Statin-Associated Muscle Symptoms: Impact on Statin Therapy
Statin-Associated Muscle Symptoms: Impact on Statin Therapy
Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7–29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.
Statin therapy is the cornerstone for prevention and treatment of cardiovascular disease (CVD), and is generally safe and well tolerated. In randomized, controlled trials (RCTs), adverse event rates (including complaints of muscle pain) are similar in statin and placebo groups, and compare favourably with event rates for other agents commonly used in CVD prevention, such as angiotensin-converting enzyme inhibitors and beta-blockers. However, statins do cause a rare side-effect known as myositis, defined as muscle symptoms in association with a substantially elevated serum creatine kinase (CK) concentration. Creatine kinase is the enzyme released from damaged muscle cells, and CK elevations >10× the upper limit of normal (ULN) occur in 1 per 1000 to 1 per 10 000 people per year, depending on the statin, its dose, and the presence of other risk factors. Over the last decade, a series of observational studies have attributed a number of other adverse effects to statins, including musculoskeletal complaints, gastro-intestinal discomfort, fatigue, liver enzyme elevation, peripheral neuropathy, insomnia, and neurocognitive symptoms. In addition, randomized trials have shown a small increase in the risk of incident diabetes. Muscle symptoms, the most prevalent of these effects, are the focus of this review.
In contrast to RCTs, patient registries, together with clinical experience, indicate that 7–29% of patients complain of statin-associated muscle symptoms (SAMS). These are usually associated with normal or slightly elevated CK concentrations. Statin-associated muscle symptoms likely contribute significantly to the very high discontinuation rates of statin therapy (up to 75%) within 2 years of initiation. Indeed, in 65% of former statin users, the main reason for statin non-adherence or discontinuation was the onset of side effects, predominantly muscle-related effects. Such non-adherence/discontinuation from treatment may have a marked impact on CVD benefit, as suggested by the higher mortality in elderly secondary prevention patients with low vs. high adherence to statin therapy (24% vs. 16%, respectively; adjusted hazard ratio, 1.25; P = 0.001). Similarly, a meta-analysis showed a 15% lower CVD risk in patients who were adherent to statins compared with those with low adherence.
The clinical presentation of muscle symptoms is highly heterogeneous, as reflected by the variety of definitions in the literature (see Supplementary material online, Table S1 http://eurheartj.oxfordjournals.org/content/suppl/2015/02/18/ehv043.DC1). Muscle pain or aching, stiffness, tenderness or cramp (often referred to as 'myalgia') attributed by patients to their statin use is usually symmetrical but may be localized, and can be accompanied by muscle weakness; any of these effects occur predominantly without an elevation of CK.
As indicated above, reported rates of muscle symptoms are invariably lower in blinded RCTs when compared with those in registries and observational studies, with myalgia rates similar in subjects on statin or placebo. Admittedly, patients with comorbidities that would predispose to an increased risk for musculoskeletal symptoms may have been underrepresented in RCTs. In addition, dedicated questionnaires into muscle complaints are not always incorporated within trial methodology. Conversely, the lack of a placebo comparator in observational studies precludes the ability to establish a causal relationship between statin and muscle complaints. The Effects of Statins on Muscle Performance (STOMP) study is, to our knowledge, the only randomized, double-blind, placebo-controlled study specifically designed to examine the effect of statins on skeletal muscle symptoms and performance. Among the 420 statin-naïve subjects randomized to atorvastatin 80 mg daily or placebo for 6 months, 9.4% of the statin-treated and 4.6% of control subjects met the study definition of myalgia (P = 0.054), suggesting that the incidence of muscle complaints due to the statin is considerably less than that reported in observational trials. The STOMP study also found no differences in the measures of muscle strength or exercise performance between statin-treated and placebo subjects. Few other RCTs have queried for muscle complaints among participants. Muscle complaints in other clinical trials have been similar in statin-treated and placebo subjects. However, even a small increase in myalgia rates would still represent a substantial number of patients given the widespread use of statins.
From a treatment viewpoint, Zhang et al. showed that 90% of patients reporting SAMS to one statin were able to tolerate an alternative statin with continued use after 12 months, suggesting that statin-attributed symptoms may have had other causes or were not generalizable to other statins. Similar results were reported by Mampuya et al. Furthermore, increased prescription of statins itself appears to be associated with increased non-adherence or discontinuation, as illustrated for Denmark over the period 1995–2010 (Figure 1). Different factors may have contributed to this finding. Increased media coverage of statins and their perceived side-effects, as well as wider prescription in primary prevention where the benefits may be less obvious to patients, may be contributing to greater non-adherence and discontinuation.
(Enlarge Image)
Figure 1.
Trends in statin use (upper panel) and statin non-adherence/discontinuation (lower panel) in adults ≥40 years, in Denmark over the period 1995–2010. Statin use from 1 January 1995 to 31 December 2010 was classified according to the Anatomical Therapeutic Classification of Drugs code C10AA, as registered in the national Danish Registry of Medicinal Products Statistics, recording information on all prescribed drugs dispensed at all Danish pharmacies from 1995 onwards (for details see references). The percentage of the Danish population aged ≥40 years on statins increased from <1% in 1995 to 11% in 2010. Correspondingly, non-adherence or discontinuation (defined as the percentage of patients starting statins who only redeemed one prescription) increased from 2% in 1995 to 13% in 2010. Figure designed by Dr Sune F. Nielsen and Prof Børge G. Nordestgaard.
Here, this European Atherosclerosis Society (EAS) Consensus Panel provides an overview of the science underlying the pathophysiology of statin-induced myopathy, as well as guidance for clinicians on the diagnosis and management of SAMS. We have avoided the use of the term 'statin intolerance', as this is not specific for muscle symptoms. These recommendations can assist in improving the likelihood that patients experiencing SAMS receive optimal low-density lipoprotein-cholesterol (LDL-C) lowering therapy to minimize their risk for CVD.
Abstract and Introduction
Abstract
Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7–29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.
Introduction
Statin therapy is the cornerstone for prevention and treatment of cardiovascular disease (CVD), and is generally safe and well tolerated. In randomized, controlled trials (RCTs), adverse event rates (including complaints of muscle pain) are similar in statin and placebo groups, and compare favourably with event rates for other agents commonly used in CVD prevention, such as angiotensin-converting enzyme inhibitors and beta-blockers. However, statins do cause a rare side-effect known as myositis, defined as muscle symptoms in association with a substantially elevated serum creatine kinase (CK) concentration. Creatine kinase is the enzyme released from damaged muscle cells, and CK elevations >10× the upper limit of normal (ULN) occur in 1 per 1000 to 1 per 10 000 people per year, depending on the statin, its dose, and the presence of other risk factors. Over the last decade, a series of observational studies have attributed a number of other adverse effects to statins, including musculoskeletal complaints, gastro-intestinal discomfort, fatigue, liver enzyme elevation, peripheral neuropathy, insomnia, and neurocognitive symptoms. In addition, randomized trials have shown a small increase in the risk of incident diabetes. Muscle symptoms, the most prevalent of these effects, are the focus of this review.
In contrast to RCTs, patient registries, together with clinical experience, indicate that 7–29% of patients complain of statin-associated muscle symptoms (SAMS). These are usually associated with normal or slightly elevated CK concentrations. Statin-associated muscle symptoms likely contribute significantly to the very high discontinuation rates of statin therapy (up to 75%) within 2 years of initiation. Indeed, in 65% of former statin users, the main reason for statin non-adherence or discontinuation was the onset of side effects, predominantly muscle-related effects. Such non-adherence/discontinuation from treatment may have a marked impact on CVD benefit, as suggested by the higher mortality in elderly secondary prevention patients with low vs. high adherence to statin therapy (24% vs. 16%, respectively; adjusted hazard ratio, 1.25; P = 0.001). Similarly, a meta-analysis showed a 15% lower CVD risk in patients who were adherent to statins compared with those with low adherence.
The clinical presentation of muscle symptoms is highly heterogeneous, as reflected by the variety of definitions in the literature (see Supplementary material online, Table S1 http://eurheartj.oxfordjournals.org/content/suppl/2015/02/18/ehv043.DC1). Muscle pain or aching, stiffness, tenderness or cramp (often referred to as 'myalgia') attributed by patients to their statin use is usually symmetrical but may be localized, and can be accompanied by muscle weakness; any of these effects occur predominantly without an elevation of CK.
As indicated above, reported rates of muscle symptoms are invariably lower in blinded RCTs when compared with those in registries and observational studies, with myalgia rates similar in subjects on statin or placebo. Admittedly, patients with comorbidities that would predispose to an increased risk for musculoskeletal symptoms may have been underrepresented in RCTs. In addition, dedicated questionnaires into muscle complaints are not always incorporated within trial methodology. Conversely, the lack of a placebo comparator in observational studies precludes the ability to establish a causal relationship between statin and muscle complaints. The Effects of Statins on Muscle Performance (STOMP) study is, to our knowledge, the only randomized, double-blind, placebo-controlled study specifically designed to examine the effect of statins on skeletal muscle symptoms and performance. Among the 420 statin-naïve subjects randomized to atorvastatin 80 mg daily or placebo for 6 months, 9.4% of the statin-treated and 4.6% of control subjects met the study definition of myalgia (P = 0.054), suggesting that the incidence of muscle complaints due to the statin is considerably less than that reported in observational trials. The STOMP study also found no differences in the measures of muscle strength or exercise performance between statin-treated and placebo subjects. Few other RCTs have queried for muscle complaints among participants. Muscle complaints in other clinical trials have been similar in statin-treated and placebo subjects. However, even a small increase in myalgia rates would still represent a substantial number of patients given the widespread use of statins.
From a treatment viewpoint, Zhang et al. showed that 90% of patients reporting SAMS to one statin were able to tolerate an alternative statin with continued use after 12 months, suggesting that statin-attributed symptoms may have had other causes or were not generalizable to other statins. Similar results were reported by Mampuya et al. Furthermore, increased prescription of statins itself appears to be associated with increased non-adherence or discontinuation, as illustrated for Denmark over the period 1995–2010 (Figure 1). Different factors may have contributed to this finding. Increased media coverage of statins and their perceived side-effects, as well as wider prescription in primary prevention where the benefits may be less obvious to patients, may be contributing to greater non-adherence and discontinuation.
(Enlarge Image)
Figure 1.
Trends in statin use (upper panel) and statin non-adherence/discontinuation (lower panel) in adults ≥40 years, in Denmark over the period 1995–2010. Statin use from 1 January 1995 to 31 December 2010 was classified according to the Anatomical Therapeutic Classification of Drugs code C10AA, as registered in the national Danish Registry of Medicinal Products Statistics, recording information on all prescribed drugs dispensed at all Danish pharmacies from 1995 onwards (for details see references). The percentage of the Danish population aged ≥40 years on statins increased from <1% in 1995 to 11% in 2010. Correspondingly, non-adherence or discontinuation (defined as the percentage of patients starting statins who only redeemed one prescription) increased from 2% in 1995 to 13% in 2010. Figure designed by Dr Sune F. Nielsen and Prof Børge G. Nordestgaard.
Here, this European Atherosclerosis Society (EAS) Consensus Panel provides an overview of the science underlying the pathophysiology of statin-induced myopathy, as well as guidance for clinicians on the diagnosis and management of SAMS. We have avoided the use of the term 'statin intolerance', as this is not specific for muscle symptoms. These recommendations can assist in improving the likelihood that patients experiencing SAMS receive optimal low-density lipoprotein-cholesterol (LDL-C) lowering therapy to minimize their risk for CVD.
