HMG CoA reductase-inhibitor-related myopathy and the influence of drug interactions

We report four cases of rhabdomyolysis and severe, disabling myopathy associated with HMG CoA reductase-inhibitor therapy. Patient developed symptoms following the addition of roxithromycin to combination lipid-lowering therapy with simvastatin and gemfibrozil. Patients 2 and 3 became symptomatic after developing acute on chronic renal impairment while taking simvastatin. The muscle biopsy of patient 3 revealed a necrotizing myopathy and the presence of inclusion bodies. Patient 4 developed symptoms within 4 weeks of starting cerivastatin monotherapy. The four cases illustrate the importance of considering the potential for drug interactions and making appropriate dosage adjustments for renal insufficiency in patients receiving HMG CoA reductase therapy.     

Fatal toxic myopathy attributed to propofol,methylprednisolone, and cyclosporine after prior exposure to colchicine and simvastatin

We report a fatal case of toxic myopathy in a patient with a transplanted heart for severe ischemic coronary artery disease. He was on long-term cyclosporine, prednisone, and mycofenolate. Four months before the development of proximal muscle weakness, his simvastatin dose was doubled, and he was also started on colchicine for acute exacerbation of gout. He developed progressive muscle weakness leading to shortness of breath and hospitalization for respiratory failure. Colchicine and simvastatin were stopped on admission. He received high-dose methylprednisolone for continued muscle weakness while he was sedated with propofol. These changes led to a marked elevation of creatine kinase, peaking at 33,580 U/ml. The muscle biopsy revealed toxic vacuolization, mitochondrial damage, and no evidence of inflammation. Based on the timing of events, the combination of propofol, high-dose methylprednisolone, and cyclosporine have triggered rhabdomyolysis, which may have been facilitated by prior administration of colchicine and simvastatin.     

Presymptomatic neuromuscular disorders disclosed following statin treatment

It is well recognized that statins affect muscular tissue adversely and that their use is associated with clinically important myositis, rhabdomyolysis, mild elevation of serum creatine kinase (CK) levels, myalgias, muscle weakness, muscle cramps, and persistent myalgias or serum CK level elevations after statin treatment is discontinued. The association between statins and the disclosure of presymptomatic metabolic myopathy is another underrated phenomenon related to statin therapy that was recently recognized in rare cases. The purpose of this report is to provide additional support for this association and to report other neuromuscular disorders that have also been seen following statin intake. The present case series illustrates that statins may act as unmasking agents in asymptomatic patients with a latent neuromuscular disorder. Thus, it may be postulated that statin intake may be a sufficient insult to precipitate neuromuscular symptoms and substantially increase muscle enzymes in presymptomatic patients with an abnormal neuromuscular substrate. In conclusion, muscular symptoms or increased serum CK levels persisting after statin treatment discontinuation should alert the clinician to pursue further diagnostic evaluations for the detection of potential underlying neuromuscular diseases.     

Outcomes in 45 patients with statin-associated myopathy

BACKGROUND: Published studies regarding statin-associated myopathy may describe more dramatic patient presentations, potentially leading to inaccurate characterization of the condition. Furthermore, long-term outcomes and responses to statin rechallenge in patients with statin-associated myopathy are largely unknown. METHODS: The University of Wisconsin Hospital and Clinics Medical Informatics Department identified 437 patients with International Classification of Diseases, Ninth Revision codes potentially representing cases of statin-associated myopathy from more than 13 years of inpatient and outpatient data; 45 of these individuals were diagnosed as having statin-associated myopathy. Using a standardized form, 2 researchers abstracted all the case records to define the clinical course of statin-induced myopathy. RESULTS: The mean (SD) duration of statin therapy before symptom onset was 6.3 (9.8) months. Resolution of muscle pain occurred a mean (SD) of 2.3 (3.0) months after discontinuation of statin therapy. Six patients (13%) were hospitalized for the management of rhabdomyolysis; 2 had reversible renal dysfunction, and 1 with preexisting renal insufficiency subsequently began lifelong dialysis. Hospitalized patients developed myopathy more quickly after initiating statin therapy (1.3 vs 7.1 months; P = .048) and were more likely to be taking concomitant medications known to increase the risk of statin-associated myopathy (P = .03). Thirty-seven patients received another statin after an episode of statin-associated myopathy; 21 (57%) reported recurrent muscle pain, whereas 16 (43%) tolerated other statins without recurrent symptoms. CONCLUSIONS: Patients with statin-associated myopathy experienced full resolution of muscle pain on cessation of statin therapy. Although no deaths occurred, 13% of the patients required hospitalization for rhabdomyolysis. Recurrent muscle pain was common on statin rechallenge.     

An Unusual Case of Statin-Induced Myopathy: Anti-HMGCoA Necrotizing Autoimmune Myopathy

Statins are some of the most widely prescribed medications, and though generally well tolerated, can lead to a self-limited myopathy in a minority of patients. Recently, these medications have been associated with a necrotizing autoimmune myopathy (NAM). Statin-associated NAM is characterized by irritable myopathy on electromyography (EMG) and muscle necrosis with minimal inflammation on muscle biopsy. The case presented is a 63-year-old woman who has continued elevation of creatine kinase (CK) after discontinuation of statin therapy. She has irritable myopathy on EMG and NAM is confirmed by muscle biopsy. She subsequently tests positive for an experimental anti-3-hydroxy-3-methylglutaryl-coenzyme A (anti-HMGCoA) antibody that is found to be present in patients with statin-associated NAM. Though statin-associated NAM is a relatively rare entity, it is an important consideration for the general internist in patients who continue to have CK elevation and weakness after discontinuation of statin therapy. Continued research is necessary to better define statin-specific and dose-dependent risk, as well as optimal treatment for this condition.KEY WORDS: statin, anti-HMGCR antibody, necrotizing autoimmune myopathy, idiopathic inflammatory myopathy     

Do the Frequencies of Adverse Events Increase, Decrease, or Stay the Same with Long-Term Use of Statins?

Statins are widely used for their cholesterol-lowering properties and proven reduction of cardiovascular disease risk. Many patients take statins as long-term treatment for a variety of conditions without a clear-cut understanding of how treatment duration affects the frequency of adverse effects. We aimed to evaluate whether the frequencies of documented adverse events increase, decrease, or remain unchanged with long-term statin use. We reviewed the established literature to define the currently known adverse effects of statin therapy, including myopathy, central nervous system effects, and the appearance of diabetes, and the frequency of these events with long-term medication use. The frequency of adverse effects associated with long-term statin therapy appears to be low. Many patients who develop side effects from statin therapy do so relatively soon after initiation of therapy, so the frequency of side effects from statin therapy when expressed as a percentage of current users decreases over time. Nevertheless, patients may develop side effects such as muscle pain and weakness years after starting statin therapy; however, the absolute number of patients affected by statin myopathy increases with treatment duration. Also, clinical trials of statin therapy rarely exceed 5 years, so it is impossible to determine with certainty the frequency of long-term side effects with these drugs.     

Lipidstoffwechsel aktuell: statininduzierte Myopathien

Cardiovascular diseases are the most common causes of death in Germany and the prevalence is increased in patients with inflammatory rheumatic diseases. Statins are often employed for primary and secondary prophylaxis of cardiovascular events but can potentially induce myopathy as a side-effect. In addition to an asymptomatic elevation of muscle enzymes, myalgia and myositis as well as rhabdomyolysis, the most severe side-effect, have been observed, which are mostly manifested within 6 months after initiation of therapy. Statin-induced myopathy is rare but if risk factors are present, the individual risk can be much higher. Such factors are in particular interaction with other medications, statin dosage, the characteristics of the statin preparation used, comorbidities, age and sex of the patient. Regular testing of muscle enzymes after induction of statin therapy is not generally recommended for asymptomatic patients, but is indispensable when muscle symptoms appear. Statin therapy must be immediately terminated and a diagnostic evaluation must be carried out at the latest when creatine kinase values show a more than 10-fold increase.     

Statin-induced necrotizing autoimmune myopathy: An uncommon complication of a commonly used medication

A well-known side effect of statin therapy is myopathy. We report a case of statin induced necrotizing autoimmune myopathy, a rare variant of statin-induced myopathy. A 64-year-old gentleman on atorvastatin presented with muscle weakness. Initial laboratory results showed elevated liver function tests, a creatine phosphokinase (CPK) of 8200 IU/L, and positive urine myoglobin. Despite discontinuing atorvastatin, his CPK remained persistently elevated. Muscle biopsy was consistent with necrotizing myopathy. Anti-HMG CoA reductase antibody was strongly positive. Steroids followed by intravenous immunoglobulin were given. The patient’s muscle weakness, CPK, and liver functions gradually improved, and he was eventually discharged on oral steroids. Statin induced necrotizing autoimmune myopathy should be considered when discontinuing statin does not lead to muscle recovery and improvement in CPK. Diagnosis is confirmed by positive anti-HMG-CoA reductase autoantibody.     

Enzyme elevation in patients with juvenile dermatomyositis and steroid myopathy

OBJECTIVE: Steroid myopathy can occur in patients with juvenile dermatomyositis (JDM) receiving chronic steroid therapy. We report an elevation of serum muscle enzymes, normal strength by manual muscle testing (MMT), and electromyographic (EMG) findings of steroid myopathy in children with JDM. METHODS: We prospectively studied children with JDM with a history of chronic steroid use (> 3 mo) and ongoing inflammatory myositis who were referred to our institution. RESULTS: We identified 5/9 children with JDM receiving longterm high dose steroids who had muscle enzyme elevation with no definable weakness and EMG findings consistent with steroid myopathy. All subjects improved after withdrawal of their steroid therapy. CONCLUSION: Longterm high dose steroids may lead to steroid myopathy with muscle enzyme elevation, previously reported only with acute steroid myopathy. We recommend that muscle derived enzyme levels should not be used to differentiate steroid myopathy from inflammatory myopathies.     

Fenofibrate-induced acute renal failure due to massive rhabdomyolysis after coadministration of statin in two patients

Fibric acid derivatives and statins have been increasingly recognized as causes of rhabdomyolysis and acute renal failure. We report severe rhabdomyolysis and acute renal failure associated to combination treatment with statin and fenofibrate in two patients with underlying coronary artery disease. Both patients developed rhabdomyolysis-induced acute renal failure after their hyperlipidemia treatment was changed from statin to statin plus fenofibrate. Both patients experienced intense muscle symptoms, hemoglobinuria, oliguria, and elevation of blood urea nitrogen and serum creatinine. Their serum creatine kinase levels were markedly elevated (case 1; 97,392 IU/l and case 2; 96,639 IU/l). Rhabdomyolysis induced acute renal failure was diagnosed in both patients. Both patients were managed with cessation of the statin-fibrate combination, adequate fluid resuscitation and forced alkaline-mannitol diuresis. Although both patients required hemodialysis, their renal function recovered. Fenofibrate initiation is associated with an increased risk for rhabdomyolysis in patients receiving statin therapy. To prevent future events, it is crucial that clinicians recognize the interaction risk associated with concurrent use of statin and fenofibrate. We recommend careful monitoring when fenofibrate is given to patients receiving statin therapy.     

Statin myopathy: a lipid clinic experience on the tolerability of statin rechallenge

Introduction: Statin myopathy is a generally encountered side effect of statin usage. Both muscle symptoms and a raised serum creatine kinase (CK) are used in case definition, but these are common manifestations of other conditions, which may not be statin related. Statin rechallenge assuming no contraindication in selected cases is an option before considering a different class of lipid‐lowering agent. Aims: We aim to characterize retrospectively the patients referred to our Lipid Clinic with a diagnosis of statin myopathy. The tolerability of different statins was assessed to determine a strategy for rechallenging statins in such patients in the future. Results: Patients with statin myopathy constitute 10.2% of our Lipid Clinic workload. They are predominantly female (62.0%), Caucasian (63.9%), with a mean age of 58.3 years and mean body mass index (BMI) of 29.3 kg/m². The serum CK and erythrocyte sedimentation rate (ESR) were statistically higher compared to patients with statin intolerances with no muscular component or CK elevations. Secondary causes of statin myopathy were implicated in 2.7% of cases. Following statin myopathy to simvastatin we found no statistical difference between the tolerability rates between atorvastatin, rosuvastatin, pravastatin, and fluvastatin. Fibrates, cholestyramine, and ezetimibe were statistically better tolerated in these patients. Conclusions: Statin rechallenge is a real treatment option in patients with statin myopathy. Detailed history and examination is required to exclude muscle diseases unrelated to statin usage. In patients developing statin myopathy on simvastatin, we did not find any statistical difference between subsequent tolerability rates to rosuvastatin, pravastatin, and fluvastatin.     

Risk of Colchicine-Associated Myopathy in Gout: Influence of Concomitant Use of Statin

Objective

The purpose of this study was to investigate the risk of myopathy when statins are coadministered with colchicine in patients with gout.

Interaction atorvastatine et acide fusidique : une cause de rhabdomyolyse sévère

Introduction

The incidence of rhabdomyolysis associated with statin therapy is underestimated, especially when they are coprescribed with other drugs.

Case report

We report a 68-year-old man who presented with rhabdomyolysis causing muscle weakness that occurred seven months after fusidic acid was coprescribed with atorvastatin. A literature review identified eight additional cases of rhabdomyolysis with fusidic acid and atorvastatin and six with fusidic acid and simvastatin. The risk of rhabdomyolysis associated with statin therapy is dependent of the extent to which an individual statin is metabolized by P450 3A4 isoenzyme and to the degree of inhibition of this isoenzyme activity by some antimicrobial.

Conclusion

Our case report highlights the importance of the close monitoring of patients on statins, especially when new drugs are started or if patients become symptomatic, with testing for occurrence of muscle weakness and creatine kinase serum level.     

Rhabdomyolyse sévère révélant une myopathie hypothyroïdienne d’origine auto-immune: À propos de deux cas

While muscular manifestations are common of hypothyroidism, hypothyroid myopathy is most often limited to myalgia, muscular stiffness and cramps with, in some patients, elevated levels of muscle enzymes. We report two cases of rhabdomyolysis related to hypothyroid myopathy. One of the patients developed acute renal failure. Thyroid hormone replacement therapy improved thyroid and renal function with involution of rhabdomyolysis. Hypothyroidism appears to be an authentic cause of rhabdomyolysis and should be carefully ruled out in all patients with elevated serum levels of muscle enzymes.     

Safety of aggressive lipid management

Data from recent clinical trials of high- versus moderate-dose statin therapy support the recommendation to achieve a low-density lipoprotein (LDL) <100 mg/dl in high-risk patients and reveal that many patients will require a high-dose statin to achieve this goal. Overall, low rates of serious musculoskeletal (<0.6%) and hepatic (<1.3%) toxicity have been observed with high-dose statin therapy. In the long-term trials, atorvastatin 80 mg had higher rates of persistent transaminase elevations but rates of myopathy and rhabdomyolysis similar to lower doses of statins. The rate of myopathy and rhabdomyolysis for simvastatin 80 mg, although still low, was about 4x higher than for atorvastatin 80 mg and lower doses of statin. A similar margin of safety would be expected in properly selected patients with characteristics similar to those who participated in the clinical trials. High-dose statin therapy or combination therapy will be required for the large majority of very high-risk patients to achieve the optional LDL goal of <70 mg/dl. While the combination of ezetimibe, bile-acid sequestering agents, niacin, and fenofibrate with moderate dose statins appears to be reasonably safe, the long-term safety of combination with high-dose statins remains to be established. In order to optimize patient outcomes, clinicians should be aware of specific patient characteristics, such as advancing age, gender, body mass index, or glomerular filtration rate, which predict muscle and hepatic statin toxicity.     

Safety of aggressive lipid management.

Data from recent clinical trials of high- versus moderate-dose statin therapy support the recommendation to achieve a low-density lipoprotein (LDL) <100 mg/dl in high-risk patients and reveal that many patients will require a high-dose statin to achieve this goal. Overall, low rates of serious musculoskeletal (<0.6%) and hepatic (<1.3%) toxicity have been observed with high-dose statin therapy. In the long-term trials, atorvastatin 80 mg had higher rates of persistent transaminase elevations but rates of myopathy and rhabdomyolysis similar to lower doses of statins. The rate of myopathy and rhabdomyolysis for simvastatin 80 mg, although still low, was about 4x higher than for atorvastatin 80 mg and lower doses of statin. A similar margin of safety would be expected in properly selected patients with characteristics similar to those who participated in the clinical trials. High-dose statin therapy or combination therapy will be required for the large majority of very high-risk patients to achieve the optional LDL goal of <70 mg/dl. While the combination of ezetimibe, bile-acid sequestering agents, niacin, and fenofibrate with moderate dose statins appears to be reasonably safe, the long-term safety of combination with high-dose statins remains to be established. In order to optimize patient outcomes, clinicians should be aware of specific patient characteristics, such as advancing age, gender, body mass index, or glomerular filtration rate, which predict muscle and hepatic statin toxicity.     

The safety of statins in clinical practice

Statins are effective cholesterol-lowering drugs that reduce the risk of cardiovascular disease events (heart attacks, strokes, and the need for arterial revascularisation). Adverse effects from some statins on muscle, such as myopathy and rhabdomyolysis, are rare at standard doses, and on the liver, in increasing levels of transaminases, are unusual. Myopathy--muscle pain or weakness with blood creatine kinase levels more than ten times the upper limit of the normal range--typically occurs in fewer than one in 10,000 patients on standard statin doses. However, this risk varies between statins, and increases with use of higher doses and interacting drugs. Rhabdomyolysis is a rarer and more severe form of myopathy, with myoglobin release into the circulation and risk of renal failure. Stopping statin use reverses these side-effects, usually leading to a full recovery. Asymptomatic increases in concentrations of liver transaminases are recorded with all statins, but are not clearly associated with an increased risk of liver disease. For most people, statins are safe and well-tolerated, and their widespread use has the potential to have a major effect on the global burden of cardiovascular disease.     

Which statin should be used together with colchicine? Clinical experience in three patients with nephrotic syndrome due to AA type amyloidosis

Colchicine and statins are well known drugs that cause myopathy and neuropathy. Co-administration of certain drugs with statins may increase myotoxic effect, causing myopathy and varying degrees of rhabdomyolysis. Therefore, it is very crucial to know which statin should be used during a combination therapy including colchicine and other drugs. We present three cases with AA amyloidosis secondary to familial Mediterranean fever, who developed neuromyopathy while receiving the combination of colchicine and statin. We also briefly discussed the different metabolic pathways of statins and colchicine when used together.     

Rhabdomyolysis after midazolam administration in a cirrhotic patient treated with atorvastatin

The administration of statins in patients with liver disease is not an absolute contraindication. Hepatotoxicity is a rare and often dose-related event and in the literature there are only a few described cases of fatal rhab-domyolysis in patients with chronic liver disease after statin administration. During treatment with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors,the factors responsible for myopathy may either be related to the patient,or due to interactions with other medications that are metabolic substrates of the same isozymes and therefore able to increase blood statin concentration. The most important side effects consist of increased transaminase levels,abdominal pain or muscle weakness,increased serum levels of creatine kinase and rhabdomyolysis. In this article we report a case of fatal rhabdomyolysis with acute renal failure after gastric endoscopy,where midazolam was used as a sedation agent in a patient with chronic liver disease treated with a high dose of atorvastatin. Therefore,we suggest paying particular attention to the potential risks of associating atorvastatin and midazolam in patients with chronic liver disease who need to undergo gastric endoscopy.     

Renal failure and rhabdomyolysis associated with sitagliptin and simvastatin use

Background Sitagliptin is a new oral glucose‐lowering medication that acts via the incretin hormone system. The most common side‐effects are headache and pharyngitis, and few serious adverse events were observed during clinical trials. Dose adjustment is recommended in renal insufficiency, but long‐term safety experience is limited. Case report We present a patient with chronic renal insufficiency who developed leg pain, weakness and tenderness after starting treatment with high‐dose sitagliptin while on simvastatin. The patient had acute renal failure and rhabdomyolysis that resolved with cessation of sitagliptin, simvastatin, ezetimibe, diuretics and olmesartan. All drugs except sitagliptin, ezetimibe and simvastatin were resumed, and the patient was subsequently started on lovastatin without recurrence of rhabdomyolysis. Conclusions High doses of sitagliptin may have worsened this patient's renal failure and precipitated rhabdomyolysis by increasing circulating levels of simvastatin. Given the high likelihood that sitagliptin will be co‐administered with statins and renally active medications, further study of long‐term safety of sitagliptin in renal sufficiency may be warranted.