Therapy of Lipid Disorders

Cholesterol - the basics

lipoproteins: triglycerides (TG) and cholesterol esters surrounded by phospholipids, unesterified cholesterol, and apoproteins; there are four major types, the last three are the ones measured clinically

chylomicrons: largest LP; mostly composed of TG

VLDL (very low density LP): large, mostly composed of TG

LDL (low density LP): ~50% cholesterol; much reduced TG; the most atherogenic LP

HDL (high density LP): the smallest LP; mostly composed of proteins and phospholipids

basic cholesterol metabolism

exogenous pathway: cholesterol is absorbed by the intestine and passes into the bloodstream in chylomicrons; peripheral lipoprotein lipase extracts the TG and the chylomicron remnants are re-absorbed into the liver; cholesterol from the liver can be converted into bile acids which are secreted into the intestine

endogenous pathway: the liver releases TG and cholesterol in the form of VLDL; lipoprotein lipase extracts the TG, resulting in IDL, and then LDL (both of which may be taken up by the liver); LDL that is not taken up by the liver can be taken up by peripheral tissues and converted into free cholesterol; the peripheral tissues recycle excess cholesterol back to the liver via HDL – obviously, these to paths overlap at the liver

LDL receptors: there are 1000s of LDL-R lying in coated pits on hepatocytes; LDL-R recognizes Apo-B on the LDL partilcle and thereby takes up the LDL and uses the cholesterol for steroid and bile acid synthesis

LDL-R are regulated by a feedback mechanism that keeps the intracellular free cholesterol at a constant level; if intracellular cholesterol drops, more LDL are sent to the surface, and de novo cholesterol synthesis increases

Hypercholesterolemia

Familial

autosomal dominant; pleomorphic: hundreds of different mutations known
results in an increased cholesterol level from birth in heterozygotes (350-600 is common)
MI start at age 35 in men, 60 in women ; FH accounts for 5% of MI for people < 60
1/500 heterozygotes in the population makes this one of the most common genetic disorders
homozygotes are about 1/1M in the population; may have cholesterol of 800-1000 at birth; MI during childhood
liver transplant can be an effective treatment

Non-Familial

epidemiology: there are 19.9 M drug eligible patients in the US (high cholesterol, unresponsive to lifestyle changes)

27% already have CHD; 56% have multiple risk factors Þ these people need drugs!

17% have uncomplicated elevated cholesterol Þ drugs for these people is controversial due to high cost of treatment, need for lifetime therapy, possible side effects, etc

detection: all adults over 20 should have their cholesterol checked regularly

serum cholesterol < 200 is desirable; 200-239 is borderline high; > 240 is high

why should we treat it? - sparing the gory details of the studies, it has been shown that reducing blood cholesterol and triglycerides decreases the risk of CAD and CHD considerably

cholesterol of 240 results in 2x greater risk of CHD over a level of 200; other risk factors being constant

Pharmacologic Treatment

to be used only after diet changes have failed; only an adjunct to diet therapy, not a replacement

(1) Bile Acid Sequesterants (cholestyramine, colestipol)

work by blocking intestinal re-uptake of bile acids; BUT effects are blunted by elevated de novo cholesterol synthesis by the hepatocytes, therefore, can be used to complement statins, but rarely alone

side effects: it tastes like crap, causes constipation, abdominal distention, and indigestion Þ 80% non-compliance after 1 yr

also interferes with absorption of some nutrients and drugs in the gut (coumadin, digitalis)

(2) Nicotinic Acid (Niacin): vitamin in low doses, but pharmacologic effect at high doses

highly effective: decreases hepatic secretion of VLDL, ß VLDL, LDL; Ý HDL (most potent agent for Ý HDL)

side effects: flushing is very common; hepatotoxicity Þ narrow therapeutic window (most toxic of these drugs)

(3) Fibrates (phenofibrate, gemfibrozil)

modest effects on LDL and HDL, but very good at lowering TG
side effects: uncommon – GI distress, myalgia, gallstones

(4) Statins (lovastatin, etc) – currently the first choice drug

works by blocking HMG-CoA reductase, the rate limiting step in cholesterol synthesis
very effective and low incidence of side effects (can cause elevated liver transaminases; unknown long-term effects)

	Drugs indicated if:	Goal of Therapy
no CHD; < 2 risk factors	LDL > 190 after 6-12 months of lifestyle therapy	< 160
no CHD; ³ 2 risk factors	LDL > 160 after 3-6 months	< 130
CHD	LDL > 130 after 6-12 weeks	< 100

	% ß LDL	Ý HDL	ß TG
Statins	20-60	3-15	10-40
Bile Acid Sequesterants	10-20	3-5	-
Niacin	10-15	15-35	20-50
Fibrates	5-15	6-15	20-50