that is formed by HMG-CoA reductase in the synthesis of mevalonate. These analogs cause partial inhibition of the enzyme and thus may impair the synthesis of isoprenoids such as ubiquinone and dolichol and the prenylation of proteins. It is not known whether this has biologic significance. However, the reductase inhibitors clearly induce an increase in high-affinity LDL receptors. This effect increases both the fractional catabolic rate of LDL and the liver’s extraction of LDL precursors (VLDL remnants) from the blood, thus reducing LDL (Figure 35–2). Because of marked first-pass hepatic extraction, the major effect is on the liver. Preferential activity in liver of some congeners appears to be attributable to tissue-specific differences in uptake. Modest decreases in plasma triglycerides and small increases in HDL also occur.
Clinical trials involving many of the statins have demonstrated significant reduction of new coronary events and atherothrombotic stroke. Mechanisms other than reduction of lipoprotein levels appear to be involved. The availability of isoprenyl groups from the HMG-CoA pathway for prenylation of proteins is reduced by statins, resulting in reduced prenylation of Rho and Rab proteins. Prenylated Rho activates Rho kinase, which mediates a number of mechanisms in vascular biology. The observation that reduction in new coronary events occurs more rapidly than changes in morphology of arterial plaques suggests that these pleiotropic effects may be important. Likewise, decreased prenylation of Rab reduces the accumulation of Aβ protein in neurons, possibly mitigating the manifestations of Alzheimer’s disease.
Reductase inhibitors are useful alone or with resins, niacin, or ezetimibe in reducing levels of LDL. Women with hyperlipidemia who are pregnant, lactating, or likely to become pregnant should not be given these agents. Use in children is restricted to selected patients with familial hypercholesterolemias.
Because cholesterol synthesis occurs predominantly at night, reductase inhibitors—except atorvastatin, rosuvastatin, and pitavastatin—should be given in the evening. Absorption generally (with the exception of pravastatin and pitavastatin) is enhanced by food. Daily doses of lovastatin vary from 10 to 80 mg. Pravastatin is nearly as potent on a mass basis as lovastatin with a maximum recommended daily dose of 80 mg. Simvastatin is twice as potent and is given in doses of 5–80 mg daily. Because of increased risk of myopathy with the 80-mg/d dose, the U.S. Food and Drug Administration (FDA) issued labeling for scaled dosing of simvastatin and combined ezetimibe/simvastatin in 2011. Pitavastatin is given in doses of 1–4 mg daily. Fluvastatin appears to be about half as potent as lovastatin on a mass basis and is given in doses of 10–80 mg daily. Atorvastatin is given in doses of 10–80 mg/d, and rosuvastatin at 5–40 mg/d. The dose-response curves of pravastatin and especially of fluvastatin tend to level off in the upper part of the dosage range in patients with moderate to severe hypercholesterolemia. Those of other statins are somewhat more linear.