Statins and Endothelial Function. A variety of studies have established that the vascular endothelium plays a dynamic role in vasoconstriction/relaxation. Hypercholesterolemia adversely affects the processes by which the endothelium modulates arterial tone. Statin therapy enhances endothelial production of the vasodilator nitric oxide, leading to improved endothelial function. Statin therapy improves endothelial function independent of changes in plasma cholesterol levels.
Statins and Plaque Stability. The vulnerability of plaques to rupture and thrombosis is of greater clinical relevance than the degree of stenosis they cause (Corti et al., 2003). Statins affect plaque stability in a variety of ways. They inhibit monocyte infiltration into the artery wall and inhibit macrophage secretion of matrix metalloproteinases in vitro. The metalloproteinases degrade extracellular matrix components and thus weaken the fibrous cap of atherosclerotic plaques.
Statins also appear to modulate the cellularity of the artery wall by inhibiting proliferation of smooth muscle cells and enhancing apoptosis. It is debatable whether these effects would be beneficial or harmful if they occurred in vivo. Reduced proliferation of smooth muscle cells and enhanced apoptosis could retard initial hyperplasia and restenosis, but they also could weaken the fibrous cap and destabilize the lesion. Interestingly, statin-induced suppression of cell proliferation and the induction of apoptosis have been extended to tumor biology. The effects of statins on isoprenoid biosynthesis and protein phenylation associated with reduced synthesis of the cholesterol precursor mevalonate may alter the development of malignancies (Li et al., 2003; Wong et al., 2002).
Statins and Inflammation. Appreciation of the importance of inflammatory processes in atherogenesis is growing, and statins may have an anti-inflammatory role. Statins decreased the risk of CHD and levels of CRP (an independent marker for inflammation and high CHD risk) independently of cholesterol lowering (Libby and Aikawa, 2003; Libby and Ridker, 2004). Body weight and the metabolic syndrome are associated with elevated levels of highly sensitive CRP, leading some to suggest that the CRP may simply be a marker of obesity and insulin resistance (Pearson et al., 2003). It remains to be determined whether the CRP is simply a marker of inflammation or if it contributes to the pathogenesis of atherosclerosis. The clinical utility of measuring CRP with "highly sensitive" assays appears to be limited to those primary prevention subjects with a moderate (10-20%) 10-year risk of sustaining a CHD event. Values of highly sensitive CRP >3 mg/L suggest that such patients should be managed as secondary prevention patients (Pearson et al., 2003).
Statins and Lipoprotein Oxidation. Oxidative modification of LDL appears to play a key role in mediating the uptake of lipoprotein cholesterol by macrophages and in other processes, including cytotoxicity within lesions. Statins reduce the susceptibility of lipoproteins to oxidation both in vitro and ex vivo.
Statins and Coagulation. The most compelling evidence of a non–lipid-lowering effect of a statin is the rosuvastatin-mediated reduction in venous thromboembolic events, a prespecified endpoint, in JUPITER. This trial demonstrated a 43% reduction in venous thromboembolic events in patients treated with rosuvastatin, 20 mg daily, compared with placebo during a median follow-up period of 1.9 years (Glynn et al., 2009). Statins reduce platelet aggregation and reduce the deposition of platelet thrombi. In addition, the different statins have variable effects on fibrinogen levels. Elevated plasma fibrinogen levels are associated with an increase in the incidence of CHD.
Absorption, Metabolism, and Excretion
Absorption from the Small Intestine. After oral administration, intestinal absorption of the statins is variable (30-85%). All the statins, except simvastatin and lovastatin, are administered in the β-hydroxy acid form, which is the form that inhibits HMG-CoA reductase. Simvastatin and lovastatin are administered as inactive lactones that must be transformed in the liver to their respective β-hydroxy acids, simvastatin acid (SVA) and lovastatin acid (LVA). There is extensive first-pass hepatic uptake of all statins, mediated primarily by the organic anion transporter OATP1B1 (see Chapter 5).
Due to extensive first-pass hepatic uptake, systemic bioavailability of the statins and their hepatic metabolites varies between 5% and 30% of administered doses. The metabolites of all statins, except fluvastatin and pravastatin, have some HMG-CoA reductase inhibitory activity (Bellosta et al., 2004). Under steady-state conditions, small amounts of the parent drug and its metabolites produced in the liver can be found in the systemic circulation. After the lactones of simvastatin and lovastatin are transformed in the liver to SVA and LVA, small amounts of these active inhibitors of HMG-CoA reductase, as well as small amounts of the lactone forms, 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, which are only 50% bound (Schachter, 2005).
After an oral dose, plasma concentrations of statins peak in 1-4 hours. The t1/2 of the parent compounds are 1-4 hours, except in the case of atorvastatin and rosuvastatin, which have half-lives of ∼20 hours, and simvastatin with a t1/2 ∼12 hours (Ieiri et al., 2007). The longer t1/2 of atorvastatin and rosuvastatin may contribute to their greater cholesterol-lowering efficacy (Corsini et al., 1999). The liver biotransforms all statins, and more than 70% of statin metabolites are excreted by the liver, with subsequent elimination in the feces (Bellosta et al., 2004). Inhibition by other drugs of OATP1B1, which transports several statins into hepatocytes, and inhibition or induction of CYP3A4 by a variety of pharmacological agents provide rationales for drug-drug interactions involving statins (Shitara and Sugiyama, 2006).
Adverse Effects and Drug Interactions
Hepatotoxicity. Initial post-marketing surveillance studies of the statins revealed an elevation in hepatic transaminase to values greater than three times the upper limit of normal, with an incidence as great as 1%. The incidence appeared to be dose related. However, in the placebo-controlled outcome trials in which 10- to 40-mg doses of simvastatin, lovastatin, fluvastatin, atorvastatin, pravastatin, or rosuvastatin were used, the incidence of 3-fold elevations in hepatic transaminases was 1-3% in the active drug treatment groups and 1.1% in placebo patients (Law et al., 2006; Ridker et al., 2008). No cases of liver failure occurred in these trials. Although serious hepatotoxicity is rare, 30 cases of liver failure associated with statin use were reported to the FDA between 1987 and 2000, a rate of about one case per million person-years of use (Law et al., 2006). It is therefore reasonable to measure alanine aminotransferase (ALT) at baseline and thereafter when clinically indicated.
Observational studies and a prospective trial suggest that transaminase elevations in patients with nonalcoholic fatty liver disease and hepatitis C are not at risk of statin-induced liver toxicity (Alqahtani and Sanchez, 2008; Chalasani et al., 2004; Lewis et al., 2007; Norris et al., 2008). This is important, as many insulin-resistant patients are affected by nonalcoholic fatty liver disease and have elevated transaminases. As insulin resistance is associated with increased CVD risk, insulin-resistant patients, especially those with type 2 diabetes mellitus, benefit from lipid-lowering therapy with statins (Cholesterol Treatment Trialists' Collaborators, 2008). It is reassuring that these patients with elevated transaminases can safely take statins.
Myopathy. The major adverse effect associated with statin use is myopathy (Wilke et al., 2007). Between 1987 and 2001, the FDA recorded 42 deaths from rhabdomyolysis induced by statins (excluding cerivastatin, which has been withdrawn from the market worldwide). This is a rate of one death per million prescriptions (30-day supply). In the statin trials described earlier (under "Hepatotoxicity"), rhabdomyolysis occurred in eight active drug recipients versus five placebo subjects. Among active drug recipients, 0.17% had CK values exceeding 10 times the upper limit of normal; among placebo-treated subjects, the incidence was 0.13%. Only 13 out of 55 drug-treated subjects and 4 out of 43 placebo subjects with greater than 10-fold elevations of CK reported any muscle symptoms (Law et al., 2006).
The risk of myopathy and rhabdomyolysis increases in proportion to statin dose and plasma concentrations. Consequently, factors inhibiting statin catabolism are associated with increased myopathy risk, including advanced age (especially >80 years of age), hepatic or renal dysfunction, perioperative periods, multi-system disease (especially in association with diabetes mellitus), small body size, and untreated hypothyroidism (Pasternak et al., 2002; Thompson et al., 2003). Concomitant use of drugs that diminish statin catabolism or interfere with hepatic uptake is associated with myopathy and rhabdomyolysis in 50-60% of all cases (Law and Rudnicka, 2006; Thompson et al., 2003). Thus, avoiding these drug interactions should reduce myopathy and rhabdomyolysis by about one-half (Law and Rudnicka, 2006). The most common statin interactions occurred with fibrates, especially gemfibrozil (38%), cyclosporine (4%), digoxin (5%), warfarin (4%), macrolide antibiotics (3%), mibefradil (2%), and azole antifungals (1%) (Thompson et al., 2003). Other drugs that increase the risk of statin-induced myopathy include niacin (rare), HIV protease inhibitors, amiodarone, and nefazodone (Pasternak et al., 2002).
There are a variety of pharmacokinetic mechanisms by which these drugs increase myopathy risk when administered concomitantly with statins. Gemfibrozil, the drug most commonly associated with statin-induced myopathy, inhibits both uptake of the active hydroxy acid forms of statins into hepatocytes by OATP1B1 and interferes with the transformation of most statins by glucuronidases (Prueksaritanont et al., 2002a; Prueksaritanont et al., 2002b; Prueksaritanont et al., 2002c). Primarily due to inhibition of OATP1B1-mediated hepatic uptake, co-administration of gemfibrozil nearly doubles the plasma concentration of the statin hydroxy acids (Neuvonen et al., 2006). Other fibrates, especially fenofibrate, do not interfere with the glucuronidation of statins and pose less risk of myopathy when used in combination with statin therapy. (For reviews of statin interactions with other drugs, see Bellosta et al., 2004 and Neuvonen et al., 2006). Concomitant therapy with simvastatin, 80 mg daily, and fenofibrate, 160 mg daily, results in no clinically significant pharmacokinetic interaction (Bergman et al., 2004). Similar results were obtained in a study of low-dose rosuvastatin, 10 mg daily, plus fenofibrate, 67 mg three times a day. When statins are administered with niacin, the myopathy probably is caused by an enhanced inhibition of skeletal muscle cholesterol synthesis (a pharmacodynamic interaction).
Drugs that interfere with statin oxidation are those metabolized primarily by CYP3A4 and include certain macrolide antibiotics (e.g., erythromycin); azole antifungals (e.g., itraconazole); cyclosporine; nefazodone, a phenylpiperazine antidepressant; HIV protease inhibitors; and amiodarone (Alsheikh-Ali and Karas, 2005; Bellosta et al., 2004; Corsini, 2003). These pharmacokinetic interactions are associated with increased plasma concentrations of statins and their active metabolites. Atorvastatin, lovastatin, and simvastatin are primarily metabolized by CYPs 3A4 and 3A5. Fluvastatin is mostly (50-80%) metabolized by CYP2C9 to inactive metabolites, but CYP3A4 and CYP2C8 also contribute to its metabolism. Pravastatin, however, is not metabolized to any appreciable extent by the CYP system and is excreted unchanged in the urine. Pravastatin, fluvastatin, and rosuvastatin are not extensively metabolized by CYP3A4. Pravastatin and fluvastatin may be less likely to cause myopathy when used with one of the predisposing drugs. However, because cases of myopathy have been reported with both drugs, the benefits of combined therapy with any statin should be carefully weighed against the risk of myopathy. Although rosuvastatin is not transformed to any appreciable extent by oxidation, cases of myopathy have been reported, particularly in association with concomitant use of gemfibrozil (Schneck et al., 2004). Experience with pitavastatin is limited. There are no data regarding myopathy and rhabdomyolysis that might be associated with its use.
Despite the rarity of 10-fold elevations of CK, many patients complain of muscle aches (myalgias) while taking statins. It is unclear if such myalgias are caused by taking a statin. In one clinical trial involving 20,000 subjects randomized to simvastatin (40 mg daily) or placebo, it was observed over the 5 years of the study that one-third of patients complained of myalgia at least once, whether the active drug or the placebo was being taken (Heart Protection Study Collaborative Group, 2002).
Replacing vitamin D in patients with a vitamin D deficiency reportedly reduces statin-associated myalgias and improves statin tolerance (Ahmed et al., 2009). The observation needs to be confirmed, but it is potentially significant because vitamin D deficiency is associated with myopathy, insulin resistance, and increased incidence of CVD (Lee et al., 2008).
Pregnancy. The safety of statins during pregnancy has not been established. Women wishing to conceive should not take statins. During their childbearing years, women taking statins should use highly effective contraception (see Chapter 40). Nursing mothers also are advised to avoid taking statins.