HMG coenzyme-A reductase inhibitors

Observational studies

In a multicenter, open, phase III study in 104 Korean patients there were eight adverse drug reactions in six patients taking pitavastatin and 19 adverse drug reactions in 12 patients taking simvastatin [ ]. However, there were no reports of serious reactions in either group.

Systematic reviews

In a meta-analysis of four trials of statins in 27 548 patients, representing 108 049 patient-years, high-dose therapy with atorvastatin or simvastatin 80 mg/day was associated with a significant increase in the risk of any adverse event (OR = 1.44; 95% CI = 1.33, 1.55) and adverse events requiring withdrawal of therapy (OR = 1.28; 95% CI = 1.18, 1.39) [ ]. High-dose therapy was also associated with an increased risk of abnormalities of liver function testing (OR = 4.48; 95% CI = 3.27, 6.16) and rises in creatine kinase activity (OR = 9.97; 95% CI = 1.28, 78). The authors concluded that moderate-dose statin therapy may be most appropriate for achieving cardiovascular risk reduction in most individuals, reserving high-dose statins for those at highest risk.

Cardiovascular

In 14 asymptomatic patients statin therapy worsened left ventricular diastolic function; ubidecarenone (co-enzyme Q10) supplementation produced improvement. There were several limitations of this study, including a small sample size and the lack of a control arm, but the patients did serve as contemporary controls for themselves [ ].

Respiratory

Interstitial pneumonitis has been attributed to statins in seven patients [ ].

• A 60-year-old man, a non-smoker, developed bilateral serosanguinous pleural effusions after taking pravastatin 40 mg/day for about 1 year; the effusions resolved rapidly after withdrawal of pravastatin, although that could have been coincidental [ ].

Ear, nose, throat

Several statins inhibit T-helper 1 cell development and induce T-helper 2 cell polarization and production of T-helper 2 cytokines, which promote the activation and chemotaxis of eosinophils. This prompts the question of whether statins cause nasal polyps. Among 200 patients who were using statins and 200 who were not, nasal polyps were detected in four of the former and five of the latter [ ].

Nervous system

Statins interfere with the production of isoprene, which is somehow connected with sleep, but there have been neither changes in sleep EEG measures relevant to insomnia nor changes in the quality of sleep [ ]. However, there has been a report of sleep disturbances [ ].

• A 55-year-old man reported restless nights and nightmares, which he had not previously experienced, after taking metoprolol 100 mg bd and simvastatin 10 mg/day for 3 months. The dose of metoprolol was reduced to 50 mg bd, with no observable benefit. Simvastatin was withdrawn 2 weeks later and pravastatin 20 mg/day was prescribed, with substantial improvement in the quality of sleep, although some unpleasant nightmares still occurred. Four weeks later, metoprolol was also withdrawn and atenolol 100 mg/day was prescribed. Thereafter, the quality of sleep was significantly improved, and 6 months later the patient did not report any nightmares. Sleep disturbances recurred after a later attempt to reintroduce simvastatin in place of pravastatin. The same effect occurred when, during treatment with pravastatin, substitution of atenolol with metoprolol was attempted.

In this case, the statins may have interacted with metoprolol, and it may have been relevant that metoprolol is more lipid-soluble than atenolol.

Peripheral neuropathy occurs with statins, and perhaps with all cholesterol-lowering drugs, and may be related to reduced production of ubidecarenone, as suggested in a review [ ]. The possible link between statins and peripheral neuropathy has been evaluated [ ]. Based on epidemiological studies and case reports the risk appears to be minimal. These findings should alert prescribers to a potential risk of peripheral neuropathy in patients taking any statin; that is, statins should be considered the cause of peripheral neuropathy when other causes have been excluded. It appears that once a statin produces a neuropathy, rechallenge with any other statin is likely to cause a recurrence. This is reported to occur 1–3 weeks after rechallenge, whereas resolution takes 4–6 weeks after withdrawal [ ].

Peripheral polyneuropathies attributed to statins have been briefly reviewed [ ]. They are rare (about one per 10 000 per year) and include sensory or sensorimotor polyneuropathies with signs of sensory impairment, and reduced or sometimes suppressed tendon reflexes. There may be markedly reduced muscle strength. Renal failure and diabetes are susceptibility factors.

In 42 patients (mean age 52 years; 23 men, 19 women) neurophysiological investigation of the peroneal, tibial, and sural nerves before and for 24 months after treatment with simvastatin 20 mg/day was initiated., although none of the patients reported subjective symptoms typical of polyneuropathy; nevertheless, there was electrophysiological evidence of damage to the peripheral nerves [ ].

In a case-control analysis using the UK-based General Practice Research Database (GPRD), 3637 patients with idiopathic Parkinson’s disease were identified; there was no association with the use of statins or fibrates [ ].

Of seven cases of neuropathy, all were axonal peripheral neuropathies and both thick and thin nerve fibers were affected [ ]. No cause of peripheral neuropathy other than statin treatment could be identified. In this series at least four of the cases were irreversible, probably because of long exposure to statins (4–7 years versus 1–2 years in previous reports). Besides an effect on ubidecarenone, interference with cholesterol synthesis may alter nerve membrane function, since cholesterol is a ubiquitous component of human cell membranes. Neuropathy has not been observed in extensive long-term trials of lipid-lowering drugs. It could be due to patient selection, a low frequency of the adverse reaction, or lack of attention to symptoms of peripheral neuropathy. The observed association may also not be causal.

In a case-control study of 166 cases of idiopathic polyneuropathy, of which 35 had a definite diagnosis, the odds ratio for neuropathy was 14 for statin users compared with non-users [ ].

• A 58-year-old man developed a disorder resembling Guillain–Barré syndrome at the start of simvastatin therapy [ ]. He had had a similar but milder episode after taking pravastatin 6 months before.

This case suggests that acute polyradiculoneuropathy may represent a rare but serious adverse reaction to statin treatment. The pathophysiology of acute neuropathy on statin exposure is unknown; a hypersensitivity reaction resulting in an immune-mediated process has been suggested. It is possible that this patient had relapsing Guillain–Barré syndrome unrelated to the use of statins.

With the current level of information, it is prudent to consider withdrawal of statins in patients with symptoms compatible with polyneuropathy.

Sensory systems

One should be alert to the possibility of color blindness due to statins [ ], although the risk is uncertain.

Owing to the high cholesterol content of the human lens, ocular changes have been looked for during trials with statins. It has been concluded that cataract does not occur. Although the degree of lens opacities increases during treatment, the incidence does not differ from that seen in an untreated control population [ ]. With fenofibrate serving as control, lovastatin or simvastatin did not reduce visual acuity during treatment for 2 years [ ]. According to a review, there is no danger during long-term treatment and there should be no requirement for regular ophthalmological examination [ ].

In a nested case-control study involving 2867 cases and 11 468 controls, current users of ACE inhibitors or statins were at a slightly higher risk of developing macular degeneration (RR = 1.19; 95% CI = 1.07, 1.33 and 1.30; 1.17, 1.44 respectively) [ ].

Psychological

Animal and cross-sectional studies have suggested that serum lipid concentrations can cause altered cognitive function, mood, and behavior [ ].

When the MedWatch drug surveillance system of the Food and Drug Administration (FDA) from November 1997 to February 2002 was searched for reports of statin-associated memory loss, 60 patients were identified; 36 had taken simvastatin, 23 atorvastatin, and one pravastatin [ ]. About a half of the patients noted cognitive adverse reactions within 2 months of therapy and 14 of 25 patients noted improvement when the statin was withdrawn. Memory loss recurred in four patients who were rechallenged. The current literature is conflicting with regard to the effects of statins on memory loss. Experimental studies support links between cholesterol intake and amyloid synthesis; however, observational studies suggest that patients taking statins have a reduced risk of dementia. Available prospective studies have shown no cognitive or antiamyloid benefits of any statin.

Psychiatric

Emerging data associate statins with a reduced risk of Alzheimer’s disease; however, two women had significant cognitive impairment temporally related to statin therapy [ ]. One took atorvastatin, and the other first took atorvastatin then simvastatin. Cognitive impairment and dementia as potential adverse reactions to statins has been reviewed [ ].

In 308 adults aged 35–70 years with hypercholesterolemia, daily treatment with placebo, simvastatin 10 mg, or simvastatin 40 mg for 6 months was associated with decremental effects of simvastatin on tests previously observed to be sensitive to statins and on tests not previously administered, but not on tests previously observed to be insensitive to statins [ ]. For the three tests specifically affected by simvastatin, effects on cognitive performance were small, manifesting only as a failure to improve during the 6 months of treatment, and were confounded by baseline differences on one test. This study provides partial support for minor decrements in cognitive functioning with statins. Whether such effects have any long-term sequelae or occur with other cholesterol-lowering interventions is not known.

Ratings on a depression scale rose in four out of six men given cholesterol-lowering drugs, in two of them to a degree that met the criteria for mild clinical depression [ ].

Some studies have shown increased risks of violent death and depression in subjects with reduced serum cholesterol concentrations. Serum and membrane cholesterol concentrations, the microviscosity of erythrocyte membranes, and platelet serotonin uptake have been determined in 17 patients with hypercholesterolemia [ ]. There was a significant increase in serotonin transporter activity only during the first month of simvastatin therapy. This suggests that within this period some patients could be vulnerable to depression, violence, or suicide. This may explain why mood disorders are not regularly seen in clinical trials with statins, as has been summarized in a review [ ].

Paranoia, anxiety, and behavioral changes have been attributed to atorvastatin 10 mg/day in a 79-year-old woman after about 17 days [ ].

Psychiatric adverse events during statin therapy have been evaluated using the Interregional Group of Pharmacovigilance database of reports of suspected adverse drug reactions submitted since 1988 from eight Italian regions [ ]. There were 35 314 reports, in 60 of which 71 psychiatric preferred terms combined with statins were identified. Among them, 14 were associated with positive rechallenge. The five most frequently reported psychiatric events were insomnia, somnolence, agitation, confusion, and hallucinations, but only insomnia was reported with a higher frequency for statins than with all other drugs (ROR = 3.3; 95% CI = 1.9, 5.7); while confusion was reported at a lower frequency (ROR = 0.4; 95% CI = 0.1, 0.9). Among statins available in Italy, only simvastatin (ROR = 0.5; 95% CI = 0.2, 0.9) showed a significantly lower rate of reports of psychiatric events than all other drugs together.

Metabolism

Although the statins seem to be similar in their ability to lower LDL, there are also dissimilarities. For instance, simvastatin increases HDL cholesterol with increasing doses, whereas atorvastatin does not [ ]. The clinical significance of this is unknown.

Statins inhibit the production of 2,3-dimethoxy-5-methyl-6-polyisoprene parabenzoquinone (ubidecarenone, ubiquinone, or coenzyme Q10), which is required for mitochondrial electron transport. Idiopathic or primary deficiency of ubidecarenone can cause a mitochondrial encephalomyopathy. A patient developed a mitochondrial syndrome, consisting of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), the symptoms being temporally related to statin therapy [ ].

Hematologic

Hematological adverse effects can occur during treatment with both simvastatin and atorvastatin [ ]. They include thrombotic thrombocytopenic purpura and severe thrombocytopenic purpura.

Mouth

In 26 patients aged 50–70 years statin therapy was withdrawn and the patients were reviewed after 7–15 days [ ]. Dry mouth in 23 patients improved in 17 after withdrawal; itchiness in 15 patients improved in 6 after withdrawal; a bitter taste in 14 improved in 13 after withdrawal.

Liver

HMG CoA reductase inhibitors can be associated with small rises in alanine aminotransferase activity, but have not been definitely associated with severe morbidity involving altered hepatic function. The results of randomized trials do not suggest that statins in standard doses are hepatotoxic. In none of the large randomized studies in which standard doses were assessed (atorvastatin 10 mg/day, fluvastatin 40–80 mg/day, pravastatin 40 mg/day, simvastatin 20–40 mg/day) was there any clear excess risk of hepatitis or any other serious liver-related adverse events. Long-term large randomized trials have confirmed an excess of persistent rises in aminotransferases with atorvastatin 80 mg/day compared with lower doses or placebo, and similarly some excess with simvastatin 80 mg/day, but hepatitis and liver failure were not reported [ ].

All cases of acute liver failure related to the use of lovastatin have been reviewed, and probably the frequency is similar to the background rate. This suggests that periodic monitoring of alanine aminotransferase in these patients would be burdensome and expensive [ ].

The term “transaminitis” has been coined to describe raised serum aminotransferases without clinical symptoms. One author has suggested that in such cases one should switch from one statin to another, thereby preventing unnecessary withdrawal of statin treatment in dyslipidemic patients at high cardiovascular risk [ ].

A return to normal or only slightly increased values of aminotransferases is often seen after a short period. The overall probability of having an increase in aminotransferase activity more than three times the top of the reference range is 0.7% [ ]. The probability may be increased in patients with pre-existing minor hepatic changes, as has been seen in one patient with systemic lupus erythematosus [ ]. There seems to be no difference between the various drugs in this respect [ ], but when simvastatin and atorvastatin, each at a dose of 80 mg/day, were compared in 826 hypercholesterolemic patients there were fewer drug-related gastrointestinal symptoms and clinically significant aminotransferase rises with simvastatin [ ]. Frank hepatitis is rare. A cholestatic picture has also been reported [ ].

In one series, the frequency of liver toxicity was similar in patients taking pravastatin or simvastatin [ ], while in another study there was a difference 6 months after the start of the study when the simvastatin group showed increased liver enzymes [ ].

In a comparison of atorvastatin with pravastatin, of 224 patients taking atorvastatin, two had clinically significant increases in alanine aminotransferase activity [ ]. They recovered during the next 4 months, one after withdrawal of atorvastatin and the other after a dosage reduction. Withdrawals due to adverse reactions were similar in the two groups. One patient developed hepatitis while taking atorvastatin, but was able to tolerate simvastatin [ ]. The authors concluded that this adverse reaction was not due to a class effect. Eosinophils in a liver-biopsy specimen pointed to an immunological mechanism.

In a retrospective review of a registry of 146 men with hepatitis C who took a statin there were no significant increases in alanine aminotransferase activity and only one patient discontinued therapy because of an increase in alanine aminotransferase to more than 3 times the upper limit of the reference range [ ].

In one case a rise in alanine aminotransferase due to fluvastatin 80 mg/day for 6 weeks, confirmed by dechallenge and rechallenge, led to an incidental diagnosis of hepatitis C infection [ ].

Pancreas

Pancreatitis has been observed during treatment with simvastatin (q.v.).

• A 77-year-old woman taking rosuvastatin developed acute pancreatitis, which resolved on withdrawal [ ]. No other cause for the pancreatitis was found. She had had a similar episode 1 year before precipitated by atorvastatin, which resolved on withdrawal.

The authors suggested that pancreatitis may result from a class effect of the statins.

Urinary tract

In 90 patients who were randomly assigned to rosuvastatin 10 mg/day (n = 45) or 20 mg/day (n = 45) there was a dose-related increase in the urinary excretion of alpha ₁ -microglobulin but no adverse effect on renal function, as assessed by eGFR [ ].

Skin

Adverse skin reactions to statins are rare, although they can affect cutaneous lipid content. A series of skin reactions have been described in patients using statins [ ], including a lichenoid eruption in a 59-year-old woman [ ].

Eosinophilic fasciitis has been attributed to simvastatin [ ].

• A 71-year-old woman developed progressive induration of the skin on her arms and legs, with weakness and dyspnea on moderate exertion, after taking simvastatin for 3 weeks. The effects worsened progressively until the drug was withdrawn 1 month later, after which the symptoms stabilized but did not improve. There was erythema, induration, and dimpling of the skin on the arms and legs. There was a mild eosinophilia (650 × 106/l). A skin biopsy showed fibrosis in the reticular dermis, the septa of the superficial fascia, and striated muscle; there was also a perivascular and interstitial lymphocytic infiltrate.

Musculoskeletal

Myopathy and rhabdomyolysis

Rhabdomyolysis continues to be reported in patients taking statins [ ], including one with McArdle’s syndrome [ ]. Rarely, focal myositis can occur [ ]. An algorithm for monitoring statin therapy and managing suspected statin-associated myopathy has been published [ ]. The EIDOS and DoTS descriptions are shown in Figure 1 .

Frequency . In a case-crossover study in 93 831 patients using two independent primary care databases (1991–2006) the risk ratios associated with all classes of statins and fibrates for myopathy were 11 (95% CI = 9.8, 11) and 20 (18, 23) respectively [ ]. At 26 weeks, the largest risks were with fluvastatin (RR = 33; 95% CI = 17, 66) and ciprofibrate with previous statin use (RR = 41; 95% CI = 13, 122). At 12 weeks there were significant differences between cerivastatin and atorvastatin (RR = 2.05; 95% CI = 1.2, 3.5), and between rosuvastatin and fluvastatin (RR = 3.0; 95% CI = 1.6, 5.7). After 12 months, the relative risk for all statins and fibrates increased to 26 (95% CI = 22, 30). The authors estimated the annual incidence of statin-induced myopathy or myalgia at around 700 per million per year.

The prevalence of myopathic events, particularly myalgia, myositis, and rhabdomyolysis, has been assessed retrospectively in a community-based practice among 32 225 subjects with diabetes (n = 10 247) or without diabetes (n = 21 978), some of whom took statins [ ]. More statin users than non-users had myopathic events, both among those with diabetes (7.9% versus 5.5%) and those without (9.0% versus 3.7%). However, 95% of the events were myalgia or mild myositis. The prevalence of severe myositis was 0.4 per 1000 person-years (95% CI = 0.2, 0.7) and 0.8 per 1000 person-years (95% CI = 0.6, 1.1) among statin users with or without diabetes respectively. By comparison, the rates were 0.3 (95% CI = 0.1, 0.5) and 0.2 (95% CI = 0.1, 0.4) per 1000 person-years among non-users with and without diabetes respectively. Rates of rhabdomyolysis were 0.1 (95% CI = 0.1, 0.3) and 0.2 (95% CI = 0.1, 0.5) per 1000 person-years among statin and non-statin users with diabetes respectively, and 0.2 (95% CI = 0.1, 0.4) in both groups without diabetes. The authors concluded that statin use was associated with an approximate doubling of the risk of any myopathic event but was not associated with an increased risk of rhabdomyolysis.

The incidence of rhabdomyolysis in patients taking different statins and fibrates, alone and in combination, has been estimated using data from 11 managed health care plans across the USA [ ]. The incidences of rhabdomyolysis were 0.44 per 10 000 person-years of treatment with atorvastatin, pravastatin, or simvastatin, 5.34 with cerivastatin, and 2.82 with fibrates. The incidence increased to 5.98 when atorvastatin, pravastatin, or simvastatin was with a fibrate, and to 1035 when cerivastatin was combined with a fibrate.

Myopathy, defined as muscle symptoms with a rise in creatine kinase greater than 10 times the upper limit of the reference range, was found in one study in only one patient who was taking 40 mg od and in four patients taking 80 mg/day, out of a total of 8245 patients. The number of patients with rhabdomyolysis was, according to postmarketing reporting from the first million individuals taking lovastatin, 24 in all; 17 of those had taken other medications that are known to increase the risk [ ]. There is some evidence that patients with other concomitant illnesses may be at greater risk of myopathy than would be anticipated from experience in controlled trials.

Symptomatic rises in creatine kinase activity to over 10 times the upper end of the reference range occurred in 0%, 1%, and 0.9% of patients taking placebo, cerivastatin 0.4 mg, or cerivastatin 0.8 mg respectively [ ], and rhabdomyolysis has been described in patients taking cerivastatin [ , ]. However, in a review of the pharmacological properties and therapeutic efficacy of cerivastatin in hypercholesterolemia, it was stated that cerivastatin only infrequently causes rhabdomyolysis when given alone [ ].

Mechanisms . The mechanisms of the myopathic effects of statins have been reviewed, stressing possible actions on mitochondria, including actions on ubidecarenone and inhibition of mevalonate metabolism [ ]. It has been suggested that mitochondrial impairment leads to a mitochondrial calcium leak that directly interferes with the regulation of sarcoplasmic reticulum calcium cycling although there may also be a direct effect of statin on the sarcoplasmic reticulum; these actions may result in apoptosis, oxidative stress, and muscle remodelling and degeneration [ ].

Statins reduce circulating concentrations of ubidecarenone (ubiquinone, coenzyme Q10), a co-factor for mitochondrial energy production, although in one study pitavastatin had no such effect, while atorvastatin did [ ]. Furthermore, their effects on intramuscular ubidecarenone in patients with symptomatic statin-associated myopathy are not well described [ ]. Supplementation with ubidecarenone (100 mg/day, n = 18) has been studied in patients with myopathic symptoms in a double-blind randomized comparison with vitamin E (400 IU/day, n = 14) for 30 days [ ]. Ubidecarenone reduced pain severity by 40% and interference by pain with daily activities by 38%; vitamin E had no effect. However, in contrast, ubidecarenone supplementation in a placebo-controlled study in 44 patients had no effect on statin-related myalgia when the dose of simvastatin was titrated from 10 mg/day, doubling every 4 weeks, if tolerated, to a maximum of 40 mg/day [ ].

Dose relation . For all types of statin the risk is higher with higher doses in the therapeutic range. The risk is not clearly related to LDL-lowering efficacy; for example, cerivastatin was not particularly effective but was much more likely than other statins to cause rhabdomyolysis. Despite the fact that they can cause a myopathy, there is no clear evidence from randomized trials that statins cause myalgia, and reports of muscle cramp do not seem to be increased [ ]. However, these assertions, which are based on results from randomized clinical trials, are difficult to reconcile with observations made in the Primo study [ ]. This was an observational study in an unselected population in France taking high doses of various statins. Muscle symptoms were reported by 832 of 7924 patients (11%), with a median time of onset of 1 month after the start of statin therapy. Muscle pain prevented even moderate exertion during everyday activities in 315 patients (38%), while 31 (4%) were confined to bed or unable to work. Among individual statins fluvastatin was associated with the lowest rate of muscular symptoms (5.1%). Creatine kinase activity was not measured.

Susceptibility factors . The susceptibility factors for rhabdomyolysis in patients taking statin monotherapy or a statin plus a fibrate have been elicited in a nested case-control study in 252 460 new users of lipid-lowering medications across 11 geographically dispersed US health plans [ ]. There were 21 cases of rhabdomyolysis (0.008% or about 1 in 12 000) and they were compared with 200 individually matched controls without rhabdomyolysis. Statin users aged 65 years of age and older had four times the risk of hospitalization for rhabdomyolysis than those under 65 (OR = 4.36; 95% CI = 1.5, 14). There was a joint effect of high statin dosage and renal disease; when these two variables were added to the model with age, the OR was 5.73 for dosage (95% CI = 0.63, 53) and 6.26 for renal disease (95% CI = 0.46, 63). Although not statistically significant, there was a greater than two-fold increase in the risk of rhabdomyolysis among women (OR = 2.53; 95% CI = 0.91, 7.32).

There is an increased risk of rhabdomyolysis in patients with hypothyroidism, which is a susceptibility factor for statin-induced rhabdomyolysis [ ]. Screening thyroid function has been advocated before starting hypolipidemic drugs [ ]. However, an unusual interaction between a statin and hypothyroidism has been reported in a patient with rhabdomyolysis [ ].

• An 85-year-old woman with renal impairment and hypothyroidism was given simvastatin 80 mg/day and soon after developed severe muscle weakness and laboratory evidence of rhabdomyolysis. Although her hypothyroidism had been well controlled for years with levothyroxine 100 micrograms/day, her biochemistry now suggested hypothyroidism. On withdrawal of the simvastatin her serum TSH fell to within the reference range within 4 weeks without any change in the dosage of levothyroxine.

There is an increased risk of rhabdomyolysis when people taking statins undertake exercise. In 79 subjects who were randomized to atorvastatin 10 mg/day (n = 42) or 80 mg/day (n = 37) for 5 weeks, a downhill walk increased plasma CK and CK-MB activities, but there were no differences between the high and low doses [ ]. The authors concluded that exercise increases the risk of rhabdomyolysis even at low doses of a statin.

Early-onset rhabdomyolysis has been reported in a patient with nephrotic syndrome who was taking atorvastatin [ ]. Atorvastatin is highly protein bound, and a reduction in serum albumin concentration because of the nephrotic syndrome could have caused an increase in the unbound fraction in the plasma and hence greater distribution to muscle.

Rhabdomyolysis with lipid-lowering drugs [ , ] is especially problematic when they are used in combination [ ]. In individuals with pre-existing renal insufficiency this can lead to an earlier need for chronic dialysis [ ].

Differences between statins . All statins can cause myopathy and rhabdomyolysis, but not all statins are alike. For example, the evidence to date, based on almost 2 decades of experience, points to an extremely low risk of myopathy and rhabdomyolysis with lovastatin, and lovastatin 20 mg tablets are being considered for non-prescription availability in several countries [ ]. Furthermore, muscle adverse reactions do not necessarily occur after a change from one statin to another [ ].

Drug–drug interactions . Interactions between various hypolipidemic drugs and other drugs also sometimes cause rhabdomyolysis [ , ]. For instance, itraconazole markedly increases plasma concentrations of lovastatin, and in one subject plasma creatine kinase was increased 10-fold within 24 hours of administration of this combination [ ].

• A 59-year-old woman taking pravastatin 20 mg/day tolerated immunosuppression with ciclosporin, prednisone, and mycophenolate mofetil for 4 years after heart transplantation. After switching from pravastatin to simvastatin she developed severe muscle weakness and laboratory evidence of muscle breakdown. The biochemical markers of rhabdomyolysis did not normalize until after repeat hemodialysis. Clinical improvement did not occur until after 5 months.

Presentation . Myopathic symptoms, predominantly stiffness and tenderness of proximal limb muscles and difficulty in rising from a low chair, can develop within a month of starting therapy and most cases develop within 3 months. Most patients recover after withdrawal. Sometimes a glucocorticoid is needed to reverse the myopathy. In one patient, histological investigation of muscle biopsies suggested that the myopathy was due, at least in part, to an inflammatory reaction [ ]. The serum ubidecarenone concentration is reduced by about 30% during statin treatment, because the enzyme is carried by LDL particles, although the concentrations during long-term treatment are equal to those in healthy controls [ , ]. Ubidecarenone is part of the oxidative respiratory pathway generating ATP, and deficiency could impede the function of myocytes, leading to an increase in serum creatine kinase and even cell destruction, with release of myoglobin, which in its turn can block kidney tubules and thereby produce anuria.

The clinical course and muscle biopsy findings have been described in eight patients with hyperlipoproteinemia taking lipid-lowering drugs who developed myalgias or proximal muscle weakness [ ]. All became asymptomatic after withdrawal of the drug, although creatine kinase activity remained high. Muscle biopsy in six cases from 3 months to 2 years after withdrawal of the drug showed variation in fiber diameters in all cases, with necrosis of fibers in five cases, inflammatory infiltration in one, vacuolated fibers in one, and ragged-red fibers in three. Although the muscle biopsy findings were not specific, the authors concluded that prolonged use of statins or fibrates might cause a chronic myopathy, even in the absence of symptoms.

In four patients with muscle symptoms while taking statins, creatine kinase activity was normal, but they were subsequently able to distinguish from their symptoms whether they were taking drug or placebo; muscle biopsies showed evidence of mitochondrial dysfunction [ ].

• Simvastatin 5 mg/day caused rhabdomyolysis in a 61-year-old man who was not taking concomitant interacting drugs [ ].

• An elderly lady with chronic renal insufficiency developed rhabdomyolysis during simvastatin therapy [ ]. Her symptoms of muscle pain, fatigue, myoglobulinuria, oliguria, and pulmonary edema occurred 48 hours after the first dose of simvastatin. Simvastatin was immediately withdrawn, and she was dialysed for 1 week.

In some case statin-induced myopathy can persist or even progress after the drug is withdrawn. In eight such cases there was muscle fiber necrosis, but only three had an inflammatory infiltrate. In all cases there was diffuse or multifocal up-regulation of myosin heavy chain, MHC-I, expression, even in non-necrotic fibers. There was progressive improvement in seven cases when prednisolone and methotrexate were introduced; in one case recover occurred spontaneously [ ].

Diplopia may be an early sign of generalized drug-induced muscle dysfunction. Altogether, 71 cases of diplopia, possibly related to various HMG-CoA inhibitors, have been collected from adverse drug reactions-reporting databases. The information was mostly too scanty to judge a causal relation, but improvement occurred in 33 on withdrawal, and two patients had positive rechallenge data [ ].

• A 67-year-old woman had ocular myasthenia while taking various statins and also bezafibrate [ ]. Atorvastatin had the smallest effect.

The authors suggested that this was a variant of a generalized myopathy and was due to a low ubidecarenone concentration.

Exercise-induced muscle pain, without myopathy and a rise in creatine kinase activity, can probably be caused by statins. Seven patients with heterozygous familial hypercholesterolemia had pain during exercise and cramps in the following hours [ ].