Treatment Options for Statin-Associated Muscle Symptoms
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Background: About 4.6 million persons in Germany are now taking statins, i.e., drugs that inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Statins lower the concentration of low-density lipoproteins (LDL) and thereby lessen the rate of cardiovascular events; the size of this effect depends on the extent of lowering of the LDL cholesterol concentration. Muscle symptoms are a clinically relevant side effect of statin treatment.
Methods: This review is based on pertinent publications retrieved by a selective literature search, and on the current recommendations of the European Atherosclerosis Society.
Results: At least 5% of patients taking statins have statin-associated muscle symptoms (SAMS). The etiology of SAMS is heterogeneous. SAMS may seriously impair quality of life and cause complications of variable severity, up to and including rhabdomyolysis (in about 1 in 100 000 cases). SAMS often lead to a reduction in the prescribed dose of the statin, while also negatively affecting drug adherence. More than 90% of patients with SAMS can keep on taking statins over the long term and gain the full clinical benefit of statin treatment after a switch to another type of statin or a readjustment of the dose or frequency of administration. If the LDL cholesterol concentration is not adequately lowered while the patient is taking a statin in the highest tolerable dose, combination therapy is indicated.
Conclusion: SAMS are important adverse effects of statin treatment because they lessen drug adherence. Patients with SAMS should undergo a thorough diagnostic evaluation followed by appropriate counseling. In most cases, statins can be continued, with appropriate adjustments, even in the aftermath of SAMS.
Low-density lipoproteins (LDL) are causally involved in the pathogenesis of atherosclerosis (e1–e5). Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and are among the most studied drugs. Both the efficacy of statins in reducing cardiovascular risk as well as their safety are undisputed (1, 2). Statins are therefore recommended in guidelines for cardiovascular prevention (e6–e8). Nonetheless, about one-third of those undergoing long-term treatment report difficulties with routinely taking their medication (3, 4). A reduced adherence to statin therapy is linearly associated with increased mortality (5). Improving statin adherence is associated with a reduction in cardiovascular morbidity and mortality, making this an important aim in medical care (Table) (5, e9).
Incidence of muscle symptoms during statin therapy
In clinical practice and observational studies, 10–30% of patients report statin-associated muscle symptoms (SAMS) (4, e10–e13). SAMS are relevant causes of reduced adherence (6, e14). However, there is a striking discrepancy between incidences reported and those documented in randomized trials. The incidence of muscle symptoms in randomized trials was low, with little difference between the statin and placebo groups (7–9, e15, e16), which could be attributed to numerous factors. For instance, in some studies, patients were excluded if they presented muscle symptoms or statin intolerance. Slight muscle symptoms were not always systematically recorded. For observational studies without a control group, the actual incidence of SAMS can be overestimated. Evaluation of muscle symptoms in 420 statin-naïve people in one prospective randomized trial revealed that the incidence of myalgia (muscle pain) was 9.4% for individuals taking 80 mg of atorvastatin daily over six months, compared to 4.6% for those taking a placebo (e17). According to the Arzneiverordnungs-Report (Drug Prescription Report), about 4.7 million people were treated with statins in Germany in 2013, with 1.707 billion prescribed statin daily doses. Thus, with an estimated SAMS prevalence of 5–10%, approximately 235 000 to 470 000 people experience SAMS annually in Germany.
SAMS are clinically heterogeneous, with patients reporting proximal, symmetric pain, tension, stiffness, or cramps, which may be accompanied by muscle weakness. From our clinical experience, it seems that people who are physically active are particularly affected (10). Creatine kinase (CK; EC 2.7. 3.2) is often not increased; however, in physically active patients a slight post-exercise increase in CK (of up to 400 U/L) can often not be differentiated from a physiological increase. SAMS has been graded differently in the literature. Our proposal for grading is given in eTable 1.
CK levels that are elevated to more than ten times the upper limit of normal have an incidence of 1:1000 to 1:10 000 per year (11). Severe muscle damage with massive release of myoglobin (rhabdomyolysis) is even more rare (about 1 per 100 000 patients). Rhabdomyolysis is accompanied by very high CK activity and myoglobinuria, and it can lead to acute renal failure and death.
Macro CK—a CK variant with a high molecular mass—occurs in approximately 4% of asymptomatic patients with an incidental finding of increased CK levels. In this case, the values of troponin, myoglobin, lactate dehydrogenase (LDH), glutamic-oxaloacetic transaminase (GOT), and glutamate pyruvate transaminase (GPT) are within a normal range, and the CK level does not vary over time. Macro CK can be specifically diagnosed by isoenzyme electrophoresis. Macro CK type 1, in which CK-BB (a brain isoform) binds to specific antibodies, has no clinical significance. However, macro CK type 2, which is characterized by mitochondrial CK in an oligomeric form, occurs in malignomas, cirrhosis, and Lyell’s syndrome.
A typical sequence of events for SAMS is that CK activity decreases within a few weeks after statin therapy is discontinued, but the symptoms recur and/or CK increases within one to a maximum of four weeks after the statin therapy is reinstated. For physically active patients, a control examination should be carried out following a training break of one week. The clinical procedure depends on the symptoms and the extent of the CK increase. A distinction is made between patients reporting muscle problems who have a CK increase of less than four times the upper limit of normal and those who have it above this limit. Patients with a CK increase of more than 4 times the upper limit of normal should first discontinue their statin (2). This recommendation is not based on clinical data but rather comes from clinical experience about the potential risks of rhabdomyolysis.
The pathophysiology of SAMS is not yet fully understood. Several molecular mechanisms have been proposed (Box 1) (12–18), which include changes affecting the cellular energy metabolism, signaling protein isoprenylation, and mitochondria (11–20, e18–e25). Muscle biopsy analyses support the hypothesis of impaired mitochondrial function, although this has yet to be confirmed (e18–e24).
The risk of SAMS increases with a number of clinical and constitutional factors (Box 2), and its frequency also depends on the statin dose and plasma concentration. Using standard dosages, such as 20–40 mg of simvastatin daily, leads to pronounced symptoms in one of 10 000 patients annually. However, the risk increases exponentially with higher dosages. Of particular clinical relevance, the effective concentration of statins can be increased by the concomitant use of medications that interfere with statin degradation, such as macrolide antibiotics or azole antifungals, or grapefruit juice (eBox 1) (11, 19).
The differential diagnosis of statin-induced and exercise-induced muscle symptoms after endurance sports (such as bicycling or running) or strength training is difficult, but symptoms induced by statins persist longer and often prevent a further exercise session. For correct diagnosis, it is important to note that muscular stress can increase CK levels to 500–600 U/L. Including an exercise break and then monitoring the CK values can be useful for this. Further, alcohol abuse should be excluded, as this is a common cause of CK level increases and rhabdomyolysis.
In the search for causal genetic factors, a strong association between polymorphisms in the SLCO1B1 (solute carrier organic anion transporter family member 1B1) gene and SAMS has been found with simvastatin (20, e25). SLCO1B1 is a hepatic transporter responsible for the uptake of statins into the liver, among other things. A SLCO1B1 polymorphism (c.521T>C, p.V174A) increases the blood concentrations of statins (e26). When combined with simvastatin treatment, this genetic defect confers an increased risk for myopathy of 4.5-fold for heterozygous carriers and of 17-fold for homozygote carriers. This SLCO1B1 variant affects the plasma concentrations of the following statins (listed from most to least affected) (21, 22):
Statins increase the detection rate of hemoglobin A1C (HbA1C) from >6.5% to about 9% (e35). In particular, patients with diabetes mellitus benefit from statin therapy (e36). There is no correlation between diabetes mellitus and an increased risk of SAMS under statin therapy.
CK activity is neither sensitive to nor specific for SAMS. More appropriate laboratory parameters are not known. In our opinion, it is advisable to measure CK activity once prior to initiating therapy, to be able to better determine abnormal elevations of CK activity during therapy. Additionally, urine measurements for the thyroid stimulating hormone (TSH), transaminases, a calculated glomerular filtration rate, and protein should be made (24).
We do not believe that a general screening for the gene variant SLCO1B1 makes sense, although it can be considered in isolated cases if there is a high risk for SAMS. Such cases include:
- Long-term treatment with drugs that increase the risk of myopathy (Box 2, eBox 1) (25)
- An increased risk of SAMS during statin therapy (e.g., due to hypothyroidism, myopathies, SAMS in family members, high muscle stress) (Box 2)
- Documentation of statin intolerance during assessment for indication of apheresis.
There are currently no imaging methods that can detect SAMS, although clinical diagnostic algorithms have been proposed in the literature (4, 27, e17). In accordance with the European Atherosclerosis Society (EAS), we recommend the criteria catalog from Rosenson et al. (eTable 1) (27). Diagnosis is based on a detailed medical history that includes the typical form of presentation as well as a clear temporal association of symptoms with statin intake, discontinuation, and rechallenge. Symptoms occur typically four to six weeks after therapy initiation, mostly affecting large muscle groups, such as thighs, shoulder girdle, and upper arm muscles. However, SAMS may even occur after many years of treatment. SAMS often occurs following a dose increase or if an interacting drug has been prescribed (eBox 1).
Neurological differential diagnoses
A pre-existing asymptomatic myopathy may be unmasked by statins (e37). The typical characteristics of this situation are a pre-existing CK increase or a lack of a decrease in elevated CK activities after statin discontinuation. Additionally, the delayed disappearance of muscle symptoms after discontinuation may indicate a subclinical myopathy of a different origin. As electromyograms (EMG) do not even give specific findings for SAMS with elevated CK levels, they are indicated to distinguish myopathies of other origins from SAMS. Additional differential diagnostic information on muscle symptoms and CK increases is given in Box 3a and Box 3b (28).
In the majority of cases, no identifiable specific muscle or neurological pathology, or relevant drug interaction is found (29, 30, e11). Large case series show however that patients with muscle complaints during statin therapy can still be treated with a statin. Thus, of 11 124 patients who discontinued a statin therapy due to muscle symptoms, 92% were able to resume statin therapy subsequently (e11). In the Cleveland Clinic (Ohio, USA) from 1995 to 2010, 1605 patients with a suspected diagnosis of statin intolerance were examined; 1165 patients were subsequently able to undergo continuous statin therapy (30). In so-called n-of-1 trials, patients took a medication break and then were individually assigned to either first a statin and then a placebo, or the reverse, in a double-blind and random manner (29). The patient-reported symptoms were not significantly different between the statin and placebo phases, and most patients were able to return to their original medication after rechallenge.
Taken together, these data show that a very large proportion of the muscle symptoms are not specifically associated with statin therapy. In agreement with this, results from the Heart Protection Study (HPS) showed that 32.9% of participants who received simvastatin (40 mg), and 33.2% of those who received a placebo, complained of myalgia or muscle weakness at least once (8). These results are consistent with experiences from other areas of pain research. The challenge in everyday clinical practice is thus to distinguish perception and psychological transfer phenomena, as well as the Hawthorne Effect, from classic, organic myopathies. Only an extremely small proportion of patients will need to permanently discontinue statin medications; for instance, for the HPS participants, only 0.5% had to discontinue of the more than 30% who complained of muscle problems (2). However, those affected frequently do not tolerate high statin dosages.
Therapy monitoring and prophylaxis
Prior to initiating a statin therapy, a detailed medical history and the basis investigations outlined should be carried out. The following advice can help prevent SAMS:
- Observe the contraindications for statins and avoid interfering drugs (eBox 2)
- Interrupt the statin therapy if a patient plans to undertake severe physical exertion, such as a marathon
- CK does not need to be controlled on a regular basis if no muscle symptoms are present. However, controls are indicated for patients with an increased risk of myopathy, for example due to concomitant medication (Box 2, eBox 1) or due to an existing, low elevation of CK
- Follow the dose recommendations in eTable 2 for patients with renal failure (from stage 3a) (31).
Course of action
Take enough time
Taking sufficient time for a patient is an important factor for the diagnosis and, in many cases, the key to success.
Many symptoms can be traced back to viral infections, unaccustomed physical activity, and drug interactions. Non–statin-associated muscle diseases also need to be considered (Box 3).
The doctor–patient interview should take into account fears and expectations, as well as the psychosocial situation, of the person concerned. A large proportion of allegedly statin-associated muscle symptoms can be otherwise re-assigned.
According to expert recommendations (2), further actions should differentiate between affected patients with a CK elevation of over four times the upper limit of normal and those with no or a low elevation of CK but who are still symptomatic (Figure). In any case, the statin medication should be interrupted if the patient is symptomatic. If the CK levels exceed four times the reference range limit, a rechallenge should be done cautiously under close supervision, using a lower dose or a less potent statin. If the CK levels are not elevated or only elevated to a low level, a statin rechallenge can be carried out more quickly and with the original preparation. This interruption and rechallenge can help the patient and doctor to determine whether the described symptoms are indeed related to the statin medication (eTable 1). However, this is usually not the case.
Clinical experience shows that it may be psychologically favorable to carry out the rechallenge with other statins. Due to simvastatin’s high interaction potential, more patients appear to report muscle symptoms when using it (eBox 2). Switching to the more potent atorvastatin is often successful, even though it shares the same degradation pathway via cytochrome P450 3A4 as simvastatin. However, there are no set rules for this. In fact, some patients presenting muscle symptoms when using atorvastatin can tolerate simvastatin better. It can be advantageous to use statins that are independent of the cytochrome P450 3A4 pathway, such as fluvastatin, pravastatin, and to a large extent rosuvastatin.
To be able to assess the tolerability of individual statins, it is important to use equipotential doses. Fluvastatin and pravastatin have a low potency, with 40 mg fluvastatin corresponding to 5–10 mg atorvastatin, and 40 mg pravastatin, to 10–20 mg atorvastatin. Contrary to pharmacological considerations, no differences have been observed in clinical practice between the incidence of SAMS under therapy with hydrophilic (e.g., pravastatin and rosuvastatin) or lipophilic statins (e16).
Determine the maximum tolerated dose
If the complaints stop after a discontinuation break but re-occur after rechallenge, the next step is to determine the highest tolerated statin doses. It is advisable to start with a very low statin dose, for example 5 mg atorvastatin (note that the tablets must be divided in this case). Alternatively, statin can be taken only every other day or even less frequently (30). Because of the long half-life of atorvastatin and rosuvastatin, there will be no significant loss of activity. However, this can adversely affect therapy adherence (30). Finding the correct dose is time consuming, as the dosage should not be increased any more frequently than every two weeks.
Combination therapy for insufficient LDL reduction
Often, even the highest tolerated dosages are not sufficient to bring the LDL-C levels to its target. In these cases, combined therapy is indicated. Given the results of the IMPROVE-IT trial (32), we recommend ezetimibe as the first line treatment for patients with statin-associated muscle symptoms and high LDL-C values (2). The study showed that the combination of simvastatin with ezetimibe (10 mg) leads to a further reduction of myocardial infarction. No reduction was observed in overall mortality or mortality due to cardiovascular and cardiac events. If the concomitant use of a statin and ezetimibe does not bring the LDL-C to its target value, medication adherence may be the problem. Additionally, in selected cases, if the statin-ezetimibe combination does not achieve the target, bile acid-binding ion exchangers can be used. In complicated situations referral to a lipid clinic should be considered.
If the patient has familial hypercholesterolemia or a particularly pronounced statin intolerance and high cardiovascular risk, lipoprotein apheresis should be considered.
As with all pain conditions, a placebo treatment improves symptoms in many patients. In the literature, coenzyme Q10 and vitamin D have been proposed for treating SAMS. Nonetheless, as their effect is not supported by robust randomized trials, we can not recommend these (e38–e46).
Two new LDL-C–lowering drug classes are in advanced stages of clinical testing: cholesteryl ester transfer protein (CETP) (33–35) and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The latter were specifically tested in patients with statin intolerance and are currently approved for the treatment. They lower LDL-C in this cohort significantly (36, 37, e47, e48). It remains to be determined whether they are superior in terms of their tolerability.
Conflict of interest statement
Prof. Laufs has received consultant and/or speaking fees, study support (third-party funds), travel expenses, or registration fee reimbursement from ABDA, AkdA, Amgen, AstraZeneca, Bayer, Berlin-Chemie, BNK, Boehringer-Ingelheim, DACH, Daiichi-Sankyo, i-cor , Lilly, Medtronik, MSD, Pfizer, Roche, Sanofi, Servier, Synlab, UdS and UKS.
Prof. Hall has received consulting and/or speaking honoraria and travel expenses and/or conference fee reimbursement from Sanofi-Aventis, MSD, BMS, Roche, AstraZeneca, Amgen, and Berlin-Chemie.
Prof. Windler has received speaking and consulting honoraria from Amgen, AstraZeneca, Bayer, Danone, MSD Sharp & Dohme, Novartis, Pfizer, Roche Pharma, Unilever, and Sanofi.
Prof. Endres has received consulting or speaking honoraria, study support (third-party funds), travel expenses, or registration fee reimbursement from Amgen, Bayer, Boston Scientific, BMS, Boehringer-Ingelheim, Ever, GSK, MSD, Novartis, Pfizer, and Sanofi.
Prof. März is employed by Synlab Services GmbH and is a shareholder of Synlab Holding GmbH, Augsburg. He has received speaking and consulting honoraria from the companies Aegerion Pharmaceuticals, Amgen, AstraZeneca, Danone Research, Sanofi, MSD, Synageva, and Unilever.
Assoc. Prof. Scharnagl declares that no conflict of interests exists.
Manuscript received on 29 April 2015, revised version accepted on
10 August 2015.
Translated from the original German by Veronica A. Raker, PhD.
Prof. Dr. med Ulrich Laufs
Klinik Innere Medizin III, Universitätsklinikum des Saarlandes
66421 Homburg, Germany
For eReferences please refer to:
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz:
Assoz. Prof. Dr. rer. nat. Scharnagl, Prof. Dr. med. März
Department of Prevention, Rehabilitation and Sports Medicine and Else Kroener-Fresenius-Center for Nutritional Medicine, Klinikum rechts der Isar, Technische Universität München: Prof. Dr. med. Halle
Preventive Medicine, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Hamburg: Prof. Dr. med. Windler
Department and Out-Patient Care of Neurology, Charité-Universitätsmedizin Berlin: Prof. Dr. med. Endres
Synlab Akademie, Synlab Services GmbH, Mannheim and Augsburg: Prof. Dr. med. März
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