The HMG-CoA reductase inhibitors, also known as statins, are highly effective and safe lipid-lowering agents, used by 100 million people worldwide. The most common side effects are muscle pain and weakness, occurring in roughly 5%-7% of patients. Discontinuation of the medication is usually adequate treatment, and the symptoms resolve in a few weeks. However, they are not well-studied in active individuals or athletes, where the stress of training may amplify the side effects. The following case report reviews the experience of one elite amateur cyclist and his prolonged course of myalgia and fatigue following the use of a statin medication. The natural history of this disorder, possible pathophysiology, and treatment guidelines will be discussed. Statins may not be the best choice for lipid-lowering in this subset of the population.
MB is a 49-yr-old marketing engineer and elite amateur cyclist. He is a bit compulsive with respect to athletics, so he trains with inadequate rest cycles, keeps meticulous records in a training log, and develops spreadsheets of his progress. In the years 2005 and 2006, he was training 30 hr a week and participated in many races. Sometime in May 2006, he was diagnosed with hyperlipidemia and placed on atorvastatin (Lipitor®), 10 mg at bedtime. In June of that year, he began to notice a decline in performance, and complained to his primary physician about profound muscle weakness after workouts. He characterized his symptoms as feeling "wiped out" or "cooked." After a particularly hard training session, he had a deep-tissue massage and claims he has never felt right since then. Two weeks later he stopped the medication for about 3 months and continued to train. He kept accurate records of his heart rate and perceived exertion, but had no formal laboratory evaluation. He would back off for a few weeks, but at no time did he actually stop training. Improvement was modest, so he restarted atorvastatin at the same dose. Again he "crashed" and noticed less power and strength in his muscles, saying that they felt like lead after a workout. Intermittently during this time period he attempted physical therapy, but it seemed to only temporarily relieve the muscular symptoms, so he discontinued it. In December 2006 he was found to have an elevated level of creatine phosphokinase (CPK) at 1500 U·L−1 (normal 25-287 U·L−1 for men). He again discontinued the medication in February 2007 and has not used it since then. His CPK levels have been normal at 112-127 U·L−1, and the main complaint remains muscle weakness, soreness after exercise, and decreased exercise tolerance.
He was referred to a neurologist who specializes in neuromuscular disease for a thorough evaluation. Past medical history was significant for known degenerative disease at L4-5, but that only produced intermittent numbness in his right foot. He took no prescribed medication, but was using one adult aspirin a day, with vitamins A and D, as well as fish oil supplements. He was noted to be a nonsmoker, drinking one glass of wine in the evening, family history was negative for neuromuscular disorder and arthritis, but there was hyperlipidemia. Review of symptoms revealed only intermittent back pain and insomnia. Upon physical examination, he was average height and weighed 175 lb. His blood pressure was 126/86, pulse 72, and respirations 12-15. The head, eye, ear, nose, and throat (HEENT) exam was unremarkable, neck supple without nodes or bruits, thyroid also was normal in size and consistency. His chest was clear, heart sounds normal, and abdomen benign, with no organomegaly. There was good motion of the joints, palpable pulses, and no edema. There was good muscle bulk and tone, no wasting or fasciculations visible, and no palpable muscle tenderness. Neurologic exam included normal orientation, concentration, memory, and intact cranial nerves. The motor and sensory exams were unremarkable, reflexes symmetric at 1+ in the upper extremities, 3+ at the knees, and 2+ at the ankle, with negative Babinski sign and Rhomberg test.
Additional laboratory work was entirely normal and included a complete blood count, chemistry panel, and serum immunofixation. The antinuclear antibody (ANA) was negative, thyroxine (T4) 7.8 ug·dL−1, thyroid-stimulating hormone (TSH) 1.17 uIU·mL−1, and 25-hydroxy-vitamin D 36 ng·mL−1 (normal 20-57). Angiotensin-converting enzyme was 3 U·L−1, fasting AM cortisol 5.89 ug·dL−1, and acetylcholine receptor binding antibody 0.0 nmol·L−1. Electrodiagnostics demonstrated normal amplitude, distal latency, and conduction velocity. Pre- and post-exercise 3 Hz repetitive stimulation testing was done, recording over the left abductor pollicis brevis (APB) and showed no abnormal decrement. Needle electromyography of the left deltoid, biceps, first dorsal interosseous, vastus lateralis, gluteus medius, and medial gastrocnemius were entirely normal. There was no abnormal insertional activity, spontaneous activity, or myotonic discharges, and the motor unit architecture and recruitment were entirely normal. The clinical impression was a mild, lingering disorder of muscle metabolism, probably triggered by statin use.
The differential diagnosis of myopathy with decreased exercise tolerance in this athlete would include one of the muscular dystrophies, such as myotonic dystrophy, which can present with muscle cramping or spasms. Another possibility would be a glycogen-storage disease, which results from abnormal utilization of glucose or fat by muscle cells. Infantile and childhood forms often have cardiac, hepatic, and endocrine abnormalities that overshadow the muscular symptoms, but those that develop in adulthood can mimic polymyositis, or muscle dystrophy. Connective tissue disorders are unlikely in this case, and endocrinopathies are generally associated with abnormal function of the thyroid, parathyroid, or adrenal glands. Finally, we have the toxic myopathies, induced by a variety of medications, including the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly known as statins.
The spectrum of muscle damage caused by these compounds ranges from mild muscle pain and fatigue to potentially fatal rhabdomyolysis. Non-specific muscle pain and weakness are among the most common adverse events associated with statin use. Myalgia has a reported incidence of 5%-7%, which is not different from placebo in most major trials. Myositis, defined as muscle injury with elevation in CPK of roughly 500-1500 U·L−1, has a similar incidence of 6%. Although statin myotoxicity is generally non-inflammatory, some authors have described an auto-immune reaction to these medications, with elevated ANA. Statins have specific binding sites on lymphocytes, which may lead to altered immune response, B-cell reactivity, and the formation of pathogenic antibodies. Rhabdomyolysis is a severe and occasionally fatal muscle injury, characterized by CPK levels of greater than 10 times normal (2500 U·L−1). Fortunately, the incidence is less common (roughly 0.01%), and death from statin therapy is rare at 0.15 out of every million prescriptions (1).
The pathophysiology of statin myopathy has not been well elucidated, but the following is known from animal studies. Formation of mevalonic acid from HMG-CoA is the rate-limiting step in cholesterol synthesis. Blocking HMG-CoA reductase decreases the levels of intracellular cholesterol, but also several important intermediates of cholesterol synthesis, specifically the isoprenoids, farnesyl pyrophosphate, and Coenzyme Q10 (CoQ10). Cholesterol is an essential component of cell membranes, and depletion is believed to render the myocyte unstable. Statins also are known to affect chlorine conductance through the gated channel CIC-1, affecting muscle contractility. The sarcolemma becomes more excitable, which manifests as involuntary contraction, muscle cramping, and cellular microtrauma. More severe muscle injury and rhabdomyolysis may be caused by further suppression of farnesyl pyrophosphate, which is indirectly responsible for cell replication and growth. Mitochondria, known for their role in oxidative metabolism, also may be involved because they direct programmed cell death and apoptosis. Statins are believed to cross cell membranes and exert a dose-dependent effect upon mitochondrial function. One would assume that those that are lipophilic (simvastatin, atorvastatin, fluvastatin, and lovastatin) may therefore be more toxic to muscle cells. While the hydrophilic pravastatin and rosuvastatin seem to cause less myalgia and fatigue, there is no difference in the incidence of rhabdomyolysis or fatal adverse events with any statin (2).
Statin-induced myopathy will generally resolve in a few weeks, once the medication is discontinued. Obviously, severe myositis or rhabdomyolysis will require further treatment. In a few cases, the symptoms persist for more than a year but generally do not progress during that time period. Current management guidelines recommend a baseline CPK, with another drawn if a patient complains of muscle soreness, tenderness, or pain. The routine monitoring of CPK in asymptomatic patients is not advised. If at any time the level exceeds 10 times the upper limit of normal (even if the patient is asymptomatic), the medication should be stopped. Moderate elevations in CPK may be followed with weekly lab draws until the symptoms resolve. Obviously, there also should be a search for other secondary causes of myalgia and weakness. While it is advisable to recommend patients with symptoms of statin toxicity limit physical activity, the role of Coenzyme Q10 has not been well established.
Statins are highly effective lipid-lowering agents, used by 100 million people worldwide. Generally, their side effect profile is quite favorable, with myalgia and weakness the most common side effects. However, because 40%-80% of the general population is sedentary, these medications have not been well-studied in active individuals. In one study of statin myopathy, 20% of patients reported some novel exercise prior to the onset of symptoms. In another, following Austrian professional athletes for 8 yr, only 6 of 22 (27%) tolerated at least one of the statins, without developing muscle pain and weakness (3).
In the absence of any other cause for the prolonged symptoms of myalgia and fatigue, our cyclist likely suffered from statin myotoxicity. This case draws attention to a potential "serious" adverse event for our patients that is not seen in the general population. Could exercise, with increased demands on the mitochondria for oxidative metabolism, potentiate muscle toxicity of statins? As mentioned previously, these medications have a direct effect upon mitochondrial function and oxidative metabolism. There is a shift toward carbohydrate utilization, and away from fatty acid metabolism. Muscle biopsies from patients with statin-induced myopathy show unusual amounts of lipid accumulation, consistent with decreased oxidative metabolism. While studies to date have not shown a consistent benefit from CoQ10 supplementation in reducing the effects of myopathy, it is intriguing to consider what effect it might have upon mitochondrial energy production (4). Until further research is carried out with active and athletic subjects, I would caution the use of HMG-CoA reductase inhibitors in this population, especially athletes who rely on fat metabolism for endurance.