Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a
precursor of sterols, including cholesterol. Cholesterol and triglycerides circulate in the
bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes
separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein),
LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions.
Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released
into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is
catabolized primarily through the high-affinity LDL receptor. Clinical and pathologic
studies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol
(LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk
factors for developing cardiovascular disease, while increased levels of HDL-C are
associated with a decreased cardiovascular risk.
In animal models, Lipitor lowers plasma cholesterol and lipoprotein levels by inhibiting
HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number
of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL;
Lipitor also reduces LDL production and the number of LDL particles. Lipitor reduces
LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a
population that rarely responds to other lipid-lowering medication(s).
A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C,
and apo B (a membrane complex for LDL-C) promote human atherosclerosis. Similarly,
decreased levels of HDL-C (and its transport complex, apo A) are associated with the
development of atherosclerosis. Epidemiologic investigations have established that
cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C,
and inversely with the level of HDL-C.
Lipitor reduces total-C, LDL-C, and apo B in patients with homozygous and
heterozygous FH, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia.
Lipitor also reduces VLDL-C and TG and produces variable increases in HDL-C and
apolipoprotein A-1. Lipitor reduces total-C, LDL-C, VLDL-C, apo B, TG, and
non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. Lipitor
reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with
dysbetalipoproteinemia.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL,
intermediate density lipoprotein (IDL), and remnants, can also promote atherosclerosis.
Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and
small LDL particles, as well as in association with non-lipid metabolic risk factors for
coronary heart disease. As such, total plasma TG has not consistently been shown to be
an independent risk factor for CHD. Furthermore, the independent effect of raising HDL
or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.