Statin myopathy as a metabolic muscle disease

The etiology of statin myopathy remains unclear and concern about this toxicity is a leading reason that statins are underutilized. A number of observations suggest that this toxicity may be due to the metabolic effects of lipid-lowering in patients with minor muscle disorders. These patients have a high frequency of mutations for metabolic muscle diseases and often have depleted mitochondrial enzymes. Their exercise physiology and biopsy findings indicate reduced oxidation of fats and mitochondrial dysfunction. These subjects are often intolerant of other lipid-lowering therapies in addition to statins, which suggests that the myopathy is due to lipid-lowering itself more than a simple pharmacokinetic reaction to high statin levels. Altogether, these findings support the concept that statin myopathy is a metabolic muscle disease.     

Clinical characterization and molecular mechanisms of statin myopathy

Myopathy has been reported in a small percentage of statin-treated patients for the past 30 years, but the etiologic mechanisms for inducing muscle injury have not yet been fully characterized. Statin-induced myopathy is now understood to be a heterogeneous condition that may be due to: mechanisms of the drug itself; interactions with other drugs; or genetic, metabolic and immunological vulnerabilities in individual patients. In some cases, statins may unmask latent conditions (e.g., asymptomatic baseline myopathy) that predispose patients to muscle toxicity. The definitions, epidemiology, clinical features, risk factors and proposed mechanisms of statin-induced myopathy are reviewed. Muscle metabolism can be adversely impacted by statin therapy, including changes in fatty acid oxidation, possibly reduced coenzyme Q(10) biosynthesis, and increased myocyte protein degradation via the activity of atrogin-1 and the ubiquitin-proteasome pathway. Statin therapy may also activate a variety of autoimmune phenomena that potentiate myocellular injury. Improving our understanding of statin-induced myopathy is a high clinical priority given the large number of patients eligible for statin therapy and the fact that the development of myalgia and myopathy are leading reasons cited by patients for statin discontinuation.     

Clinical characterization and molecular mechanisms of statin myopathy

Myopathy has been reported in a small percentage of statin-treated patients for the past 30 years, but the etiologic mechanisms for inducing muscle injury have not yet been fully characterized. Statin-induced myopathy is now understood to be a heterogeneous condition that may be due to: mechanisms of the drug itself; interactions with other drugs; or genetic, metabolic and immunological vulnerabilities in individual patients. In some cases, statins may unmask latent conditions (e.g., asymptomatic baseline myopathy) that predispose patients to muscle toxicity. The definitions, epidemiology, clinical features, risk factors and proposed mechanisms of statin-induced myopathy are reviewed. Muscle metabolism can be adversely impacted by statin therapy, including changes in fatty acid oxidation, possibly reduced coenzyme Q₁₀ biosynthesis, and increased myocyte protein degradation via the activity of atrogin-1 and the ubiquitin–proteasome pathway. Statin therapy may also activate a variety of autoimmune phenomena that potentiate myocellular injury. Improving our understanding of statin-induced myopathy is a high clinical priority given the large number of patients eligible for statin therapy and the fact that the development of myalgia and myopathy are leading reasons cited by patients for statin discontinuation.     

Statin myopathy: a common dilemma not reflected in clinical trials

Although statins are remarkably effective, they are still underprescribed because of concerns about muscle toxicity. We review the aspects of statin myopathy that are important to the primary care physician and provide a guide for evaluating patients on statins who present with muscle complaints. We outline the differential diagnosis, the risks and benefits of statin therapy in patients with possible toxicity, and the subsequent treatment options.     

The use of statins in optimising reduction of cardiovascular risk: focus on fluvastatin

Patients with widely differing degrees of cardiovascular risk can derive benefit from effective lipid-lowering therapy with statins, including patients with normal or low cholesterol levels. Clinical trials with fluvastatin have shown that it is effective in patients across a broad spectrum of cardiovascular risk. The lipid-lowering effects of fluvastatin are smaller than some statins, but major clinical outcome studies have consistently demonstrated morbidity and mortality benefits with reductions of low-density lipoprotein cholesterol of <30%. As treatment with statins is generally life-long and patients often receive multiple concomitant medications, optimal statin therapy should be well tolerated and serious consideration should be given to the avoidance of drug interactions. Although serious side-effects of statins are very rare, it is important that fluvastatin is less susceptible to drug interactions than other statins, because serious side-effects of statin therapy are generally associated with concomitant medications affecting statin metabolism. In addition, an extended-release formulation of fluvastatin has been developed to provide liver selectivity with a sustained exposure to the drug, thus improving its efficacy, and safety and tolerability profiles.     

Managing statin-induced muscle toxicity in a lipid clinic

What is known and objective: Muscle toxicity is the most significant adverse effect related to statins. The aim of the study was to analyse the clinical course and achievement of LDL‐C target levels in patients with statin‐induced muscle toxicity. Methods: All patients who were referred to the lipid clinic because of statin‐induced muscle toxicity, or developed it during follow‐up, or did not reach LDL‐C target levels because of its previous occurrence, and attended the clinic for at least three follow‐up visits, were eligible. Files were reviewed for demographic and clinical parameters, coronary heart disease risk level, the severity of muscle injury, the type of statin and dose that caused the adverse effects, the clinical approach and outcome, and whether the LDL‐C target level was achieved. Results: The study group consisted of 54 patients. Twenty‐three (43%) patients complained of myalgia, 23 (43%) had asymptomatic serum creatine kinase (CK) level elevation, five (9%) had myopathy and three (5%) had rhabdomyolysis. Fifty of the patients (93%) continued statin therapy and 43 (80%) achieved the LDL‐C target level. What is new and conclusion: We show that for the majority of patients with statin‐induced muscle toxicity, statin therapy can be safely and effectively continued. In cases of asymptomatic CK levels <3–5 upper limit of normal (ULN), statin treatment should not be interrupted. When CK levels >3–5 ULN or when various symptomatic muscle adverse reactions are present, statins rechallenge, after a recovery period, should be individualized either by a low dose of a potent statin or by a less potent statin. An additional lipid medication is advised if the target levels are not achieved.     

Common nonsynonymous substitutions in SLCO1B1 predispose to statin intolerance in routinely treated individuals with type 2 diabetes: a go-DARTS study

SLCO1B1 gene variants are associated with severe statin-induced myopathy. We examined whether these variants are also associated with general statin intolerance in a large population of patients with type 2 diabetes receiving statins as part of routine clinical care. A total of 4,196 individuals were genotyped for rs4149056 (Val174Ala) and rs2306283 (Asp130Asn). Intolerance was defined by serum biochemistry and also by discontinuation, switching, or reduction in dose of the prescribed statin drug. Ala174 was associated with higher intolerance (odds ratio = 2.05, P = 0.043), whereas Asp130 was associated with lower intolerance (odds ratio = 0.71, P = 0.026). Ala174 was associated with a lower low-density lipoprotein cholesterol (LDLc) response to statins (P = 0.01) whereas 130D was associated with a greater LDLc response to statins (P = 0.048), as previously reported; however, this association was no longer present when data for statin-intolerant individuals were removed from the analysis. This study suggests that common genetic variants selected for an extreme phenotype of statin-induced myopathy also predispose to more common milder statin intolerance and may, for this reason, impact lipid-lowering efficacy.     

Considerations for safe use of statins: liver enzyme abnormalities and muscle toxicitiy

Statins play an important role in the care of patients with cardiovascular disease and have a good safety record in clinical practice. The risk of hepatic injury caused by statins is estimated to be about 1 percent, similar to that of patients taking a placebo. Patients with transaminase levels no more than three times the upper limit of normal can continue taking statins; often the elevations will resolve spontaneously. Coexisting elevations of transaminase levels from nonalcoholic fatty liver disease and stable hepatitis B and C viral infections are not contra- indications to statin use. Although myalgias are common with statin use, myositis and rhabdomyolysis are rare. When prescribed at one-half the recommended maximal dosage or less, statins are associated with an incidence of myopathy similar to that of placebo; therefore, rou- tine monitoring of creatine kinase levels in asymptomatic patients is not recommended. Myopathic symptoms usually resolve approximately two months after discontinuing the statin, and the same statin can be restarted at a lower dosage, or patients can try a different statin. Clinically important drugs that interact with statins and increase the risk of adverse effects include fibrates, diltiazem, verapamil, and amiodarone.     

Toward "pain-free" statin prescribing: clinical algorithm for diagnosis and management of myalgia

Myalgia, which often manifests as pain or soreness in skeletal muscles, is among the most salient adverse events associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Clinical issues related to statin-associated myotoxicity include (1) incidence in randomized controlled trials and occurrence in postmarketing surveillance databases; (2) potential differences between statins in their associations with such adverse events; and (3) diagnostic and treatment strategies to prevent, recognize, and manage these events. Data from systematic reviews, meta-analyses, clinical and observational trials, and post-marketing surveillance indicate that statin-associated myalgia typically affects approximately 5.0% of patients, as myopathy in 0.1% and as rhabdomyolysis in 0.01%. However, studies also suggest that myalgia is among the leading reasons patients discontinue statins (particularly high-dose statin monotherapy) and that treatment with certain statins (eg, fluvastatin) is unlikely to result in such adverse events. This review presents a clinical algorithm for monitoring and managing statin-associated myotoxicity. The algorithm highlights risk factors for muscle toxicity and provides recommendations for (1) creatine kinase measurements and monitoring; (2) statin dosage reduction, discontinuation, and rechallenge; and (3) treatment alternatives, such as extended-release fluvastatin with or without ezetimibe, low-dose or alternate-day rosuvastatin, or ezetimibe with or without colesevelam. The algorithm should help to inform and enhance patient care and reduce the risk of myalgia and other potentially treatment-limiting muscle effects that might undermine patient adherence and compromise the overall cardioprotective benefits of statins.     

Novel actions of HMG-CoA reductase inhibitors(statins)--vascular and cerebral protection through inhibition of small GTPase Rho]

Clinical trials have demonstrated the beneficial effect of HMG-CoA reductase inhibitors(statins) for stroke prevention, independent of their lipid-lowering effects. Recent experimental progress indicated the effects of statins for brain protection on both vascular walls(endothelium, smooth muscle, inflammatory cells and platelets) and extra-vascular tissues(brain parenchyma). These pleiotropic effects of statins have been, at least in part, ascribed to inhibition of small GTPases Rho and Ras, which require isoprenoids (intermediates of the cholesterol biosynthesis pathway) for activation. Importantly, statin inhibition of Rho (1) attenuates the infarct size in a rat model of brain ischemia via the elevation of eNOS expression, and (2) suppresses vascular smooth muscle proliferation through up-regulation of CDK inhibitor p27kip1. The novel action of statin, as inhibitor of small GTPase family, should expand its potential toward integrative organ protection, beyond its conventional lipid-lowering and anti-atherogenic effects.     

Genetic predisposition to atorvastatin-induced myopathy: a case report

What is known and Objective: The major clinical complication of statins is a variety of muscle complaints ranging from myalgia to rhabdomyolysis. There is growing evidence that carriers of genetic polymorphisms in the enzymes and transporters implicated in statin disposition, particularly the SLCO1B1 gene, are at increased risk of myotoxicity. Our objective is to report on two cases of statin‐induced myopathy occurring in a family with two patients who are carriers of the loss of function SLCO1B1 genetic variant and to briefly review the related literature. Case summary: Patient 1, a 48‐year‐old man with history of coronary artery disease, experienced rapidly evolving muscle pain and weakness of the extremities during treatment with atorvastatin 40 mg. Patient 2, a 65‐year‐old man, father of patient 1, had symptoms similar to those of his son after 2 weeks’ treatment with the same statin. Atorvastatin was stopped in both cases, and symptoms resolved. On the basis of family relationship between the two patients, it was possible to hypothesize a genetic basis for the myopathy. Genotyping showed the patients to be carriers of the rs4363657 polymorphism of SLCO1B1 gene. What is new and Conclusion: The two cases reported here and the brief literature review emphasize the impact of genetic factors on the risk of myopathy with statins. Although genotyping all patients before initiating therapy is not recommended at present, pharmacogenetic testing may be useful for new patients who have a family history of statin‐induced myopathy.     

Statins in the intensive care unit

PURPOSE OF REVIEW: Statins are effective lipid-lowering agents used extensively in medical practice. This review summarizes the evidence for statin treatment of cardiovascular patients in the intensive care unit and briefly discusses the role of statins in prevention and treatment of sepsis as a potential future application of statins in critical care. RECENT FINDINGS: Recent studies have extended the use of statin therapy to the acute manifestations of cardiovascular disease and have suggested cholesterol-independent therapeutic benefits, termed pleiotropic effects, which have added a wide scope of potential targets for statin therapy. SUMMARY: Statin therapy should be continued in intensive-care patients in whom statin therapy is warranted due to underlying cardiovascular disease or significant risk thereof. In acute coronary syndromes, statin therapy should be initiated within 24-96 h regardless of pretreatment cholesterol levels. Patients undergoing vascular surgery should receive peri-operative statin therapy. Placebo-controlled clinical trials are required to consolidate the experimental and observational evidence for prevention and treatment of sepsis.     

Adverse effects of statins

The safety of the hydroxymethyl glutaryl-coenzyme A reductase inhibitors (statins) has been called into question following the recent withdrawal from the market of one of the class, cerivastatin. The withdrawal of cerivastatin highlighted concerns regarding the safety of the entire class. According to data from several large clinical trials, the statins (except cerivastatin) are well tolerated. The most important and clinically relevant adverse effect reported with statins is myopathy. Myopathy is a clinical diagnosis of elevated creatine phosphokinase and/or myalgia along with fatigue. However, the severe from (i.e. statin-associated rhabdomyolysis) is an uncommon syndrome and occurs at a rate of approximately 1/100,000 patients/years. Statin-associated myopathy is related to statin doses, and often to drug/drug interactions. Other clinically relevant adverse effects associated with statin therapy include liver transminases elevation, which is relatively mild and often self-limiting There is no evidence from clinical trials of a significant alteration of ophthalmological function with statins. The issue of statin-induced cancer remains inconclusive. Overall, the statins seem to exhibit a favourable risk/benefit ratio, and this undoubtedly justifies life-long clinical use of statins for cardiovascular prevention.     

Optimizing LDL-C lowering with statins

Clinical studies have demonstrated the efficacy of statins in reducing low-density lipoprotein cholesterol (LDL-C) and lowering coronary heart disease risk. However, many patients receiving statin therapy in clinical practice are not achieving their LDL-C goals. Generally, statins are initiated at starting doses, and doses should be titrated as needed until the goal of therapy is achieved or a second lipid-lowering drug is required; titration is required in the majority of patients who receive less efficacious agents. Most patients receiving statin therapy in clinical practice are maintained on their starting dose, and this frequently results in inadequate control of elevated cholesterol levels. A number of factors may limit dose titration in clinical practice, including the cost of therapy, safety of prescribing statins at high doses and the additional office visits required for evaluations and monitoring. There may be several solutions to this problem. The choice of statin appears to be one of the important factors influencing the success of therapy. Selecting a statin that provides greater LDL-C lowering enables more patients to achieve LDL-C goals, and the majority of patients can be effectively treated with starting doses of the more efficacious statins. Another factor influencing the success of therapy is the willingness to add other drugs to a statin to enhance LDL-C lowering. Choices here include niacin, a bile acid sequestrant, and ezetimibe, a new cholesterol absorption inhibitor. Of these approaches, use of a more efficacious statin is preferred to combination therapy because of cost, safety, effectiveness, and simplicity issues.     

The Safety of Aggressive Statin Therapy: How Much Can Low-Density Lipoprotein Cholesterol Be Lowered?

Recent clinical trials have consistently demonstrated that reducing low-density lipoprotein cholesterol to very low levels will substantially reduce cardiovascular morbidity and mortality. The lipid-lowering agents of choice are the statins, which are generally considered safe and effective. Of the various agents available, atorvastatin and rosuvastatin are the most powerful, followed by simvastatin. Serious adverse effects with statin therapy are uncommon and primarily involve effects on the liver and skeletal muscle. The risk increases with the statin dose and coadministration with other drugs metabolized by the same metabolic pathway, such as the cytochrome P-450 system. For patients who do not achieve adequate reduction in low-density lipoprotein cholesterol levels with statin therapy of moderate potency, the clinician can up-titrate the dose of the initial statin, institute combination therapy and carefully monitor for adverse effects, or switch to a lower dose of a more potent statin. The strategy chosen depends on the degree of lipid lowering required and on safety, cost, and compliance issues. This article reviews evidence concerning the benefits of reducing low-density lipoprotein cholesterol levels below currently established targets and addresses the question of whether Intensive statin therapy is likely to Increase the risk of adverse events or concomitant comorbidity.     

Musculoskeletal Safety Outcomes of Patients Receiving Daptomycin with HMG-CoA Reductase Inhibitors

Daptomycin, a cyclic lipopeptide antibiotic, and 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors (statins) are commonly administered in the inpatient setting and are associated with creatine phosphokinase (CPK) elevations, myalgias, and muscle weakness. Safety data for coadministration of daptomycin with statins are limited. To determine the safety of coadministration of daptomycin with statin therapy, a multicenter, retrospective, observational study was performed at 13 institutions in the Southeastern United States. Forty-nine adult patients receiving statins concurrently with daptomycin were compared with 171 patients receiving daptomycin without statin therapy. Detailed information, including treatment indication and duration, infecting pathogen, baseline and subsequent CPK levels, and presence of myalgias or muscle complaints, was collected. Myalgias were noted in 3/49 (6.1%) patients receiving combination therapy compared with 5/171 (2.9%) of patients receiving daptomycin alone (P = 0.38). CPK elevations of >1,000 U/liter occurred in 5/49 (10.2%) patients receiving combination therapy compared to 9/171 (5.3%) patients receiving daptomycin alone (P = 0.32). Two of five patients experiencing CPK elevations of >1,000 U/liter in the combination group had symptoms of myopathy. Three patients (6.1%) discontinued therapy due to CPK elevations with concurrent myalgias in the combination group versus 6 patients (3.5%) in the daptomycin-alone group (P = 0.42). CPK levels and myalgias reversed upon discontinuation of daptomycin therapy. Overall musculoskeletal toxicity was numerically higher in the combination group but this result was not statistically significant. Further prospective study is warranted in a larger population.     

Statin pleiotropy: fact or fiction?

Accumulating evidence from clinical trials and basic research indicates that statin therapy favorably influences a number of diverse clinical events through both effects related to lowering of LDL cholesterol levels and effects independent of the lowering of LDL cholesterol levels. The latter effects are referred to as pleiotropic. The full potential of this exciting class of drugs in vascular and nonvascular protection is only just being realized. The pleiotropic effects of the statins improve vascular relaxation, promote new vessel formation, and stabilize unstable plaques. Statins reduce glomerular injury, renal disease progression, insulin resistance, and bone resorption. Ezetimibe, a recently approved medication, enhances the lipid-lowering effects of the statins by lowering LDL and increasing HDL levels through its property of inhibiting absorption of cholesterol in the small intestine. These salutary effects of ezetimibe on statin levels presumably enhance the beneficial effects attributed to statin pleiotropy. It is noteworthy that the pleiotropic properties of the statins have been beneficial in a variety of diseases that involve a number of organs and organ systems. No other therapeutic agent can claim equally stellar results in such a wide variety of diseases. The common denominator in all of the diseases that have been shown to improve with statin pleiotropy could be arteriolar pathology due to hyperlipidemia, which improves in response to statins by a return of arteriolar function to normal rather than through statin pleiotropy. Recent reports indicate that higher doses of statins reverse atheromatous changes in the coronary artery when the LDL cholesterol level is lowered to well below 2.59 mmol/L (100 mg/dL). These results lend additional support to the probability that similar pathological changes that may be present in the small arteries and arterioles also can respond to adequate statin therapy. Statin pleiotropy: fact or fiction?     

Statin-fibrate combination therapy

BACKGROUND: Precautionary warnings for severe myopathy and rhabdomyolysis from the coadministration of statins and fibrates have been well publicized. However, a recent cerivastatin labeling change made the combined use with fibric acid derivatives a contraindication. Practical recommendations for clinicians who care for patients with refractory mixed hyperlipidemia are needed. OBJECTIVE: To provide recommendations for clinicians in the treatment of refractory mixed hyperlipidemia. DATA SOURCES: A comprehensive MEDLINE (1966-July 2000) and bibliographic search was performed. DATA SYNTHESIS: Thirty-six published clinical trials and 29 case reports involving combination therapy with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and fibric acid derivatives regarding the occurrence of rhabdomyolysis or myopathy were reviewed. The literature review demonstrated that combination therapy with a statin and fibrate increases the risk of muscle damage, with an incidence of 0.12%. Risk factors that predispose patients to myopathy caused by combination statin-fibrate therapy include increased age, female gender, renal or liver disease, diabetes, hypothyroidism, debilitated status, surgery, trauma, excessive alcohol intake, and heavy exercise. CONCLUSIONS: Combination therapy with a statin and fibrate offers significant therapeutic advantage for the treatment of severe or refractory mixed hyperlipidemia. Although such a combination does increase the risk of myopathy, with an incidence of approximately 0.12%, this small risk of myopathy rarely outweighs the established morbidity and mortality benefits of achieving lipid goals. Nevertheless, a higher incidence of myopathy has been reported with statin monotherapy. When monotherapy with a statin fails to control mixed hyperlipidemia, combination therapy may be considered. Niacin may be added before a fibrate is considered, as it appears to have less risk of myopathy. Statin-fibrate combination therapy must be undertaken cautiously and only after careful risk-benefit analysis. Patient counseling on the risks and warning signs of myopathy is extremely important.     

Lipid-lowering: can ezetimibe help close the treatment gap?

Most patients who should be on lipid-lowering therapy are not receiving it, and most patients who are receiving it are not reaching their appropriate low-density lipoprotein (LDL) goals. This is in part because physicians and patients fear side effects of statins and other lipid-lowering agents. Ezetimibe (Zetia), a new lipid-lowering drug, may help physicians close this "treatment gap" in more patients, especially in combination with a statin.