Primary Forms of Lipids

Triglycerides and cholesterol are the two primary forms of lipids in the blood. Triglycerides function as an energy source and are stored in adipose (fat) tissue. Cholesterol is primarily used to make steroid hormones, cell membranes, and bile acids. Triglycerides and cholesterol are both water-insoluble fats that must be bound to specialized lipid-carrying proteins called apolipoproteins. The combination of triglycerides and cholesterol with an apolipoprotein is referred to as a lipoprotein.

Cholesterol Homeostasis

The liver is the major organ where lipid metabolism occurs. The liver produces very-low-density lipoprotein (VLDL) from both endogenous and exogenous sources. The major role of VLDL is the transport of endogenous lipids to peripheral cells. Once VLDL is circulating, it is enzymatically cleaved by lipoprotein lipase and then loses triglycerides. This creates intermediate-density lipoprotein (IDL), which is soon also cleaved by lipoprotein lipase to create low-density lipoprotein (LDL). Cholesterol is almost all that remains in LDL after this process. Any tissues that require LDL, such as endocrine cells, have LDL receptors. LDL and about half of IDL are reabsorbed from the circulation into the liver by means of LDL receptors on the liver.

High-density lipoprotein (HDL) is produced in the liver and intestines and is also formed when chylomicrons are broken down. Lipids that are not used by peripheral cells are transferred as cholesterol esters to HDL. HDL then transfers the cholesterol esters to IDL to be returned to the liver. HDL is responsible for the “recycling” of cholesterol. HDL is sometimes referred to as the good lipid (or good cholesterol) because it is believed to be cardioprotective.

If the liver has an excess amount of cholesterol, the number of LDL receptors on the liver decreases, which results in an accumulation of LDL in the blood. One explanation for hypercholesterolemia (cholesterol in the blood), therefore, is downregulation (reduced production) of hepatic LDL receptors. A major function of the liver is to manufacture cholesterol, a process that requires acetyl coenzyme A (CoA) reductase. Inhibition of this enzyme thus results in decreased cholesterol production by the liver.

Hydroxymethylglutaryl–Coenzyme a Reductase Inhibitors

The rate-limiting enzyme in cholesterol synthesis is known as HMG–CoA reductase. The class of medications that competitively inhibit this enzyme, called the hydroxymethylglutaryl–coenzyme A (HMG–CoA) reductase inhibitors, are the most potent of the drugs available for reducing plasma concentrations of LDL cholesterol. Lovastatin was the first drug in this class to be approved for use, which occurred in 1987. Since that time, six other HMG–CoA reductase inhibitors have become available on the U.S. market: pravastatin, simvastatin, atorvastatin, fluvastatin, rosuvastatin, and pitavastatin. Because of the shared suffix of their generic names, these drugs are often collectively referred to as statins. Lipid levels may not be lowered to their maximum extent until 6 to 8 weeks after the start of therapy. Few direct comparisons of the statins have been reported in the literature. The following doses of drugs are considered to be “therapeutically equivalent,” meaning they produce the same therapeutic effect: simvastatin 20 mg, pravastatin 40 mg, lovastatin 40 mg, atorvastatin 10 mg, fluvastatin 80 mg, rosuvastatin 5 mg, and pitavastatin 2 mg.

Mechanism of Action and Drug Effects

Statins lower the blood cholesterol level by decreasing the rate of cholesterol production. The liver requires HMG–CoA reductase to produce cholesterol. It is the rate-limiting enzyme in the reactions needed to make cholesterol. The statins inhibit this enzyme, thereby decreasing cholesterol production. When less cholesterol is produced, the liver increases the number of LDL receptors to recycle LDL from the circulation back into the liver, where it is needed for the synthesis of other required substances such as steroids, bile acids, and cell membranes. Lovastatin and simvastatin are administered as inactive drugs or prodrugs that must be biotransformed into their active metabolites in the liver. In contrast, pravastatin is administered in its active form.

Indications

The statins are recommended as first-line drug therapy for hypercholesterolemia (especially elevated levels of LDL cholesterol), the most common and dangerous form of dyslipidemia. More specifically, they are indicated for the treatment of type IIa and IIb hyperlipidemia and have been shown to reduce the plasma concentrations of LDL cholesterol by 30% to 40%. Their cholesterol-lowering properties are dose dependent; that is, the larger the dose, the greater the cholesterol-lowering effects. A 10% to 30% decrease in the concentrations of plasma triglycerides has also been observed in patients receiving these drugs. Another very important therapeutic effect of the statins is an overall tendency for the HDL cholesterol level to increase by 2% to 15%, a known beneficial factor that reduces risk (i.e., a negative risk factor) for cardiovascular disease.

These drugs appear to be equally effective in their ability to reduce LDL cholesterol concentrations. However, simvastatin, atorvastatin, and pitavastatin are more potent on a milligram basis. Atorvastatin appears to be more effective in lowering triglyceride levels than other HMG–CoA reductase inhibitors. Combined drug therapy with more than one class of antilipemic drug may be necessary for desired results. The statins are often combined with niacin or fibrates for this purpose, though this combination can increase the risk of adverse drug effects (see Adverse Effects).

Adverse Effects