1) Cancer — Preclinical studies found that very high-dose statin therapy increased the risk of liver tumors in rodents

2)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 [71-76].

3)Hepatic dysfunction — Clinical studies of statins have demonstrated a 0.5 to 3 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.

4) Muscle injury — Development of muscle toxicity remains .................
•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.

5) Hypothyroidism is a potential cause of dyslipidemia (see "Lipid abnormalities in thyroid disease"), and hypothyroidism may predispose patients to statin-induced myopathy [45,46]. As such, we suggest checking a TSH level prior to initiating statin therapy.

6) Renal dysfunction — (ЗДЕСЬ ПОПОДРОБНЕЕ ) Statins appear to be able to cause proteinuria through tubular inhibition of active transport of small molecular weight proteins [47,48]. There have been a number of reports to the FDA about proteinuria with statins, particularly in patients receiving rosuvastatin or simvastatin [49]. However, it is believed that proteinuria with statins is a benign finding [50,51]. (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 [49], subsequent information suggests that renal adverse events with rosuvastatin are rare and are similar to those seen with other statins

7)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

ЕСТЬ ЦЕЛЫЙ СПИСОК ДРУГИХ ОСЛОЖНЕНИЙ ,ПОД ГЛАВОЙ Other
•Cataract – In preclinical toxicity testing, dogs developed cataracts when given doses of statins much higher than human doses [82]. While most large case-control and cohort studies [83-85], as well as a small randomized trial [86], 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 [38].

In a subset analysis, one cohort study reported an association between statins and a decreased risk of one type of cataract (nuclear cataract) [85]; 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) [87]. 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) [88].

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 [89,90], but not all [91], studies suggest that statins may lower androgen levels in men, although it appears unlikely that this effect is clinically significant [92]. Statins may also reduce androgen levels in women, including in women with androgen excess [76].

Risks in pregnancy and breastfeeding — In the United States, statins are rated category X in pregnancy (table 4), and the recommendation is to discontinue their use prior to conception if possible.

Muscle injury associated with lipid lowering drugs

Authors
Marc L Miller, MD
Robert S Rosenson, MD
Steven Baker, MD Section Editor
Mason W Freeman, MD Deputy Editor
David M Rind, MD

INTRODUCTION — The statins are increasingly used to lower the serum cholesterol concentration for both primary and secondary prevention of coronary disease. (See "Lipid lowering with statins").

Statins are both effective and generally safe. Although uncommon, muscle toxicity remains a concern. However, severe myopathy is unusual, affecting perhaps 0.1 percent of patients and, in patients with normal serum CK, there is no evidence of permanent or progressive muscle injury [1] .

MYOPATHIC SYNDROMES ASSOCIATED WITH STATIN THERAPY — Myopathic syndromes associated with statin therapy range from myalgias to myositis to overt rhabdomyolysis, which may be associated with acute renal failure [2,3] . (See "Rhabdomyolysis").

Information about muscle injury and statins has come both from large clinical trials of statin therapy and from observational studies of statins in clinical use [4] . A meta-analysis of 35 randomized trials of statins found no excess risk of myalgias, creatine kinase elevations, rhabdomyolysis, or discontinuation of therapy versus placebo [5] . 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 [6] .

As will be discussed below, the incidence of clinically significant myopathy is substantially increased in patients treated with certain other drugs, particularly cyclosporine, gemfibrozil, azole antifungals, and certain macrolide antibiotics.

Time course of myopathy — The onset of muscle symptoms is usually within weeks to months after the initiation of statin therapy but may occur at any time during treatment. As an example, a review of 44 cases of statin-associated myopathy found a mean duration of therapy before symptom onset of 6.3 months (range 0.25 to 48 months); approximately two-thirds of patients had onset of symptoms within six months of starting therapy [7] . Myalgias and weakness resolve and serum creatine kinase concentrations return to normal over days to weeks after discontinuation of the drug. In the above study, the mean time to resolution of symptoms in 43 patients who discontinued statin therapy was 2.3 months (range 0.25 to 14 months); 58 percent had resolution of symptoms within one month and 93 percent had resolution within six months [7] .

No other treatment is necessary except for supportive care in patients who develop rhabdomyolysis.

Myalgias — The incidence of "benign" myalgias in large clinical trials of statin therapy ranged from 2 to 11 percent, a value not different from placebo-treated controls [8-11] . Similarly, an elevation in serum CK above normal occurred in approximately 30 percent of both statin-treated and placebo-treated groups [9] . However, we have seen patients who had new onset myalgias and easy fatiguability temporally related to statin therapy that gradually resolved when the drug was discontinued.

The issue of statin-associated myopathy with normal serum CK has been directly addressed in a crossover study in which 4 of 21 patients who had muscle symptoms while taking a statin (aching, weakness, decreased exercise tolerance) could distinguish blinded statin therapy from placebo because of reproducible muscle symptoms [12] . Strength testing confirmed muscle weakness during statin therapy that resolved with placebo, and muscle biopsy showed evidence of mitochondrial dysfunction that also reversed with cessation of therapy. Serum statin concentrations were not inappropriately elevated.

Statin-induced myalgia typically presents as proximal, symmetric muscle weakness and soreness [13] . There may be muscle tenderness and there may be functional impairments such as difficulty raising the arms above the head, arising from a seated position, or climbing stairs. Less often the discomfort is asymmetric. Other reported symptoms include cramping (including nocturnal cramping) and tendon pain [13] .

Myositis — Clinically significant myopathy, defined as a serum CK elevation more than 10 times normal in association with muscle symptoms, occurred in less than 0.5 percent of patients in the large clinical trials [8-11] . A review of one year of records for 1014 patients taking statins in a primary care practice found that 0.9 percent of patients had CK elevations more than five times normal, and none of these appeared to be related to statin use [14] . Fourteen patients (2.1 percent) had elevations 2.5 to 5 times normal and, of these, two appeared to be potentially related to statin use.

Rhabdomyolysis — In the large clinical trials, massive rhabdomyolysis with acute renal failure was not seen in patients who did not have other risk factors. Rhabdomyolysis has primarily been seen when a statin is given concurrently with cyclosporine or gemfibrozil (see "Concurrent drug therapy" below) [15-17] . In addition, there have been case reports of rhabdomyolysis in patients taking statins in combination with niacin, macrolide antibiotics, digoxin, antifungal medications, and warfarin [18] .

Other possible predisposing factors include hypothyroidism and inflammatory myopathies (polymyositis and dermatomyositis) [19-21] . (See "Hypothyroid myopathy", section on Rhabdomyolysis, and see "Clinical manifestations and diagnosis of adult dermatomyositis and polymyositis").

One study examined claims data from 11 managed care plans that included 252,460 patients treated with lipid lowering agents [22] . The average incidence of hospitalization for rhabdomyolysis was 0.44 per 10,000 patient-years (95% CI 0.20-0.84) for patients treated with atorvastatin, pravastatin, or simvastatin monotherapy. Although the study did not find a statistical difference in the incidence of rhabdomyolysis among these three statins, no cases of rhabdomyolysis were seen with pravastatin. The incidence was higher with cerivastatin monotherapy (5.34 per 10,000 patient-years).

Reported deaths due to statin-induced rhabdomyolysis have averaged 0.15 per million prescriptions dispensed in the United States [23] . This risk is greater with cerivastatin, which was withdrawn from the market in August 2001 after reports of 31 deaths from rhabdomyolysis, most often in elderly patients who were also taking gemfibrozil [23] . (See "Rhabdomyolysis").

Muscle biopsy obtained early in the course of rhabdomyolysis shows myonecrosis without vasculitis or significant inflammation. Biopsy later in the course may show some mononuclear cell infiltration suggestive of an inflammatory repair process [15-17] .

Patients with a history of statin-induced rhabdomyolysis should generally not be treated with another statin (including pravastatin and fluvastatin), because of the risk of recurrence [19] . In some cases, it may be reasonable to retry statin therapy after the resolution of an acute reversible event that contributed to muscle toxicity (eg, undetected hypothyroidism, acute renal failure, biliary obstruction, use of other medications that increase statin levels). Nonstatin lipid-lowering therapies may also cause recurrences in patients with statin-induced rhabdomyolysis and should only be used cautiously and with careful monitoring [19] .

Asymptomatic myopathy — The possible existence of asymptomatic myopathy was evaluated in a study that examined muscle biopsies obtained during vascular surgery from patients without muscle symptoms [24] . Morphological analysis by an investigator blinded to treatment status found compromise of the structural integrity of muscle fibers in 10 of 14 patients treated with statins and in 1 of 8 control patients.

Most of the 14 patients were receiving atorvastatin or simvastatin, but both patients in the study who were receiving pravastatin also had damaged fibers. This observation suggests that even asymptomatic patients receiving statins may show some degree of muscle pathology on biopsy.

PATHOGENESIS — The mechanism by which statins cause muscle toxicity is not well understood. They inhibit the conversion of HMG-CoA to mevalonic acid, which is an important early step in cholesterol synthesis.

Statins can also decrease the synthesis of coenzyme Q10 (CoQ10, ubiquinone), which plays an important role in muscle cell energy production. It has been speculated that the reduction in CoQ10 may contribute to statin-induced muscle injury. Some studies have found that statins decrease plasma concentrations of CoQ10 [25-27] ; however, other studies have not [28] , and studies have come to different conclusions about whether statin treatment decreases levels of CoQ10 in skeletal muscle [27,29,30] .

One study found increased levels of plant sterols in skeletal muscle in patients treated with high dose statins [27] . The authors of the study proposed that these increased cellular levels could contribute to the muscle toxicity of statins.

Atrogin-1, a muscle-specific ubiquitin protein ligase, may play an important role in statin toxicity. Lovastatin induces expression of atrogin-1 in humans with statin myopathy and in several in vitro models; in the models, myopathy could be prevented by knockdown of atrogin-1 [31] .

RISK FACTORS

Statin characteristics — The susceptibility to muscle injury appears to vary among the different statins. Myositis has been described in less than 0.5 percent overall, primarily occurring at higher doses. With simvastatin, for example, the incidence in clinical trials, in which patients were carefully monitored and some interacting drugs described below excluded, was 0.02 percent at 20 mg/day, 0.07 percent at 40 mg/day, and 0.3 percent at 80 mg/day [32] .

The risk of myopathy appears to be lowest with pravastatin (<0.1 percent) and perhaps fluvastatin [22,33] . The safety of pravastatin (40 mg/day) was confirmed in an analysis of more than 112,000 patient-years of experience in three large controlled trials [34] . The incidence of serum CK elevations was not different from placebo, and there were no cases of confirmed clinical myositis or rhabdomyolysis.

The possible differential sensitivity of statins on striated muscle has been evaluated in cell culture experiments [35] . Simvastatin and lovastatin reduced cell viability by 50 percent at concentrations of 1 and 5 µmol/L, respectively; a much higher level of 300 µmol/L was required with pravastatin, suggesting less toxicity. The toxic effect of these agents on dividing myocytes may contribute to the development of myositis. The more hydrophilic statins, pravastatin and rosuvastatin, may have less penetration into muscle than the other more lipophilic statins. (See "Lipid lowering with statins", section on Side effects).

In addition to this difference in direct toxicity, pravastatin and fluvastatin are also less likely to be involved with drug interactions since they are not extensively metabolized by CYP3A4 (show table 1).

Rosuvastatin, like pravastatin, is not extensively metabolized by CYP3A4 and is hydrophilic. In a trial in 17,802 apparently healthy adults, rates of muscle toxicity with rosuvastatin 20 mg daily were similar to placebo [36] . There have been reports of rhabdomyolysis with rosuvastatin, particularly in myopathy-prone patients treated with doses higher than those recommended by the FDA product labeling, and product labeling in Europe highlights this risk, particularly at the highest dose of 40 mg daily [37] .

Neuromuscular Disorders — Another issue to consider is the presence of muscle disease, both pre-existing or induced. A growing number of reports have found associations between statin therapy and a variety of muscle disorders, which include idiopathic inflammatory myopathies (eg, polymyositis [38] , dermatomyositis [39-42] , and inclusion body myositis [43] ), mononeuritis multiplex [44] , myasthenia gravis [45,46] , mitochondrial myopathy [12,47,48] , McArdle disease [48-50] , acid maltase deficiency [51] , carnitine-palmitoyl transferase deficiency [52] , rippling muscle disease (RMD) [53] , malignant hyperthermia [54,55] , myotonic dystrophy type 1 [48] , and Kennedy disease [48] . For genetically-based muscle disorders, statins are believed to trigger myogenic symptoms more readily than in healthy subjects, due to a reduced ability to compensate for drug-induced myotoxicity. It seems likely that the diverse neuromuscular phenotypes associated with statin use reflect multiple mechanisms acting either singly or synergistically.

Patient characteristics — Enhanced susceptibility to statin-associated myopathy occurs in patients with acute or chronic renal failure, obstructive liver disease, and hypothyroidism. In one hypothyroid patient, the myopathy resolved promptly after discontinuation of pravastatin and before initiation of thyroid hormone replacement [56] , but in a second case the myopathy persisted until thyroid hormone was replaced [57] . These reports suggest that hypothyroidism may predispose to the development of statin-associated myopathy and that use of statins may "unmask" hypothyroid myopathy. (See "Hypothyroid myopathy").

Genetic factors appear to increase the risk of statin myopathy [58] . A genomewide association study found that common variants of the gene SLCO1B1, which encodes human the organic anion-transporting polypeptide OATP1B1 that mediates hepatic uptake of most statins, substantially increased or decreased the risk of myopathy in patients treated with simvastatin [59] .

Concurrent drug therapy — The increase in susceptibility to myopathy is substantially greater in patients receiving concurrent therapy with a number of drugs, particularly those that inhibit CYP3A4. These include cyclosporine, gemfibrozil, macrolide antibiotics (eg, erythromycin) [60] , itraconazole [61] , and HIV protease inhibitors (show table 1) [2,62,63] . Drugs that do not inhibit CYP3A4 but are CYP3A4 substrates may also have myopathic interactions with statins, as has been reported with myotoxicity with simvastatin and colchicine [64] . 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). Furthermore, concurrent use of a drug which is independently considered a risk factor for myopathy (ie, antipsychotics) may further increase risk [65] .

In a small controlled trial of healthy individuals treated with ritonavir plus saquinavir, the increase in serum concentration was 3059 percent for simvastatin (which should be avoided), 79 percent for atorvastatin, and 0 percent for pravastatin [63] .

Nicotinic acid (niacin) is also metabolized by CYP3A4, and initial studies described cases of myopathy when it was given with a statin [66] . However, this complication of combined therapy appears to be rare [67] .

The increased risk of muscle injury has been best described in initial studies of lovastatin in which clinically significant myopathy was noted in almost 30 percent of patients also receiving cyclosporine and 5 percent also treated with gemfibrozil [8] . The increased risk of myopathy seen with these drug combinations is probably due, at least in part, to increased serum levels of the statin. With cyclosporine, for example, this could result from competitive interference with CYP3A4 and associated renal or hepatic dysfunction. Two observations are compatible with this hypothesis: Serum lovastatin levels much higher than the therapeutic range have been noted in patients with rhabdomyolysis who were also treated with cyclosporine [8] . Low-dose lovastatin in renal transplant recipients, in an attempt to minimize muscle toxicity (see below), is associated with serum lovastatin concentrations and a degree of lipid-lowering effect similar to those in patients not treated with cyclosporine who are given a higher lovastatin dose [68] .

The importance of competitive interference with CYP3A4 is suggested by the apparent lack of increased muscle toxicity with pravastatin and fluvastatin, which are not extensively metabolized by CYP3A4, in patients also treated with cyclosporine (see below).

Lovastatin, simvastatin and, to a lesser extent, atorvastatin are extensively metabolized by CYP3A4. Pravastatin, fluvastatin, and rosuvastatin are preferred when concurrent therapy with a strong inhibitor of CYP3A4 (show table 1) cannot be avoided.

There are two additional issues with simvastatin. First, polymorphisms in CYP2D6 can affect both its efficacy and tolerability; patients with one or two mutant alleles are much more likely not to tolerate the drug compared with those with two wild-type alleles [69] .

Second, unpublished data from the manufacturer indicate that, at a simvastatin dose of 80 mg/day, there is a 6 percent risk of myopathy in patients also treated with amiodarone and, at doses of 20 to 80 mg/day, a 0.6 percent incidence in patients also treated with verapamil (a value 10 times higher than seen in patients taking simvastatin without a calcium channel blocker) [32] . The risk of rhabdomyolysis in patients treated concurrently with amiodarone appears to be higher with simvastatin than with other statins [70] . The manufacturer recommends a 20 mg/day limit for simvastatin in patients treated with amiodarone or verapamil and a 10 mg/day limit in patients treated with cyclosporine, a fibrate, or lipid lowering doses of niacin. The applicability of these observations to other statins is not known.

Cyclosporine — Regular dose lovastatin (40 to 80 mg/day) and simvastatin (20 mg/day) are associated with an appreciable risk of myositis (as high as 13 to 30 percent) in cyclosporine-treated patients [2,8,71] . Although the data are limited, myositis has also been described when cyclosporine is given with atorvastatin, which is metabolized by CYP3A4 [72,73] . In contrast, pravastatin and fluvastatin, which are not extensively metabolized by CYP3A4, do not appear to increase the risk of myopathy when given concurrently with cyclosporine [71,74-76] .

The safety of pravastatin in such patients was illustrated in an open-label study that compared pravastatin (40 mg/day) with simvastatin (20 mg/day) in 87 cardiac transplant recipients [71] . Rhabdomyolysis or myositis occurred only with simvastatin therapy (13.3 percent). A similar lack of muscle toxicity was noted in a placebo-controlled trial in which none of 50 cardiac transplant recipients treated with pravastatin (40 mg/day) developed myalgia or myositis during one year of therapy [74] .

The ability to give pravastatin with cyclosporine in cardiac transplant recipients is important clinically because it is associated with important improvements in outcome. In the preceding controlled trial, the following significant benefits were seen with pravastatin at one year follow-up: a higher survival rate (94 versus 78 percent); and reductions in transplant vasculopathy (6 versus 20 percent) and cardiac rejection episodes with hemodynamic compromise (6 versus 28 percent) [74] . A similar reduction in rejection episodes may occur in renal transplant recipients [77] . These findings suggest that the statins may have immunosuppressive activity [78] . (See "Lipid abnormalities after cardiac transplantation" and see "Lipid abnormalities after renal transplantation").

Pravastatin is the only statin approved by the Food and Drug Administration for combination therapy in cyclosporine-treated patients. An alternative is low-dose therapy with other statins to prevent excessive serum drug concentrations. As an example, the combination of lovastatin and cyclosporine is associated with little risk of muscle toxicity (0 to 2 percent) if only low doses of lovastatin are used (10 mg or 20 mg/day) [68,79] . Similar results have been reported with low-dose simvastatin (5 mg/day, with gradual increments to a maximum of 20 mg/day) [80,81] . (See "Cyclosporine: Drug information").

Fibrates — An increased risk of muscle toxicity, as high as 1 to 5 percent, has been described with the administration of some statins (eg, lovastatin and atorvastatin) with gemfibrozil [8,17,82,83] . As with concurrent therapy with cyclosporine, pravastatin and fluvastatin appear to have little muscle toxicity when used in combination with gemfibrozil [84-87] , despite the observation that gemfibrozil increases plasma concentrations of pravastatin twofold [88] .

The potential importance of the type of statin was evaluated in a study that examined claims data from 11 managed care plans, which included 252,460 patients treated with lipid lowering agents [22] . The average incidence of hospitalization for rhabdomyolysis was 5.98 per 10,000 patient-years (95% CI 0.72-216.0) for patients treated with atorvastatin, pravastatin, or simvastatin in combination with a fibrate. The incidence of hospitalization was approximately 10-fold higher with combination fibrates and statins than with statin monotherapy.

Although the study did not find a statistical difference in the incidence of rhabdomyolysis among these three statins, no cases of rhabdomyolysis were seen with pravastatin. The incidence of hospitalization was higher with cerivastatin combined with a fibrate (1035 per 10,000 patient-years).

Toxicity can also be minimized by using other statins in relatively low doses [86,89,90] . This was illustrated in a trial of 389 patients with refractory familial combined hyperlipidemia who were randomly assigned to pravastatin (20 mg/day) plus gemfibrozil or simvastatin (20 mg/day) plus either gemfibrozil or ciprofibrate [86] . After a mean follow-up of 29 months, no patient developed myopathy or rhabdomyolysis.

It is recommended that pravastatin or perhaps fluvastatin (at 80 mg/day) 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.

Glucuronidation, which is an important pathway for renal excretion of lipophilic statins, appears to be significantly inhibited by gemfibrozil but not fenofibrate [91,92] . In clinical studies, serum levels of statins increase 1.9- to 5.7-fold in gemfibrozil-treated subjects but are unchanged in fenofibrate-treated subjects.

Fenofibrate may be safer. In the randomized, placebo-controlled FIELD trial of fenofibrate in almost 10,000 patients with type 2 diabetes, there was a low incidence of myopathy (less than 1 percent) that was not different from placebo, whether or not patients were also taking a statin [93] . Thus, fenofibrate is the preferred fibrate in patients who require combined therapy with a statin and fibrate [94] .

MONITORING — Despite the increased risk of myopathy associated with statin therapy, routine monitoring of serum creatine kinase (CK) levels is not recommended [14,95,96] . However, it is useful to obtain a baseline serum CK before initiation of statin therapy for reference in case symptoms develop.

There are important differences in serum CK levels among racial groups; as an example, high concentrations of CK are observed in African-Americans [97,98] . Additionally, many standard normal ranges on assays of CK appear to have an inappropriately low "upper limit of normal" even for non-African-American populations (show table 2) [99] .

Patients treated with statins should be alerted to report the new onset of myalgias or weakness.

COENZYME Q10 SUPPLEMENTATION — As discussed above, CoQ10 depletion may play a role in statin myopathy (see "Pathogenesis" above). Some clinicians recommend that patients taking statins take CoQ10 to try to prevent myopathy. Although there is anecdotal evidence for benefit, there are no published controlled trials or even moderate-size case series. A few case reports have noted benefit with doses of 30 to 250 mg daily [100] .

There is also little published evidence of benefit of CoQ10 for the treatment of myopathy: A small thirty-day randomized trial that compared CoQ10 100 mg daily with vitamin E 400 IU daily in 32 patients with myopathic pain while receiving statins found a significant reduction in pain in patients treated with CoQ10, but not in patients treated with vitamin E; neither treatment affected plasma CK levels [101] . Short-term administration of CoQ10 would not be expected to substantially increase tissue levels of ubiquinone, and the findings from this trial need confirmation in a larger trial with a longer duration of CoQ10 therapy. In a preliminary report, a small randomized trial compared twelve weeks of CoQ10 200 mg daily with placebo in 44 patients with statin-induced myalgia [102] . Patients were off lipid-lowering therapy for two weeks prior to randomization and were then treated with escalating doses of simvastatin (10 to 40 mg daily as tolerated). CoQ10 supplementation increased plasma CoQ10 levels but reportedly did not increase the proportion of patients who tolerated simvastatin or decrease myalgia scores.

There is currently inadequate evidence to recommend CoQ10 supplementation for prevention of statin-induced muscle toxicity [103] . Although there is only limited evidence for benefit, if a patient requires a statin and experiences muscle pain while on pravastatin or fluvastatin (the two statins felt to have the lowest risk of myopathy), we suggest a trial of supplementation with CoQ10 at a dose of 150 mg to 200 mg daily prior to rechallenge and during the course of statin therapy. (See "Statin characteristics" above).

OTHER LIPID LOWERING DRUGS — Case reports have documented the rare occurrence of myalgias and elevated serum CK in patients treated with other lipid lowering drugs, without concurrent statin therapy. This group includes clofibrate [104] , nicotinic acid (niacin) [105] , gemfibrozil [106] , and ezetimibe [107] .

A study examined claims data from 11 managed care plans that included 252,460 patients treated with lipid lowering agents [22] . The average incidence of hospitalization for rhabdomyolysis was 2.82 per 10,000 patient-years (95% CI 0.58-8.24) for patients treated with fibrate monotherapy. Although the study did not find a statistical difference in the incidence of rhabdomyolysis among the fibrates, all the cases seen with monotherapy were with gemfibrozil.

SUMMARY AND RECOMMENDATIONS

Clinical presentation and diagnosis 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. (See "Myopathic syndromes associated with statin therapy" above). 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. (See "Time course of myopathy" above). Routine monitoring of serum CK levels is not recommended, 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 "Monitoring" above). Clinical judgment is necessary in interpreting elevated CK levels in patients on statins. CK elevations can be related to hypothyroidism or muscle injury 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.

Prevention and management Pravastatin and fluvastatin appear to have much less intrinsic muscle toxicity than other statins. (See "Statin characteristics" above). The risk of muscle injury is a substantially increased when taking both statins extensively metabolized by cytochrome P-450 3A4 (lovastatin, simvastatin, atorvastatin) and drugs that interfere with CYP3A4 (show table 1). Pravastatin and fluvastatin 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 "Statin characteristics" above). Enhanced susceptibility to statin-associated myopathy occurs in patients with acute or chronic renal failure, obstructive liver disease, and hypothyroidism. (See "Patient characteristics" above). Pravastatin or perhaps fluvastatin is the statin of choice in patients treated with gemfibrozil (or other fibric acid derivatives). However, these drugs 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. (See "Concurrent drug therapy" above). In the absence of clinical symptoms, a CK level >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 CK. After the CK has returned to baseline, patients may be tried on a statin less likely to cause muscle toxicity (as above) with careful monitoring. (See "Monitoring" above). 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. (See "Monitoring" above). Although there is only limited evidence for benefit, if a patient requires a statin and experiences muscle pain while on pravastatin or fluvastatin, we suggest a trial of supplementation with CoQ10 at a dose of 150 mg to 200 mg daily prior to rechallenge and during the course of statin therapy. (See "Coenzyme Q10 supplementation" above).

Lipid lowering with statins
Author
Robert S Rosenson, MD Section Editor
Mason W Freeman, MD Deputy Editor
David M Rind, MD

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 Table 1 (show table 1) and the range of expected changes in the lipid profile are listed in Table 2 (show table 2).

Lipid lowering 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 see "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 (show table 3). The efficacy of fibrates, lipid lowering drugs other than statins and fibrates, and diet and dietary supplements are discussed separately. (See "Lipid lowering with fibric acid derivatives" and see "Lipid lowering with drugs other than statins and fibrates" and see "Lipid lowering with diet or dietary supplements").

MECHANISM OF ACTION — Currently available statins in the United States include lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, and rosuvastatin (show table 3). These agents are competitive inhibitors of HMG CoA reductase, the rate-limiting step in cholesterol biosynthesis (show 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] . Atorvastatin also reduces VLDL production, via an effect mediated by hepatic apo B secretion [3] , and it is associated with a diminished rate of recovery of HMG CoA reductase activity after drug treatment [4] .

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").

Timing of administration — The majority of cholesterol synthesis appears to occur at night [5] , 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 (show 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 [6,7] . 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 [8] .

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 (show 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 [9-13] . Every other day regimens, and even once weekly regimens, have also been evaluated as strategies for improving tolerability [14-16] .

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 [9,10,12,16] . 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 [17] .

EFFICACY — The statins are commonly used in the treatment of hypercholesterolemia and mixed hyperlipidemia.

Effect on LDL — The statins are the most powerful drugs for lowering LDL-cholesterol (LDL-C), with reductions in the range of 30 to 63 percent (show figure 2) [18-22] . In a study of patients with documented atherosclerosis and serum LDL-C ≥ 130 mg/dL (3.4 mmol/L), the percentage of patients reaching the target LDL-C level (<100 mg/dL [2.6 mmol/L]) was much higher with atorvastatin than with fluvastatin, lovastatin, or simvastatin (32 versus 1, 10, and 22 percent, respectively) [23] .

Rosuvastatin appears to be even more potent than atorvastatin [22,24] . In several studies, rosuvastatin (20 to 40 mg/day) reduced LDL-C by up to 63 percent. As an example, an open-label randomized trial compared rosuvastatin (10 to 40 mg/day), atorvastatin (10 to 80 mg/day), simvastatin (10 to 80 mg/day), and pravastatin (10 to 40 mg/day) in 2431 adults with hypercholesterolemia (LDL-C between 160 and 240 mg/dL) [24] . After six weeks of treatment, more patients taking rosuvastatin achieved their ATP-III LDL-C targets with rosuvastatin; 82, 89, and 89 percent of patients achieved LDL-C targets on 10, 20, and 40 mg of rosuvastatin respectively, while, for example, the highest percentages achieving targets in the atorvastatin and simvastatin groups were 85 and 82 percent, respectively.

Rosuvastatin has been approved by the US Food and Drug Administration at a dose range of 5 to 40 mg/day (www.fda.gov); rare episodes of renal failure have been seen in patients treated with 80 mg/day of rosuvastatin [24] . (See "Renal dysfunction" below). The maximum recommended starting dose of rosuvastatin is 20 mg/day for patients with LDL-C levels above 190 mg/dL (4.9 mmol/L); the labeling information was changed in 2005 to recommend a starting dose of 5 mg/day for patients requiring less aggressive LDL-C lowering and in patients who have predisposing factors for myopathy including Asian patients, patients taking cyclosporine, and patients with severe renal insufficiency [25] . If a patient is found to tolerate rosuvastatin at this dose, and the need for more intensive lipid lowering therapy is established with a repeat lipid profile, the dose may be increased to a maximum of 40 mg/day. This is intended to increase the likelihood that a 40 mg/day dose will be prescribed only to patients who truly need it.

At doses of up to 40 mg/day, fluvastatin is the least potent statin (show 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 [26] . Fluvastatin is less likely to have drug interactions or produce muscle toxicity than some other statins (see "Side effects" below).

An additional benefit of statin therapy is a reduction in the concentration of small, dense LDL in patients with the atherogenic lipoprotein phenotype, shifting the LDL subfractions to more buoyant, less atherogenic LDL [27-29] . (See "Primary disorders of LDL-cholesterol metabolism", section on Small dense LDL (LDL phenotype b) and see "Lipoprotein classification; metabolism; and role in atherosclerosis", sections on Low density lipoprotein and Intermediate density lipoprotein (remnant lipoproteins)).

There is an additive hypolipidemic effect when any of the statins is used in combination with a bile acid sequestrant (show figure 3) [30-32] .

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 [33] . However, rosuvastatin may be even more effective, raising HDL-C by up to 10 percent [24] . (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 [24,34-36] . This was illustrated in a study that compared atorvastatin (10 to 80 mg/day), rosuvastatin (10 to 40 mg/day), simvastatin (10 to 80 mg/day), and pravastatin (10 to 40 mg/day) in 2431 adults with hypercholesterolemia [24] . After six weeks of treatment, those taking atorvastatin and rosuvastatin had a greater reduction in triglycerides than those taking simvastatin and pravastatin; for example, for the 40-mg dose the reductions were 26.8, 26.1, 14.8, and 13.2 percent, respectively. Similar results have been seen when atorvastatin was compared with lovastatin [35] .

The effects of atorvastatin and rosuvastatin on serum triglycerides are dose-dependent [24,34] . 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 [34] .

Genetic determinants of response — 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 [37] .

Polymorphisms in the gene coding for HMG CoA reductase also appear to affect the response to statins. In a study of treatment with pravastatin (40 mg/day), individuals with two common (heterozygote prevalence of 6.7 percent) and tightly linked single nucleotide polymorphisms of the HMG CoA reductase gene had, when compared with individuals homozygous for the major allele, a smaller reduction in both total cholesterol (-32.8 versus -42.0 mg/dL [-0.85 versus -1.09 mmol/L]) and LDL-C (-27.7 versus -34.1 mg/dL [-0.72 versus -0.88 mmol/L]) [38] . There was no apparent effect of the polymorphism on change in HDL-C level with treatment.

Concerns have been raised that Asians may have greater responses to low doses of statins than Caucasians [39] . Prescribing information for rosuvastatin recommends starting therapy at a lower initial dose in Asians than in other groups, given observed differences in pharmacokinetics [40] . There is no strong evidence supporting such an approach with other statins.

Effect on 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" and see "Treatment of lipids (including hypercholesterolemia) in secondary prevention", and see "Clinical trials of cholesterol lowering for primary prevention of coronary heart disease" and see "Clinical trials of cholesterol lowering in patients with coronary heart disease or coronary risk equivalents" and see "Cholesterol lowering after an acute coronary syndrome" and 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 the 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, although it is relatively uncommon.

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) [41,42] .

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 [43,44] . 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.

Hepatic dysfunction — Clinical studies of statins have demonstrated a 0.5 to 3 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.

However, several randomized trials have reported no significant difference in the incidence of persistently elevated aminotransferases between statin and placebo therapy [45-47] . A similar finding was noted in a review of three pravastatin trials with over 112,000 patient-years of exposure [48] . 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 [43] .

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 [49] . 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 [50] . Of these, all but four were associated with drug interactions.

The US Food and Drug Administration labeling information includes liver function testing before and at 12 weeks following the initiation of statins, and at any elevation of dose and periodically thereafter. This recommendation is based upon expert opinion, and many authorities do not feel that routine monitoring of liver function is necessary except to identify and then monitor patients with preexisting liver disease or who are receiving concomitant medications with a potential for drug interactions [47,50-52] .

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 [41,53] . 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. This problem, including predisposing drug interactions, is discussed in detail elsewhere. (See "Muscle injury associated with lipid lowering drugs"). 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 much less intrinsic muscle toxicity. Enhanced susceptibility to statin-associated myopathy occurs in patients with acute or chronic renal failure, obstructive liver disease, and hypothyroidism. The risk is substantially increased for most statins extensively metabolized by cytochrome P-450 3A4 (lovastatin, simvastatin and to a lesser extent atorvastatin) with concurrent therapy with drugs that interfere with CYP3A4 (show table 4). Pravastatin, fluvastatin, and rosuvastatin 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.) The risk is substantially increased for most statins with concurrent therapy with drugs that interfere with CYP3A4 (show table 4). (See individual drug monographs for more detailed information on interactions.) 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. Routine monitoring of serum creatine kinase (CK) levels is not recommended, 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. 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.

Renal dysfunction — Statins appear to be able to cause proteinuria through tubular inhibition of active transport of small molecular weight proteins [54,55] . There have been a number of reports to the FDA about proteinuria with statins, particularly in patients receiving rosuvastatin or simvastatin [56] , however it is believed that proteinuria with statins is a benign finding [57,58] . (See "Statins and chronic kidney disease", section on Effect on proteinuria).

There have also been rare episodes of renal failure in clinical trials of patients treated with 80 mg/day of rosuvastatin [24] . However, it is unclear if rosuvastatin was responsible for the renal failure, as these patients were on other potentially nephrotoxic medications. Although concerns have been raised about high rates of adverse event reports to the FDA regarding rosuvastatin [56] , it is unclear whether the number of reports about renal failure is out of proportion to what would be expected soon after a new statin is released [57,58] .

Drug interactions — Drug interactions that can predispose to statin-induced muscle injury, such as with other lipid-lowering agents, are discussed above (see "Muscle injury" above).

The antiplatelet agent clopidogrel is a prodrug that is activated via metabolism by CYP3A4. An initial observation, using a novel method of assessing platelet function, suggested that concurrent atorvastatin therapy impairs the antiplatelet activity of clopidogrel [59] . However, a subsequent study did not confirm an effect of atorvastatin on the ability of clopidogrel to inhibit platelet function [60] .

In addition, subgroup analyses of randomized trials have not demonstrated clinical significance of such an interaction [61-63] , and thus a change in practice is not recommended. In an analysis from the CREDO trial of clopidogrel therapy before and after a planned percutaneous coronary intervention, the patients who were not treated with a statin had less benefit from clopidogrel than those treated with a statin; there were too few patients receiving pravastatin or fluvastatin to determine whether these agents conferred any advantage compared with the other statins [61] . In addition, the statin dose was not examined in this study, so that the possibility of a dose-dependent effect on the activity of clopidogrel could not be investigated.

Use in pregnancy — 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 [64] . In the United States, statins are rated category X in pregnancy (show table 5), and the recommendation is to discontinue their use prior to conception if possible. Although some authors have recommended that pregnant women can be reassured that the fetal risk is low if inadvertent exposure occurs [64] , 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 [65] .

Behavioral and cognitive effects — 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 [66] . (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 [67] . 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 [68] , however it is difficult to tell whether this association was causal [69] . 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 [70,71] . 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 [72] . 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 [73,74] .

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, or fluvastatin) and has a strong indication for lipid lowering therapy, it would be reasonable to attempt treatment with a more hydrophilic statin (pravastatin or rosuvastatin).

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 — Several animal studies suggested that statin therapy is associated with an increased risk of cancer [75] . In humans, an association between low cholesterol levels and certain cancers of the gastrointestinal tract has been suggested, though not proven [76,77] .

As discussed below, meta-analyses of randomized trials have shown no effect of statins on cancer incidence or cancer mortality [78-80] . A potential limitation of the meta-analyses is relatively short duration of follow-up. However, ten-year follow-up of both the 4S trial and the West of Scotland Coronary Prevention Study (WOSCOPS) showed no increases in cancer deaths [81,82] .

In summary, there is no convincing evidence that statins increase or decrease the risk of cancer (see "Cancer prevention" below).

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) [83] . 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) [84] .

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

Diabetes mellitus — Statins could have effects on glucose metabolism and thus the development of diabetes mellitus or glycemic control in patients with 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 [85-90] .

Similarly, clinical trials have come to conflicting results. In the WOSCOPS trial, men treated with pravastatin for primary prevention had a decreased risk of developing diabetes [91] ; in the JUPITER trial, adults treated with rosuvastatin for primary prevention had an increased risk of developing diabetes [92] . (See "Clinical trials of cholesterol lowering for primary prevention of coronary heart disease", sections on West of Scotland Coronary Prevention Study and JUPITER trial.)

A 2008 meta-analysis of randomized trials, published prior to the results from JUPITER, found no effect of statins as a class on risk of diabetes but suggested statistical heterogeneity with pravastatin reducing the risk of diabetes and other statins increasing the risk [93] . However, in the PROSPER trial, it appeared that patients treated with pravastatin also had an increased risk of diabetes [94] .

At this point it remains uncertain whether statins as a class or individual statins increase or decrease the risk of developing diabetes or improve or worsen glycemic control in established diabetics.

Cataract — Animal studies have raised the possibility that statins can induce cataract formation [95] . However, studies in humans, including large case-control and cohort studies [96-98] , as well as a small randomized trial [99] , have not found an increased risk of cataract in patients treated with statins.

In a subset analysis, one cohort study reported an association between statins and a decreased risk of one type of cataract (nuclear cataract) [98] ; however, additional study is clearly needed before it can be concluded that statins actually have any such protective effect.

Other — There have been case reports of drug-induced lupus in patients receiving statins. (See "Drug-induced lupus").

USE IN 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 [100,101] .

Dose adjustment is warranted with other statins in patients with severe kidney disease (CrCl less than 30 mL/min). If statins other than atorvastatin or fluvastatin are used, hydrophilic statins may be safer than lipophilic 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 [102] .

USE IN CHRONIC LIVER DISEASE — Patients who simply have baseline elevations in aminotransferases do not appear to be at increased risk when prescribed a statin [103] . 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 [104] . 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 [105] .

A 36-week randomized trial comparing pravastatin 80 mg daily or placebo in 326 patients with well-compensated noncholestatic chronic liver disease (64 percent with nonalcoholic steatohepatitis; 23 percent with hepatitis C) found similar evidence of safety [106] . 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.

In a small study of patients with primary biliary cirrhosis who were treated with atorvastatin, significant transaminase elevations were common [107] . (See "Hypercholesterolemia and atherosclerosis in primary biliary cirrhosis", section on Drug therapy). Most statins are ultimately excreted in the bile, and toxic levels can develop in patients with cholestasis [108] . We generally avoid statin therapy in patients with significant cholestasis.

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 a hydrophilic statin (pravastatin or rosuvastatin) at a low dose. If the LDL-C remains elevated, combined therapy with a bile acid sequestrant or ezetimibe may allow such patients to achieve their LDL-C target.

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SECONDARY BENEFITS — In addition to cholesterol lowering and the primary and secondary prevention of cardiovascular disease, statin therapy may be associated with other benefits.

Bone metabolism — Although the statins are used primarily for the treatment of hypercholesterolemia, there is some evidence that they may increase bone formation, volume and density, and reduce the risk of osteoporotic fractures, particularly in older patients; however, there have been conflicting results. (See "Drugs that affect bone metabolism").

Hypertension — There is some evidence that statins may lower blood pressure [48,109] . (See "Antihypertensive drugs and lipids").

Heart failure — There is evidence that statins may improve outcomes in patients with heart failure; this effect may be independent of the effect of statins on myocardial infarction. (See "Statin therapy in patients with heart failure").

Dementia — Some observational studies have suggested that statins may decrease the risk of dementia and at least one small randomized trial has suggested that statins may slow the progression of dementia. (See "Prevention of dementia", section on Statins, and see "Treatment of dementia", section on Risk factor control).

Cancer prevention — Some, but not all, observational studies have raised the possibility that use of statins may decrease overall risk of cancer and of specific cancers. A population-based cohort study of 334,754 adults from Denmark found a decreased incidence of cancer in patients receiving statins compared with the general population (rate ratio [RR] 0.86, 95% CI 0.78-0.95) and compared with users of other lipid lowering drugs (RR 0.73, CI 0.55-0.98) [110] . In a case-control study of 3129 patients with cancer and 16,976 matched controls, the use of statins was associated with a 20 percent reduction in the risk of cancer [111] . There was a trend toward greater reduction in risk with longer use of statins. In contrast, another case-control study did not find a protective effect of statins [112] . A retrospective cohort study in 30,076 post-myocardial infarction patients from Canada found that prescription of a statin (atorvastatin, simvastatin, fluvastatin, or lovastatin) was associated with a decreased risk of cancer [113] . A dose response effect was found such that high dose statin use was associated with a greater reduction in risk than low dose statin use. Studies on colon cancer in particular have also come to differing conclusions. A case-control study from Israel found that the use of statins for at least five years was associated with a 47 percent reduction in the risk of colorectal cancer [114] . However, other large case-control studies have found no decrease in the risk of colon cancer with statin use [115-117] . The explanation for these conflicting results is unclear. A report from the Nurses' Health Study, which included 79,994 women, found no association between breast cancer risk and use of statins [118] . Similar findings were noted in a meta-analysis of observational studies and randomized trials [119] . A case-control study found an association between statin use and a decreased risk of lung cancer that was seen after six months of statin therapy (odds ratio 0.45) [120] .

In contrast, meta-analyses of randomized trials have consistently shown no effect of statins on cancer incidence or cancer mortality [78-80] : A meta-analysis of 14 randomized trials of statins involving 90,056 patients found no increased risk of cancer death after a mean follow-up of five years (HR 1.01, CI 0.91-1.12) [78] . A second meta-analysis of 26 randomized trials of statins involving 86,936 patients, where the trials were required to have a mean follow-up of at least one year, also found no effect of statins on cancer incidence (odds ratio [OR] 1.02, CI 0.97-1.07) or cancer death (OR 1.01, CI 0.93-1.09) [79] . This lack of effect on cancer was true across different cancers and for various statin subtypes (ie, hydrophilic, lipophilic, natural, synthetic).

It is implausible that a large early reduction in risk for a common cancer, such as the 55 percent reduction seen in the lung cancer study discussed above [120] , would have been missed in these meta-analyses. It is likely that most of the positive results seen in observational studies of statins and cancer are due to bias or confounding.

In summary, there is no convincing evidence that statins increase or decrease the risk of cancer. (See "Cancer" above).

Renal function — Post-hoc analyses of clinical trials have raised the possibility that statins may be of some benefit in preserving renal function, both in patients with moderate chronic renal insufficiency [121] , and in patients with normal renal function [54] . (See "Secondary factors and progression of chronic kidney disease", section on Hyperlipidemia and see "Statins and chronic kidney disease").

Sepsis and infections — Animal models of sepsis suggested that statins may improve outcomes [122-126] and initial observational studies in bacteremic patients suggested that prior statin therapy may decrease the rates of severe sepsis and mortality from sepsis [127-129] .

This issue has been addressed in large cohort studies with conflicting findings: A large population-based cohort analysis from Canada found a reduced risk of sepsis in patients with cardiovascular disease who were treated with statins (hazard ratio 0.81, 95% CI 0.72-0.90) [130] . A prospective cohort study of 1041 dialysis patients also found a reduction in the risk of sepsis with statin therapy (incidence rate ratio 0.41, CI 0.25-0.68); the apparent protective effect was even larger with additional adjustment for comorbidities or with propensity matching [131] . In contrast, a second study from Canada in patients with pneumonia found that an apparent protective effect of prior statin therapy on mortality and requirement for intensive care disappeared with more complete adjustment for confounders [132] . However, subsequent studies from Denmark and Scotland did find an association between statin therapy and a reduced risk of mortality in patients with pneumonia [133,134] .

Further evidence is needed before it can be concluded that statins reduce the risk of sepsis [135] . In addition, the utility of initiating statins in ill patients to prevent or ameliorate sepsis has not been studied in prospective trials. (See "Investigational and ineffective therapies for sepsis", section on Statins).

Venous thromboembolism — There is some evidence that statin therapy may decrease the risk of venous thromboembolic disease. (See "Prevention of venous thromboembolic disease in medical patients", section on Statins.)

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: High cholesterol and lipids (hyperlipidemia)"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

SUMMARY — Statins are the most powerful drugs for lowering LDL-C and are the most effective lipid lowering drugs 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 [100] : Rosuvastatin, atorvastatin, and simvastatin cause the greatest percentage change in LDL-C; they are preferred in patients who require >35 percent reduction in LDL-C. Given the limited long-term data on safety, until there is more experience with rosuvastatin, some have suggested limiting its use to those patients who do not adequately respond to other statins [136,137] . Atorvastatin and fluvastatin do not require dose adjustment in patients with renal dysfunction and are preferred in patients with severe renal impairment. In patients with chronic liver disease who require a statin because of high cardiovascular risk, we recommend complete abstinence from alcohol and the use of a hydrophilic statin (pravastatin or rosuvastatin) at a low dose. Fewer pharmacokinetic drug interactions are likely to occur with pravastatin, fluvastatin, and rosuvastatin because they are not metabolized through the CYP3A4 (show table 4). 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 "Muscle injury associated with lipid lowering drugs"). Routine monitoring of serum creatine kinase (CK) levels is not recommended, 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.

UpToDate

Rosuvastatin in Diabetic Hemodialysis Patients
Hallvard Holdaas*, Ingar Holme†, Roland E. Schmieder‡, Alan G. Jardine§, Faiez Zannad‖, Gudrun E. Norby*, Bengt C. Fellström¶ and on behalf of the AURORA study group

Рандомизированное, плацебо-контролируемое исследование пациентов с диабетом на гемодиализе не показало влияния аторвастатина на композитную сердечнососудистую конечную точку, однако анализ сердечных составляющих конечных точек говорит о том, что аторвастатин может значительно уменьшить риск. Так как в исследование "Аврора" (Исследование для оценки применения розувастатина у пациентов на обычном гемодиализе: Оценка выживаемости и сердечно-сосудистых событий) были включены пациенты с диабетом и без, мы провели постфактум анализ для определения возможности розувастатина в снижении риска сердечных событий у пацинтов с диабетом получающих гемодиализ. Среди 731 участников с диабетом, традиционные факторы риска, такие как ЛПНП, курение, и гипертония не связывались с ссердечными событиями (сердечная смертность и нефатальный инфаркт миокарда). В начале исследования, только возраст и высоко чувствительный С-реактивный белок являлись независимыми факторами риска сердечных событий. Назначение розувастатина, связывалось с незначительным 16,2% снижением риска сердечной смертности, нефатального ИМ, нефатального и фатального инсульта для композитной конечной точки исследования «Аврора». Не было никакой разницы по всем инсультам, но в группе розувастатина было больше геморрагических инсультов, чем в группе плацебо (12 против 2, соответственно).Лечение Розувастатином существенно(на 32%) снизило количество сердечных событий у пациентов с сахарным диабетом. Заключение - у гемодиализных пациентов с сахарным диабетом розувастатин может уменьшить риск фатальных и нефатальных сердечных событий.