17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&searc… 1/19

Official reprint from UpToDate www.uptodate.com ©2014 UpToDate

AuthorRobert S Rosenson, MD

Section EditorMason W Freeman, MD

Deputy EditorDavid M Rind, MD

Statins: Actions, side effects, and administration

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: May 2014. | This topic last updated: Feb 24, 2014.

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 tomechanism of action and to the degree and type of lipid lowering. Thus, the indications for a particular drug are influenced by the underlying lipidabnormality. Conventional dosing regimens and common adverse reactions are described in a table (table 1) and the range of expected changes in thelipid 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 withcardiovascular disease or diabetes".)

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 mustcontribute; these include plaque stabilization, reversal of endothelial dysfunction, and decreased thrombogenicity. (See "Mechanisms of benefit of lipid­lowering 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 dietarysupplements are also discussed separately. (See "Lipid lowering with fibric acid derivatives" and "Lipid lowering with drugs other than statins andfibrates" 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:

MECHANISM OF ACTION — Currently available statins include lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, and, insome countries, pitavastatin (table 3). These agents are competitive inhibitors of HMG CoA reductase, the rate­limiting 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 ofrecovery of HMG CoA reductase activity after drug treatment [5].

Most of the statins have modest HDL­cholesterol (HDL­C) raising properties (about 5 percent), although rosuvastatin has a larger effect (see 'Effect onHDL' 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 lipid­lowering drugs inpatients 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 LDL­cholesterol (LDL­C), with reductions in the range of 30 to 63 percent (table3) [6­10]. When switching between statin drugs, equipotent doses with regard to LDL­C 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, LDL­C reduction is greater with rosuvastatin and atorvastatin than with the otheravailable 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 loweringLDL­C as most statins other than rosuvastatin and atorvastatin [13]. Fluvastatin is less likely to have drug interactions or produce muscle toxicity thansome other statins. (See 'Side effects' below.)

Although simvastatin 80 mg/day is a moderately­potent 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 switchingeven patients who are currently tolerating simvastatin 80 mg/day to one of these other statin options, since future medication therapy or illness couldincrease the risk for development of myopathy on high­dose simvastatin. High­dose simvastatin may be appropriate for a small number of patients whohave tolerated it well for many years or who are intolerant of other high­potency statin options.

There is an additive hypolipidemic effect when any of the statins is used in combination with a bile acid sequestrant (figure 3) [15­17], or the cholesterolabsorption 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 reducingLDL subclasses; they reduce the predominant subclass [18]. Among patients with the atherogenic dyslipidemia profile, the reduction in the predominantsubclass of small, dense LDL particles results in a shift of the LDL subfractions to more buoyant, and potentially less atherogenic, LDL [19­21]. (See

®®

(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 cardiovascular disease".)

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&searc… 2/19

"Inherited disorders of LDL­cholesterol metabolism", section on 'Small dense LDL (LDL phenotype B)' and "Lipoprotein classification; metabolism; androle in atherosclerosis", section on 'Intermediate density lipoprotein (remnant lipoproteins)' and "Lipoprotein classification; metabolism; and role inatherosclerosis", 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 HDL­C andapolipoprotein A­I concentrations [22]. However, rosuvastatin may be even more effective, raising HDL­C by up to 10 percent [11]. In metabolicsyndrome 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 HDL­cholesterol levels".)

Effect on triglycerides — Atorvastatin and rosuvastatin are more effective at lowering triglycerides (14 to 33 percent) than other statins in patients withhypercholesterolemia [11,23­25]. The magnitude of triglyceride lowering with statins may be larger in patients with hypertriglyceridemia.

The effects of atorvastatin and rosuvastatin on serum triglycerides are dose­dependent [11,23]. As an example, in a series of 56 patients with primaryhypertriglyceridemia in whom the average triglyceride concentration was 600 mg/dL and LDL­C concentration was 120 mg/dL (3.1 mmol/L), theadministration of atorvastatin at doses of 5, 20, or 80 mg/day produced reductions in triglycerides of 27, 32, and 46 percent, respectively, and in LDL­Cof 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 drugmetabolism. As an example, CYP2D6 is a member of the cytochrome P450 superfamily of drug oxidizing enzymes. CYP2D6 is functionally absent in 7percent of Caucasians and African­Americans, 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 LDL­C response to statins, but not the HDL­C response [27].

Concerns have been raised that Asians may have greater responses to low doses of statins than Caucasians [28]. Prescribing information forrosuvastatin recommends 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 isdiscussed extensively elsewhere:

SIDE EFFECTS — Adverse reactions occur less frequently with the statins than with most other classes of lipid lowering agents. Hepatic dysfunctionhas 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 adverseevents than the more hydrophilic statins (pravastatin and rosuvastatin) [30,31]; however, fluvastatin (a lipophilic statin) appears to have a low rate ofmuscle 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 ofdiscontinuation of therapy compared with placebo [33,34]. However, experience in clinical practice suggests that muscle side effects are relativelycommon, including side effects requiring discontinuation of statin therapy. The explanation for this difference is uncertain, but may relate to selectioncriteria 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 samestatin 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 inpatients receiving statins. This has primarily occurred during the first three months of therapy and is dose­dependent. Rare episodes of more severeliver 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 theincidence in the general population [37].

Several randomized trials have reported no significant difference in the incidence of persistently elevated aminotransferases between statin and placebotherapy [38­40]. A similar finding was noted in a review of three pravastatin trials with over 112,000 patient­years of exposure [41]. There was nodifference in the incidence or severity of serum aminotransferase elevations with pravastatin or placebo, including patients with aminotransferaseelevations at study entry. A meta­analysis of 35 randomized trials found an excess risk of aminotransferase elevation with statin therapy versusplacebo 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 elevationsmore than three times normal, and 0.5 percent had transaminase elevations two to three times normal [43]. None of these elevations appeared to berelated to statin use. Similarly, a review of five years of a health maintenance organization's computerized records on 23,000 patients who werereceiving statins found that 17 (0.1 percent) had an alanine aminotransferase level more than 10 times the upper limit of normal that appeared to beattributable 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 ofstatin therapy and to only repeat such testing for clinical indications [45]. We and others agree that routine monitoring of liver function tests in patients

(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 cardiovascular disease".)

(See "Clinical trials of cholesterol lowering for primary prevention of coronary heart disease".)

(See "Clinical trials of cholesterol lowering in patients with cardiovascular disease or diabetes".)

(See "Low density lipoprotein­cholesterol (LDL­C) lowering after an acute coronary syndrome".)

(See "Mechanisms of benefit of lipid­lowering drugs in patients with coronary heart disease".)

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&searc… 3/19

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 thanthree 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 withstatins span a spectrum of complaints ranging from myalgias to myositis to overt rhabdomyolysis, which may be associated with acute renal failurefrom myoglobinuria. This problem, including predisposing drug interactions, is discussed in detail elsewhere. (See "Statin myopathy".) Summarizedbriefly:

Hypothyroidism is a potential cause of dyslipidemia (see "Lipid abnormalities in thyroid disease"), and hypothyroidism may predispose patients tostatin­induced 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 onprotein 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 isavailable. However, it is unclear if rosuvastatin was responsible for the renal failure, as these patients were on other potentially nephrotoxicmedications. Although concerns had been raised about high rates of adverse event reports to the FDA regarding rosuvastatin [54], subsequentinformation suggests that renal adverse events with rosuvastatin are rare and are similar to those seen with other statins [57­60].

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) insecondary 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 whetherthe 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 isdifficult 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 ofadverse events reported to the US Food and Drug Administration between November 1997 and February 2002 found 60 reports of patients who hadmemory loss associated with statins [67]. Fourteen of 25 patients had improvement when the statin was discontinued, and four had recurrence ofmemory 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 lovastatinand simvastatin have shown some evidence of minor decrements in cognitive function as measured by neuropsychological testing [68,69]. Asystematic review of randomized trials and observational studies found that published data do not suggest that statins harm cognition; however, thequality of the evidence was felt to be only low to moderate, particularly with regard to high­intensity statin therapy [70].

In the absence of more definitive data, it may be appropriate for physicians to determine whether statin therapy was recently initiated in patients whodevelop new memory loss. If an individual patient appears to have memory loss associated with lipophilic statin therapy (simvastatin, lovastatin,atorvastatin, or fluvastatin) and has a strong indication for lipid lowering therapy, it would be reasonable to attempt treatment with a more hydrophilicstatin (pravastatin or rosuvastatin) [71].

In contrast to the above observations suggesting that statins may produce cognitive impairment, other studies have suggested that statins may have arole in the prevention of dementia. (See "Prevention of dementia", section on 'Statins'.)

Cancer — Preclinical studies found that very high­dose statin therapy increased the risk of liver tumors in rodents [72].

As discussed elsewhere, meta­analyses of randomized trials have shown no effect of statins on cancer incidence or cancer mortality [73­75]. (See"Statins: Possible noncardiovascular benefits", section on 'Cancer'.) A potential limitation of the meta­analyses is relatively short duration of follow­up.However, ten­year follow­up of the 4S trial and the West of Scotland Coronary Prevention Study (WOSCOPS) and 11­year follow­up of the HeartProtection Study (HPS) showed no increases in cancer deaths [76­78].

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 0.1percent for rhabdomyolysis.

Patients can experience statin­induced 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 returnto normal over days to weeks after drug discontinuation.

Pravastatin and fluvastatin appear to have less intrinsic muscle toxicity.

Enhanced susceptibility to statin­associated myopathy occurs in patients with acute or chronic renal failure, obstructive liver disease, andhypothyroidism.

If a patient requires a statin and experiences muscle toxicity (other than rhabdomyolysis) with a statin other than pravastatin or fluvastatin, oncesymptoms 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 traumaduring sports (running, diving for a volleyball, hockey), and patients who engage in high­impact sports should be advised to have a CK measuredbefore 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 tobe due to a statin is an indication for discontinuing the medication. Patients should drink large quantities of fluids to facilitate renal excretion ofmyoglobin. After the CK and/or myoglobin have returned to baseline, patients may be tried on a statin less likely to cause muscle toxicity (asabove) with careful monitoring.

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&searc… 4/19

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 oraffect glycemic control in patients with existing diabetes. Experimental evidence has been conflicting about whether statins as a group improve glucosemetabolism or whether some statins show beneficial effects while others show harmful effects [79­84].

Previously, some clinical trials of statins had reported conflicting results on the issue of glucose metabolism [85­88]. However, a 2010 meta­analysis of13 trials (N = 91,140) found little evidence of heterogeneity among large­scale chronic treatment trials [89]. For inclusion, trials were required to havemore than 1000 patients and a duration of follow­up of more than one year. This meta­analysis found an overall small increased risk for diabetes inpatients treated with statins (odds ratio [OR] for incident diabetes 1.09, 95% CI 1.02­1.17). Subgroup analyses found very similar diabetes risks in trialsof hydrophilic or lipophilic statins, and no clear differences among individual statins. The results were also similar after the exclusion of the JUPITERtrial. Since JUPITER had raised much of the concern about diabetes and statins [86], the stability of the result without JUPITER lowers the likelihoodthat the glucose findings in the meta­analysis were due to chance.

A 2011 meta­analysis of five randomized trials (N = 32,752) also found an increased risk of incident diabetes with intensive statin therapy comparedwith moderate statin therapy (OR 1.12, CI 1.04­1.22) with little or no heterogeneity across trials [90]. This translates into approximately one additionalcase of diabetes for every 500 patients treated with intensive rather than moderate statin therapy. Similarly, a large observational study usingadministrative data found a higher risk of diabetes with high­potency statins, an intermediate risk with moderate­potency statins, and a lower risk withlow­potency statins [91].

It appears likely that statin therapy confers a small increased risk of developing diabetes, and that the risk is slightly greater with intensive statintherapy than moderate statin therapy. As would be expected, given the evidence from clinical trials that statins reduce CV events in patient withdiabetes (see "Clinical trials of cholesterol lowering in patients with cardiovascular disease or diabetes"), both randomized trials and observationalstudies suggest that the beneficial effects of statins on CV events and mortality outweigh any increased risk conferred by promoting the developmentof diabetes [92,93].

Other

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 statinsare not major human teratogens [106]. Although some authors have recommended that pregnant women can be reassured that the fetal risk is low ifinadvertent exposure occurs [106], an analysis of an FDA surveillance database suggests a possible increase in congenital central nervous system andlimb abnormalities with exposure to lipophilic statins during the first trimester [107].

The risk of statins in pregnancy remains uncertain, however it appears that if statins are in fact harmful, the effect is likely relatively small [108­110].

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 [111], presumably reflecting the effects of a fasting state.For this reason, it is typically recommended that the statins with shorter half­lives 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 half­life, isadministered in the evening rather than in the morning [112,113]. A small study of atorvastatin, which has a long half­life, found no significantdifferences whether it was administered in the morning or the evening [114].

While it is unknown whether the timing of statin administration is important for clinical outcomes, we typically administer statins at the timerecommended by the manufacturer (table 3). Lovastatin absorption is increased by food, and it should be administered with the morning and eveningmeals.

Alternative dosing regimens — Every other day statin therapy has been suggested as a strategy to improve utilization and decrease cost. Smallstudies have compared daily statin use with alternate day dosing, and measured effects on lipid parameters and, in some cases, attainment of

Cataract – In preclinical toxicity testing, dogs developed cataracts when given doses of statins much higher than human doses [94]. While mostlarge case­control and cohort studies [95­97], as well as a small randomized trial [98], have not found an increased risk of cataract, large cohortstudies from England and Wales and from the United States military health system have found that statin use was associated with an increasedrisk of cataract [42,99].

In a subset analysis, one cohort study reported an association between statins and a decreased risk of one type of cataract (nuclear cataract)[97]; 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 acase­control 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 1.8­7.6) and 14.2 for definite cases (95% CI 5.3­38)[100]. 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 ofidiopathic polyneuropathy for every 2200 person­years of statin use.

A subsequent case­control study using a computer database to identify 272 patients with idiopathic polyneuropathy based on diagnosis codes didnot confirm a significantly increased risk with statin use, however there may have been problems with misclassification and the confidenceintervals were wide (odds ratio 1.30, 95% CI 0.3­2.1) [101].

As such, a causal association between statin use and neuropathy remains possible but has not been proven.

Lupus – There have been case reports of drug­induced lupus in patients receiving statins. (See "Drug­induced lupus".)

Androgen synthesis – Some [102,103], but not all [104], studies suggest that statins may lower androgen levels in men, although it appearsunlikely that this effect is clinically significant [105]. Statins may also reduce androgen levels in women, including in women with androgen excess[84].

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&searc… 5/19

cholesterol goals over six to twelve weeks [115­119]. Every other day regimens, and even once weekly regimens, have also been evaluated asstrategies for improving tolerability [120­122].

Results with atorvastatin, fluvastatin, and rosuvastatin suggest that to yield similar LDL­C lowering, the every other day dose needs to be on averagenearly twice that of the daily dose [115,116,118,122]. There are few data on alternate day regimens using a dose greater than 40 mg or on how patientadherence is impacted.

Major outcomes trials of statins have used daily statin therapy. In the absence of data from large randomized trials demonstrating equivalent effects onclinical outcomes with alternative dosing regimens, we suggest daily dosing in patients who are treated with statins. We prefer other measures for costcontrol, such as price comparison among generic statins [123]. Clinical experience suggests that alternate day dosing may improve the tolerability ofstatins 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 LDL­C 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 lipid­lowering agents, can predispose to statin­induced muscle injury. These are discussedin more detail separately. (See "Statin myopathy".) Summarized briefly:

The antiplatelet agent clopidogrel is a prodrug that is activated via metabolism by CYP­450. Based on current evidence clopidogrel therapy need notaffect 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 baselineCK level for reference purposes prior to starting statin therapy. Patients treated with statins should be alerted to report the new onset of myalgias orweakness. (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 'Hepaticdysfunction' above.)

Monitoring of the lipid response to statin therapy is discussed separately. (See "Treatment of lipids (including hypercholesterolemia) in primaryprevention", 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 notrequire dose adjustment and are the statins of choice in patients with severe renal impairment [125,126].

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 outcomescompared with placebo without an increase in side effects [127].

Chronic liver disease — In patients with chronic liver disease who require a statin because of high cardiovascular risk, we suggest completeabstinence from alcohol and the use of pravastatin at a low dose. If the LDL­C remains elevated, combined therapy with a bile acid sequestrant mayallow such patients to achieve their LDL­C 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 thatlooked at patients without evidence of alcohol abuse, hepatitis B, or hepatitis C compared a cohort of 342 patients (many of whom presumably had fattyliver or nonalcoholic steatohepatitis) with hyperlipidemia and baseline aminotransferase elevation (AST >40 IU/L [mean 55 IU/L] or ALT >35 IU/L [mean43 IU/L]) who were prescribed a statin with a cohort of 2245 patients with baseline aminotransferase elevation who were not prescribed a statin [128].There was no significant difference between the cohorts in the incidence of mild to moderate aminotransferase elevations (4.7 versus 6.4 percent) orsevere elevations (0.6 versus 0.4 percent). Rates of aminotransferase elevations were also similar in a cohort of hyperlipidemic patients with andwithout hepatitis C who were prescribed a statin [129].

A 36­week 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 [130]. Over the course of the trial, rates ofaminotransferase elevations were low in the group receiving pravastatin and no different from placebo, and none of the patients had an exacerbation oftheir underlying liver disease. Similarly, a post­hoc analysis of a randomized trial of statin therapy (mainly atorvastatin, 24 mg daily) found no evidenceof increased hepatic risk in patients with moderately abnormal liver function tests at baseline who were treated with a statin [131].

In a small study of patients with primary biliary cirrhosis who were treated with atorvastatin, significant transaminase elevations were common [132].Most statins are ultimately excreted in the bile, and toxic levels can develop in patients with cholestasis [133]. Additionally, the standard calculation ofLDL­C 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

The risk is substantially increased for most statins extensively metabolized by cytochrome P­450 3A4 (lovastatin, simvastatin and to a lesserextent atorvastatin) with concurrent therapy with drugs that interfere with CYP3A4 (table 5). Pravastatin, fluvastatin, rosuvastatin, and pitavastatinare preferred when concurrent therapy with a strong inhibitor of CYP3A4 cannot be avoided. Grapefruit juice inhibits CYP3A4, however dailyconsumption 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 interactionor 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/ritonavirand atazanavir/ritonavir [124].

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 beused cautiously and only if the benefit is likely to outweigh the low risk of muscle toxicity. Fenofibrate is the preferred fibrate in patients whorequire combined therapy with a statin.

In patients taking amlodipine, the dose of simvastatin should be no more than 20 mg daily.

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&searc… 6/19

possible to use statins safely in patients with mild cholestasis who have an appropriate indication for therapy [134], we avoid statin therapy in patientswith significant cholestasis unless there are compelling indications such as established atherosclerotic vascular disease that is considered clinicallyimportant. (See "Hypercholesterolemia and atherosclerosis in primary biliary cirrhosis", section on 'Cholesterol profile' and "Hypercholesterolemia andatherosclerosis in primary biliary cirrhosis", section on 'Drug therapy'.)

The use of statins is believed to be safe in patients with Gilbert’s syndrome. (See "Gilbert syndrome and unconjugated hyperbilirubinemia due tobilirubin overproduction".)

STATIN INTOLERANCE — As discussed above, while data from clinical trials suggest low rates of statin side effects leading to discontinuation, inclinical 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 anotherclass of cholesterol­lowering therapy.

Options for managing statin­induced muscle injury are discussed in detail separately. (See "Statin myopathy", section on 'Prevention andmanagement'.)

Options in patients with aminotransferase elevations (more than three times the upper limit of normal; confirmed on repeat testing) are similar, andinclude (see 'Hepatic dysfunction' above):

Despite these measures, many patients do not tolerate statin therapy. The clinical management of patients unable to take statin therapy for primary orsecondary 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 Basicspatient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patientmight have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy­to­read materials.Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 to 12 gradereading level and are best for patients who want in­depth 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 e­mail these topics to your patients. (You can alsolocate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS — Statins are the most powerful drugs available for lowering LDL­C and are the most effective lipid loweringdrugs for improving clinical outcomes when used for primary and secondary prevention of cardiovascular disease. The choice of statin depends upon anumber of factors, including the degree of hyperlipidemia, pharmacokinetic properties, drug interactions, the presence of renal impairment, and cost.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG­CoA reductase. Science 2001; 292:1160.2. Ness GC, Zhao Z, Lopez D. Inhibitors of cholesterol biosynthesis increase hepatic low­density lipoprotein receptor protein degradation. Arch

Biochem Biophys 1996; 325:242.3. Conde K, Vergara­Jimenez M, Krause BR, et al. Hypocholesterolemic actions of atorvastatin are associated with alterations on hepatic

Use of a different statin (particularly pravastatin)Dose reductionAlternate day therapy (see 'Alternative dosing regimens' above)

th th

th th

Beyond the Basics topics (see "Patient information: High cholesterol and lipids (hyperlipidemia) (Beyond the Basics)")

Rosuvastatin, atorvastatin, and simvastatin cause the greatest percentage change in LDL­C; they are preferred in patients who require a potentstatin because of high cardiovascular risk or who require >35 percent reduction in LDL­C. (See 'Potency' above.)

In patients with severe renal impairment, we suggest treatment with atorvastatin or fluvastatin (Grade 2C). These medications do not require doseadjustment. (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 andthe 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 notmetabolized 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 tocause 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 tostarting 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 forpatients 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 cardiovascular disease")•

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&searc… 7/19

cholesterol metabolism and lipoprotein composition in the guinea pig. J Lipid Res 1996; 37:2372.4. Arad Y, Ramakrishnan R, Ginsberg HN. Lovastatin therapy reduces low density lipoprotein apoB levels in subjects with combined hyperlipidemia

by reducing the production of apoB­containing lipoproteins: implications for the pathophysiology of apoB production. J Lipid Res 1990; 31:567.5. Ness GC, Chambers CM, Lopez D. Atorvastatin action involves diminished recovery of hepatic HMG­CoA reductase activity. J Lipid Res 1998;

39:75.6. Larsen ML, Illingworth DR. Drug treatment of dyslipoproteinemia. Med Clin North Am 1994; 78:225.7. Levy RI, Troendle AJ, Fattu JM. A quarter century of drug treatment of dyslipoproteinemia, with a focus on the new HMG­CoA reductase inhibitor

fluvastatin. Circulation 1993; 87:III45.8. Illingworth DR, Stein EA, Mitchel YB, et al. Comparative effects of lovastatin and niacin in primary hypercholesterolemia. A prospective trial. Arch

Intern Med 1994; 154:1586.9. Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and

fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998; 81:582.10. Rosenson RS. Rosuvastatin: a new inhibitor of HMG­coA reductase for the treatment of dyslipidemia. Expert Rev Cardiovasc Ther 2003; 1:495.11. Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin

across doses (STELLAR* Trial). Am J Cardiol 2003; 92:152.12. Brown AS, Bakker­Arkema RG, Yellen L, et al. Treating patients with documented atherosclerosis to National Cholesterol Education Program­

recommended low­density­lipoprotein cholesterol goals with atorvastatin, fluvastatin, lovastatin and simvastatin. J Am Coll Cardiol 1998; 32:665.13. Eidelman RS, Lamas GA, Hennekens CH. The new National Cholesterol Education Program guidelines: clinical challenges for more widespread

therapy of lipids to treat and prevent coronary heart disease. Arch Intern Med 2002; 162:2033.14. www.fda.gov/Drugs/DrugSafety/ucm256581.htm (Accessed on March 15, 2013).15. Sprecher DL, Abrams J, Allen JW, et al. Low­dose combined therapy with fluvastatin and cholestyramine in hyperlipidemic patients. Ann Intern

Med 1994; 120:537.16. Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid­lowering therapy in men with high levels

of apolipoprotein B. N Engl J Med 1990; 323:1289.17. Pan HY, DeVault AR, Swites BJ, et al. Pharmacokinetics and pharmacodynamics of pravastatin alone and with cholestyramine in

hypercholesterolemia. Clin Pharmacol Ther 1990; 48:201.18. Rosenson RS, Otvos JD, Hsia J. Effects of rosuvastatin and atorvastatin on LDL and HDL particle concentrations in patients with metabolic

syndrome: a randomized, double­blind, controlled study. Diabetes Care 2009; 32:1087.19. März W, Scharnagl H, Abletshauser C, et al. Fluvastatin lowers atherogenic dense low­density lipoproteins in postmenopausal women with the

atherogenic lipoprotein phenotype. Circulation 2001; 103:1942.20. Otvos JD, Shalaurova I, Freedman DS, Rosenson RS. Effects of pravastatin treatment on lipoprotein subclass profiles and particle size in the

PLAC­I trial. Atherosclerosis 2002; 160:41.21. Albert MA, Danielson E, Rifai N, et al. Effect of statin therapy on C­reactive protein levels: the pravastatin inflammation/CRP evaluation

(PRINCE): a randomized trial and cohort study. JAMA 2001; 286:64.22. Kastelein JJ, Isaacsohn JL, Ose L, et al. Comparison of effects of simvastatin versus atorvastatin on high­density lipoprotein cholesterol and

apolipoprotein A­I levels. Am J Cardiol 2000; 86:221.23. Bakker­Arkema RG, Davidson MH, Goldstein RJ, et al. Efficacy and safety of a new HMG­CoA reductase inhibitor, atorvastatin, in patients with

hypertriglyceridemia. JAMA 1996; 275:128.24. Davidson M, McKenney J, Stein E, et al. Comparison of one­year efficacy and safety of atorvastatin versus lovastatin in primary

hypercholesterolemia. Atorvastatin Study Group I. Am J Cardiol 1997; 79:1475.25. Dart A, Jerums G, Nicholson G, et al. A multicenter, double­blind, one­year study comparing safety and efficacy of atorvastatin versus

simvastatin in patients with hypercholesterolemia. Am J Cardiol 1997; 80:39.26. Mulder AB, van Lijf HJ, Bon MA, et al. Association of polymorphism in the cytochrome CYP2D6 and the efficacy and tolerability of simvastatin.

Clin Pharmacol Ther 2001; 70:546.27. Chasman DI, Posada D, Subrahmanyan L, et al. Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 2004; 291:2821.28. Liao JK. Safety and efficacy of statins in Asians. Am J Cardiol 2007; 99:410.29. www.astrazeneca­us.com/pi/crestor.pdf (Accessed on February 08, 2007).30. Rosenson RS. Current overview of statin­induced myopathy. Am J Med 2004; 116:408.31. Brewer HB Jr. Benefit­risk assessment of Rosuvastatin 10 to 40 milligrams. Am J Cardiol 2003; 92:23K.32. Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high­dosage statin therapy in hyperlipidemic patients­­the

PRIMO study. Cardiovasc Drugs Ther 2005; 19:403.33. Kashani A, Phillips CO, Foody JM, et al. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation

2006; 114:2788.34. Armitage J. The safety of statins in clinical practice. Lancet 2007; 370:1781.35. Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med 2013; 158:526.36. Björnsson E, Jacobsen EI, Kalaitzakis E. Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post­marketing. J Hepatol

2012; 56:374.37. Cohen DE, Anania FA, Chalasani N, National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by

hepatologists. Am J Cardiol 2006; 97:77C.38. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol

levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279:1615.39. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet

1994; 344:1383.40. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high­risk

individuals: a randomised placebo­controlled trial. Lancet 2002; 360:7.41. Pfeffer MA, Keech A, Sacks FM, et al. Safety and tolerability of pravastatin in long­term clinical trials: prospective Pravastatin Pooling (PPP)

Project. Circulation 2002; 105:2341.42. Hippisley­Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the

QResearch database. BMJ 2010; 340:c2197.43. Smith CC, Bernstein LI, Davis RB, et al. Screening for statin­related toxicity: the yield of transaminase and creatine kinase measurements in a

primary care setting. Arch Intern Med 2003; 163:688.

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&searc… 8/19

44. Charles EC, Olson KL, Sandhoff BG, et al. Evaluation of cases of severe statin­related transaminitis within a large health maintenanceorganization. Am J Med 2005; 118:618.

45. http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm (Accessed on February 28, 2012).46. Weismantel D, Danis P. Clinical inquiries. What laboratory monitoring is appropriate to detect adverse drug reactions in patients on cholesterol­

lowering agents? J Fam Pract 2001; 50:927.47. Gotto AM Jr. Safety and statin therapy: reconsidering the risks and benefits. Arch Intern Med 2003; 163:657.48. Ballantyne CM, Corsini A, Davidson MH, et al. Risk for myopathy with statin therapy in high­risk patients. Arch Intern Med 2003; 163:553.49. Thompson PD, Clarkson PM, Rosenson RS, National Lipid Association Statin Safety Task Force Muscle Safety Expert Panel. An assessment of

statin safety by muscle experts. Am J Cardiol 2006; 97:69C.50. Bar SL, Holmes DT, Frohlich J. Asymptomatic hypothyroidism and statin­induced myopathy. Can Fam Physician 2007; 53:428.51. Lando HM, Burman KD. Two cases of statin­induced myopathy caused by induced hypothyroidism. Endocr Pract 2008; 14:726.52. Vidt DG, Cressman MD, Harris S, et al. Rosuvastatin­induced arrest in progression of renal disease. Cardiology 2004; 102:52.53. Sidaway JE, Davidson RG, McTaggart F, et al. Inhibitors of 3­hydroxy­3­methylglutaryl­CoA reductase reduce receptor­mediated endocytosis in

opossum kidney cells. J Am Soc Nephrol 2004; 15:2258.54. Alsheikh­Ali AA, Ambrose MS, Kuvin JT, Karas RH. The safety of rosuvastatin as used in common clinical practice: a postmarketing analysis.

Circulation 2005; 111:3051.55. Grundy SM. The issue of statin safety: where do we stand? Circulation 2005; 111:3016.56. www.fda.gov/cder/drug/infopage/rosuvastatin/crestor_CP.pdf (Accessed on June 10, 2005).57. McAfee AT, Ming EE, Seeger JD, et al. The comparative safety of rosuvastatin: a retrospective matched cohort study in over 48,000 initiators of

statin therapy. Pharmacoepidemiol Drug Saf 2006; 15:444.58. Guthrie RM, Martin DR. The safety of rosuvastatin: effects on renal and hepatic function. Expert Opin Drug Saf 2007; 6:573.59. García­Rodríguez LA, Massó­González EL, Wallander MA, Johansson S. The safety of rosuvastatin in comparison with other statins in over

100,000 statin users in UK primary care. Pharmacoepidemiol Drug Saf 2008; 17:943.60. García­Rodríguez LA, González­Pérez A, Stang MR, et al. The safety of rosuvastatin in comparison with other statins in over 25,000 statin users

in the Saskatchewan Health Databases. Pharmacoepidemiol Drug Saf 2008; 17:953.61. Yang CC, Jick SS, Jick H. Lipid­lowering drugs and the risk of depression and suicidal behavior. Arch Intern Med 2003; 163:1926.62. Golomb BA, Kane T, Dimsdale JE. Severe irritability associated with statin cholesterol­lowering drugs. QJM 2004; 97:229.63. Redelmeier DA, Thiruchelvam D, Daneman N. Delirium after elective surgery among elderly patients taking statins. CMAJ 2008; 179:645.64. Marcantonio ER. Statins and postoperative delirium. CMAJ 2008; 179:627.65. CGS News www.cbsnews.com/stories/2004/05/24/eveningnews/main619351.shtml (Accessed on March 07, 2005).66. Graveline D. Lipitor: Thief of memory: Statin Drugs and the Misguided War on Cholesterol, Infinity Publishing, Haverford, PA 2004.67. Wagstaff LR, Mitton MW, Arvik BM, Doraiswamy PM. Statin­associated memory loss: analysis of 60 case reports and review of the literature.

Pharmacotherapy 2003; 23:871.68. Muldoon MF, Barger SD, Ryan CM, et al. Effects of lovastatin on cognitive function and psychological well­being. Am J Med 2000; 108:538.69. Muldoon MF, Ryan CM, Sereika SM, et al. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults.

Am J Med 2004; 117:823.70. Richardson K, Schoen M, French B, et al. Statins and cognitive function: a systematic review. Ann Intern Med 2013; 159:688.71. Rojas­Fernandez CH, Cameron JC. Is statin­associated cognitive impairment clinically relevant? A narrative review and clinical

recommendations. Ann Pharmacother 2012; 46:549.72. Newman TB, Hulley SB. Carcinogenicity of lipid­lowering drugs. JAMA 1996; 275:55.73. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol­lowering treatment: prospective meta­analysis of data from 90,056

participants in 14 randomised trials of statins. Lancet 2005; 366:1267.74. Dale KM, Coleman CI, Henyan NN, et al. Statins and cancer risk: a meta­analysis. JAMA 2006; 295:74.75. Browning DR, Martin RM. Statins and risk of cancer: a systematic review and metaanalysis. Int J Cancer 2007; 120:833.76. Strandberg TE, Pyörälä K, Cook TJ, et al. Mortality and incidence of cancer during 10­year follow­up of the Scandinavian Simvastatin Survival

Study (4S). Lancet 2004; 364:771.77. Ford I, Murray H, Packard CJ, et al. Long­term follow­up of the West of Scotland Coronary Prevention Study. N Engl J Med 2007; 357:1477.78. Heart Protection Study Collaborative Group, Bulbulia R, Bowman L, et al. Effects on 11­year mortality and morbidity of lowering LDL cholesterol

with simvastatin for about 5 years in 20,536 high­risk individuals: a randomised controlled trial. Lancet 2011; 378:2013.79. Yu Y, Ohmori K, Chen Y, et al. Effects of pravastatin on progression of glucose intolerance and cardiovascular remodeling in a type II diabetes

model. J Am Coll Cardiol 2004; 44:904.80. Wong V, Stavar L, Szeto L, et al. Atorvastatin induces insulin sensitization in Zucker lean and fatty rats. Atherosclerosis 2006; 184:348.81. Chen Y, Ohmori K, Mizukawa M, et al. Differential impact of atorvastatin vs pravastatin on progressive insulin resistance and left ventricular

diastolic dysfunction in a rat model of type II diabetes. Circ J 2007; 71:144.82. Mita T, Watada H, Nakayama S, et al. Preferable effect of pravastatin compared to atorvastatin on beta cell function in Japanese early­state type

2 diabetes with hypercholesterolemia. Endocr J 2007; 54:441.83. Yamakawa T, Takano T, Tanaka S, et al. Influence of pitavastatin on glucose tolerance in patients with type 2 diabetes mellitus. J Atheroscler

Thromb 2008; 15:269.84. Sathyapalan T, Kilpatrick ES, Coady AM, Atkin SL. The effect of atorvastatin in patients with polycystic ovary syndrome: a randomized double­

blind placebo­controlled study. J Clin Endocrinol Metab 2009; 94:103.85. Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the

West of Scotland Coronary Prevention Study. Circulation 2001; 103:357.86. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C­reactive protein. N Engl

J Med 2008; 359:2195.87. Shepherd J. Glasgow Royal Infirmary, 2008, personal communication.88. Coleman CI, Reinhart K, Kluger J, White CM. The effect of statins on the development of new­onset type 2 diabetes: a meta­analysis of

randomized controlled trials. Curr Med Res Opin 2008; 24:1359.89. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta­analysis of randomised statin trials. Lancet 2010;

375:735.

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&searc… 9/19

90. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive­dose compared with moderate­dose statin therapy: a meta­analysis. JAMA 2011; 305:2556.

91. Carter AA, Gomes T, Camacho X, et al. Risk of incident diabetes among patients treated with statins: population based study. BMJ 2013;346:f2610.

92. Ridker PM, Pradhan A, MacFadyen JG, et al. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis fromthe JUPITER trial. Lancet 2012; 380:565.

93. Wang KL, Liu CJ, Chao TF, et al. Statins, risk of diabetes, and implications on outcomes in the general population. J Am Coll Cardiol 2012.94. Gerson RJ, MacDonald JS, Alberts AW, et al. On the etiology of subcapsular lenticular opacities produced in dogs receiving HMG­CoA reductase

inhibitors. Exp Eye Res 1990; 50:65.95. Schlienger RG, Haefeli WE, Jick H, Meier CR. Risk of cataract in patients treated with statins. Arch Intern Med 2001; 161:2021.96. Smeeth L, Hubbard R, Fletcher AE. Cataract and the use of statins: a case­control study. QJM 2003; 96:337.97. Klein BE, Klein R, Lee KE, Grady LM. Statin use and incident nuclear cataract. JAMA 2006; 295:2752.98. Harris ML, Bron AJ, Brown NA, et al. Absence of effect of simvastatin on the progression of lens opacities in a randomised placebo controlled

study. Oxford Cholesterol Study Group. Br J Ophthalmol 1995; 79:996.99. Leuschen J, Mortensen EM, Frei CR, et al. Association of statin use with cataracts: a propensity score­matched analysis. JAMA Ophthalmol

2013; 131:1427.100. Gaist D, Jeppesen U, Andersen M, et al. Statins and risk of polyneuropathy: a case­control study. Neurology 2002; 58:1333.101. Anderson JL, Muhlestein JB, Bair TL, et al. Do statins increase the risk of idiopathic polyneuropathy? Am J Cardiol 2005; 95:1097.102. Dobs AS, Schrott H, Davidson MH, et al. Effects of high­dose simvastatin on adrenal and gonadal steroidogenesis in men with

hypercholesterolemia. Metabolism 2000; 49:1234.103. Davidson MH, Stein EA, Dujovne CA, et al. The efficacy and six­week tolerability of simvastatin 80 and 160 mg/day. Am J Cardiol 1997; 79:38.104. Azzarito C, Boiardi L, Vergoni W, et al. Testicular function in hypercholesterolemic male patients during prolonged simvastatin treatment. Horm

Metab Res 1996; 28:193.105. Santini SA, Carrozza C, Lulli P, et al. Atorvastatin treatment does not affect gonadal and adrenal hormones in type 2 diabetes patients with mild

to moderate hypercholesterolemia. J Atheroscler Thromb 2003; 10:160.106. Hosokawa A, Bar­Oz B, Ito S. Use of lipid­lowering agents (statins) during pregnancy. Can Fam Physician 2003; 49:747.107. Edison RJ, Muenke M. Central nervous system and limb anomalies in case reports of first­trimester statin exposure. N Engl J Med 2004;

350:1579.108. Kazmin A, Garcia­Bournissen F, Koren G. Risks of statin use during pregnancy: a systematic review. J Obstet Gynaecol Can 2007; 29:906.109. Taguchi N, Rubin ET, Hosokawa A, et al. Prenatal exposure to HMG­CoA reductase inhibitors: effects on fetal and neonatal outcomes. Reprod

Toxicol 2008; 26:175.110. Costantine MM, Cleary K, Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric­­Fetal Pharmacology

Research Units Network. Pravastatin for the prevention of preeclampsia in high­risk pregnant women. Obstet Gynecol 2013; 121:349.111. Miettinen TA. Diurnal variation of cholesterol precursors squalene and methyl sterols in human plasma lipoproteins. J Lipid Res 1982; 23:466.112. Saito Y, Yoshida S, Nakaya N, et al. Comparison between morning and evening doses of simvastatin in hyperlipidemic subjects. A double­blind

comparative study. Arterioscler Thromb 1991; 11:816.113. Wallace A, Chinn D, Rubin G. Taking simvastatin in the morning compared with in the evening: randomised controlled trial. BMJ 2003; 327:788.114. Cilla DD Jr, Gibson DM, Whitfield LR, Sedman AJ. Pharmacodynamic effects and pharmacokinetics of atorvastatin after administration to

normocholesterolemic subjects in the morning and evening. J Clin Pharmacol 1996; 36:604.115. Rindone JP, Hiller D, Arriola G. A comparison of fluvastatin 40 mg every other day versus 20 mg every day in patients with hypercholesterolemia.

Pharmacotherapy 1998; 18:836.116. Matalka MS, Ravnan MC, Deedwania PC. Is alternate daily dose of atorvastatin effective in treating patients with hyperlipidemia? The Alternate

Day Versus Daily Dosing of Atorvastatin Study (ADDAS). Am Heart J 2002; 144:674.117. Jafari M, Ebrahimi R, Ahmadi­Kashani M, et al. Efficacy of alternate­day dosing versus daily dosing of atorvastatin. J Cardiovasc Pharmacol

Ther 2003; 8:123.118. Ferrer­García JC, Pérez­Silvestre J, Martínez­Mir I, Herrera­Ballester A. Alternate­day dosing of atorvastatin: effects in treating type 2 diabetic

patients with dyslipidaemia. Acta Diabetol 2006; 43:75.119. Wongwiwatthananukit S, Sansanayudh N, Dhummauppakorn R, Kitiyadisai C. Efficacy and safety of rosuvastatin every other day compared with

once daily in patients with hypercholesterolemia. Ann Pharmacother 2006; 40:1917.120. Backes JM, Venero CV, Gibson CA, et al. Effectiveness and tolerability of every­other­day rosuvastatin dosing in patients with prior statin

intolerance. Ann Pharmacother 2008; 42:341.121. Kayikçioğlu M, Ozerkan F, Soydan I. Effectiveness and safety of alternate­day simvastatin and fenofibrate on mixed hyperlipidemia. Am J

Cardiol 1999; 83:1135.122. Ruisinger JF, Backes JM, Gibson CA, Moriarty PM. Once­a­week rosuvastatin (2.5 to 20 mg) in patients with a previous statin intolerance. Am J

Cardiol 2009; 103:393.123. Drugs for lipids. Treat Guidel Med Lett 2008; 6:9.124. www.fda.gov/Safety/MedWatch/SafetyInformation/ucm200635.htm (Accessed on February 19, 2010).125. Chong PH, Seeger JD, Franklin C. Clinically relevant differences between the statins: implications for therapeutic selection. Am J Med 2001;

111:390.126. Kasiske BL, Wanner C, O'Neill WC, National Lipid Association Statin Safety Task Force Kidney Expert Panel. An assessment of statin safety by

nephrologists. Am J Cardiol 2006; 97:82C.127. Tonelli M, Moyé L, Sacks FM, et al. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal

insufficiency. Ann Intern Med 2003; 138:98.128. Chalasani N, Aljadhey H, Kesterson J, et al. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology

2004; 126:1287.129. Khorashadi S, Hasson NK, Cheung RC. Incidence of statin hepatotoxicity in patients with hepatitis C. Clin Gastroenterol Hepatol 2006; 4:902.130. Lewis JH, Mortensen ME, Zweig S, et al. Efficacy and safety of high­dose pravastatin in hypercholesterolemic patients with well­compensated

chronic liver disease: Results of a prospective, randomized, double­blind, placebo­controlled, multicenter trial. Hepatology 2007; 46:1453.131. Athyros VG, Tziomalos K, Gossios TD, et al. Safety and efficacy of long­term statin treatment for cardiovascular events in patients with coronary

heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post­hoc analysis.Lancet 2010; 376:1916.

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&sear… 10/19

132. Stojakovic T, Putz­Bankuti C, Fauler G, et al. Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response toursodeoxycholic acid. Hepatology 2007; 46:776.

133. Sorokin A, Brown JL, Thompson PD. Primary biliary cirrhosis, hyperlipidemia, and atherosclerotic risk: a systematic review. Atherosclerosis2007; 194:293.

134. Abu Rajab M, Kaplan MM. Statins in primary biliary cirrhosis: are they safe? Dig Dis Sci 2010; 55:2086.

Topic 4564 Version 36.0

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&sear… 11/19

GRAPHICS

Adult dosing, side effects, and drug interactions of lipid lowering drugs

Drug class Dose Dosing Major side effects and drug interactions

Statins (HMG CoA reductase inhibitors)

Lovastatin 20­80mg/day

IR take with eveningmeal. BID with meals ifdose >20 mg/day. XRtake any time.

Headache; nausea; sleep disturbance; elevations in hepatocellularenzymes and alkaline phosphatase. Myositis and rhabdomyolysis,primarily when given with gemfibrozil or cyclosporine; myositis is alsoseen with severe renal insufficiency (CrCl <30 mL/min). Lovastatin,atorvastatin, rosuvastatin, and simvastatin potentiate effect of warfarin;this interaction is not seen with pravastatin, fluvastatin, or pitavastatin.Most statins can also affect digoxin metabolism and levels.

Pravastatin 10­80mg/day

Simvastatin 5­40mg/day

Take in the evening

Fluvastatin 20­80mg/day

IR take in the evening;if dose >40 mg/daytake morning andevening. XR take anytime.

80 mgXR/day

Atorvastatin 10­80mg/day

Rosuvastatin 5­40mg/day

Pitavastatin 1­4 mg/day

Gemfibrozil 600 mgBID

30 to 60 min beforemeals

Potentiates warfarin action. Absorption of gemfibrozil diminished by bileacid sequestrants.

Fenofibrate Nanocrystal145mg/day

Micronized160­200mg/day

Micronized taken withmeals. Use lower doseswith renalinsufficiency.

Skin rash, gastrointestinal (nausea, bloating, cramping) myalgia; lowersblood cyclosporine levels; potentially nephrotoxic in cyclosporine treatedpatients. Avoid in patients with CrCl <30 mL/min.

Nicotinic acid 1­12 g/day Given with meals.Start with 100 mg BIDand titrate to 500 mgTID. After six weeks,check lipids, glucose,liver function, and uricacid. Increase dose asneeded.

Prostaglandin­mediated cutaneous flushing, headache, warm sensation,and pruritus; hyperpigmentation (particularly in intertriginous regions);acanthosis nigricans; dry skin; nausea; vomiting; diarrhea; and myositis

Bile acid sequestrants

Cholestyramine 4­24 g/day Take within 30 min ofa meal. A double dosewith dinner producessame lipid­loweringeffect as BID dosing.

Nausea, bloating, cramping, and constipation; elevations in hepatictransaminases and alkaline phosphatase. Impaired absorption of fatsoluble vitamins, digoxin, warfarin, thiazides, β­blockers, thyroxine, andphenobarbital.Colestipol 5­30 g/day

Colesevelam 3.75 g/day Take with meals QD ordivided BID

Similar

Cholesterol absorption inhibitors

Ezetimibe 10 mg/day Increased transaminases in combination with statins

Neomycin 1 g BID Ototoxicity; nephrotoxicity

Probucol 500 mgBID

Loose stools; eosinophilia; QT prolongation; angioneurotic edema

BID: twice daily; QD: daily; TID: three times daily; IR: immediate release; XR: extended release; CrCl: creatinine clearance.

Graphic 77498 Version 9.0

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&sear… 12/19

Average effects of different classes of lipid lowering drugs on serum lipids

Drug class Serum LDL cholesterol Serum HDL cholesterol Serum triglycerides

Bile acid sequestrants ↓ 15 to 30 percent 0 to slight increase No change*

Nicotinic acid ↓ 10 to 25 percent ↑ 15 to 35 percent ↓ 25 to 30 percent

HMG CoA reductase inhibitors ↓ 20 to 60 percent ↑ 5 to 10 percent ↓ 10 to 33 percent

Gemfibrozil ↓ 10 to 15 percent ↑ 5 to 20 percent• ↓ 35 to 50 percent

Fenofibrate (micronized form) ↓ 6 to 20 percent ↑ 5 to 20 percent• ↓ 41 to 53 percent

Cholesterol absorption inhibitors ↓ 17 percent ↑ 1 percent ↓ 7 to 8 percent

Neomycin ↓ 20 to 25 percent No change No change

Omega 3 fatty acidsΔ ↑ 4 to 49 percent ↑ 5 to 9 percent ↓ 23 to 45 percent

↑: increase; ↓: decrease.* Serum triglyceride levels may increase in patients with pre­existing hypertriglyceridemia.• Increases of 20 percent are seen in patients with very high triglycerides; increases of 5 percent are more typical with fibrate monotherapyin patients with lower triglycerides.Δ Lovaza 4 grams daily or 12 to 15 grams of less purified form of omega 3 fatty acids.

Graphic 75715 Version 5.0

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&sear… 13/19

Properties of statins

Variable Atorvastatin Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin

LDLcholesterolreductions(dose range,mg)

38 to 54percent (10 to80)

17 to 33percent (20 to80)

29 to 48percent (20to 80)

31 to 41percent (1 to 4)

19 to 40percent (10 to40)

52 to 63 percent(10 to 40)

28 to 41percent (10 to40)

Eliminationhalf­life, hours

15 to 30 0.5 to 2.3 2.9 12 1.3 to 2.8 19 2 to 3

Bioavailability,percent

12 19 to 29 5 51 18 20 5

Proteinbinding,percent

80 to 90 >99 >95 99 43 to 55 88 94 to 98

Solubility Lipophilic Lipophilic Lipophilic Lipophilic Hydrophilic Hydrophilic Lipophilic

Cytochrome450metabolismand lsozyme

3A4 2C9 3A4 Limited 2C9,2C8

­ Limited 2C9 3A4, 3A5

Activemetabolites

Yes No Yes Yes No No Yes

Effect of foodon absorptionof drug

None Negligible Increasedabsorption

Decreases Decreasedabsorption

None None

Optimal timeofadministration

Anytime IR: evening(or morningand evening iftaken twicedaily)

XR: anytime

IR: withevening meal(or withmorning andevening mealif taken twicedaily)

XR: anytime

Anytime Anytime Anytime Evening

Renalexcretion ofabsorbeddose, percent

2 <6 10 15 20 10 13

IR: immediate release; XR: extended release.

Graphic 53730 Version 5.0

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&sear… 14/19

Statins and cholesterol synthesis

Inhibition of HMG CoA reductase reduces intracellular cholesterol levels; thisactivates a protease, which in turn cleaves sterol regulatory element­bindingproteins (SREBP's) from the endoplasmic reticulum. The SREBP's translocate tothe nucleus where they upregulate expression of the LDL receptor gene.Enhanced LDL receptor expression increases receptor­mediated endocytosis ofLDL and thus lowers serum LDL. Inhibition of HMG CoA reductase also reducesintracellular levels of isoprenoids, which are intermediates in cholesterolbiosynthesis.

Reprinted with permission from: Vaughan, CJ, Gotto, AM, Basson, CT. J Am Coll Cardiol2000; 35:1. Copyright © 2000 American College of Cardiology.

Graphic 57263 Version 1.0

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&sear… 15/19

Comparison of the efficacy of statin drugs

Comparison of the percent reduction in serum low density lipoprotein (LDL)­cholesterol with various statin drugs.

Graphic 60663 Version 1.0

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&sear… 16/19

The combination of a statin and a bile acid bindingresin is more effective than either alone

The reduction in low­density lipoprotein (LDL) cholesterolconcentration and the increase in high­density lipoprotein (HDL)concentration is greater with the combination of a statin and a bileacid binding resin, given as cholestyramine, when compared withtherapy with either drug alone. The effects of both drugs declineexponentially with increasing doses.

Data from The Prevastatin Multicenter Study Group II, Arch Intern Med 1993;153:1321.

Graphic 63912 Version 1.0

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&sear… 17/19

Drug ratings in pregnancy (US Food & Drug Administration)

Category Interpretation

A Controlled human studies show no risk

Controlled studies in pregnant women fail to demonstrate a risk to the fetus in the first trimester with no evidence ofrisk in later trimesters. The possibility of fetal harm appears remote.

B No evidence of risk in studies

Either animal­reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnantwomen, or animal­reproduction studies have shown an adverse effect (other than a decrease in fertility) that wasnot confirmed in controlled studies in women in the first trimester and there is no evidence of a risk in latertrimesters.

C Risk cannot be ruled out

Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal effects or other) andthere are no controlled studies in women, or studies in women and animals are not available. Drugs should be givenonly if the potential benefits justify the potential risk to the fetus.

D Positive evidence of risk

There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptabledespite the risk (eg, if the drug is needed in a life­threatening situation or for a serious disease for which safer drugscannot be used or are ineffective).

X Contraindicated in pregnancy

Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based onhuman experience, or both, and the risk of the use of the drug in pregnant women clearly outweighs any possiblebenefit. The drug is contraindicated in women who are or may become pregnant.

Reproduced with permission from: Lexicomp Online. Copyright © 1978­2014 Lexicomp, Inc. All Rights Reserved.

Graphic 50021 Version 16.0

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&sear… 18/19

Inhibitors and inducers of cytochrome P450 3A4 (CYP3A4)*

Strong inhibitors

Atazanavir

Boceprevir

Chloramphenicol

Clarithromycin

Cobicistat containingcoformulations

Conivaptan

Darunavir

Delavirdine

Fosamprenavir

Indinavir

Itraconazole

Ketoconazole

Lopinavir

Nefazodone

Nelfinavir

Nicardipine

Posaconazole

Ritonavir and ritonavircontaining coformulations

Saquinavir

Telaprevir

Telithromycin

Voriconazole

Moderate inhibitors

Abiraterone

Amiodarone

Aprepitant

Bicalutamide

Cimetidine

Ciprofloxacin

Clotrimazole

Crizotinib

Cyclosporine

Desipramine

Diltiazem

Danazol

Dasatinib

Dronedarone

Efavirenz

Erythromycin

Fluconazole

Fosaprepitant

Grapefruit juice

Haloperidol

Iloperidone

Imatinib

Lapatinib

Lomitapide

Metronidazole

Miconazole

Mifepristone

Norfloxacin

Quinupristin­dalfopristin

Sertraline

Sitaxsentan

Tamoxifen

Tetracycline

Verapamil

Zafirlukast

Strong inducers

Carbamazepine

Dexamethasone

Enzalutamide

Fosphenytoin

Mitotane

Nafcillin

Nevirapine

Oxcarbazepine

Pentobarbital

Phenobarbital

Phenytoin

Primidone

Rifabutin

Rifampin (rifampicin)

Rifapentine

St. John's wort

Moderate or weakinducers

Aprepitant

Armodafinil

Artemether

Bexarotene

Bosentan

Calcitriol

Clobazam

Colchicine

Dabrafenib

Deferasirox

Desvenlafaxine

Dicloxacillin

Efavirenz

Eslicarbazepine

Estrogens

Etravirine

Exemestane

Felbamate

Fosaprepitant

Griseofulvin

Hydrocortisone

Medroxyprogesterone

Metyrapone

Modafinil

Paclitaxel

Perampanel

Pioglitazone

Prednisone

Ritonavir

Rufinamide

Terbinafine

Topiramate

Trametinib

Vemurafenib

NOTES: Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose and method ofadministration. Specific drug interactions and management suggestions may be determined by using Lexi­Interact, the druginteractions program included with UpToDate.

* The CYP3A4 inhibitors and inducers listed in this table are relevant for determining potential interactions of drugs that are CYP3A subfamilysubstrates.• Less potent effect on CYP3A4 reported in some references.

Data from:1. Lexicomp Online. Copyright © 1978­2014 Lexicomp, Inc. All Rights Reserved.2. Hansten PD, Horn JR. Top 100 drug interactions: guide to patient management, 13th ed, H&H Publications, 2013.3. Inhibitors and inducers of CYP enzymes and P­glycoprotein; The Medical Letter 2013; 55(1417):44.

Graphic 76992 Version 15.0

•

•

•

•

•

•

•

•

17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&sear… 19/19

Disclosures: Robert S Rosenson, MD Grant/Research/Clinical Trial Support: Amgen [Lipids (Evolocumab)]; Sanofi [Lipids(Alirocumab)]; Astra Zeneca [Lipids (Epanova); Peripheral artery disease (Ticagrelor)]. Speaker's Bureau: Astra Zeneca [Lipids(Disease state management)]. Consulant/Advisory Boards: Aegerion [Lipids (Limitapide)]; Amgen [Lipids (Evolocumab)]; AstraZeneca [Lipids (Epanova)]; Eli Lilly [Lipids (Disease state)]; Janssen [Diabetes (Canagliflozin)]; Novartis [DMC (Hedgehog inhibitor)];Regeneron [Lipids (Disease state)]; Sanofi [Lipids (Alirocumab)]. Equity Ownership/Stock Options: LipoScience; Medicines Co;Mesoblast; Teva. Mason W Freeman, MD Grant/Research Support/Clinical Trial Support: Sanofi [Rx of LDL­c (PCSK9 Ab)]. David MRind, MD Employee of UpToDate, Inc. Equity Ownership/Stock Options (Spouse): Bonfire Development Advisors [CBT (iCBT)].Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vettingthrough a multi­level review process, and through requirements for references to be provided to support the content. Appropriatelyreferenced content is required of all authors and must conform to UpToDate standards of evidence.Conflict of interest policy

Disclosures