Statin-related Myalgia Research Articles

PREVALENCE AND PREDICTORS OF ADVERSE DRUG REACTIONS IN OLDER HYPERTENSIVE ADULTS

Objective: Polipharmacy is common in older people, thus increasing the risk of adverse drufg reactrions. This study aimed to analyse prevalence and predictors of the most relevant adverse drug reactions in older hypertensive adults. Design and method: We retrospectively analysed data on antihypertensive- and statin-related adverse drug reactions in adults aged 65 or older evaluated at the Hypertension Clinic of Careggi Hospital, Florance, Italy, between January 2018 and December 2019. Predictors were investigated using multivariate logistic regression. Results: Of 262 participants (mean age 75.9 years, 55.3% female), the 19% of the patients taking ACE-inhibitors reported cough while 33.6% of the patients taking calcium channel blockers (CCB) reported peripheral edema, occuring more frequently of amlodipine. The prevalence of statin-related myalgia was 23.5%. At multivariate analysis SNRI antidepressants and gastroesophageal reflux disease (GERD) were predictive of ACE-inibitors induced cough (OR 16.220, 95% CI 1.243 – 211.621; OR 4.207, 95% CI 1.249 – 4.171, respectively) and angiotensin-receptor antagonists were associated with an increased risk of peripheral edema on CCB (OR 2.500, 95% CI 1.095 - 5.710). GERD was predictive for statin-induced myalgia (OR 6.737, 95% CI 1.530 - 29.662). Conclusions: ACE inhibitor-induced cough, CCB-related peripheral edema and statin-induced myalgia are common in older hypertensive adults. SNRI antidepressants and GERD are independently associated with ACE inhibitor-induced cough, while angiotensin-receptor antagonists are predictive of CCB-related peripheral edema. GERD is also associated with statin myalgia.

Atorvastatin in nano-particulate formulation abates muscle and liver affliction when coalesced with coenzyme Q10 and/or vitamin E in hyperlipidemic rats

AimsStatins are the most widely used to lower elevated low-density lipoprotein levels and preventing cardiovascular diseases in humans. However, about 20% of patients treated with this medication suffer from statin-related myalgia. To this end, this study investigated the potential effect of nano-particulate formulation in alleviating the muscles and liver damage either alone or when co-administered with nano coenzyme Q10 and nano vitamin E. Materials and methodsMale Wistar rats were fed normal diet or high-fat diet for 12 weeks, following which rats were treated with either (i) atorvastatin (5 or 20 mg/kg/day, p.o.) or (ii) atorvastatin with CoQ10 (10 mg/kg/day, p.o.) (iii) and/or vitamin E (30 mg/kg/day, p.o.) in free particle or nanoparticle forms for another 4 weeks. In all rats, serum total cholesterol (CH), triglycerides (TGs), low (LDL) and high (HDL) density lipoproteins, alanine (ALT) and aspartate (AST) transaminases, alkaline phosphatase (ALP), creatine kinase (CK), albumin (ALB), as well as hepatic malondialdehyde (MDA) and antioxidants “reduced glutathione (GSH) and superoxide dismutase (SOD)” were measured. Additionally quadriceps muscles and liver tissues were used for histopathological examination. Key findingsThe antihyperlipidemic effect of statins was not altered when formulated as nanoparticles; albeit the former showed a prominent reduction in the liver and muscle enzymes and histopathological alterations together with a marked decline in the oxidative stress as compared to the free particulate form. These results were augmented when atorvastatin was combined with CoQ10 and/or Vit.E. SignificanceNanoparticulate formulation alleviated the statins induced liver and muscle damage especially when combined with CoQ10 and/or Vit.E.

N-of-1 Trials for Myalgia in People Taking a Statin

About 1 in 5 patients taking statins report some degree of muscular pain or other musculoskeletal symptom, but there is great controversy over what proportion is due to statin therapy. This uncertainty has considerable clinical significance, given the importance of adherence to statins and the increasing number of therapies available for statin intolerance. N-of-1 trials provide the most reliable assessment of causality for an individual person. However, only 8 N-of-1 trials have been reported for patients with possible statin-related myalgia, and for all 8 there was no evidence that the statin was causal 1DOI:10.7326/M13-19211DOI:10.7326/M13-1921. This study aims to evaluate the feasibility and sustainability of an information technology-enhanced N-of-1 trial service to improve the diagnosis of statin-induced myalgia in Australian general practice setting. N-of-1 (single-patient multiple crossover) trials (n = 15) of patients with prior history of intolerance of both atorvastatin 10 mg and rosuvastatin 5 mg monotherapy, who had myalgia occurring within three weeks of starting statin therapy and consequently discontinued statin use. Each person will go through 3 double-blind, crossover comparisons of statin versus matching placebo for a total of 27 weeks. Myalgia scores and Brief Pain Inventory Questionnaire will be recorded on a weekly basis during the study period. Blood sample collection will be done at baseline and at the end of each active treatment and control period to measure serum CK, ALT, AST, FGF21 and creatinine levels. To avoid unblinding of treatment allocation during the trial period, additional blood samples will be stored to measure lipid levels upon study completion. Genotype analysis will also be done at the end of the study to determine if genotype is associated with statin-induced myalgia. Patient and prescriber intentions to continue statin therapy at the end of the trial will also be assessed.

Additional therapy for cholesterol lowering in ezetimibe-treated, statin-intolerant patients in clinical practice: results from an internal audit of a university lipid clinic

Objective: The aim of our study was to evaluate the tolerability and efficacy of alternative approaches to improve cholesterolemia control in patients with statin-related myalgia treated with ezetimibe.Research design and methods: We retrospectively evaluated 3534 Clinical Report Forms (CRFs) filled in the period June 2012–June 2015 for first visits to the lipid clinic of the University of Bologna. For this study, we selected 252 CRFs based on the following criteria: statin-related myalgia, previous failed treatment with at least two low-dosed statins, well tolerated treatment with ezetimibe. Then, the following lipid-lowering treatments were added in order to improve the ezetimibe low density lipoprotein cholesterol (LDL-C) lowering efficacy, based on clinical judgment: fenofibrate 145 mg, rosuvastatin 5 mg 1 tablet/week, rosuvastatin 5 mg 2 tablets/week, red yeast rice (standardized in monacolin K 3 mg) + berberine 500 mg, berberine 500 mg b.i.d., phytosterols 900 mg + psyllium fiber 3.5 g b.i.d. Patients continuing to claim a tolerable myalgia were then treated with coenzyme Q10 nanoemulsions 200 mg/day.Results: The treatment with standard lipid-lowering diet plus ezetimibe alone was associated with a mean LDL-C reduction of 17 ± 2%. The additive LDL-lowering effect with the various tested treatment was: −16 ± 2% with fenofibrate 145 mg/day, −13 ± 1% with rosuvastatin 5 mg 1 tablet/week, −17 ± 3% with rosuvastatin 5 mg 2 tablets/week, −19 ± 4% with red yeast rice + berberine, −17 ± 4% with berberine b.i.d. and −10 ± 3% with phytosterols + psyllium b.i.d.; 11% of the patients treated with fenofibrate required treatment modification because of myalgia recurrence, while the percentage was negligible for the other tested treatments. In patients with residual tolerable myalgia, treatment with coenzyme Q10 for 8 weeks was associated with a mean improvement of the graduated myalgia score from 4.8 ± 1.9 to 2.9 ± 1.3 (p = 0.013).Conclusions: Some alternative treatments seems to be effective and well tolerated, thus improving the ezetimibe effect on cholesterolemia.

Effect of Coenzyme Q10 Supplementation in Patients with Statin‐related Myalgia

Statins (Hydroxy‐methylglutaryl CoA reductase inhibitors) are routinely prescribed to treat hypercholesterolemia because they inhibit endogenous cholesterol synthesis but in some patients their use is associated with increased incidence of myalgia and myopathic symptoms. Statins also inhibit the synthesis of CoQ10 and CoQ10 depletion may be a contributing factor to statin‐related myopathy.The aim of this study was to evaluate the ability of supplementation with coQ10 to reduce muscle symptoms associated with statin use. In a randomized double‐blind placebo controlled trial, statin‐treated patients complaining of myopathic symptoms (i.e. pain, fatigue, weakness) were supplemented with coQ10 (ubiquinol, 300 mg/d) or placebo for 1 month. Muscle pain was assessed before and after supplementation with the validated Brief Pain Inventory, Short Form. Patients in the two groups were comparable for age (55±2 vs. 57±2 y), BMI (31±1 vs. 29±1), gender and statin use. After 1 month of supplementation, CoQ10 plasma levels were significantly elevated in patients treated with CoQ10 (P<0.001). The intensity of pain (i.e. Pain Severity Score, PSS) was significantly reduced both in the CoQ10 (3.78 ± 0.47 vs. 2.72 ± 0.56, n=19) and placebo (3.97 ± 0.39 vs. 1.99 ± 0.46, n=18) groups, P<0.01. However, the changes in PSS before and after intervention were comparable between the two groups. The results of the study suggest that in this population, improvement in statin‐related myalgia with supplementation with CoQ10 was not superior to placebo.Supported by NIH grants 5R21AT004204 and 5‐MO1‐RR‐10710. CoQ10 was kindly provided by Kaneka Corp. (Pasadena, TX)

Statin myopathy: A problem looking for a solution

Statins are one of the most commonly used classes of drugs because they have been shown to significantly reduce cardiovascular disease in both primary and secondary prevention trials. A major problem with the widespread use of statin therapy is that a significant percent of patients develop muscle side effects, which are the most frequent complaint of patients on statin therapy [1]. In clinical practice it has been estimated that 10e25% of patients develop muscle symptoms and this frequently leads to patients discontinuing statin therapy [1]. In contrast in the large randomized outcome trials the occurrence of muscle symptoms has been similar in the statin treated group and the placebo group [2]. For example, in the Jupiter Trial 18,902 subjects were randomized to rosuvastatin 20 mg per day or placebo [3]. During the course of the study muscle symptoms were noted in 16% of the subjects treated with rosuvastatin [3]. However, in the placebo group muscle symptoms occurred in 15.4% of subjects [3]. Similarly, in the AFCAPS/TexCAPs study 62% of the patients treated with lovastatin and 60% of the placebo treated patients developed muscle symptoms [4]. The patient population typically treated with statins (patients 50e80 years of age) often has muscle symptoms in the absence of statin therapy and therefore it is very difficult to be certain that the muscle symptoms described by the patient are actually due to statin therapy. In a recent publication a small number of patients with statin related myalgia were challenged with statin or placebo and the occurrence of symptoms was carefully documented [5]. Interestedly none of the eight patients in this trial had a difference in muscle symptoms when challenged with either the statin or placebo, strongly suggesting that the myalgia was not due to statin treatment [5]. While in the typical clinical setting it is often very difficult to be

When compliance is an issue-how to enhance statin adherence and address adverse effects.

Cardiovascular disease is prevalent and costly. Interventions and therapies that reduce morbidity and mortality associated with cardiovascular disease could have an enormous impact on clinical and economic outcomes. Statins reduce atherosclerotic cardiovascular disease-related morbidity and mortality; however, adherence to statins is less than optimal. It is important for clinicians as well as health plan managers to be aware of the patient- and insurance plan-specific factors that have been shown to influence adherence. Perceived statin-related side effects may also decrease adherence. Statin-related myalgia may be difficult to distinguish from myalgia caused by other conditions, and statin therapy may be discontinued unnecessarily in patients who would otherwise benefit. It is imperative that clinicians work closely with patients to improve adherence to statin therapy and be knowledgable in managing potential statin-related side effects.

Low Vitamin D as a Risk Factor for the Development of Myalgia in Patients Taking High-Dose Simvastatin: A Retrospective Review

BackgroundStatins are the treatment of choice for dyslipidemia, primarily lowering elevated LDL-C levels and reducing the occurrence of major cardiovascular events. In June 2011, the Food and Drug Administration issued a warning regarding the use of high-dose simvastatin 80 mg and its risk of myopathy. ObjectiveThe incidence of myalgia, myopathy, and rhabdomyolysis was analyzed in a veteran population prescribed simvastatin 80 mg. Risk factors for myalgia were examined and compared with the results of recently published studies. MethodsThis was a retrospective medical record review of 450 patients who were prescribed simvastatin 80 mg at the Veterans Affairs Western New York Healthcare System between August 1, 2006, and July 31, 2011. Records were examined for evidence of myalgia, myopathy (incipient or definite), and rhabdomyolysis. Variables that may have contributed to the development of myalgia were also collected and analyzed. ResultsMyalgia was reported by 50 patients (11.1%), whereas rhabdomyolysis developed in 1 patient (0.22%). No patient fit the criteria for myopathy (incipient or definite). Myalgia was statistically more likely to occur in younger patients, patients with a history of myalgia, and patients with low vitamin D levels. The mean (SD) vitamin D level in patients experiencing myalgia was 26.2 (12.9) versus 36.3 (11.8) ng/mL. The 25-hydroxyvitamin D level in those who reported myalgia was approximately 10 ng/mL lower compared with those who tolerated simvastatin 80 mg (P = 0.0003). There was no statistically significant association between length of therapy and development of myalgia. ConclusionA lower incidence of adverse muscle events with high-dose simvastatin 80 mg was found in patients with higher vitamin D levels, suggesting that correction of 25-hydroxyvitamin D levels before statin therapy initiation may mitigate one risk factor in the development of statin-related myalgia. Vitamin D insufficiency appears to be a risk factor for the development of myalgia.

N-of-1 (single-patient) trials for statin-related myalgia.

Statin-related myalgia is difficult to distinguish from other conditions causing myalgia and may often lead to statin discontinuation. To compare the effect of statin rechallenge with placebo in patients with prior statin-related myalgia and to determine whether patients resumed statin therapy after evaluating the results. N-of-1 trial with 3 double-blind, crossover comparisons separated by 3-week washout periods. (Clinicaltrials.gov: NCT01259791) SETTING: Tertiary care lipid clinic. Patients with prior statin-related myalgia with or without mild elevation of creatine kinase levels. Rechallenge with the statin that was previously associated with myalgia within 3 weeks of open-label use versus matching placebo. Weekly visual analogue scale (VAS) scores for myalgia and specific symptoms (VAS myalgia score and symptom-specific VAS score, respectively), pain interference scores, and pain severity scores were recorded during the 3-week periods when patients were receiving placebo or statin. The primary outcome was the VAS myalgia score (range, 0 to 100 mm). Eight patients (mean age, 66 years [SD, 8 years]; 88% women, all with high 10-year Framingham cardiovascular risk) participated in n-of-1 trials. Seven patients completed 3 treatment pairs, and 1 completed 2 treatment pairs. For each n-of-1 trial, no statistically significant differences were seen between statin and placebo in the VAS myalgia score, symptom-specific VAS score, pain interference score, and pain severity score. Five patients resumed open-label statin treatment, with a median posttrial follow-up of 10 months. Results are limited by the small sample size and cannot be extended to patients with longer onset of myalgia after statin initiation. In selected patients with a history of statin-related myalgia whose symptoms are difficult to evaluate, n-of-1 trials may be a useful method for determining statin tolerability. Western University, London, Ontario, Canada.

A randomized trial of coenzyme Q10 in patients with statin myopathy: Rationale and study design

Statins are the most commonly prescribed and effective medications for reducing low-density lipoprotein levels. Some patients experience myopathic symptoms during statin treatment. The etiology is not known, but depletion of mevalonate pathway metabolites, including coenzyme Q10(CoQ10), has been suggested. Despite a lack of conclusive evidence supporting its utility, CoQ10 supplementation has been recommended to patients who experience myalgic symptoms. The Co-Enzyme Q10 in Statin Myopathy study is designed to examine the effect of CoQ10 supplementation on the extent and intensity of muscle pain during treatment with simvastatin. We will recruit patients with a documented history of myalgia during statin treatment. The presence of statin-related myalgia will be confirmed in a crossover run-in trial during which the presence and absence of symptoms will be documented during statin and placebo treatment, respectively. Individuals experience myalgic symptoms while taking statins but not placebo will be randomized to receive simvastatin 20 mg daily plus either 600 mg daily of CoQ10 or placebo. Muscle pain intensity will be documented during weekly phone calls via use of the Brief Pain Inventory, Short Form. Treatment will continue for 8 weeks or until muscle symptoms are reported continuously for 1 week or become intolerable, and then subjects will crossover to the alternative treatment (CoQ10 or placebo). This study is an ongoing clinical trial. This study will determine the utility of CoQ10 for reducing pain intensity in myalgic patients and will provide guidance for clinicians treating patients with hypercholesterolemia who are intolerant to statins.

Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance

We congratulate Kennedy et al 1 Kennedy S.P. Barnas G.P. Schmidt M.J. Glisczinski M.S. Paniagua A.C. Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance. J Clin Lipidol. 2011; 5: 308-315 Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar on publishing the first randomized controlled trial that investigated the use of once-weekly rosuvastatin in patients with previous myalgia on statins. Some additional comments may be of interest. It would be useful to document factors that may increase the risk of statin myopathy (eg, impaired renal function, hypothyroidism or ethnicity). 2 Tziomalos K. Athyros V.G. Karagiannis A. Mikhailidis D.P. Management of statin-intolerant high-risk patients. Curr Vasc Pharmacol. 2010; 8: 632-637 Crossref PubMed Scopus (21) Google Scholar More specifically, did the patients who did not tolerate rosuvastatin once a week have any of these characteristics? An additional factor to consider is vitamin D deficiency. There is evidence suggesting that vitamin D replacement in deficient patients decreases their risk of developing statin-related myalgia. 3 Katsiki N. Athyros V.G. Karagiannis A. Mikhailidis D.P. Vitamin D deficiency, statin-related myopathy and other links with vascular risk. Curr Med Res Opin. 2011; 27: 1691-1692 Crossref PubMed Scopus (15) Google Scholar , 4 Glueck C.J. Budhani S.B. Masineni S.S. Abuchaibe C. Khan N. Wang P. Goldenberg N. Vitamin D deficiency, myositis-myalgia, and reversible statin intolerance. Curr Med Res Opin. 2011; 27: 1683-1690 Crossref PubMed Scopus (69) Google Scholar

Enfermedades que simulan polimialgia reumática

Objective To examine the main clinical and laboratory data of patients initially diagnosed with polymyalgia rheumatica (PMR), which then developed another conditions. Material and methods We reviewed the clinical records of patients diagnosed with PMR in three hospitals in Argentina. Patients had a diagnosis of PMR if they met the following criteria: age ≥ 50 years, erythrocyte sedimentation rate (ESR) at the time of diagnosis > 40 mm, persistent pain and stiffness of at least one month of evolution in two of the following areas: neck, shoulders or proximal arms, hips or proximal lower limbs. Special attention was paid to symptoms or signs of “alarm” (beginning or during disease progression) for suspecting the presence of other non PMR disease within a period of ≤ 12 months. Results Sixteen of the 200 patients (8%) had other diseases during follow up. Malignancies (n = 4) and rheumatic diseases (n = 4) were the most common entities, in addition to infective endocarditis (n = 1), narrow cervical canal (n = 1), Parkinson's disease (n = 1), statin-related myalgia (n = 1), hypothyroidism (n = 1), vitamin D deficiency (n = 1) and Calcium Pyrophosphate Deposition Disease (CPDD) (n = 2). The average length change of diagnosis was 4.5 ± 3 months. Ten patients had no response to steroids and two had persistently elevated ESR. Conclusion In this study we highlight the importance of recognizing signs and symptoms along with laboratory data and lack of response to treatment as suspects for the diagnosis of other disease manifestations in patients with PMR symptoms.

Conditions mimicking polymyalgia rheumatica

ObjectiveTo examine the main clinical and laboratory data of patients initially diagnosed with polymyalgia rheumatica (PMR), which then developed another conditions. Material and methodsWe reviewed the clinical records of patients diagnosed with PMR in three hospitals in Argentina. Patients had a diagnosis of PMR if they met the following criteria: age≥50 years, erythrocyte sedimentation rate (ESR) at the time of diagnosis>40 mm, persistent pain and stiffness of at least one month of evolution in two of the following areas: neck, shoulders or proximal arms, hips or proximal lower limbs. Special attention was paid to symptoms or signs of “alarm (beginning or during disease progression) for suspecting the presence of other non PMR disease within a period of≤12 months. ResultsSixteen of the 200 patients (8%) had other diseases during follow up. Malignancies (n=4) and rheumatic diseases (n=4) were the most common entities, in addition to infective endocarditis (n=1), narrow cervical canal (n=1), Parkinson's disease (n=1), statin-related myalgia (n=1), hypothyroidism (n=1), vitamin D deficiency (n=1) and Calcium Pyrophosphate Deposition Disease (CPPD) (n=2). The average length change of diagnosis was 4.5±3months. Ten patients had no response to steroids and two had persistently elevated ESR. ConclusionIn this study we highlight the importance of recognizing signs and symptoms along with laboratory data and lack of response to treatment as suspects for the diagnosis of other disease manifestations in patients with PMR symptoms.

Effect of Coenzyme Q 10 Supplementation on Simvastatin-Induced Myalgia

Myalgia is the most frequently reported adverse side effect associated with statin therapy and often necessitates reduction in dose, or the cessation of therapy, compromising cardiovascular risk management. One postulated mechanism for statin-related myalgia is mitochondrial dysfunction through the depletion of coenzyme Q(10), a key component of the mitochondrial electron transport chain. This pilot study evaluated the effect of coenzyme Q(10) supplementation on statin tolerance and myalgia in patients with previous statin-related myalgia. Forty-four patients were randomized to coenzyme Q(10) (200 mg/day) or placebo for 12 weeks in combination with upward dose titration of simvastatin from 10 mg/day, doubling every 4 weeks if tolerated to a maximum of 40 mg/day. Patients experiencing significant myalgia reduced their statin dose or discontinued treatment. Myalgia was assessed using a visual analogue scale. There was no difference between combined therapy and statin alone in the myalgia score change (median 6.0 [interquartile range 2.1 to 8.8] vs 2.3 [0 to 12.8], p = 0.63), in the number of patients tolerating simvastatin 40 mg/day (16 of 22 [73%] with coenzyme Q(10) vs 13 of 22 [59%] with placebo, p = 0.34), or in the number of patients remaining on therapy (16 of 22 [73%] with coenzyme Q(10) vs 18 of 22 [82%] with placebo, p = 0.47). In conclusion, coenzyme Q(10) supplementation did not improve statin tolerance or myalgia, although further studies are warranted.