No benefit of vitamin D supplementation on muscle function and health-related quality of life in primary cardiovascular prevention patients with statin-associated muscle symptoms: A randomized controlled trial

Statin-associated muscle symptoms (SAMS) are frequently reported. Nevertheless, few data on objective measures of muscle function are available. Recent data suggesting an important nocebo effect with statin use could confound such effects. The objective was to assess if subjective and objective measures of muscle function improve after drug withdrawal in SAMS reporters. Patients (59 men, 33 women, 50.3±9.6 yrs.) in primary cardiovascular prevention composed three cohorts: statin users with (SAMS, n = 61) or without symptoms (No SAMS, n = 15), and controls (n = 16) (registered at clinicaltrials.gov, NCT01493648). Force (F), endurance (E) and power (P) of the leg extensors (ext) and flexors (fle) and handgrip strength (Fhg) were measured using isokinetic and handheld dynamometers, respectively. A 10-point visual analogue scale (VAS) was used to self-assess SAMS intensity. Measures were taken before and after two months of withdrawal. Following withdrawal, repeated-measures analyses show improvements for the entire cohort in Eext, Efle, Ffle, Pext and Pfle (range +7.2 to +13.3%, all p≤0.02). Post-hoc analyses show these changes to occur notably in SAMS (+8.8 to +16.6%), concurrent with a decrease in subjective perception of effects in SAMS (VAS, from 5.09 to 1.85). Fhg was also improved in SAMS (+4.0 to +6.2%) when compared to No SAMS (-1.7 to -4.2%) (all p = 0.02). Whether suffering from "true" SAMS or nocebo, those who reported SAMS had modest but relevant improvements in muscle function concurrent with a decrease in subjective symptoms intensity after drug withdrawal. Greater attention by clinicians to muscle function in frail statin users appears warranted. This study is registered in clinicaltrials.gov (NCT01493648).

While some work has been done on Health-Related Quality of Life (HRQoL) in statin users, none has focused specifically on statin-associated muscle symptoms (SAMS) sufferers. The objective was to assess self-reported HRQoL, before and after statin withdrawal, in patients reporting SAMS. We hypothesized that the presence of SAMS associated with decreased self-reported physical and mental well-being. Patients (50 men/28 women [M/W], aged 49 ± 9years [Mean ± SD]) in primary cardiovascular prevention were recruited into three cohorts: statin users with (SAMS, 29M/18W) or without symptoms (No SAMS, 10M/5W) and controls (11M/5W). The Short Form 36 Health Survey (SF-36) was used to assess HRQoL. All variables were measured before and after 2months of statin withdrawal, and repeated measures analyses were used to verify withdrawal and group effects as well as their interaction. SF-36 physical and mental component scores (respectively, PCS and MCS) were lower in the SAMS group compared with other groups (both p < 0.01). Statin withdrawal led to an increase in LDL cholesterol for statin users (+69.0%, p < 0.01) and an improvement in well-being in the SAMS group, other groups showing no change. A time x category interaction (p = 0.02) was seen for PCS and post hoc analyses showed that statin withdrawal improved PCS and MCS (respectively, +12.5% [ES 0.77] and +5.1% [ES 0.27], both p < 0.05) in the SAMS group. Patients self-reporting SAMS showed improved HRQoL following drug withdrawal, but this was mirrored by a rise in LDL cholesterol. These findings should be considered by clinicians in the evaluation and follow-up of treatment with statins.

Introduction Statins are benchmark lipid-lowering drugs, reducing blood cholesterol by controlling its synthesis. There are side effects linked to statins use, including statin-associated muscle symptoms (SAMS). These symptoms typically include myalgia, stiffness, weakness, fatigue and/or cramps. SAMS can lead to a reduction in muscle performance, as well as an altered health-related quality of life. Nevertheless, the potential effects of SAMS on sleep remains poorly documented. The objective of this exploratory work was to assess if measures of sleep disturbances and its consequences improve after drug withdrawal in SAMS self-reporters. Methods Patients (5 men [M] / 3 women [W], 44.8±6.3 yrs.) in a primary cardiovascular prevention cohort composed two groups: statin users with (SAMS, 2M/2W) or without symptoms (No SAMS, 3M/1W). All patients were required to have a low cardiovascular risk over ten years (i.e. Framingham Risk Score &amp;lt; 10%) and were using different types and doses of statins for more than two months. Sleep was measured objectively by actigraphy and subjectively using the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI). Finally, a 10-point visual analog scale (VAS) was used to self-assess the intensity of SAMS, specifically at night. Measures were taken before and after two months of statins withdrawal. Results After withdrawal, we observed an improvement of objective sleep quality in the SAMS group (sleep efficiency: +3.79%, effect size [ES]: 0.33 [small effect]; wake after sleep onset: -15.6%, ES: -0.30 [small effect]; number of awakenings after sleep onset: -12.7%, ES: -0.45 [small effect]), concurrent with a decrease of subjective perception of SAMS intensity at night (VAS, from 4.5 to 1.0, ES: -0.79 [moderate effect]). A decrease of subjective daytime sleepiness (ESS, from 11.3 to 8.3, ES: -0.45 [small effect]) and an increase of subjective sleep quality (PSQI, from 7.66 to 6.33, ES: -0.31 [small effect]) were also seen in this group. On the other hand, the No SAMS group showed no change after drug withdrawal for any of the different objective and subjective sleep parameters (ES: -0.08 to 0.15 [trivial effects]). Conclusion Our preliminary data suggest that SAMS are associated with sleep disturbances and impaired sleep quality. Support (if any)

Interactions Between Statins, Exercise, and Health: A Clinical Update

Low vitamin D does not predict statin associated muscle symptoms but is associated with transient increases in muscle damage and pain

Statin-associated muscle symptoms (SAMS) can lead to medication non-adherence among statin users. There is a complex relationship between SAMS, vitamin D and low-density lipoprotein cholesterol (LDL-C). The objective of this study was to evaluate the relationship between vitamin D, LDL-C and occurrence of SAMS. This was a cross-sectional study in patients using statins. Thorough patient histories were taken, a clinical examination was conducted and SAMS were recorded. Levels of vitamin D, creatine phosphokinase (CPK) and LDL-C were measured. These parameters were compared amongst statin users with SAMS and those without SAMS. Levels of vitamin D and LDL-C were converted into percentiles and their relationship with SAMS was evaluated in terms of odds ratio. Receiver operating characteristics (ROC) were drawn, taking vitamin D and LDL-C as predictors of SAMS. A total of 121 statin users were enrolled in this study. Thirty-eight patients (31.4%) presented with SAMS. Significantly lower levels of serum vitamin D were observed amongst statin users with SAMS compared with those without SAMS (19.8 ± 9.67 ng/mL versus 25.0 ± 14.6 ng/mL; 95% confidence interval -10.4 to -0.07; p=0.04). With vitamin D levels less than or equal to 5th, 10th and 25th percentile, the chances of occurrence of SAMS were significantly higher, but not at the 50th percentile (corresponding vitamin D level of 20.21 ng/mL). LDL-C did not show any conclusive relationship with SAMS. ROC curves showed a significant discrimination for vitamin D levels, but not for LDL-C. Statin users with low levels of vitamin D are at increased risk of developing SAMS. However, LDL-C status of statin users failed to predict any meaningful association with SAMS. Given the small sample size of this study, these results should be regarded as preliminary.

To investigate whether implementation of a celiac disease (CD)-specific health-related quality of life (HRQOL) questionnaire would add value to CD follow-up visits; we compared patients' self-reported CD-specific HRQOL with the physician's report provided during a regular CD follow-up visit in children and young adults. A cross-sectional study in the control group of a study on self-management in CD (CoelKids). Eligible patients had CD for ≥1 year and were 25 years or younger. They completed a CD-specific HRQOL questionnaire (CDDUX) after their regular follow-up visit. Their physicians were unaware of the present study's objectives or self-reported HRQOL. agreement between physician-reported and self-reported HRQOL. patient variables predicting a discrepancy between reports, or a lower HRQOL. Physician-reported HRQOL was available in 70 of 78 enrolled patients. The self-reported and physician-reported HRQOL were concordant in 30 of 70 (K = 0.093), 6 of them had a poor self-reported HRQOL. Reports were discrepant in 40 of 70; all 40 self-reported a poor HRQOL. Discrepancies occurred more frequently in patients with a disease duration <9 years (32/40 with discrepant reports were diagnosed <9 years ago vs 17/30 with no discrepancy, P<0.001) and in females (35/40 with discrepant reports were girls versus 16 of 30 with no discrepancy, P = 0.001). Both factors were predictors of a poorer HRQOL. During regular CD follow-up visits, physicians did not report a poor HRQOL in 40 of 46 children and young adults with a poor self-reported HRQOL. This is consistent with previous studies examining other chronic diseases and supports the implementation of self-reported CD-specific HRQOL measurements in CD follow-up visits.

Health-related quality of life (HRQoL) is an important patient-reported outcome, yet research regarding HRQoL during pregnancy is limited. We examined HRQoL during pregnancy using the Patient Reported Outcomes Measurement Information System (PROMIS) Global Short Form (GSF) and validated the GSF compared to legacy HRQoL measures. We evaluated HRQoL among 161 women seeking pregnancy care in urban clinic settings. Participants completed measures of HRQoL, social support, antenatal depression, and utility. Descriptive statistics and correlation coefficients were calculated. Participants averaged 27(±6.6) years and were culturally diverse: 42% self-identified as Hispanic, 37% Black, non-Hispanic, 14% White, non-Hispanic and 7% multiracial or other. Mean estimated gestational age was 9 (±4.6) weeks. PROMIS GSF Physical T-scores were significantly correlated with SF-12 Physical Component Score (PCS) and Mental Component Score (MCS) HRQoL measures (correlation coefficient=0.40 and 0.49, p-value<0.0001, respectively), the Modified Kendler Social Support Index (MKSSI) (correlation coefficient=0.42, p-value<0.0001), and the Visual Analog Scale (VAS) measure of utility (correlation coefficient=0.19, p-value =0.04). GSF Mental T-scores were associated with SF-12 MCS and PCS (correlation coefficient=0.66, p-value<0.0001, and 0.26, p-value<0.01, respectively), MKSSI (correlation coefficient=0.50, p-value<0.0001), and VAS (correlation coefficient=0.29, p-value<0.01). GSF Physical and Mental scores were inversely associated with the Edinburgh Postpartum Depression Scale (EPDS), correlation coefficient= −0.62 and − 0.71, respectively (p-value<0.0001). GSF-derived utility measures demonstrate significant correlation with SF-12 PCS and MCS, MKSSI, EPDS, and VAS. Overall, PROMIS GSF domains demonstrate correlation with legacy HRQoL measures as well as validated measures of social support, depression, and utility among a diverse cohort of pregnant women.

There is no clearly defined clinical presentation of statin-associated muscle symptoms (SAMS) because there is no objective test to verify the presence of SAMS. Experts agree that many more patients complain of statin-associated symptoms than have these symptoms demonstrated in blinded clinical trials or during placebo–statin, crossover studies designed to verify SAMS. Consequently, any description of the clinical presentation of SAMS depends primarily on expert opinion. Also, the clinical presentation of SAMS varies widely from mild myalgia to life-threatening rhabdomyolysis. The most frequent SAMS is myalgia which often occurs soon after statin onset, affects large muscle groups, is usually symmetric on both sides of the body, is not necessarily associated with increases in creatine kinase (CK), resolves promptly with statin cessation and reappears with statin re-initiation. Many patients present with convincing symptoms that vary from this classical description, however. Consequently, the primary approach to determining if muscle symptoms are SAMS is cessation and re-initiation of the statin. This approach is compromised by the “nocebo effect” or the patient’s expectation that the intervention will produce harm. This chapter summarizes the variable clinical presentation of SAMS.

This article aims to review the spectrum of statin-associated muscle symptoms (SAMS), the consequences of downtitration of statin therapy on cardiovascular events, the published trials of nonstatin therapy in patients who report SAMS, and to provide a framework for future trials in SAMS patients. SAMS is reported in 10-25% of patients prescribed statin therapy; however, the few patients enrolled in randomized, double-blind, controlled clinical trials (RCTs) discontinue statin therapy due to adverse events. Several possible reasons for this discrepancy in clinical practice versus RCTs may results from patient selection in clinical trials that excludes patients with characteristics that increase the risk of SAMS, widespread use of higher intensity statins in low-risk populations that evaluated in nearly all RCTs, and perceptions concerning harm of statin therapy. Clinical trials of nonstatin therapy have shown that most patients tolerate statin therapy upon repeat challenge, and thus better tools are needed to more accurately identify SAMS patients and enroll these patients in RCTs of nonstatin therapy. Clinical trials in patients who report SAMS have shown better tolerability of certain classes of nonstatin therapy. Low rates of recurrent SAMS in double-blind rechallenge have led some to challenge the concept of statin muscle intolerance. However, patients with perceived SAMS downtitrate their statin therapy and suffer more cardiovascular events. A revised paradigm for evaluation of SAMS is proposed.

Assessment and management of statin-associated muscle symptoms (SAMS): A clinical perspective from the National Lipid Association

Introduction There is conflicting evidence regarding the prevalence of statin-associated muscle symptoms (SAMS) in clinical practice and randomized clinical trials. Aims We aimed to record SAMS prevalence in the setting of a specialized lipid clinic. Methods This was a retrospective study including adults with dyslipidemia who were followed-up for ≥3 years (1999–2015) at the outpatient Lipid Clinic of our University General Hospital, Greece. We evaluated subjects' clinical and laboratory data with an emphasis on the prevalence of SAMS (including myalgias, muscle crumps and creatine kinase, CK, increase &amp;gt;10 upper limit of normal values) and recorded the rates of low-density lipoprotein cholesterol (LDL-C) target attainment according to the current ESC/EAS guidelines. Results Among 1,334 dyslipidemic subjects followed-up for 6 years (4–10), the prevalence of SAMS was 3% (n=41); 2% reported myalgias/crumples and 1% exhibited increased CK levels once. Only 7% (n=3) of those were statin intolerant, whereas the rest were able to receive any maximally tolerated statin dose. The corresponding prescription rates for low-, moderate- and high-intensity statins were 12%, 61% and 20%, respectively, whereas 32% received combination treatment with ezetimibe. None of the statin intolerant patients and 12% of those treated with any tolerated statin dose had optimal LDL-C levels. Conclusions The prevalence of SAMS is low in the setting of a specialized lipid clinic. Therefore, physicians should cautiously work-up to identify individuals with clinically relevant SAMS to offer alternative therapeutic regimens satisfactorily addressing their cardiovascular risk. Funding Acknowledgement Type of funding sources: None.

BackgroundThe role of artisanal and small-scale gold mining (ASGM) as a source of income is rapidly gaining importance in the economically difficult times in Zimbabwe. Besides limited epidemiological data, no data about the self-reported health-related quality of life (HRQoL) of artisanal and small-scale gold miners exist. The aim of the project was to access HRQoL of ASGM workers to improve the data base and compare the data to the urban Zimbabwean population.MethodsData from 83 artisanal and small-scale gold miners in Kadoma, Zimbabwe was analysed. The HRQoL was assessed using the EuroQol dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) accompanied by the cognition add-on questionnaire (EQ-5D-3L+C) and associated visual analogue scale (VAS). We described the EQ-5D dimensions and VAS values and computed health utility (HU) values using the Zimbabwean tariff. The proportions of miners reporting no problem in each EQ-5D dimension were compared with corresponding proportions reporting any problem (moderate or severe), and mean HU and VAS values were analysed across subgroups of the sample. To test differences between subgroups, Fisher’s exact test was used and between urban and mining population, Student’s t-test was used.ResultsThe reported health states of miners were homogenous, with a large amount (42%) reporting ‘full health’. Mean (SD) VAS and HU values were 81.0 (17.5) and 0.896 (0.13), respectively. Subgroup analysis showed that miners with a lower education reported significantly more problems in the dimension of daily activities and miners with mercury contact had more problems in the dimensions of pain/discomfort and cognition. Comparison between mining and urban population showed that in the oldest age group, self-rated VAS values of miners were significantly higher than of their urban counterparts.ConclusionsThere were no significant differences in the HRQoL of mining and urban populations. However, the reason might be adverse health effects faced by the urban population that do not apply to rural mining areas. A higher education level of miners can improve the HRQoL, which is especially impaired by problems in the cognition dimension.

Statins are among the most widely prescribed medications worldwide. Considered the 'gold-standard' treatment for cardiovascular disease (CVD), statins inhibit HMG-CoA reductase to ultimately reduce serum LDL-cholesterol levels. Unfortunately, the main adverse event of statin use is the development of muscle-associated problems, referred to as SAMS (statin-associated muscle symptoms). While regular moderate physical activity also decreases CVD risk, there is apprehension that physical activity may induce and/or exacerbate SAMS. While much work has gone into identifying the epidemiology of SAMS, only recent research has focused on the extent to which these muscle symptoms are accompanied by functional declines. The purpose of this review is to provide an overview of possible mechanisms underlying SAMS and summarize current evidence regarding the relationship between statin treatment, physical activity, exercise capacity, and SAMS development. PubMed and Google Scholar databases were used to search the most relevant and up-to-date peer-reviewed research on the topic. The mechanism(s) behind SAMS, including altered mitochondrial metabolism, reduced coenzyme Q10 levels, reduced vitamin D levels, impaired calcium homeostasis, elevated extracellular glutamate, and genetic polymorphisms, still lack consensus and remain up for debate. Our summation of the evidence leads us to suggest that the etiology of SAMS development is likely multifactorial. Our review also demonstrates that there is limited evidence for statins impairing exercise adaptations or reducing exercise capacity for the majority of the investigated populations. The available evidence indicates that the benefits of engaging in physical activity while on statin medication largely outweigh the risks.

Effect of rosuvastatin 20 mg versus rosuvastatin 5 mg plus ezetimibe on statin side-effects in elderly patients with atherosclerotic cardiovascular disease: Rationale and design of a randomized, controlled SaveSAMS trial