Epidemiology of statin-induced myopathy

The exact incidence of statin-associated myopathy is difficult to assess because of the various definitions of myopathy used in describing this problem in the literature. Clinicians should be aware of the different terminology. “Myopathy” is defined as any muscle pain or problem. “Myalgia” refers to muscle aches and pains without elevation of serum creatine kinase (CK) levels. “Myositis” includes CK elevation with muscle discomfort. “Rhabdomyolysis” is muscle complaint with CK elevation greater than 10 times the normal upper limit (UNL) .

Given these limitations, the incidence of statin myopathy is approximately 1% to 5% of patients who are on statin therapy . Overall the incidence of rhabdomyolysis is 1.6 to 6.5 per 100,000 persons per year for monotherapy, with the exception of cerivastatin . The incidence for cerivastatin is 10 times greater than other statin monotherapy . The incidence of rhabdomyolysis increases to 5.98 per 10,000 persons per year when the statin is combined with fibrate . Combination of statin with gemfibrozil has a 15 times higher incidence of rhabdomyolysis than with fenofibrate .

Fatality from rhabdomyolysis is 10% . The death rate for statin-associated myopathy has been reported as 0.15 per 1 million prescriptions . Cerivastatin is reported to have 16 to 80 times higher incidence of fatal rhabdomyolysis than other statins and was withdrawn from the market in August 2001 . Discussion of cerivastatin is limited here because it is no longer available.

Currently there are several types of statins on the market: fluvastatin (Lescol), pravastatin (Pravachol), atorvastatin (Lipitor), simvastatin (Zocor), lovastatin (Mevacor), and rosuvastatin (Crestor). All the statins except fluvastatin have reports of fatal cases of rhabdomyolysis ranging from 3 to 19 cases . The incidence of rhabdomyolysis for lovastatin, atorvastatin, and simvastatin is approximately 4 per 100,000 person-years, whereas for pravastatin it is 1 per 100,000 per year . Statistically there is no difference in the incidence of rhabdomyolysis between these statins. Fatal rhabdomyolysis has not been reported when fluvastatin is used alone. A recent case report, however, showed that a combination of fluvastatin and gemfibrozil can lead to rhabdomyolysis . Use of either fluvastatin or pravastatin seems to have a safety advantage, but they are less effective in lowering serum LDL levels .

Mechanism of statin-induced myopathy

The precise mechanism of statin-induced myopathy is unclear. One theory is that statins may have cholesterol-independent or pleiotropic effects. Statins reversibly inhibit HMG-CoA reductase, which is the rate-limiting enzyme for cholesterol synthesis. HMG-CoA reductase converts HMG-CoA to mevalonate. Mevalonate is an essential component in cholesterol synthesis. Mevalonate is also an intermediate for many other metabolites, including isoprenylated pyrophosphate (IPP). This leads to formation of farnesylated pyrophosphate and geranylgeranyl pyrophosphate . Farnesyl pyrophosphate leads to formation of farnesylated protein (Ras) and ubiquinone (coenzyme Q10). Geranylgeranyl pyrophosphate leads to the formation of geranylgeranylated proteins (Rho) . The Ras and Rho play an important role in cellular differentiation, proliferation, and cell stability . Statins are hypothesized to reduce Ras and Rho. As a result, muscle cells may be impaired in cellular differentiation, proliferation, and cell stability, and this may lead to myopathy. The reduction of Ras and Rho also increases cytosolic calcium, which increases the activation of apoptosis by way of the mitochondrial transition pore . Another theory is that statin therapy increases apoptosis in skeletal muscle, which may lead to the clinical presentation of myopathy .

In addition to these pleiotropic metabolic consequences, statins may also have effects on ubiquinones, such as coenzyme Q10 (Co Q10) . Ubiquinone is an antioxidant and membrane stabilizer that is an essential cofactor in the electron transport chain in mitochondria, where adenosine triphosphate (ATP) is generated . By reducing the production of ubiquinone, the energy source may get impaired, which may lead to impaired metabolism in myocytes . This may lead to membrane instability and to myopathy. The evidence of this is marginal, however. One study showed no difference in ubiquinone concentration in patients receiving simvastatin (20 mg/day) for 6 months compared with the control group as demonstrated by muscle biopsy . Another recent research study showed that statin may cause a mild reduction of CoQ10 in muscle, but not enough to cause myopathy . In that study, CoQ10 level was measured from muscle biopsy of 18 patients who had proven statin-related myopathy. The results showed muscle CoQ10 concentration was not statistically different between the statin and control groups, although the absolute level was slightly lower in the statin group. Three patients had CoQ10 levels greater than 2 standard deviations below the lower limit of normal. Fourteen of 18 patients had normal muscle structure . In contrast, another recent study involving 48 patients showed that muscle ubiquinone concentration was significantly lower in the simvastatin group than in the placebo group . Given the mixed results of the studies to date, low ubiquinone is not clearly defined as a cause for statin-induced myopathy; however, some clinicians found that ubiquinone supplements have improved the myalgia symptoms that started after statin therapy . Further research on ubiquinone is necessary to clarify the significance of ubiquinone supplementation and statin-associated myopathy.

Another theory is that hydrophilic statins may have a lower risk for myopathy than hydrophobic statins. Statins enter cells by high lipid solubility or by active transport. One of the important transport systems is the organic anion transporting polypeptide 1B1 (OATP), which actively takes up the statin into hepatocytes. The statins are most effective in the hepatocytes. Human muscles do not have OATP active transporters. Statins thus need to enter muscle cells by lipid solubility. If the statin is hydrophilic (less lipid soluble), the statin is therefore less likely to enter the muscle cell and less likely to cause myotoxicity . Among the statins, pravastatin and rosuvastatin are the most hydrophilic statins .These statins, however, have been reported to cause myopathy . The theory that hydrophilic statins have a protective effect against myopathy is plausible but has not been clearly proven, and further studies need to be done .

Mechanism of statin-induced myopathy

The precise mechanism of statin-induced myopathy is unclear. One theory is that statins may have cholesterol-independent or pleiotropic effects. Statins reversibly inhibit HMG-CoA reductase, which is the rate-limiting enzyme for cholesterol synthesis. HMG-CoA reductase converts HMG-CoA to mevalonate. Mevalonate is an essential component in cholesterol synthesis. Mevalonate is also an intermediate for many other metabolites, including isoprenylated pyrophosphate (IPP). This leads to formation of farnesylated pyrophosphate and geranylgeranyl pyrophosphate . Farnesyl pyrophosphate leads to formation of farnesylated protein (Ras) and ubiquinone (coenzyme Q10). Geranylgeranyl pyrophosphate leads to the formation of geranylgeranylated proteins (Rho) . The Ras and Rho play an important role in cellular differentiation, proliferation, and cell stability . Statins are hypothesized to reduce Ras and Rho. As a result, muscle cells may be impaired in cellular differentiation, proliferation, and cell stability, and this may lead to myopathy. The reduction of Ras and Rho also increases cytosolic calcium, which increases the activation of apoptosis by way of the mitochondrial transition pore . Another theory is that statin therapy increases apoptosis in skeletal muscle, which may lead to the clinical presentation of myopathy .

In addition to these pleiotropic metabolic consequences, statins may also have effects on ubiquinones, such as coenzyme Q10 (Co Q10) . Ubiquinone is an antioxidant and membrane stabilizer that is an essential cofactor in the electron transport chain in mitochondria, where adenosine triphosphate (ATP) is generated . By reducing the production of ubiquinone, the energy source may get impaired, which may lead to impaired metabolism in myocytes . This may lead to membrane instability and to myopathy. The evidence of this is marginal, however. One study showed no difference in ubiquinone concentration in patients receiving simvastatin (20 mg/day) for 6 months compared with the control group as demonstrated by muscle biopsy . Another recent research study showed that statin may cause a mild reduction of CoQ10 in muscle, but not enough to cause myopathy . In that study, CoQ10 level was measured from muscle biopsy of 18 patients who had proven statin-related myopathy. The results showed muscle CoQ10 concentration was not statistically different between the statin and control groups, although the absolute level was slightly lower in the statin group. Three patients had CoQ10 levels greater than 2 standard deviations below the lower limit of normal. Fourteen of 18 patients had normal muscle structure . In contrast, another recent study involving 48 patients showed that muscle ubiquinone concentration was significantly lower in the simvastatin group than in the placebo group . Given the mixed results of the studies to date, low ubiquinone is not clearly defined as a cause for statin-induced myopathy; however, some clinicians found that ubiquinone supplements have improved the myalgia symptoms that started after statin therapy . Further research on ubiquinone is necessary to clarify the significance of ubiquinone supplementation and statin-associated myopathy.

Another theory is that hydrophilic statins may have a lower risk for myopathy than hydrophobic statins. Statins enter cells by high lipid solubility or by active transport. One of the important transport systems is the organic anion transporting polypeptide 1B1 (OATP), which actively takes up the statin into hepatocytes. The statins are most effective in the hepatocytes. Human muscles do not have OATP active transporters. Statins thus need to enter muscle cells by lipid solubility. If the statin is hydrophilic (less lipid soluble), the statin is therefore less likely to enter the muscle cell and less likely to cause myotoxicity . Among the statins, pravastatin and rosuvastatin are the most hydrophilic statins .These statins, however, have been reported to cause myopathy . The theory that hydrophilic statins have a protective effect against myopathy is plausible but has not been clearly proven, and further studies need to be done .

Risk factors for statin-induced myopathy

Several factors can increase risk for statin-associated myopathy. Patient characteristics that include advanced age (greater than 65 years), female gender, and small body habitus have been reported as risk factors . Comorbid conditions, such as hypothyroidism, chronic renal disease, hepatic dysfunction, and diabetes, can also increase the risk for myopathy . When the statin is given to hypothyroid patients, the patient’s CK level can be increased and may cause myopathy .

The risk can also be increased with increased concentration of serum statin in the peripheral blood and muscle cells .The statin concentration, however, is not linearly correlated with the incidence of myotoxicity. One significant way to increase serum statin concentration is drug–drug interactions with the statin. Statin monotherapy rarely causes myopathy that leads to rhabdomyolysis, but concomitant medications metabolized by the cytochrome P450 (CYP) pathway seem to increase the risk for myopathy. Most statins are metabolized by CYP enzymes. Specifically, simvastatin, lovastatin, and atorvastatin are metabolized primarily by CYP 3A4 and some CYP 2C8 enzymes . Fluvastatin and rosuvastatin are metabolized by CYP2C9 enzymes. Pravastatin is the only statin that is metabolized by a non-CYP enzyme . Administration of medications that inhibit CYP 3A4 enzymes reduces the metabolism of simvastatin, lovastatin, and atorvastatin. As a result, these statin concentrations are increased. For example, itraconazole inhibits CYP 3A4 enzyme, and it is known to increase the concentration of simvastatin and lovastatin . Studies also show that some CYP3A4 inhibitors are more potent than others. Ritonavir, itraconazole, and ketoconazole are considered strong CYP3A4 inhibitors . Erythromycin, clarithromycin, telithromycin, verapamil, and diltiazem are considered potent CYP inhibitors. Table 1 outlines common medications that increase the risk for myopathy with concomitant use of statins. Many reports showed that the combination of simvastatin, lovastatin, or atorvastatin with CYP 3A4 inhibitor led to rhabdomyolysis .

Not only can medications inhibit the CYP3A4, but grapefruit juice can inhibit CYP3A4 enzymes. Recent studies show that regular grapefruit juice intake can increase the atorvastatin, lovastatin, and simvastatin concentration from three- to fourfold up to as high as 10-fold . Grapefruit juice does not seem to increase pravastatin concentration , most likely because pravastatin is not metabolized by way of the CYP pathway. One case report associated statin-associated rhabdomyolysis with daily grapefruit juice consumption . The patient was asymptomatic while taking simvastatin, but developed myopathic symptoms with serum CK of 12,640 U/L after daily grapefruit juice consumption . Because grapefruit juice intake has long been considered a technique to reduce cholesterol, the interaction with statin therapy is important to remember.

Another way that serum statin concentration is increased is through inhibition of its metabolism. The glucuronidation pathway is necessary for statin metabolism. Statin elimination is reduced with inhibition of the glucuronidation pathway. Gemfibrozil is reported to inhibit the glucuronidation pathway, and this may slow statin elimination, thereby increasing the statin serum concentration . Increased serum statin concentration increases the risk for myopathy. The combination of gemfibrozil and statin is known to increase myotoxicity . Jones and Davidson reported that the combination of gemfibrozil with statins other than cerivastatin caused rhabdomyolysis in 8.6 per 1 million prescriptions. The combination of fenofibrate and statins associated with rhabdomyolysis in only 0.58 per 1 million prescriptions. One main reason for this difference is that fenofibrate does not significantly inhibit the glucuronidation pathway, whereas gemfibrozil does . As a result, statin serum concentration may be high in the gemfibrozil group, and this can lead to myopathy.