Paul S. Phillips

Statin-Associated Myopathy with Normal Creatine Kinase Levels

Context Although severe myopathy can occur with statin therapy, some patients receiving statins develop muscle symptoms but have normal serum creatine kinase levels. Contribution This report documents biopsy-confirmed myopathy in four statin-treated patients with normal creatine kinase levels. When patients were challenged with placebo or statin, symptoms and histologic changes occurred only during statin use. Implications Normal creatine kinase levels do not rule out statin-associated myopathy in patients with muscle symptoms. The frequency of this disorder is unknown. The Editors 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the mainstay of therapy for hypercholesterolemia because of their effectiveness and exceptional safety profile (1-3). Nonetheless, many patients treated with statins have muscle symptoms, and some patients develop severe muscle toxicity. Little is known about the mechanism by which statin therapy leads to muscle toxicity. The recent withdrawal of cerivastatin from the U.S. market has highlighted both our ignorance and the need for postmarketing surveillance of these therapies (4). There are credible reports of patients who have muscle symptoms and normal serum creatine kinase levels while receiving statins. One of us described 15 patients with muscle stiffness and tenderness who had normal levels of creatine kinase. Muscle biopsies in these patients revealed ragged red fibers consistent with mitochondrial myopathy (5). Other researchers have described patients with reproducible muscle pain during statin therapy despite normal creatine kinase levels (6, 7). Cell cultures and animal models have shown statin toxicity despite normal creatine kinase levels (8, 9). Thus, it appears that muscle symptoms of some patients receiving statin therapy might represent a muscle toxicity below the threshold needed to increase creatine kinase levels. We describe four such patients who had myopathy during statin therapy despite normal creatine kinase levels. Methods Four patients were identified among the first 20 patients randomly assigned in an ongoing, unfunded, double-blinded, crossover clinical trial that had been approved by an investigational review board. The objective of the trial is to determine whether patients with muscle symptoms and normal creatine kinase levels while taking statins could distinguish blinded statin therapy from placebo. We hypothesized that some patients would be able to identify blinded statin therapy and have objective findings. Patients who had muscle symptoms during statin therapy that resolved when they were not receiving statins for 2 weeks were recruited from a clinical research group. Eligible patients had to have normal creatine kinase levels while they were experiencing symptoms. End points were 1) whether patients could accurately identify blinded statin therapy and 2) standard measures of functional capacity and muscle strength. The muscular strength tests during both placebo use and statin therapy included hip abduction and flexion measured by Nicholas Manual Muscle Tester (Lafayette Instrument Co., Lafayette, Indiana) (10). The 4 patients presented here were identified during a preliminary analysis of the first 21 patients. These 4 patients correctly identified the statin therapy phase because of the reproducible muscle symptoms. Tissue samples from percutaneous muscle biopsies were fresh frozen in liquid nitrogen for metabolic and genetic analysis and were fixed for pathologic analysis according to standard techniques (11). Pathologists reading the muscle biopsy findings were not blinded to the treatment status of the patients, and requisitions read possible myopathy. Plasma concentrations of HMG-CoA reductase inhibitors were measured by using a validated enzyme inhibition assay (12). The findings of these 4 patients are presented here and summarized in the Table. Table. Patient Characteristics Some muscle specimens were analyzed for mitochondrial point mutations at an accredited mitochondrial disease laboratory by using a standard point mutation analysis panel and Southern blotting techniques. Urine specimens were analyzed for organic acids by using standard mass spectrometry techniques. Results Patient 1 Patient 1 developed muscle aches and decreased exercise tolerance during 4 years of simvastatin therapy. She found it difficult to ascend one flight of stairs without resting to relieve severe leg aching. Symptoms did not change during a brief trial of atorvastatin. After the patient entered the trial, her muscle symptoms markedly resolved during the 2-week washout period and the blinded placebo phase. Muscle aching recurred within 48 hours of initiation of the statin phase. After 2 weeks of statin therapy, the patient again found it difficult to ascend a flight of stairs because of leg pain and weakness. She repeated the protoco l and again experienced symptoms while receiving statin; the symptoms again resolved during the placebo phase. Results of serum and urine biochemical analyses are reported in the Table. Muscle biopsy revealed extensive lipid-filled vacuoles distributed within the myofibers (Figure), along with cytochrome oxidasenegative myofibers. Figure. Muscle biopsy specimens obtained while patients were receiving and not receiving statin therapy. parts A, C, and E parts B, D, and F The patients muscle symptoms and hip weakness improved 3 months after she had discontinued statin therapy. At that point, repeated muscle biopsy showed complete resolution of the pathologic abnormalities (Figure). Patient 2 Patient 2 developed muscle pains and weakness while receiving lovastatin, 40 mg/d. She could not open jars or snap her fingers. Her physician changed her therapy to niacin for 2 years. Each time simvastatin was added to improve her lipid control, the patient developed muscle aches, weakness, and shortness of breath with exertion. She entered the double-blinded trial for two separate evaluations and correctly identified the statin phases because of reproduction of her symptoms. The patient had muscle weakness and normal creatine kinase levels during each statin phase (Table). Muscle biopsy revealed accentuated lipid droplet accumulation and cytochrome oxidasenegative muscle fibers that were consistent with myopathy. Repeated muscle biopsy performed 3 months after discontinuation of statin therapy revealed complete resolution of the abnormal lipid stores. Patient 3 Patient 3 developed aching and weakness of the shoulder, hip, and thigh while taking atorvastatin, 20 mg/d, for 2 years. During a 2-week vacation, he forgot his medication and noticed a substantial resolution of his muscle symptoms. He entered the trial for two separate evaluations and correctly identified the statin arm both times after developing weakness; his creatine kinase level was normal at both evaluations (Table). A muscle biopsy performed during atorvastatin therapy revealed increased lipid droplets, ragged red fibers, and cytochrome oxidasenegative muscle fibers, all consistent with lipid myopathy. Repeated biopsy done after the patient had not received statin therapy for 5.5 months showed resolution of the increased lipid droplets. Patient 4 Patient 4 began receiving atorvastatin, 10 mg/d, for combined hyperlipidemia, and within 2 weeks he noticed leg aches when climbing stairs. His symptoms resolved 2 weeks after he had stopped taking atorvastatin. Upon enrollment in the trial, he correctly identified the blinded statin therapy and had measurable hip weakness despite a normal creatine kinase level (Table). His muscle biopsy demonstrated cytochrome oxidasenegative fibers. Electron microscopy showed abnormal lipid droplets surrounded by electron-dense membranous debris. The patient did not undergo biopsy after discontinuation of statin therapy. Testing We performed a series of tests to exclude possible causes of mitochondrial dysfunction other than statin therapy. Biochemical testing of these patients during statin therapy did not reveal any evidence of carnitine deficiency or hypothyroidism. Discussion Randomized trials and community surveillance have demonstrated an extremely low incidence of serious muscle toxicity in patients receiving statins: 1 case per 10 000 (13, 14). Despite this low incidence, many patients attribute their muscle symptoms to statin therapy. The similar clinical, pathologic, and biochemical features of our four patients suggest that the patients have the same type of myopathy. More important, these features are convincingly related to statin therapy and fulfill the accepted criteria for an adverse drug reaction: 1) Muscle symptoms occurred when the patients were receiving statins in a double-blinded fashion, 2) these symptoms normalized when the patients received placebo, 3) muscle toxicity recurred upon re-exposure to the statin, as it had occurred upon previous exposures, 4) the adverse reaction was confirmed by pathologic and biochemical findings, and 5) the pathologic abnormality reversed upon discontinuation of statin therapy (15). A limitation of our report is that the pathologists were not blinded to the treatment status of the patients at biopsy. Nonetheless, the histochemical findings in these four patients were surprisingly similar. Unusually prominent accumulations of lipid were present in the type 1 fibers on oil red O stains or electron microscopy in all four patients. Other evidence of myopathy included cytochrome oxidasenegative staining fibers and ragged red fibers. These myopathic findings reversed when three of these patients had repeated biopsy while not receiving statins. Increased lipid stores, cytochrome oxidasenegative myofibers, and ragged red fibers are features of mitochondrial respiratory chain dysfunction and suggest myopathy due to a metabolic abnormality. Although some of these findings may rarely occur in myofibers because of aging, the pattern of increased lipid is unusual. It has pre

Genetic risk factors associated with lipid-lowering drug-induced myopathies.

Lipid‐lowering drugs produce myopathic side effects in up to 7% of treated patients, with severe rhabdomyolysis occurring in as many as 0.5%. Underlying metabolic muscle diseases have not been evaluated extensively. In a cross‐sectional study of 136 patients with drug‐induced myopathies, we report a higher prevalence of underlying metabolic muscle diseases than expected in the general population. Control groups included 116 patients on therapy with no myopathic symptoms, 100 asymptomatic individuals from the general population never exposed to statins, and 106 patients with non–statin‐induced myopathies. Of 110 patients who underwent mutation testing, 10% were heterozygous or homozygous for mutations causing three metabolic myopathies, compared to 3% testing positive among asymptomatic patients on therapy (P = 0.04). The actual number of mutant alleles found in the test group patients was increased fourfold over the control group (P < 0.0001) due to an increased presence of mutation homozygotes. The number of carriers for carnitine palmitoyltransferase II deficiency and for McArdle disease was increased 13‐ and 20‐fold, respectively, over expected general population frequencies. Homozygotes for myoadenylate deaminase deficiency were increased 3.25‐fold with no increase in carrier status. In 52% of muscle biopsies from patients, significant biochemical abnormalities were found in mitochondrial or fatty acid metabolism, with 31% having multiple defects. Variable persistent symptoms occurred in 68% of patients despite cessation of therapy. The effect of statins on energy metabolism combined with a genetic susceptibility to triggering of muscle symptoms may account for myopathic outcomes in certain high‐risk groups. Muscle Nerve, 2006

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. When a patient taking a statin complains of muscle aches, is he or she experiencing statin-induced myopathy or some other problem? Should the statin be discontinued?

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.

The Modern Spectrum of Rhabdomyolysis: Drug Toxicity Revealed by Creatine Kinase Screening

PURPOSE This study describes the current etiologies, demographic characteristics, incidence of acute renal insufficiency and correlation between peak creatine kinase (CK) and peak creatinine in hospitalized patients with rhabdomyolysis. METHODS A retrospective chart review of patients with creatine kinase (CK) values greater than 5000 IU/L during a nine month period identified 106 cases of rhabdomyolysis. RESULTS The most common contributing etiologies were recreational drug and/or alcohol use in 28%, trauma in 23%, compression in 19%, shock in 17%, statin-use in 13%, seizure in 8% and quetiapine-use in 8%. 37% of cases involved multiple etiologies. Renal insufficiency occurred in 49% of cases and modestly but significantly correlated with CK (R(2) = 0.41, p < 0.0001). Myoglobinuria and a pre-renal state were associated with renal insufficiency in 49% and 52% of cases, respectively. CONCLUSIONS Rhabdomyolysis should be defined with CK values exceeding 10-25 times the upper limit of normal irrespective of renal function. Using a laboratory marker such as CK can aid diagnosis of rhabdomyolysis and identify adverse drug events.

Survey of muscle characteristics after statin‑induced rhabdomyolysis

Abstract Aims: The etiology of statin‑induced rhabdomyolysis (SIR) remains obscure. Most explanations claim deficiency of one of the main end products of the HMG‑CoA reductase pathway. Experimental work has rarely tested the skeletal muscle of humans after SIR. Methods: We compared muscle from ten SIR patients with muscle from eight age‑matched, statin‑naive control subjects. We evaluated differences in muscle histochemistry, sterol biochemistry, prenylated proteins, atrogin‑1 and mitochondrial content to assess which characteristics distinguished the rhabdomyolysis reaction from normal age‑matched muscle. Results: Plant sterols were significantly increased in muscle from SIR subjects compared with ontrol subjects. Ras was significantly reduced and there was a trend towards increased atrogin‑1 in SIR subjects compared with ontrol subject muscle. There was no difference in cholesterol concentrations, mitochondrial content or coenzyme Q10 between groups. Conclusions:This evaluation of muscle from a small sample of patients with SIR demonstrates that differences in sitosterol:cholesterol ratio, the prenylated protein Ras and signals for muscle atrophy like atrogin‑1, may distinguish this reaction from normal muscle.

How common is rhabdomyolysis in patients receiving lipid-lowering therapy?

DESIGN AND INTERVENTION In this retrospective study, Graham et al. used drug prescription records between January 1998 and June 2001 from 11 US health plans to identify patients prescribed statins or fibrates or both. Statin or fibrate type and, if applicable, the combination of statin and fibrate was recorded. The duration of each patient’s treatment was categorized as single (statin or fibrate only) or combined (statin with fibrate). Patients moved between analysis groups if lipid-lowering therapy changed and, therefore, contributed data to more than one therapy group. Medical record analysis identified patients hospitalized for and diagnosed as having serious muscle injury, indicating possible rhabdomyolysis (i.e. a primary diagnosis of, among others, myositis, myopathy or other ligament, fascia and muscle dis orders; a secondary diagnosis of any of the above with acute renal failure or a serum creatine kinase test 1 week after discharge or before admission; a diagnosis of acute renal failure and a serum creatine kinase test 1 week after discharge or before How common is rhabdomyolysis in patients receiving lipid-lowering therapy?