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 patient's 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