Drug Therapy Of Dyslipidemia


The statins are the most effective and best-tolerated agents for treating dyslipidemia. These drugs are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which catalyzes an early, rate-limiting step in cholesterol biosynthesis. Higher doses of the more potent statins (e.g., atorvastatin, simvastatin, and rosuvastatin) also can reduce triglyceride levels caused by elevated VLDL levels. Some statins also are indicated for raising HDL-C levels, although the benefits of these effects on HDL-C remain to be proven.

The efficacy and safety of the statins in reducing fatal and nonfatal CHD events, strokes, and total mortality are well established. Rates of non-CHD adverse events in clinical trials were the same in the placebo groups and in the groups receiving the drug, both with regard to noncardiac illness and two laboratory tests, hepatic transaminases and creatine kinase (CK), commonly monitored in patients taking statins.

Pravastatin and simvastatin are chemically modified derivatives of lovastatin. Atorvastatin, fluvastatin, and rosuvastatin are structurally distinct synthetic compounds. Statins exert their major effect—reduction of LDL levels—through a mevalonic acid-like moiety that competitively inhibits HMG-CoA reductase. By reducing the conversion of HMG-CoA to mevalonate, statins inhibit hepatic cholesterol biosynthesis. In response to the reduced free cholesterol content within hepato-cytes, synthesis of LDL receptors is increased and their degradation is reduced. The greater number of LDL receptors on the surface of hepatocytes increases removal of LDL from the blood, thereby lowering LDL-C levels. Statins also can reduce LDL levels by enhancing the removal of LDL precursors (VLDL and IDL) and by decreasing hepatic VLDL production. This mechanism likely accounts for the triglyceride-lowering effect of statins and may account for the reduction (~25%) of LDL-C levels in patients with homozygous familial hypercholesterolemia treated with 80 mg of atorvastatin or simvastatin.

Triglyceride levels >250 mg/dL are reduced substantially by statins, and the percent reduction achieved is similar to that in LDL-C. Accordingly, hypertriglyceridemic patients taking the highest doses of the most potent statins (simvastatin and atorvastatin, 80 mg/day; rosuvastatin, 40 mg/day) experience a 35-45% reduction in LDL-C and a comparable reduction in fasting triglyceride levels. If baseline triglyceride levels are <250 mg/dL, reductions in triglycerides are <25% irrespective of the dose or statin used. Similar reductions (35-45%) in triglycerides can be accomplished with doses of fibrates or niacin (see below), although these drugs do not reduce LDL-C to the same extent as atorvastatin or simvastatin at the 80-mg dose.

Statins lower LDL-C by 20-55%, depending on the dose and statin (Table 35-7). The fractional reductions achieved with the various doses are the same regardless of the absolute value of the baseline LDL-C level. Efficacy of LDL-C lowering is log-linear; LDL-C is reduced by ~6% (from baseline) with each doubling of the dose. Maximal effects on plasma cholesterol levels are achieved within 7-10 days. The statins are effective in almost all patients with high LDL-C levels. Patients with homozygous familial hypercholesterolemia have very attenuated responses to the usual doses of statins because both alleles of the LDL receptor gene encode dysfunctional LDL receptors; the partial response in these patients is due to a reduction in hepatic VLDL synthesis.

Although the statins clearly exert their major effects on CHD by lowering LDL-C and improving the lipid profile (Figure 35-2), a multitude of potentially cardioprotective effects are also ascribed to these drugs. It is not known whether these potential pleiotropic effects represent a class-action effect, differ amongst statins, or are biologically or clinically relevant.

Absorption, Metabolism, and Excretion

After oral administration, intestinal absorption of the statins varies between 30% and 85%. All of the statins, except simvastatin and lovastatin, are administered as active f-hydroxy acids. Sim-vastatin and lovastatin are administered as inactive lactones that must be transformed in the liver to their respective f-hydroxy acids. There is extensive first-pass hepatic uptake of all statins, but they enter the liver by different mechanisms. Uptake of atorvastatin, pravastatin, and rosuvastatin is mediated by the organic anion transporter 2 (OATP2). The lipophilic lactone forms of simvastatin and lovastatin are thought to enter the liver by simple diffusion. Due to extensive first-pass hepatic uptake, systemic bioavailability of the statins and their hepatic metabolites varies between 5% and 30% of administered doses. Except for fluvastatin and pravastatin, the metabolites of all statins have some HMG-CoA reductase inhibitory activity. Under steady-state conditions, small amounts of the parent drug and its metabolites produced in the liver can be found in the systemic circulation. In the plasma, >95% of statins and their metabolites are protein bound with the exception of pravastatin and its metabolites (50% bound).

After oral dosing, plasma concentrations of statins peak in 1-4 hours. The half-lives of the parent compounds are 1-4 hours, except for atorvastatin and rosuvastatin, which have half-lives of ~20 hours, which may contribute to their greater cholesterol-lowering efficacy. The liver biotransforms all

Table 35-7

Doses (mg) of Statins Required to Achieve Various Reductions in Low-Density-Lipoprotein Cholesterol from Baseline

Table 35-7

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