Statins: Actions, side effects, and administration Author Robert S Rosenson, MD Section Editor Mason W Freeman, MD Deputy Editor

David M Rind, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2013. | This topic last updated: jul 29, 2013. INTRODUCTION Lipid altering agents encompass several classes of drugs that include HMG CoA reductase (hydroxymethylglutaryl CoA reductase) inhibitors or statins, fibric acid derivatives, bile acid sequestrants, cholesterol absorption inhibitors, and nicotinic acid. These drugs differ with respect to mechanism of action and to the degree and type of lipid lowering. Thus, the indications for a particular drug are influenced by the underlying lipid abnormality. Conventional dosing regimens and common adverse reactions are described in a table (table 1) and the range of expected changes in the lipid profile are listed in a separate table (table 2). Lipid lowering, at least with statins, is beneficial in patients with dyslipidemias for both primary and secondary prevention of coronary heart disease. (See"Clinical trials of cholesterol lowering for primary prevention of coronary heart disease" and "Clinical trials of cholesterol lowering in patients with coronary heart disease or coronary risk equivalents".) The mechanisms of benefit seen with lipid lowering are incompletely understood. Regression of atherosclerosis occurs in only a minority of patients; furthermore, clinical benefits of lipid lowering are seen in as little as six months, before significant regression could occur. Thus, other factors must contribute; these include plaque stabilization, reversal of endothelial dysfunction, and decreased thrombogenicity. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".) The characteristics and efficacy of the statins will be reviewed here (table 3). Possible noncardiovascular benefits of statins are discussed separately. (See"Statins: Possible noncardiovascular benefits".) The efficacy of fibrates, lipid lowering drugs other than statins and fibrates, and diet and dietary supplements are also discussed separately. (See "Lipid lowering with fibric acid derivatives" and "Lipid lowering with drugs other than statins and fibrates" and "Lipid lowering with diet or dietary supplements".) Therapeutic decision making in patients with elevated lipid levels, including indications for and dosing of statins, is discussed in detail separately: (See "Treatment of lipids (including hypercholesterolemia) in primary prevention".) (See "Treatment of lipids (including hypercholesterolemia) in secondary prevention".) (See "Intensity of lipid lowering therapy in secondary prevention of coronary heart disease".)

MECHANISM OF ACTION Currently available statins include lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, and, in some countries, pitavastatin (table 3). These agents are competitive inhibitors of HMG CoA reductase, the

rate-limiting step in cholesterol biosynthesis (figure 1). They occupy a portion of the binding site of HMG CoA, blocking access of this substrate to the active site on the enzyme [1]. A reduction in intrahepatic cholesterol leads to an increase in LDL receptor turnover that results from an enhanced rate of hepatic LDL receptor cycling [2]. Statins also reduce VLDL production, via an effect mediated by hepatic apo B secretion [3,4], and it is associated with a diminished rate of recovery of HMG CoA reductase activity after drug treatment [5]. Most of the statins have modest HDL-cholesterol (HDL-C) raising properties (about 5 percent), although rosuvastatin has a larger effect (see 'Effect on HDL'below). Triglyceride concentrations fall by an average of 20 to 40 percent depending upon the statin and dose used (see 'Effect on triglycerides' below). The reduction in plasma triglycerides is due to a decrease in VLDL synthesis and to clearance of VLDL remnant particles by apo B/E (LDL) receptors. The mechanisms by which statins may affect cardiovascular disease are discussed separately. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".) EFFICACY The statins are commonly used in the treatment of hypercholesterolemia and mixed hyperlipidemia. Effect on LDL cholesterol Potency The statins are the most powerful drugs for lowering LDL-cholesterol (LDL-C), with reductions in the range of 30 to 63 percent (table 3) [6-10]. When switching between statin drugs, equipotent doses with regard to LDL-C reduction can be found in the figure (figure 2). Rosuvastatin is somewhat more potent than atorvastatin [10,11], and both these agents are significantly more potent than simvastatin, lovastatin, pravastatin, and fluvastatin [11,12]. At maximal prescribed doses, LDL-C reduction is greater with rosuvastatin and atorvastatin than with the other available statins (figure 2). At doses of up to 40 mg/day, fluvastatin is the least potent statin (figure 2). However, at doses of 80 mg/day, fluvastatin is as effective on lowering LDL-C as most statins other than rosuvastatin and atorvastatin [13]. Fluvastatin is less likely to have drug interactions or produce muscle toxicity than some other statins. (See 'Side effects' below.) Although simvastatin 80 mg/day is a moderately-potent dose of statin, given high rates of myopathy [14] and the availability of rosuvastatin and genericatorvastatin, we suggest not treating patients with doses of simvastatin above 40 mg/day. Additionally, clinicians should strongly consider switching even patients who are currently tolerating simvastatin 80 mg/day to one of these other statin options, since future medication therapy or illness could increase the risk for development of myopathy on high-dose simvastatin. High-dose simvastatin may be appropriate for a small number of patients who have tolerated it well for many years or who are intolerant of other high-potency statin options. There is an additive hypolipidemic effect when any of the statins is used in combination with a bile acid sequestrant (figure 3) [15-17], or the cholesterol absorption inhibitor ezetimibe. (See "Lipid lowering with drugs other than statins and fibrates", section on 'Ezetimibe'.) LDL subfractions Statins are the most effective agents for lowering total LDL particle concentration, however they are nonselective for reducing LDL subclasses; they reduce the predominant subclass [18]. Among patients with the atherogenic dyslipidemia profile, the reduction in the predominant subclass of small, dense LDL particles results in a shift of the LDL subfractions

to more buoyant, and potentially less atherogenic, LDL [19-21]. (See "Inherited disorders of LDLcholesterol metabolism", section on 'Small dense LDL (LDL phenotype B)' and "Lipoprotein classification; metabolism; and role in atherosclerosis", section on 'Intermediate density lipoprotein (remnant lipoproteins)' and "Lipoprotein classification; metabolism; and role in atherosclerosis", section on 'Low density lipoprotein'.) Effect on HDL Simvastatin (40 to 80 mg/day) appears to be more effective than atorvastatin (20 to 40 mg/day) for increasing serum HDL-C and apolipoprotein A-I concentrations [22]. However, rosuvastatin may be even more effective, raising HDL-C by up to 10 percent [11]. In metabolic syndrome patients, rosuvastatin (10 to 20 mg/day) was more effective than atorvastatin (10 to 20 mg/day) in increasing large HDL particles [18]. Whether this is clinically important is uncertain. (See "HDL metabolism and approach to the patient with abnormal HDL-cholesterol levels".) Effect on triglycerides Atorvastatin and rosuvastatin are more effective at lowering triglycerides (14 to 33 percent) than other statins in patients with hypercholesterolemia [11,23-25]. The magnitude of triglyceride lowering with statins may be larger in patients with hypertriglyceridemia. The effects of atorvastatin and rosuvastatin on serum triglycerides are dose-dependent [11,23]. As an example, in a series of 56 patients with primary hypertriglyceridemia in whom the average triglyceride concentration was 600 mg/dL and LDL-C concentration was 120 mg/dL (3.1 mmol/L), the administration of atorvastatin at doses of 5, 20, or 80 mg/day produced reductions in triglycerides of 27, 32, and 46 percent, respectively, and in LDL-C of 17, 33, and 41 percent, respectively [23]. Genetic/ethnic effects Part of the variability in the response to and side effects with statins may be related to genetic differences in the rate of drug metabolism. As an example, CYP2D6 is a member of the cytochrome P450 superfamily of drug oxidizing enzymes. CYP2D6 is functionally absent in 7 percent of Caucasians and African-Americans, while deficiency is rare among Asians. The CYP2D6 phenotype appears to be important in patients treated with simvastatin, as it can affect both the degree of lipid lowering and tolerability [26]. Polymorphisms in the gene coding for HMG CoA reductase also appear to affect the LDL-C response to statins, but not the HDL-C response [27]. Concerns have been raised that Asians may have greater responses to low doses of statins than Caucasians [28]. Prescribing information for rosuvastatinrecommends starting therapy at a lower initial dose in Asians than in other groups, given observed differences in pharmacokinetics [29]. There is no strong evidence supporting such an approach with other statins. Prevention of cardiovascular disease The major use of statins is in the primary and secondary prevention of cardiovascular disease. This use is discussed extensively elsewhere: (See "Treatment of lipids (including hypercholesterolemia) in primary prevention".) (See "Treatment of lipids (including hypercholesterolemia) in secondary prevention".) (See "Intensity of lipid lowering therapy in secondary prevention of coronary heart disease".) (See "Clinical trials of cholesterol lowering for primary prevention of coronary heart disease".) (See "Clinical trials of cholesterol lowering in patients with coronary heart disease or coronary risk equivalents".)

(See "Cholesterol lowering after an acute coronary syndrome".) (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)

SIDE EFFECTS Adverse reactions occur less frequently with the statins than with most other classes of lipid lowering agents. Hepatic dysfunction has been a source of concern; however, the actual risk appears to be very small. Myopathy remains an important side effect. There have been concerns that the more lipophilic statins (simvastatin, lovastatin, atorvastatin, and fluvastatin) may be associated with more adverse events than the more hydrophilic statins (pravastatin and rosuvastatin) [30,31]; however, fluvastatin (a lipophilic statin) appears to have a low rate of muscle side effects [32]. In randomized trials, statin therapy appears to cause only a slight increased risk of side effects compared with placebo, and no increased risk of discontinuation of therapy compared with placebo [33,34]. However, experience in clinical practice suggests that muscle side effects are relatively common, including side effects requiring discontinuation of statin therapy. The explanation for this difference is uncertain, but may relate to selection criteria in randomized trials that limit the ability to generalize their results to the side effect profiles seen in a broader population of patients. Observational data suggest that while discontinuation of statin therapy for side effects is relatively common, many of these patients tolerate the same statin or another statin when rechallenged [35]. Hepatic dysfunction Clinical studies of statins have demonstrated a 0.5 to 3.0 percent occurrence of persistent elevations in aminotransferases in patients receiving statins. This has primarily occurred during the first three months of therapy and is dose-dependent. Rare episodes of more severe liver injury have also been seen, and one study suggested that these predominantly occur three to four months after initiation of statin therapy [36]. However, these are sufficiently uncommon that overall the incidence of hepatic failure in patients taking statins appears to be no different from the incidence in the general population [37]. Several randomized trials have reported no significant difference in the incidence of persistently elevated aminotransferases between statin and placebo therapy [38-40]. A similar finding was noted in a review of three pravastatin trials with over 112,000 patient-years of exposure [41]. There was no difference in the incidence or severity of serum aminotransferase elevations with pravastatin or placebo, including patients with aminotransferase elevations at study entry. A meta-analysis of 35 randomized trials found an excess risk of aminotransferase elevation with statin therapy versus placebo of 4.2 cases per 1000 patients [33]. A large cohort study from England and Wales found similar risks of hepatic dysfunction with different statins, with the exception of a higher risk withfluvastatin [42]. A review of one year of records for 1014 patients taking statins in a primary care practice found that 1 percent of patients had transaminase elevations more than three times normal, and 0.5 percent had transaminase elevations two to three times normal [43]. None of these elevations appeared to be related to statin use. Similarly, a review of five years of a health maintenance organization's computerized records on 23,000 patients who were receiving statins found that 17 (0.1 percent) had an alanine aminotransferase level more than 10 times the upper limit of normal that appeared to be attributable to statin therapy [44]. Of these, all but four were associated with drug interactions.

In 2012, the US Food and Drug Administration revised its labeling information on statins to only recommend liver function testing prior to initiation of statin therapy and to only repeat such testing for clinical indications [45]. We and others agree that routine monitoring of liver function tests in patients receiving statin therapy is not necessary [40,44,46,47]. We recommend changing medications or lowering the statin dose in patients who are found to have an alanine aminotransferase (ALT) level more than three times the upper limit of normal that is confirmed on a second occasion. Muscle injury Development of muscle toxicity remains a concern with the use of the statins [30,48,49]. Myopathic syndromes associated with statins span a spectrum of complaints ranging from myalgias to myositis to overt rhabdomyolysis, which may be associated with acute renal failure from myoglobinuria. This problem, including predisposing drug interactions, is discussed in detail elsewhere. (See "Statin myopathy".) Summarized briefly: Muscle injury is uncommon with statin therapy alone, with a frequency of 2 to 11 percent for myalgias, 0.5 percent for myositis, and less than 0.1 percent for rhabdomyolysis. Patients can experience statin-induced myalgias without an elevation in serum creatine kinase (CK) concentration. Muscle symptoms usually begin within weeks to months after starting statins. Myalgias, weakness, and serum CK concentrations usually return to normal over days to weeks after drug discontinuation. Pravastatin and fluvastatin appear to have less intrinsic muscle toxicity. Enhanced susceptibility to statin-associated myopathy occurs in patients with acute or chronic renal failure, obstructive liver disease, and hypothyroidism. If a patient requires a statin and experiences muscle toxicity (other than rhabdomyolysis) with a statin other than pravastatin or fluvastatin, once symptoms have resolved off statin therapy, it is reasonable to consider a trial of pravastatin or fluvastatin with careful monitoring. Clinical judgment is necessary in interpreting elevated CK levels in patients on statins. CK elevations can be related to hypothyroidism or trauma during sports (running, diving for a volleyball, hockey), and patients who engage in high-impact sports should be advised to have a CK measured before engaging in exercise that day. In the absence of clinical symptoms, a CK level more than 10 times the upper limit of normal that is felt to be due to a statin is an indication for discontinuing the medication. Patients should drink large quantities of fluids to facilitate renal excretion of myoglobin. After the CK and/or myoglobin have returned to baseline, patients may be tried on a statin less likely to cause muscle toxicity (as above) with careful monitoring.

Hypothyroidism is a potential cause of dyslipidemia (see "Lipid abnormalities in thyroid disease"), and hypothyroidism may predispose patients to statin-induced myopathy [50,51]. As such, we suggest checking a TSH level prior to initiating statin therapy. Renal dysfunction Statins appear to be able to cause proteinuria through tubular inhibition of active transport of small molecular weight proteins [52,53]. There have been a number of reports to the FDA about proteinuria with statins, particularly in patients receiving rosuvastatin or simvastatin [54]. However, it is believed that proteinuria with statins is a benign finding [55,56]. (See "Statins and chronic kidney disease", section on 'Effect on protein excretion'.)

There have also been rare episodes of renal failure in clinical trials of patients treated with 80 mg/day of rosuvastatin [11], a higher dose than is available. However, it is unclear if rosuvastatin was responsible for the renal failure, as these patients were on other potentially nephrotoxic medications. Although concerns had been raised about high rates of adverse event reports to the FDA regarding rosuvastatin [54], subsequent information suggests that renal adverse events with rosuvastatin are rare and are similar to those seen with other statins [57-60]. Behavioral and cognitive Although concerns have been raised about increased suicide in patients treated with some lipid lowering therapies, statins do not appear to be associated with an increased risk of suicide or depression [61]. (See "Treatment of lipids (including hypercholesterolemia) in secondary prevention", section on 'Safety of cholesterol lowering'.) There have been case reports of patients developing severe irritability and aggression associated with the use of statins [62]. It is not known whether the statin use caused these symptoms, but very rare idiosyncratic reactions of this sort could be missed in controlled trials. A retrospective cohort study in elderly patients found an association between perioperative statin use and postoperative delirium [63], however it is difficult to tell whether this association was causal [64]. Perioperative administration of statins may have important cardiovascular benefits. (See "Perioperative medication management", section on 'Statins'.) Concerns have been raised in the media and popular press about cognitive dysfunction and memory loss associated with statin use [65,66]. A review of adverse events reported to the US Food and Drug Administration between November 1997 and February 2002 found 60 reports of patients who had memory loss associated with statins [67]. Fourteen of 25 patients had improvement when the statin was discontinued, and four had recurrence of memory loss on rechallenge. The statins involved were simvastatin (36 patients), atorvastatin (23 patients), and pravastatin (1 patient). Although this analysis of adverse event reports does not show that statins cause memory loss, the apparently high rate of reports with lipophilic statins (simvastatin and atorvastatin) compared with hydrophilic statins (pravastatin) does suggest a possible biologic effect. Randomized trials of lovastatin and simvastatin have shown some evidence of minor decrements in cognitive function as measured by neuropsychological testing [68,69]. In the absence of more definitive data, it may be appropriate for physicians to determine whether statin therapy was recently initiated in patients who develop new memory loss. If an individual patient appears to have memory loss associated with lipophilic statin therapy (simvastatin, lovastatin, atorvastatin, orfluvastatin) and has a strong indication for lipid lowering therapy, it would be reasonable to attempt treatment with a more hydrophilic statin (pravastatin orrosuvastatin) [70]. In contrast to the above observations suggesting that statins may produce cognitive impairment, other studies have suggested that statins may have a role in the prevention of dementia. (See "Prevention of dementia", section on 'Statins'.) Cancer Preclinical studies found that very high-dose statin therapy increased the risk of liver tumors in rodents [71]. As discussed elsewhere, meta-analyses of randomized trials have shown no effect of statins on cancer incidence or cancer mortality [72-74]. (See "Statins: Possible noncardiovascular benefits", section on 'Cancer'.) A potential limitation of the meta-analyses is relatively short duration of follow-

up. However, ten-year follow-up of the 4S trial and the West of Scotland Coronary Prevention Study (WOSCOPS) and 11-year follow-up of the Heart Protection Study (HPS) showed no increases in cancer deaths [75-77]. In summary, there is no convincing evidence that statins increase or decrease the risk of cancer. Diabetes mellitus Statins could have effects on glucose metabolism that might influence the development of diabetes mellitus in nondiabetics or affect glycemic control in patients with existing diabetes. Experimental evidence has been conflicting about whether statins as a group improve glucose metabolism or whether some statins show beneficial effects while others show harmful effects [78-83]. Previously, some clinical trials of statins had reported conflicting results on the issue of glucose metabolism [84-87]. However, a 2010 meta-analysis of 13 trials (N = 91,140) found little evidence of heterogeneity among large-scale chronic treatment trials [88]. For inclusion, trials were required to have more than 1000 patients and a duration of follow-up of more than one year. This metaanalysis found an overall small increased risk for diabetes in patients treated with statins (odds ratio [OR] for incident diabetes 1.09, 95% CI 1.02-1.17). Subgroup analyses found very similar diabetes risks in trials of hydrophilic or lipophilic statins, and no clear differences among individual statins. The results were also similar after the exclusion of the JUPITER trial. Since JUPITER had raised much of the concern about diabetes and statins [85], the stability of the result without JUPITER lowers the likelihood that the glucose findings in the meta-analysis were due to chance. A 2011 meta-analysis of five randomized trials (N = 32,752) also found an increased risk of incident diabetes with intensive statin therapy compared with moderate statin therapy (OR 1.12, CI 1.041.22) with little or no heterogeneity across trials [89]. This translates into approximately one additional case of diabetes for every 500 patients treated with intensive rather than moderate statin therapy. Similarly, a large observational study using administrative data found a higher risk of diabetes with high-potency statins, an intermediate risk with moderate-potency statins, and a lower risk with low-potency statins [90]. It appears likely that statin therapy confers a small increased risk of developing diabetes, and that the risk is slightly greater with intensive statin therapy than moderate statin therapy. As would be expected, given the evidence from clinical trials that statins reduce CV events in patient with diabetes (see "Clinical trials of cholesterol lowering in patients with coronary heart disease or coronary risk equivalents"), both randomized trials and observational studies suggest that the beneficial effects of statins on CV events and mortality outweigh any increased risk conferred by promoting the development of diabetes [91,92]. Other Cataract In preclinical toxicity testing, dogs developed cataracts when given doses of statins much higher than human doses [93]. While most large case-control and cohort studies [94-96], as well as a small randomized trial [97], have not found an increased risk of cataract, a large cohort study from England and Wales did find that statin use was associated with an increased risk of cataract [42]. In a subset analysis, one cohort study reported an association between statins and a decreased risk of one type of cataract (nuclear cataract) [96]; however, additional study is

clearly needed before it can be concluded that statins actually have any such protective effect. Neuropathy A number of case reports have suggested that statin use may be associated with the development of peripheral neuropathy. In a case-control study that included 166 patients with a first time diagnosis of idiopathic polyneuropathy (35 definite, 54 probable, and 77 possible), the odds ratio of developing polyneuropathy with statin use was 3.7 for all cases (95% CI 1.8-7.6) and 14.2 for definite cases (95% CI 5.3-38) [98]. The odds ratio increased with a duration of use of two or more years. For patients ages 50 and older, there was one excess case of idiopathic polyneuropathy for every 2200 person-years of statin use. A subsequent case-control study using a computer database to identify 272 patients with idiopathic polyneuropathy based on diagnosis codes did not confirm a significantly increased risk with statin use, however there may have been problems with misclassification and the confidence intervals were wide (odds ratio 1.30, 95% CI 0.3-2.1) [99]. As such, a causal association between statin use and neuropathy remains possible but has not been proven. Lupus There have been case reports of drug-induced lupus in patients receiving statins. (See "Drug-induced lupus".) Androgen synthesis Some [100,101], but not all [102], studies suggest that statins may lower androgen levels in men, although it appears unlikely that this effect is clinically significant [103]. Statins may also reduce androgen levels in women, including in women with androgen excess [83].

Risks in pregnancy and breastfeeding In the United States, statins are rated category X in pregnancy (table 4), and the recommendation is todiscontinue their use prior to conception if possible. Animal studies indicate that at maternally toxic doses statins are associated with adverse fetal outcomes, but limited human data suggest that statins are not major human teratogens [104]. Although some authors have recommended that pregnant women can be reassured that the fetal risk is low if inadvertent exposure occurs [104], an analysis of an FDA surveillance database suggests a possible increase in congenital central nervous system and limb abnormalities with exposure to lipophilic statins during the first trimester [105]. The risk of statins in pregnancy remains uncertain, however it appears that if statins are in fact harmful, the effect is likely relatively small [106-108]. Data on statin safety in breastfeeding are very limited. In the absence of adequate safety data, use of statins by breastfeeding mothers is discouraged. ADMINISTRATION Timing of administration The majority of cholesterol synthesis appears to occur at night [109], presumably reflecting the effects of a fasting state. For this reason, it is typically recommended that the statins with shorter half-lives be administered in the evening or at bedtime (table 3).

In support of this, trials have found greater reductions in total and LDL cholesterol when simvastatin, which has a relatively short half-life, is administered in the evening rather than in the morning [110,111]. A small study of atorvastatin, which has a long half-life, found no significant differences whether it was administered in the morning or the evening [112]. While it is unknown whether the timing of statin administration is important for clinical outcomes, we typically administer statins at the time recommended by the manufacturer (table 3). Lovastatin absorption is increased by food, and it should be administered with the morning and evening meals. Alternative dosing regimens Every other day statin therapy has been suggested as a strategy to improve utilization and decrease cost. Small studies have compared daily statin use with alternate day dosing, and measured effects on lipid parameters and, in some cases, attainment of cholesterol goals over six to twelve weeks [113-117]. Every other day regimens, and even once weekly regimens, have also been evaluated as strategies for improving tolerability [118-120]. Results with atorvastatin, fluvastatin, and rosuvastatin suggest that to yield similar LDL-C lowering, the every other day dose needs to be on average nearly twice that of the daily dose [113,114,116,120]. There are few data on alternate day regimens using a dose greater than 40 mg or on how patient adherence is impacted. Major outcomes trials of statins have used daily statin therapy. In the absence of data from large randomized trials demonstrating equivalent effects on clinical outcomes with alternative dosing regimens, we suggest daily dosing in patients who are treated with statins. We prefer other measures for cost control, such as price comparison among generic statins [121]. Clinical experience suggests that alternate day dosing may improve the tolerability of statins in patients experiencing myalgias, and this strategy can reasonably be tried in patients unable to tolerate daily statin therapy. Interchange When switching between statin drugs, equipotent doses with regard to LDL-C reduction can be found in the figure (figure 2). (See 'Potency'above.) Simvastatin and atorvastatin may be associated with more adverse events than pravastatin or fluvastatin [32]. (See 'Side effects' above.) Drug interactions Drug interactions, including with other lipid-lowering agents, can predispose to statin-induced muscle injury. These are discussed in more detail separately. (See "Statin myopathy".) Summarized briefly: The risk is substantially increased for most statins extensively metabolized by cytochrome P-450 3A4 (lovastatin, simvastatin and to a lesser extentatorvastatin) with concurrent therapy with drugs that interfere with CYP3A4 (table 5). Pravastatin, fluvastatin, rosuvastatin, and pitavastatin are preferred when concurrent therapy with a strong inhibitor of CYP3A4 cannot be avoided. Grapefruit juice inhibits CYP3A4, however daily consumption of eight ounces or less of grapefruit juice, or one half of a grapefruit or less, is unlikely to increase the risk of an adverse interaction or muscle injury. (See individual drug monographs for more detailed information on interactions). Despite not being significantly metabolized by CYP3A4, rosuvastatin levels are increased by the protease inhibitor combinations lopinavir/ritonavir andatazanavir/ritonavir [122]. Pravastatin is the statin of choice in patients on cyclosporine.

Pravastatin or perhaps fluvastatin is the statin of choice in patients treated with gemfibrozil (or other fibric acid derivatives). However, it should be used cautiously and only if the benefit is likely to outweigh the low risk of muscle toxicity. Fenofibrate is the preferred fibrate in patients who require combined therapy with a statin.

The antiplatelet agent clopidogrel is a prodrug that is activated via metabolism by CYP-450. Based on current evidence clopidogrel therapy need not affect the choice of statin. (See "Clopidogrel resistance and clopidogrel treatment failure", section on 'Interaction with other drugs'.) Monitoring Routine monitoring of serum creatine kinase (CK) levels is not recommended in patients on statins, but it is useful to obtain a baseline CK level for reference purposes prior to starting statin therapy. Patients treated with statins should be alerted to report the new onset of myalgias or weakness. (See "Statin myopathy", section on 'Monitoring'.) We check baseline aminotransferase levels prior to initiating statin therapy; we do not routinely monitor these levels in patients on statins. (See 'Hepatic dysfunction' above.) Monitoring of the lipid response to statin therapy is discussed separately. (See "Treatment of lipids (including hypercholesterolemia) in primary prevention", section on 'Side effects and monitoring' and "Treatment of lipids (including hypercholesterolemia) in secondary prevention", section on 'Monitoring therapy'.) Specific populations Chronic kidney disease Chronic kidney disease presents an additional challenge for the selection of a statin. Atorvastatin and fluvastatin do not require dose adjustment and are the statins of choice in patients with severe renal impairment [123,124]. Dose adjustment is warranted with other statins in patients with severe kidney disease (CrCl less than 30 mL/min). If statins other than atorvastatin orfluvastatin are used, pravastatin may be safer than other statins. As an example, in a subset analysis of 1711 participants with chronic kidney disease (creatinine clearance 75 mL/min) from the CARE trial, treatment with pravastatin for a median of 58.9 months significantly improved outcomes compared with placebo without an increase in side effects [125]. Chronic liver disease In patients with chronic liver disease who require a statin because of high cardiovascular risk, we suggest complete abstinence from alcohol and the use of pravastatin at a low dose. If the LDL-C remains elevated, combined therapy with a bile acid sequestrant may allow such patients to achieve their LDL-C target. Statins are contraindicated in patients with progressive liver disease. Patients who simply have baseline elevations in aminotransferases do not appear to be at increased risk when prescribed a statin [37]. A study that looked at patients without evidence of alcohol abuse, hepatitis B, or hepatitis C compared a cohort of 342 patients (many of whom presumably had fatty liver or nonalcoholic steatohepatitis) with hyperlipidemia and baseline aminotransferase elevation (AST >40 IU/L [mean 55 IU/L] or ALT >35 IU/L [mean 43 IU/L]) who were prescribed a statin with a cohort of 2245 patients with baseline aminotransferase elevation who were not prescribed a statin [126]. There was no significant difference between the cohorts in the incidence of mild to moderate aminotransferase elevations (4.7 versus 6.4 percent) or severe elevations (0.6 versus 0.4 percent). Rates of aminotransferase elevations were also similar in a cohort of hyperlipidemic patients with and without hepatitis C who were prescribed a statin [127].

A 36-week randomized trial comparing pravastatin 80 mg daily or placebo in 326 patients with wellcompensated noncholestatic chronic liver disease (64 percent with nonalcoholic steatohepatitis; 23 percent with hepatitis C) found similar evidence of safety [128]. Over the course of the trial, rates of aminotransferase elevations were low in the group receiving pravastatin and no different from placebo, and none of the patients had an exacerbation of their underlying liver disease. Similarly, a post-hoc analysis of a randomized trial of statin therapy (mainly atorvastatin, 24 mg daily) found no evidence of increased hepatic risk in patients with moderately abnormal liver function tests at baseline who were treated with a statin [129]. In a small study of patients with primary biliary cirrhosis who were treated with atorvastatin, significant transaminase elevations were common [130]. Most statins are ultimately excreted in the bile, and toxic levels can develop in patients with cholestasis [131]. Additionally, the standard calculation of LDL-C does not exclude lipoprotein X, which can accumulate in cholestasis but is not atherogenic and so not a target of therapy. While it may be possible to use statins safely in patients with mild cholestasis who have an appropriate indication for therapy [132], we avoid statin therapy in patients with significant cholestasis unless there are compelling indications such as established atherosclerotic vascular disease that is considered clinically important. (See"Hypercholesterolemia and atherosclerosis in primary biliary cirrhosis", section on 'Cholesterol profile' and "Hypercholesterolemia and atherosclerosis in primary biliary cirrhosis", section on 'Drug therapy'.) The use of statins is believed to be safe in patients with Gilberts syndrome. (See "Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction".) STATIN INTOLERANCE As discussed above, while data from clinical trials suggest low rates of statin side effects leading to discontinuation, in clinical experience it is relatively common to find patients who are intolerant of one or more statins because of myalgias or other muscular symptoms (see 'Side effects' above). Less commonly, aminotransferase elevations require making changes in the statin, the statin dosage, or changes to another class of cholesterol-lowering therapy. Options for managing statin-induced muscle injury are discussed in detail separately. (See "Statin myopathy", section on 'Prevention and management'.) Options in patients with aminotransferase elevations (more than three times the upper limit of normal; confirmed on repeat testing) are similar, and include (see 'Hepatic dysfunction' above): Use of a different statin (particularly pravastatin) Dose reduction Alternate day therapy (see 'Alternative dosing regimens' above)

Despite these measures, many patients do not tolerate statin therapy. The clinical management of patients unable to take statin therapy for primary or secondary prevention is discussed in detail separately. (See "Treatment of lipids (including hypercholesterolemia) in primary prevention", section on 'Statin intolerance' and "Treatment of lipids (including hypercholesterolemia) in secondary prevention", section on 'Drug therapy'.) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, th th at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and

who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, th th more sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topics (see "Patient information: High cholesterol and lipids (hyperlipidemia) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS Statins are the most powerful drugs available for lowering LDL-C and are the most effective lipid lowering drugs for improving clinical outcomes when used for primary and secondary prevention of cardiovascular disease. The choice of statin depends upon a number of factors, including the degree of hyperlipidemia, pharmacokinetic properties, drug interactions, the presence of renal impairment, and cost. Rosuvastatin, atorvastatin, and simvastatin cause the greatest percentage change in LDLC; they are preferred in patients who require a potent statin because of high cardiovascular risk or who require >35 percent reduction in LDL-C. (See 'Potency' above.) In patients with severe renal impairment, we suggest treatment with atorvastatin or fluvastatin (Grade 2C). These medications do not require dose adjustment. (See 'Chronic kidney disease' above.) In patients with chronic liver disease who require a statin because of high cardiovascular risk, we suggest complete abstinence from alcohol and the use of pravastatin at a low dose (Grade 2C). (See 'Chronic liver disease' above.) Fewer pharmacokinetic drug interactions are likely to occur with pravastatin, fluvastatin, rosuvastatin, and pitavastatin because they are not metabolized through the CYP3A4 (table 5). (See 'Drug interactions' above.) There are no clear data that the adverse event profile differs significantly among statins. However, pravastatin and fluvastatin appear less likely to cause muscle toxicity than other statins. (See "Statin myopathy".) We suggest not routinely monitoring serum creatine kinase (CK), but it is useful to obtain a baseline CK level for reference purposes prior to starting statin therapy. Patients treated with statins should be alerted to report the new onset of myalgias or weakness. (See "Statin myopathy", section on 'Monitoring'.) We suggest checking baseline aminotransferase levels prior to initiating statin therapy; routine monitoring of these levels is not necessary for patients on statins. (See 'Hepatic dysfunction' above.) We suggest checking a TSH level prior to initiating statin therapy. (See 'Muscle injury' above.) Therapeutic decision making in patients with elevated lipid levels, including indications for and dosing of statins, is discussed in detail separately: (see "Treatment of lipids (including hypercholesterolemia) in primary prevention") (see "Treatment of lipids (including hypercholesterolemia) in secondary prevention")

(see "Intensity of lipid lowering therapy in secondary prevention of coronary heart disease") Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES

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