Statins, or HMG-CoA-reductase inhibitors, are the primary choice of medical treatment when aiming to lower blood cholesterol concentrations. These drugs are generally well tolerated and have been shown to reduce cardiovascular morbidity and mortality (1). Before statin prescription in primary prevention current guidelines encourage change of lifestyle including diet and physical activity (PA) to lower cholesterol concentrations (2).
The positive effects of lifestyle changes and in particular PA are pleiotropic and include reduction in cardiovascular disease (CVD) in a dose dependent manner (3). Chronic pain is associated with physical inactivity (4) and muscle pain (myalgia) is the most common adverse effect reported with the use of statins (5). Although statin use has been associated with lower PA (6), the question of causality remains unanswered. The complex association can roughly be regarded in two ways: the use of statins may lead to myalgia which in turn, similar to chronic pain, leads to reduced PA. This implies that myalgic statin users become less physically active because of the myalgia and this may explain the observations of decreased leg strength and increased fall risk in older adults taking statins (7). On the other hand, the reported myalgia may be caused by the combination of statins and PA which implies that those who report myalgia are more physically active than other statin users. In support of this latter view is the reported exacerbation of myalgia with PA (8) especially in athletes (9).
Although both causative pathways may exist, they both represent problems as discontinuation of statin treatment due to myalgia compromises the proven effective treatment and prevention of CVD (1). The mechanisms underlying statin-associated myalgia remain unknown, and the prevalence varies greatly depending on the study methodology and choice of patient groups (10,11). A number of mechanisms leading to statin-associated myalgia have been proposed, including mitochondrial dysfunction, apoptosis, and genetic predisposition (5,12). Furthermore, statin use has been linked to changes in lipid metabolism (13–15), and studies have shown that statin-associated myotoxicity may be fiber type-specific (16).
The multiple causative pathways underlying statin use, myalgia, and PA may explain why previous studies show divergent results. Measurements of aerobic exercise performance and muscle strength have been used to assess the physical capabilities of statin users with some studies reporting lower or decreased aerobic exercise performance or strength with statin use (6,7,14,17) and other studies reporting no differences or changes over time (18–21). Thus, it remains unclear to what extent statin-associated myalgia is linked to changes in levels of physical capabilities and in particular the direction of causation in regard to these parameters and PA.
In the present study, we have investigated the aerobic performance and strength in statin users experiencing myalgia compared to nonmyalgic statin users and a control group. Specifically, we investigated the aerobic capacity as well as substrate utilization during exercise to assess overall aerobic exercise performance and lipid metabolism during exercise. Measurements of strength range from dynamic contractions assessing leg extension power but also the rate of force development (RFD) in the initial phase of an isometric muscle contraction as the combination allows for a more detailed and qualitative description of muscle force. Furthermore, we have conducted a population-based survey to study the prevalence of muscle and joint symptoms in Danish statin users and the associations between PA and muscle and joint symptoms. Although the experimental study provides insight into the physical capabilities of statin users with or without myalgia, the survey data provide information regarding the associations between statin use, myalgia and PA. The combination of the two types of studies will thus provide a comprehensive description of the complex associations between statin use, myalgia, physical capabilities, and PA.
As stated, the causative pathways allow for several and opposing hypotheses but the working hypothesis of the experimental study is that the experience of myalgia will be associated with impaired performance of both aerobic as well as strength performance.
MATERIALS AND METHODS
The experimental study and the survey are both part of the LIFESTAT study (ClinicalTrials.gov Identifier: NCT02250677). The studies were performed simultaneously. None of the responders from the survey participated in the experimental study. By combining these two types of studies, we believe that the power of both types complement and improve the overall description of statin use and exercise performance.
Experimental study design
The design of this study has previously been published elsewhere (22). A total of 84 subjects were included in the experimental study (Fig. 1). Men and women between 40 and 70 yr in primary prevention with simvastatin at a dose of minimum 40 mg daily for at least 3 months, and a body mass index (BMI) between 25 and 35 kg·m−2 participated in this study. Exclusion criteria were type 2 diabetes, history of CVD, family history of familial hypercholesterolemia, or medication that might interfere with the tests or the test results. The statin users were stratified into two groups; those suffering from myalgia (M; n = 25) (self-reported muscle pain, soreness, or ache starting after commencement of statin use) and those without myalgia (NM; n = 39). The control group (C; n = 20) met all of the abovementioned criteria but were not in treatment with statins despite elevated plasma cholesterol concentrations (total blood cholesterol >6.0 mmol·L−1 and/or LDL-C > 3.5 mmol·L−1).
Participants were instructed to abstain from alcohol, tobacco and strenuous exercise for 48 h before screening and the experiment. All subjects gave signed consent before inclusion in the study. The study was approved by the Copenhagen and Frederiksberg Ethical Committee (protocol number: H-2-2013-164) and was conducted according to the principles of the Declaration of Helsinki.
Testing procedure for the experimental study
The participants were studied after an overnight fast (minimum 10 h) on three separate s. Each day was separated by at least 48 h and all were completed within ~10 d. Maximal fat oxidation (MFO), exercise intensity eliciting MFO (Fatmax), peak oxygen uptake (V˙O2peak) and body composition were measured the first day. Body composition was determined from dual energy X-ray absorptiometry (Lunar iDXA; G&E Medical Systems Lunar, Madison, WI). The Fatmax protocol was done on an ergometer cycle (LODE Corival, The Netherlands) and initiated with 5 min rest followed by a workload of 30 W for 5 min and then progressive increments by 20 W for women and 25 W for men every 3 min until the RER was above 1.0 (23). Oxygen uptake was monitored on an online system (Cosmed Quark CPET, Italy). Whole-body fat oxidation was calculated from the RER during the last 60 s of each exercise step in the graded exercise test using standard indirect calorimetry equations (24). From these data, MFO and Fatmax can be calculated as described by Achten et al. (25). After a 5-min break, the V˙O2peak protocol was started with a 100-W workload for 1 min followed by a ramp test with increments of 1 W for every 4 s until exhaustion. Attainment of V˙O2peak was ascertained by the following criteria: a leveling off of V˙O2 despite an increase in power output or a respiratory exchange ratio exceeding 1.15. V˙O2peak was determined as the highest average over 15 breaths. On the second day another V˙O2peak ramp test (15 W·min−1) starting with 50 W for 5 min warm-up was performed and the test with the highest oxygen uptake was chosen for further analysis. Maximal HR (HRmax) and maximal exercise load (Wmax) were recorded.
Aerobic and anaerobic thresholds were determined from expired gasses measured during the V˙O2peak test. Aerobic threshold was determined as the inflection of the V˙CO2 versus V˙O2 using the V-slope method (26). Anaerobic threshold was determined as the inflection of the V˙E versus V˙CO2. Both thresholds were also calculated as percentage of V˙O2peak.
Muscle strength tests were performed before the second V˙O2peak test.
Maximal isometric quadriceps contractions were performed using an isokinetic dynamometer (KinCom; Kinetic Communicator, USA). Isometric knee extensions were performed for each leg separately at a fixed knee joint angle of 70°. Subjects were seated in the chair of the machine with the hip and thigh firmly strapped. The rotational axis of the dynamometer and the lateral femoral epicondyle were aligned, and the lever of the dynamometer was strapped to the lower leg. Arms were placed across the chest to avoid compensatory muscle activity. The subjects were instructed to kick as hard and fast as possible. Five contractions lasting 2 to 3 s with 30-s breaks in between were performed for each leg. Data was converted to a digital signal (Powerlab 2/26; ADInstruments, New Zealand) and recorded in LabChart (ADInstruments, New Zealand). A fourth-order zero-lag Butterworth filter smoothed the signal by using a cutoff value of 15 Hz. Maximal voluntary contraction (MVC) was calculated as the moment (N·m) peak value. The three kicks with the highest MVC were chosen from each leg and all the data from the kick with highest RFD was chosen for further analysis. RFD was calculated as the average slope of the moment-time curve (Δmoment/Δtime) at time intervals relative to onset of contraction (0–30, 0–50, 0–100, and 0–200 ms). Onset of a kick was defined as increase in moment from baseline above 2.5% of MVC. Similarly, any decrease in moment from baseline exceeding 2.5% was considered initial countermovement and that kick was disqualified. Contractile impulse was determined as the area under the moment-curve during the same time intervals. Relative moment was calculated as the moment (N·m) at time points: 30, 50, 100, and 200 ms as percentage of MVC.
Dynamic muscle contraction was measured using a leg extensor power rig (LegRig; Medical Engineering Unit, University of Nottingham). Subjects performed a minimum of five kicks with each leg and were asked to continue until two measurements in a row did not show any further increase in power (W). Resting leg was placed on the ground and arms were placed across the chest to avoid compensatory muscle activity.
Grip strength was measured using a handheld dynamometer (HandGrip; Takei Grip-D TKK5401, Japan). The dynamometer was adjusted to handgrip size and the subjects performed three 5-s compressions with 1 min breaks in between. The highest value (kg) was recorded for each hand.
Muscle biopsy analysis
On the third day, a muscle biopsy sample was obtained from the M. vastus lateralis using the Bergström needle technique with suction (27). Samples were embedded in OCT and frozen in liquid nitrogen and stored at −80°C for later analysis. From the OCT embedded biopsies, we made 20 sections of 20 μm, which were boiled with Laemmli buffer (2% SDS, 10% glycerol, 5% β-mercaptoethanol, bromophenol blue in 62.5 mM Tris pH 6.8). Proteins were separated for approximately 48 h at 10°C by SDS-PAGE (8% polyacrylamide [v/v] and 30% glycerol [v/v]). Gels were afterwards stained with Coomassie Blue and the ratio of the three myosin heavy chain isoforms I, IIa, and IIx were determined by densitometry using a CCD system LAS-4000 (GE Healthcare) and quantified by the ImageQuant TL analysis software (ver. 18.104.22.168; GE Healthcare) as described in Andersen and Aagaard (28).
Analyses of plasma substrates
All blood samples were immediately cooled to 4°C and centrifuged at 2000g for 10 min and then plasma was collected and stored at −80°C until time of analysis. Plasma creatine kinase (CK), free fatty acid (FFA) and cholesterol were measured on a Hitachi Cobas 6000 chemistry analyzer (Roche A/S, Hvidovre, Denmark).
The survey was performed in a cross-disciplinary collaboration in the LIFESTAT study and had multiple purposes including the study of health behaviors and attitudes related to high cholesterol and statin treatment. For the present study, the survey data was used to study the prevalence of myalgia among Danish statin users and to study the association between PA and myalgia in that population of subjects. The survey was distributed to a random sample of 6000 Danish men and women age 45 to 75 yr in January 2015. The study was registered at the Danish national Data Protection Agency. The response rate was 51% and, for the present study, we included only individuals who were current statin users (n = 598). Participants were restricted to those with a duration of statin treatment for at least 6 months (n = 544). Questions were regarding side effects due to statin treatment and, if confirmed, whether those side effects included muscle and joint symptoms. Consequently, the symptoms reported in the survey reflect self-reported symptoms related to statin treatment. The PA levels were assessed using questions regarding frequency of PA leading to elevated pulse rate. The PA included both sports and daily activities such as gardening. The questions had four responses: “never or rarely,” “weekly,” “several times per week,” and “daily.” The measurement of PA has been used in several Danish surveys of the general population and has been proven to be feasible and easy to administer. Further, studies have shown that the measurement is related to maximum oxygen uptake and inversely associated with waist circumference, BMI, waist hip ratio and triglycerides and positively associated with HDL (29). Three age groups (45–54, 55–64, and 65 + yr) were used as categorical variables in multivariate analysis.
The statistics were performed using Sigmaplot 13.0 (Systat Software, San Jose, CA), and GraphPad Prism 7.0 (GraphPad Software, La Jolla, CA). The experimental study was part of a study with several outcomes in the cross-disciplinary research performed in the LIFESTAT study. The sample size was, therefore, not calculated based on the primary outcomes measured in the present study; however, the sample size obtained is sufficient to determine a clinically significant difference of 10% (30,31) in aerobic capacity measurements between the groups with 80% power and a 5% level of significance. Data that were not normally distributed or had unequal variance were log-transformed before statistical analyses. Comparisons of participant characteristics were made using one-way ANOVA with the Tukey’s post hoc test for multiple comparisons. Two-way ANOVA with repeated measures was used to test for both within-group as well as between-group differences with the Bonferroni post hoc test for multiple comparisons. Score data were analyzed with a Kruskal–Wallis test and reported as medians with 25th and 75th percentiles. Data are presented as means ± SEM. A P value < 0.05 was considered significant.
For the survey, the bivariate associations between myalgia and PA, sex and age were studied using cross-tabulations, and P values were calculated from χ2 tests. Associations between PA and myalgia were analyzed using logistic regression. Results are shown as odds ratio (OR) and 95% confidence interval. The OR was adjusted for age and sex. Statistical interaction between the exposure variable and sex and age was tested, but there was no indication of interaction. SAS 9.4 (SAS Institute Inc., Cary, NC) was used for all statistical analyses of the survey data.
The characteristics of the groups have been published previously (22). Anthropometric measurements were similar between all three groups but lipid profiles were different with C having a higher concentration of LDL-C, total cholesterol and triglycerides compared to both statin groups (Table 1). Scores of myalgia were higher in M compared to both C and NM with no difference between the latter two (Table 1). There were no differences in concentrations of CK or FFA (Table 1).
V˙O2peak was similar between all three groups both in terms of absolute values and weight-adjusted (Table 2). The exercise load at which V˙O2peak occurred (Wmax) was also similar in all three groups (Table 2). The derived aerobic and anaerobic thresholds from the V˙O2peak test were similar between the three groups including measurements expressed as a percentage of V˙O2peak (Table 2).
Maximal fat oxidation expressed both in absolute values and relative to bodyweight and Fatmax were similar between the three groups (Table 2).
The RFD was not different between the three groups in any of the four time intervals (Fig. 2A). Similarly, the other derived measurements from the isokinetic dynamometer including peak RFD, relative moment, MVC, and contractile impulse showed no differences between the three groups (Fig. 2B–E). However, a small difference in the contractile impulse between C and NM at 0 to 200 ms (C, 12280 ± 781; NM, 14185 ± 772 N·m·s−1; P = 0.02) was observed. Measurements of dynamic muscle contraction for both legs and arms showed similar leg extension power (C, 2.6 ± 0.2; M, 2.3 ± 0.1; NM, 2.4 ± 0.1 W·kg−1; P = 0.89) and hand grip strength (C, 34.6 ± 2.3; M, 34.8 ± 2.1; NM, 34.3% ± 1.8 kg; P = 0.94) in all three groups.
Myosin heavy chain content
Myosin heavy chain (MHC) classification showed no difference in fiber type composition between the three groups in the proportion of type I and type IIa fibers, but C had a significantly higher proportion of type IIx compared to both M and NM (C, 23 ± 3; M, 14 ± 2; NM, 13% ± 1%; P < 0.01; Fig. 3).
Table 3 shows mean age, sex distribution, and PA levels of the population. The mean age of the population was 66 yr and 43% were women. Most of the responders were physically active several times a week (50%) and only 13% were never or rarely physically active. This level of PA was similar to that of nonstatin users (P = 0.53, data not shown). Nineteen percent of the responders reported muscle and joint side effects associated with statin use. The adjusted OR of muscle and joint side effects in the physically active was more than two for all groups of PA compared with the physically inactive (Table 3). However, there was only a significant association in those who were physically active several times per week with an OR of 2.34 (Table 3). There were no significant results in relation to sex and age (Table 3).
In this study, aerobic performance and strength properties of statin users were thoroughly examined and compared to a control group. The survey data showed a 19% prevalence of self-reported statin-associated myalgia in the population using statins which corresponds well with prevalence reported by others (8,32). This suggests that statin myalgic users are not overrepresented or underrepresented in the survey data compared with the general population.
We hypothesized that statin users experiencing myalgia would present with impaired aerobic performance and muscle strength compared to the other two groups. However, no differences in performance and strength were detected between the three groups of hypercholesterolemic subjects but we did observe a lower fraction of MHC type IIx in the statin groups compared to the control group. Statin-associated myotoxicity has been reported to be muscle fiber type-specific but studies in rats have shown diverging results with both type I (33) and type II (34) fibers being the most sensitive to treatment. Phillips et al. (16) found pathological abnormalities in muscle fibers type I obtained from muscle biopsies in humans experiencing statin-associated myopathy. In contrast, the present study showed no difference between MHC type I or IIa compositions in the M group compared to the other two groups. Age and endurance training can reduce the fraction of type IIx and increase type I (35) and resistance training leads to reduced fraction of IIx and may increase IIa (28,36). In contrast, physical inactivity lead to overexpression of type IIx (28). All three groups had similar age and the V˙O2peak measurements did not indicate the statin groups being more endurance trained or the control group less physically active, nor do any of the strength measurements point toward the statin groups being more resistance trained than C. The survey data indicate that statin-associated myalgia is more pronounced in the physically active responders in line with a study by Sinzinger and O’Grady (9) reporting a high prevalence of myopathy with statin treatment in athletes and the exacerbation of myopathy with exercise observed by Bruckert et al. (8). Collectively, the M group in the present study may represent such a group of physically active subjects and this could, at least partly, explain why no impairment in aerobic capacity or strength was observed in the M group supporting the theory of statin-associated myalgia being caused by PA.
We investigated statin users who had been in treatment with simvastatin for a minimum of 3 months and almost all (five had been in treatment for a minimum of 3 months) had been in treatment for more than 1 yr. It is plausible that a potential impairment of muscular function caused by statin treatment would have presented itself as median time of onset for muscular symptoms after statin treatment have been reported to be 1 month (8). This may explain why some studies of shorter duration have found no change in aerobic exercise performance with statin use—the muscular symptoms may not have presented themselves within the short duration of the trials. Although studies in mice and rats have shown decreased running distance after 8 and 2 wk of statin treatment, respectively (37,38) the results are less clear regarding human studies showing both improved (39), unaltered (40) and impaired aerobic performance (15). The heterogeneous populations studied including differences in comorbidities seem to complicate the overall picture. The improvement with statin treatment found by Mohler et al. (39) was in a population suffering from peripheral artery disease; the unaltered response found by Traustadóttir et al. (40) was in a healthy population; and the impaired performance found by Phillips et al. (15) was in 11 subjects suffering from statin-associated muscle symptoms with increased CK levels. In the present study, the subjects did not suffer from CVD, and we did not see a lower aerobic capacity in the group suffering from myalgia as we hypothesized. This could reflect the fact that all three groups studied were healthy and that the myalgia reported was less grave than the myositis described in the study by Phillips et al. (15).
Lipid metabolism has been suggested as a potential target for the statin-associated muscle symptoms (14,15) and our laboratory has recently shown that simvastatin treated subjects have a lower lipid synthesis capacity compared to matched controls (13). However, we found no difference in the MFO or Fatmax, suggesting no differences in the lipid metabolism during exercise and the similar FFA concentrations support this view. These results are further supported by the analyses of the aerobic and anaerobic thresholds reflecting metabolic capacity of the muscle cells as well as the systemic lactate elimination rate. We found no differences between the three groups which is in contrast to a recent study by Allard et al. (14) where both aerobic and anaerobic thresholds were lower in a statin group suffering from myalgia compared with a control group. Although the population studied was similar to the present Allard et al. used a minimum cutoff value when evaluating the intensity of myalgia and thus may have included more severe cases of myalgia which could explain the observed differences between the two studies. In line with the study by Allard et al., Phillips et al. found altered lipid metabolism with an increased respiratory exchange ratio at rest and decreased aerobic threshold during exercise (15). However, those subjects had experienced severe statin-associated muscle damage with elevated plasma CK concentrations or even rhabdomyolysis which is in contrast to the relatively low concentrations of CK found in the present study.
The cross-sectional nature of the present experimental study precludes any discussion of exercise training and the impact of statin use and/or myalgia but the results show no impairment in the aerobic capacity or substrate oxidation during exercise in line with other studies showing unaltered aerobic capacity after statin use in healthy subjects.
Muscle strength is associated with risk of falling in older adults and are predictive of mortality (41,42). In our study we have shown that statin-associated myalgia is not reflected in lower strength measurements. The PRIMO study showed that statin-associated myalgia generally affected the lower extremities (8) and we have performed two separate measurements to assess both the explosive muscle strength isometrically using a dynamometer and a more dynamic measurement of muscle power using a PowerRig. We also included handgrip strength measurements and apart from a lower contractile impulse between C and NM at 0–200 ms (dynamometer) we found similar values for muscle strength in the three groups. The overall interpretation of the data suggests no difference in muscle strength of all three groups. The handgrip strength data are in line with the Hertfordshire Cohort Study by Ashfield et al. (21) where they found no associations between statin use and handgrip strength possibly explained by the measurements of upper extremity strength which may be less affected by statins. However, our results contrast with the study by Scott et al. where older adults taking statins for 2.6 yr showed decreased leg strength and increased fall risk compared to age-matched controls (7). In that study, the statin users already had lower leg strength at baseline compared to nonusers and authors speculated that statin use exacerbated muscle performance decline. This supports an explanation formulated in The National Runners Study where decline in performance preceded statin use and not vice versa (18). Their results suggested that a decreased level of PA lead to elevated cholesterol concentrations and concomitant treatment with statins. If high cholesterol concentrations reflect PA levels and statins are secondary, then one could argue that this could be the reason why the control group in the present study had similar strength and aerobic performance as the statins groups.
Apart from the statin treatment per se, we speculated that the myalgia would impair the strength properties to a larger extent than the other statin group which would have been consistent with the report from Philips et al. (16) showing decreased strength in four subjects suffering from statin myopathy. However, Mallinson et al. showed no difference in strength measurements between subjects experiencing myalgia and subjects with no statin use and they used an isokinetic dynamometer allowing for comparison to the present study. They observed that the peak power output during repetitive contractions was similar between the two groups but achieved at a later contraction in the statin group suggesting a delay to reach peak power output (43). In contrast, the present study showed no difference in the number of contractions needed to achieve peak power between any of the three groups (data not shown).
Limitations of the current study are the cross-sectional characters of both survey and study data precluding causality. The subjective perception of myalgia deserves mentioning as we did not withdraw and re-challenge statin treatment to confirm myalgia in the experimental study. Lastly, physically active people may report more pain because they are more aware of bodily symptoms or because muscle symptoms are felt during PA (8) and the lack of measurements of daily PA is a major limitation of the current study as this would greatly improve the interpretation of the data.
In summary, we have shown a 19% prevalence of statin-associated myalgia in the population using statins and that the OR of myalgia was increased when the responders were physically active. Furthermore, we found that statin users in primary prevention experiencing myalgia do not have impaired aerobic exercise performance or muscle strength compared with other statin users or nonusers.
The skilled technical assistance of Thomas Nyegaard Beck, Regitze Kraunsøe, Jeppe Bach and Christina Neigaard Hansen are gratefully acknowledged.
J. W. H., F. D., and S. L. conceived and designed research. T. M., T. D., A. B. K., and R. S. performed the experiments. M. K. constructed and carried out the survey. T. M., M. K., J. W. H., and F. D. analyzed data. T. M., M. K., J. W. H., and F. D. interpreted results of experiments. T. M. prepared figures and tables and wrote the article; T. M., T. D., A. B. K., R. S., M. K., S. L., J. W. H., and F. D. edited and approved final version of article.
T. M. is the guarantor of the work and takes responsibility for the integrity of the publication.
The authors declare no conflict of interest in relation to the present scientific article. The results of the present study do not constitute endorsement by ACSM. Authors declare that the results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation.
This study was funded by the Nordea Foundation and the University of Copenhagen 2016 Center of Excellence grant.
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