The incidence rates of myopathy and rhabdomyolysis with pravastatin and pitavastatin appear to be comparable to other statins, with higher doses associated with increased risk but the high doses of these statins have not been well assessed in large randomized trials [ Alsheikh-Ali and Karas, ; da Silva, ; del Sol and Nanayakkara, ].
Drugs which interfere with statin metabolism or transport leading to increased systemic exposures to the drug increase the risk of myopathy, as summarized in Table 2 [ Bellosta et al.
Selected drugs that may increase the risk of statin-induced myopathy and rhabdomyolysis. In addition to drug metabolizing enzymes, drugs interfering with the transporters responsible for hepatic uptake and excretion of statins may also affect the pharmacokinetics of statins and the risk of myopathy.
Some drugs such as cyclosporine or clarithromycin will interact with statins through multiple pathways involving enzymes and transporters. Conversely, statins may cause interactions with other drugs resulting in toxicity. This is only a problem with drugs with a narrow therapeutic range, such as warfarin and digoxin. All of the statins can cause some increase in anticoagulation effect with warfarin, although the mechanisms are not clear except that fluvastatin can inhibit the metabolism of active S-warfarin through CYP2C9 [ Neuvonen et al.
To avoid statin—drug interaction related myopathy, dose limits are set when prescribing statins with known potent inhibitors of the CYP enzymes or with some other interacting drugs.
Due to the increased risk of myopathy with the high dose of simvastatin 80 mg , the FDA has recently recommended lower doses of simvastatin with certain CYP3A4 inhibitors, for example, the dose of simvastatin was limited to 10 mg daily in patients taking amiodarone, verapamil or diltiazem [ FDA, ].
Furthermore, simvastatin is now contraindicated in patients taking gemfibrozil, cyclosporine and danazol, whereas previously the FDA recommended restricting the dose of simvastatin to up to 10 mg. The disposition of pravastatin, rosuvastatin and pitavastatin does not depend on or is only marginally influenced by CYP enzymes and therefore these statins may have favorable drug interaction profiles [ Corsini and Ceska, ; del Sol and Nanayakkara, ; Toth and Dayspring, ]. As statin-induced myopathy is a plasma- concentration-dependent adverse reaction, polymorphisms in CYP enzymes and drug transporters involved in the disposition of statins may affect the pharmacokinetics and toxicity of statins [ Hu et al.
However, polymorphisms in CYP enzymes have been inconsistently associated with statin-induced myopathy and lipid responses [ Fiegenbaum et al.
The uptake transporter OATP1B1 expressed in the basolateral membrane of hepatocytes regulates the influx of statins from the portal blood to the hepatocyte. It has been suggested that this finding is likely to apply to other statins as SLCO1B1 polymorphisms affect the blood levels of most statins but the effect is greatest for simvastatin [ Niemi, ; Pasanen et al. Most recently, a pharmacogenetic study examined whether common genetic polymorphisms that lead to reduced activity of CYP enzymes or transporters would be associated with mild statin-induced adverse effects defined as discontinuation for any side effect, myalgia, or CK more than three times ULN [ Voora et al.
The study-defined adverse effects occurred in 99 patients 54 discontinuations, 49 myalgias, and 9 CK elevations with a greater risk of the side effects with the high statin doses. Similar findings were also observed by Donnelly and colleagues in patients with type 2 diabetes receiving statins as part of routine clinical care [ Donnelly et al.
There are multiple predisposing factors potentially increasing the risk of statin-induced myopathy, including advanced age, female sex, small body frame and frailty, alcoholism, complex medical problems e.
Furthermore, certain acutely acting factors such as the use of addictive drugs, serious viral or bacterial infections, major trauma, major surgery or the perioperative period, and intense physical activity could predispose patients to myopathy independently, and may trigger the development of severe myopathy in those receiving statins [ Chatzizisis et al.
It has been proposed that statin-induced coenzyme Q10 CoQ10 deficiency might be involved in the pathogenesis of statin myopathy [ Marcoff and Thompson, ]. CoQ10 plays an important role in mitochondrial energy production by participating in the electron transport chain, preventing oxidative stress, and regenerating active antioxidant vitamins C and E in mitochondria [ Joy and Hegele, ; Marcoff and Thompson, ]. Polymorphisms of genes involved in the metabolism of CoQ10 have been inconsistently shown to be associated with statin-induced myopathy [ Oh et al.
However, although statin treatment reduces circulating levels of CoQ10, largely because CoQ10 is carried in LDL particles, its effect on intramuscular levels of CoQ10 remains unclear. Furthermore, studies of the effects of oral CoQ10 supplementation which raise the plasma CoQ10 levels on myopathic symptoms are scarce and contradictory [ Joy and Hegele, ; Marcoff and Thompson, ].
Owing to a lack of firm evidence, the routine use of CoQ10 was not recommended in patients receiving statin treatment, but CoQ10 supplementation can be tested in some patients who develop statin-related myalgia and who do not benefit from other approaches.
Some patients may respond if only via a placebo effect, as shown in some preliminary trials [ Young et al. Vitamin D deficiency is associated with myositis and reduced muscle function [ Erkal et al. Serum 25 OH D levels are related to physical performance in healthy people [ Bunout et al. Several recent case series and clinical studies demonstrated an association between vitamin D deficiency and statin-induced myalgia myopathy. These reports and studies suggested that vitamin D deficiency may contribute to the development of statin-induced muscle injury.
Atorvastatin and rosuvastatin have been shown to increase serum 25 OH D levels [ Perez-Castrillon et al. However, future double-blind, placebo-controlled studies are required to verify observations on the relationship between serum vitamin D status and statin-induced myopathy. Elevation of liver enzymes in particular, alanine and aspartate transaminases [ALT and AST] is another well-recognized adverse effect of statins [ Armitage, ; Gillett and Norrell, ].
At the highest dose in the approved range, the incidence of the increases in ALT and AST is 20—30 per patients in comparison to 1—2 per patients with the lowest dose [ Brown, ]. It has been estimated that the placebo-adjusted rise in transaminases attributable to statins was approximately 0.
The asymptomatic elevations in transaminases with statins generally occur in the first several months of treatment and are reversible. They can return to normal on stopping statin treatment, with dose reduction, or even spontaneously with continuation of the same statin dosage [ McKenney et al.
It has been questioned whether the effect on transaminases indicates hepatotoxicity or just a hepatic reaction to a greater reduction in lipid levels as all lipid-lowering drugs may increase liver enzymes [ Armitage, ]. Furthermore, emerging data have demonstrated that statins are generally well tolerated in patients with chronic liver disease with elevated liver enzyme levels, such as nonalcoholic fatty liver disease NAFLD , primary biliary cirrhosis, and due to hepatitis C virus [ Argo et al.
Several short-term studies have evaluated statin treatments in patients with NAFLD and results have been promising, with some studies showing histological improvement in inflammation without changes in fibrosis [ Argo et al.
Further evidence of the safety and efficacy of statins in patients with chronic liver disease was demonstrated in two recent clinical studies with pravastatin and atorvastatin, respectively [ Athyros et al. The Justification for the Use of Statins in Primary Prevention: an intervention Trial Evaluating Rosuvastatin JUPITER study reported in showed an increased incidence of diabetes with rosuvastatin treatment and this reignited interest in the link between statin therapy and diabetes [ Ridker et al.
There was little heterogeneity among the studies included in the meta-analysis, suggesting that this risk appears to be a class effect [ Sampson et al.
The meta-regression analysis showed that the risk of development of diabetes with statins was highest in trials with older participants, but baseline body mass index and change in LDL-C concentrations were not found to be associated with the risk of new-onset diabetes [ Sampson et al.
The results showed that patients receiving intensive-dose statin therapy had increased risk of new-onset diabetes but a reduced risk of cardiovascular events compared with moderate-dose therapy over a weighted mean follow up of 4. Compared with moderate-dose statin therapy, the number needed to treat per year for intensive-dose statin therapy was for the harm of new-onset diabetes while the number needed to treat per year was for the benefit of reducing cardiovascular events.
Although statin therapy in general and intensive statin therapy in particular is associated with a slightly increased risk of developing diabetes, this risk was very small in absolute terms and relative to the reduction in coronary events [ Preiss et al. Furthermore, the benefit of statins in preventing cardiovascular events in patients with diabetes has been well established [ Kearney et al.
Thus, the cardiovascular benefits of statins are much greater than the small risk of incident diabetes in patients with moderate or high cardiovascular risk or with documented CVD [ Preiss and Sattar, ; Sampson et al. Previous studies suggested a close association between high serum cholesterol levels and stroke incidence [ Athyros et al. Statin therapy is associated with significant reductions in primary and recurrent ischemic stroke, probably via its lipid-lowering and pleiotropic effects [ Athyros et al.
A meta-analysis of data from statin and nonstatin diet or other lipid-lowering agents trials demonstrated that statins, but not other interventions, significantly decreased the risk of total stoke odds ratio 0. However, a reverse relationship between cholesterol level and haemorrhagic strokes has been reported in different populations [ Noda et al. Post hoc analysis of this study showed that this increased risk was primarily observed in older men with a history of haemorrhagic stroke and there was no association between baseline or on-treatment LDL-C levels and the risk of haemorrhagic stroke [ Goldstein et al.
Similarly, the early Heart Protection Study also suggested an increased risk of haemorrhagic stroke during simvastatin therapy among patients with previous cerebrovascular disease with no such increase evident in patients free from cerebrovascular disease [ Collins et al.
However, a recent large population-based observational study in older patients surviving from acute ischemic stroke showed that exposure to statins was not associated with subsequent intracranial hemorrhage [ Hackam et al. This result was supported by an extensive meta-analysis of 11 randomized or observational studies including SPARCL exclusively enrolling patients with cerebrovascular disease showing that there was no evidence that statins selectively increased the risk of intracerebral hemorrhage [ Hackam et al.
The other major statin trials in patients free from cerebrovascular disease did not show an increased risk of haemorrhagic stoke with cholesterol lowering [ Amarenco and Labreuche, ; Everett et al.
The meta-analysis of the efficacy and safety of studies using more intensive lowering of LDL-C found a nonsignificant increased risk of haemorrhagic stroke with more intensive LDL-C lowering treatment compared with less intensive therapy, which was clearly offset by the reduction in ischemic strokes [ Baigent et al. Overall, it would appear prudent to be cautious in assessing the risks and benefits before using statins in patients with previous haemorrhagic stroke and to ensure that blood pressure is well controlled before giving very intensive statin therapy to avoid any increased risk of haemorrhagic stroke.
Statins are a widely used and extensively studied group of drugs, which are well tolerated with good safety profiles. The recognized adverse effects of myopathy and rhabdomyolysis are rare at the approved dose ranges and the risk can be kept to a minimum by attention to the potential risk factors.
Asymptomatic increases in liver transaminases with statin treatment does not seem to be harmful and statins can be safely used in most patients with elevated transaminase levels from NAFLD or stable hepatitis B and C viral infections. The risks of other unfavorable effects, for example, the slightly increased risk of new-onset diabetes and the potentially increased risk of haemorrhagic stroke, are small compared with the greater cardiovascular benefits with the use of statins.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The other authors have no known conflict of interest. As a test is not yet readily available in the UK, alternative statins which are less affected by this genetic subtype should be considered see table. There is no need for anyone who has been using simvastatin without any problems to stop taking it on the basis of this information.
Advise patients to seek prompt medical attention if they experience muscle problems while taking statins.
Myopathy may not be clinically serious to start with, but can rarely progress to potentially fatal rhabdomyolysis.
Review statin treatment if muscle problems occur. For some patients, stopping statin treatment may be appropriate. If statin treatment must be continued despite muscle problems, consider using a lower statin dose or switching to a different statin. Patients and prescribers should also be aware that other side effects have also been reported in association with statins.
The benefits of using any statin in its licensed indication outweigh the risks in most patients. As with all medicines, the MHRA constantly reviews the safety of statins and will inform prescribers and patients when new important information becomes available. In deciding whether to offer statin therapy, carefully consider both the potential benefits and harms for each patient. Lancet ; — Taylor F et al. The Cochrane database of systematic reviews. Law et al, Am.
Cardiol ; 52C—60C. Carr et al, Clin Pharmacol Ther ; — Floyd et al, JAMA ; — Niemi, Clin Pharmacol Ther ; — Drug Safety Update Nov , vol 3 issue 4: Drug Safety Update Jan , vol 5, issue 6: A2.
Book your coronavirus vaccination and booster dose on the NHS website. To help us improve GOV. It will take only 2 minutes to fill in. Importantly, there seems to be no effects on either growth velocity or sexual maturation in children. Statins begun in early life though are likely to be continued for long durations and continued collection of long-term safety data is a top priority. For woman of childbearing age, current practice mandates a high threshold to initiate statin therapy. With the paucity of current data, statins remain a category X contraindicated drug in pregnancy by the FDA and should be stopped 3 months before attempting to conceive.
Statins remain contraindicated for breastfeeding mothers as well. Lastly, East Asians have long being considered as a separate and unique population regarding tolerance and dosing of statin therapy.
Since introduction of statins three decades ago, East Asian populations have generally been prescribed lower doses due to beliefs that they are either more sensitive to these medications or have increased therapeutic response relative to western populations; the current prescribing information for rosuvastatin and simvastatin suggest lower doses in these populations.
Pharmacokinetic studies do suggest greater plasma concentrations of some statins and their active metabolites in this population.
Clinicians should remain aware of this possible greater sensitivity of East Asians to statins in general. Statins are shown with robust data to be safe in patients with CKD stages 2 to 4, as well as for patients on dialysis. Notably there is no evidence for cardiovascular benefit or CVD reduction in patients on dialysis, likely due to the poor prognosis and competing risks in this group.
There may be a small increased absolute risk for intracranial hemorrhage when statins are used for secondary stroke prevention in those with a history of intracranial hemorrhage. However, the benefits of reducing overall stroke and other vascular events generally outweighs the possible small absolute risk of hemorrhage in secondary prevention populations.
Statins do not cause progression of liver dysfunction in those with nonalcoholic fatty liver disease or chronic viral hepatitis C. There is no need to avoid statin therapy in patients with stable chronic liver disease or normal modestly elevated transaminases levels up to three times the upper limit of normal.
Currently no reliable data exists showing statins are safe to use in advanced or decompensated liver disease. For patients who have received solid organ or bone marrow transplantation, the immunosuppressant cyclosporine is well known to interact with all statins.
Pravastatin, fluvastatin and rosuvastatin are currently recommended by the FDA for safe use in patients treated with cyclosporine, each at reduced doses; other transplant immunosuppressive agents have no evident interactions with statins. Lastly, with the development of robust and tolerable antiretroviral regimens for HIV, men and women living with this disease are now living longer and suffering the complications of cardiovascular disease due at least in part to the high prevalence of dyslipidemia.
Statins are often subject to the effects on metabolism of the antiretroviral drugs, and many of these agents will increase plasma concentrations of statins. Patients receiving protease inhibitors or a pharmacokinetically boosted antiretroviral regimen should avoid simvastatin and lovastatin, the two prodrug formulations of statins.
Pitavastatin, atorvastatin, rosuvastatin and pravastatin can be considered safe, though dosing changes may be needed based on the antiretroviral regimen. The clinician should work to choose an appropriate formulation and dose of statin, rather than altering the patient's antiretroviral regimen. The evidence relied upon is current and the questions of tolerability and safety are timely in an era of widespread vascular disease in need of good medical intervention.
Their work appropriately characterizes the degrees of statin related adverse events as often exaggerated and provides clinicians with a founded assurance that the benefits of this generally well tolerated class far outweigh their infrequent risks. Specialist and primary care providers alike should look to this work in support of our combined efforts to use directed therapy toward cardiovascular prevention.
Newly Diagnosed Diabetes The trend of newly-diagnosed or new-onset diabetes is another oft-cited effect of statin therapy. Neurologic Effects Some epidemiologic studies have found an inverse relationship between cholesterol levels and the risk of hemorrhagic stroke.
Steroid Hormone Function As inhibitors of steroid biosynthesis, a statin's theoretical effect on steroid hormone production and function has been investigated.
Cataract Formation A few animal studies suggested the formation of subscapular lens opacities when statins are given in doses well above maximal human doses.
Renal Function The adverse renal effects of statins span asymptomatic proteinuria to severe AKI associated with rhabdomyolysis. Tendon Injury Rare case reports of spontaneous tendinitis and tendon rupture in users of statins have been reported since the early s. Oncologic Risk There is no current link between statins and cancer in humans. Age and Ethnic Groups Large randomized controlled trials have included individuals over 65 years as well those in their 70s and 80s for treatment periods of up to 5 years.
Specific Disease Considerations Statins are shown with robust data to be safe in patients with CKD stages 2 to 4, as well as for patients on dialysis.
Concluding Views and Evidence Newman et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet ; Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials. Eur Heart J ; Prevalence of cholesterol treatment eligibility and medication use among adults - United States, Statin safety and associated adverse events: a scientific statement from the American Heart Association.
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