolism of statins)

• Inhibits VLDL secretion → causes decreases in VLDL, LDL, and an increase in HDL 
• HDL is increased b/c rate of catabolism of HDL is decreased 

• Any lipoprotein disorder 
• Lipoprotein disorder w/mixed hyperlipidemia + elevated triglycerides especially

• Taken in gram quantities 
• This is not acting as a vitamin 

• Itching/flushing/unpleasant sensation of being warm 
• GI distress (may activate ulcers)
• Elevates transminase levels + may cause hepatitis (rare)
• Glucose intolerance- aggravates diabetes
• Inhibits urate secrtion- hyperuricemia in 20% patients 

MOA of itching/flushing in niacin?

How are you going to blunt this reaction?

What else can you do?

• MOA of itching:  Prostaglandin mediated
• Alleviate:  Aspirin (blunts but does not remove)
• Other:  Give inositol hexanicotinate instead of niacin

What is inositol hexanicotinate

Benefit?

Negative?

• It is inositol w/6-nicotinic acid moieties (slow release form of niacin)
• There is no flushing with this drug
• Efficacy is less well established than with niacin. 
• Increased dosing has increased likelihood of liver damage 

Gemfibrozil 

Fenofibrate

What is the use of gemfibrozil/fenofibrate

(these are fibrate derivatives)

• Lowering triglycerides (major effect)
• Elevating HDL (minor effect) 

MOA of gemfibrozil/fenofibrate

(fibrate)

1. Increases activity of lipoprotein lipase → cleaves free fatty acid from triglycerides → promotes delivery of triglycerides to adipose tissue 
2. Decreases VLDL formation in the liver → leading to decrease in triglycerides → modest reduction in LDL with impressive increase in HDL 

• Note that in some patients the LDL might actually increase 

• Reduce triglycerides when VLDL is very high 
• Reduce triglycerides when IDL is elevated

**Follow VLDL**

• If VLDL is elevated, gemfibrozil is a candidate drug 
• If LDL is elevated elevated but VLDL is NOT elevated, do NOT use this drug!

• Long list but relatively low risk 
• 1)  Blood cell deficiencies
• 2)  Skin rash/ other hypersensitive rx
• 3)  GI problems
• 4)  Liver enzyme abnormalities (usually transient)
• 5)  Myositis--myopathy and rhabdomyolysis when w/"statin" 
• 6)  Lithiasis--increases biliary excretion of cholesterol  

• Do NOT give to patients with gall bladder problems, will cause lithiasis b/c increased cholesterol excretion by biliary track
• Statins: Look out for myositis when combined with statins 

• Cholestyramine 
• Colestipol
• Colesevelam 

1. Increased excretion of bile acids → increases converstion of cholesterol to bile acid in the liver 
2. Loss of cholesterol (in bile) triggers increased LDL receptors in the liver → decreases LDL 

• Hyperchoelsterolemia (elevated LDL)

• Constipation + bloating: This often causes compliance issues
• Tastes horrible (unpalatable):  Taken as a slurry

• Inhibis absorption of phytosterols + cholesterol

• Primary function is to reduce LDL (decreases absorption by 50%)
• Does NOT modify triglyceride absorption 

• Statins 

• Excreted w/bile 
• Acts at the brush border of the SI to inhibit the uptake of dietary + biliary cholesterol into enterocytes 
• Does NOT cause an increase in bild acid secretion or inhibit cholesterol synthesis 

• Unlike bile acid binders, this drug does NOT decrease absorption of other fatty substances 
• It is well tolerated 

• With statins, can lower choelsterol to essentially any level
• BUT there is no improvement in mortality from reducing LDL levels with increased dosage of ezetimibe.  
• However, there is a decrease in mortality when increased dose of statins are given 

• Benign side-effects especially compared to the GI effects of bile-acid binding resins
• Reversible change in liver function 
• Myalgia/rhabdomyolysis: 

              -If pushed too aggressively w/dose (but less than statins) 

              -If given with statins the probability of this will increase                          w/increased dose of ezetimibe  

              -But this is not like given statin + fibric which CLEARLY                           causes rhabdomyolysis 

• Mainly used to decrease triglycerides (LDL actually increases slightly) 
• But decreased triglyceride levels by itself does NOT improve cardiovascular morbidity/mortality. So there is no evidence that taking fish oils help
• So they do NOT decrease frequency/morbidity/mortality of heart attacks or stroke