Statin myopathy: the fly in the ointment for the prevention of cardiovascular disease in the 21st century?

Introduction: Cardiovascular disease (CVD) remains the leading cause of death in industrialized nations. Despite clear evidence of CVD risk reduction with HMG-CoA reductase inhibitors (statins), the side effects of these medications, particularly myopathy, limit their effectiveness. Studies into the mechanisms, aetiology and management of statin myopathy are limited by lack of an internationally agreed clinical definition and tools for assessing outcomes. Currently there is a paucity of evidence to guide the management of patients affected by statin myopathy; with the exception of dose reduction, there is little evidence that other strategies can improve statin tolerance, and even less evidence to suggest these alternate dosing strategies reduce cardiovascular risk.

Areas covered: This review will cover current definitions, clinical presentations, risk factors, pathogenesis and management. PubMed was searched (English language, to 2014) for key articles pertaining to statin myopathy. This review then briefly describes our experience of managing this condition in a tertiary lipid disorders clinic, in the setting of limited guiding evidence.

Expert opinion: Knowledge gaps in the field of statin myopathy are identified and future research directions are suggested. We urge the need for international attention to address this important, but largely neglected clinical problem, that if unresolved will remain an impediment to the effective prevention and treatment of CVD.     

Statins and their increased risk of inducing diabetes

Introduction: Statins are evidence-based drugs to prevent cardiovascular (CV) disease. However, their benefits have been disputed by a statin-related increased risk of new onset diabetes (NOD) in randomized controlled trials and meta-analyses.

Areas covered: This review provides an update based on recent outstanding evidence on the statin effect on the risk of diabetes. It also describes mechanisms potentially explaining adverse effects of statins on glucose homeostasis. PubMed was searched for original articles and reviews published from January 2010 (inclusive) to May 2015 (inclusive), which include the Search terms statins, diabetes, glucose, and insulin. NOD risk seems to be more relevant with high-intensity rather than with low-intensity statin treatment. Also, this risk is particularly increased in patients at risk for the development of diabetes. It appears that statins adversely affect glucose homeostasis in parallel with their 3-hydroxy-3-methylglutaryl-coenzyme A inhibition capacity. It was suggested that lipophilic statins are more diabetogenic than the hydrophilic ones. Mechanisms explaining statin diabetogeneicity include impaired insulin secretion by pancreatic β cells together with increased insulin resistance of various tissues.

Expert opinion: The CV outcome benefits from statin use outweigh the diabetes menace. However, patients at risk for the development of diabetes should be prescribed statins with caution.     

早期应用他汀类药物对经皮冠状动脉介入治疗患者预后的影响

目的：评价早期应用他汀类药物对行经皮冠状动脉介入治疗（PCI）患者随访结果的影响。方法：选择2001年7月1日～2002年6月30日、2003年7月1日～2004年6月30日在北京安贞医院接受PCI的患者，记录其临床与造影特征、血运重建情况和住院临床结果等。根据住院期间及出院时是否服用他汀类药物，将患者分为他汀组和非他汀组。采用Kaplan—Meier方法、单因素和多因素Cox回归模型分析，观察住院期间及出院时应用他汀类药物对主要不良心血管事件（MACE）及死亡率的影响。采用Cox回归模型分析对死亡、主要不良心血管事件的影响因素。结果：共入选3289例患者，随访成功3005例，随访率91．4％。他汀组入选2082例，非他汀组入选1207例。随访时间中位数678d。两组无MACE事件生存率差异有显著性，他汀组发生MACE事件绝对危险性较非他汀组下降7％，相对危险度下降44．3％；两组无全因死亡事件生存率差异有显著性，他汀组全因死亡事件绝对危险性较非他汀组下降0.7％，相对危险度下降23．3％。随访MACE事件的单因素Cox回归分析显示，两组差异有显著性。随访MACE事件的多因素Cox回归分析，两组差异有显著性。随访全因死亡临床结果的单因素Cox、多因素Cox回归分析显示，两组差异有显著性。结论：行经皮冠状动脉介入治疗的患者早期服用他汀类药物可显著减少MACE事件及死亡率。     

Myopathy in older people receiving statin therapy: a systematic review and meta-analysis

Objective

The aim of the present study was to determine the risk of myopathy in older people receiving statin therapy.

Methods

Eligible studies were identified searching Ovid Medline, EMBASE, Scopus, CINAHL, Cochrane and PSYCHINFO databases (1987 to July 2014). The selection criteria comprised randomized controlled studies that compared the effects of statin monotherapy and placebo on muscle adverse events in the older adult (65+ years). Data were extracted and assessed for validity by the authors. Odds ratios and 95% confidence intervals (CIs) were used to calculate binary outcomes. Evidence from included studies were pooled in a meta-analysis using Revman 5.3.

Results

The trials assessed in the systematic review showed little or no evidence of a difference in risks between treatment and placebo groups, with myalgia [odds ratio (OR) 1.03, 95% CI 0.90, 1.17; I² = 0%; P = 0.66] and combined muscle adverse events (OR 1.03, 95% CI 0.91, 1.18; I² = 0%; P = 0.61) (myopathy). No evidence was found for an increased risk of rhabdomyolysis (OR 2.93, 95% CI 0.30, 28.18; I² = 0%; P = 0.35) in the seven trials that reported this. No trials reported mortality due to a muscle-related event. Discontinuations due to an adverse effect were reduced in the treatment group compared with placebo (OR 0.74, 95% CI 0.50, 1.09; I² = 0%; P = 0.13).

Conclusion

The results obtained from the present review suggest that statins are relatively safe, even in older people. There was no evidence to suggest an increased risk of myopathy in older adults receiving statin therapy. There is slightly increased seen with rhabdomyolysis when compared with the general population, although the event is relatively rare. Statins should be prescribed to elderly people who need it, and not withheld, as its myopathy safety profile is tolerable.     

Statins and myotoxicity: a therapeutic limitation

Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors represent the most successful class of drugs for the treatment of hypercholesterolaemia and dyslipidaemia implicated in the pathogenesis of coronary heart disease and atherosclerosis. However, the popular profile of statins in terms of efficacy has been maligned by its adverse events. The myotoxicity, ranging from mild myopathy to serious rhabdomyolysis, associated with HMG-CoA reductase inhibitors, during treatment of hypercholesterolaemia is of paramount importance. Rhabdomyolysis is a rare but idiosyncratic muscle wasting disorder of different etiologies. Statin-associated rhabdomyolysis causes skeletal muscle injury by self-perpetuating events leading to fatal irreversible renal damage through a series of biochemical reactions. Preferential distribution and action of statins in liver could be the key to minimise myotoxicity concerns. Hepato-specific distribution of statins is governed by various factors such as physicochemical properties, pharmacokinetic properties and selective transporter-mediated uptake in liver rather in extrahepatic cells. The interactions of statins with concomitant drugs of different classes merit attention for their safety profile. Although pharmacokinetic as well as pharmacodynamic interactions have been implicated in pathophysiology of statin-induced muscle wasting, the underlying mechanism is not clearly understood. Besides, pharmacokinetic and phramcodynamic factors, statin-associated myotoxcity may also implicate pharmacogenomic factors. The pharmacogenomics characterised by CYP polymorphism and other genetic factors is responsible for inter-individual variations to efficacy and tolerability of statins. The pathophysiological mechanisms may include statin-induced differences in cholesterol:phospholipid ratio, isoprenoid levels, small GTP binding proteins and apoptosis. However, the present understanding of pathophysiological mechanisms, does not offer a reliable approach to address the same at preclinical level. Although statin-associated myotoxicity affects compliance, quality of life of patient and discontinuation rate, yet the low incidence of myotoxicty including rhabdomyolysis and less severity of commonly occurring myopathy and myalgia do not raise doubts about the clinical efficacy and tolerability of statins. Medical management of myotoxicity seems to be pivotal for the proper compliance of patients with statin treatment. The appropriate and judicious use of drugs would substantially reduce the likelihood of developing clinically important myopathy.     

Statin-associated muscle symptoms: position paper from the Luso-Latin American Consortium

In the last two decades, statin therapy has proved to be the most potent isolated therapy for attenuation of cardiovascular risk. Its frequent use has been seen as one of the most important elements for the reduction of cardiovascular mortality in developed countries. However, the recurrent incidence of muscle symptoms in statin users raised the possibility of causal association, leading to a disease entity known as statin associated muscle symptoms (SAMS). Mechanistic studies and clinical trials, specifically designed for the study of SAMS have allowed a deeper understanding of the natural history and accurate incidence. This set of information becomes essential to avoid an unnecessary risk of severe forms of SAMS. At the same time, this concrete understanding of SAMS prevents overdiagnosis and an inadequate suspension of one of the most powerful prevention strategies of our times. In this context, the Luso-Latin American Consortium gathered all available information on the subject and presents them in detail in this document as the basis for the identification and management of SAMS.     

阿维A致肌肉骨骼疼痛3例

3例患者服用阿维A后出现肌肉骨骼疼痛。第1例为35岁女性，因掌跖脓疱病给予阿维A30mg／d口服。治疗1周后，患者出现右侧肩、背部及右上肢肌肉酸痛，自行将阿维A减量为20mg／d，1周后症状消失。半月后因掌跖脓疱病控制不理想，再次加量至30mg／d，3d后出现同一部位的酸痛不适，再次减量至20mg／d，1周后酸痛症状消失。第2例为42岁男性，因掌跖脓疱病给予阿维A30mg／d口服治疗，9d后出现全身肌肉骨骼剧烈酸痛，明显影响日常活动。患者自行停药，1周后症状仍未缓解，服用非甾体类抗炎药，5d后症状逐渐减轻。第3例为57岁男性，因银屑病给予阿维A30mg／d口服治疗，5d后出现双膝关节疼痛，当即停药，3d后疼痛症状完全消失。     

他汀类药物与血管平滑肌细胞凋亡

血管平滑肌细胞（VSMC）的异常增殖和迁移在粥样斑块形成和冠状动脉介入治疗（PCI）后再狭窄中起非常重要的作用。他汀类药物不仅是一种有效的调脂药，同时还有多种调脂以外的作用。如他汀类药物可以抑制VSMC的增殖和迁移，并诱导其凋亡。临近病变部位的中层VSMC的凋亡可能造成斑块纤维帽容易破裂，进而引起斑块不稳定和临床事件。但研究证实他汀类药物有稳定斑块的作用，且新生内膜VSMC对他汀类药物诱导的凋亡作用比普通的血管中层VSMC更敏感。因此，他汀类药物的促新生内膜VSMC凋亡作用可能对预防PCI术后再狭窄起有益作用。具体作用机制以及临床上如何合理发挥此类作用尚待进一步研究。     

Antidotal Sodium Bicarbonate Therapy: Delayed QTc Prolongation and Cardiovascular Events

BackgroundSodium bicarbonate therapy (SBT) is currently indicated for the management of a variety of acute drug poisonings. However, SBT effects on serum potassium concentrations may lead to delayed QTc prolongation (DQTP), and subsequent risk of adverse cardiovascular events (ACVE), including death. Emergency department (ED)–based studies evaluating associations between SBT and ACVE are limited; thus, we aimed to investigate the association between antidotal SBT, ECG changes, and ACVE.MethodsThis was a secondary data analysis of a consecutive cohort of ED patients with acute drug overdose over 3 years. Demographic and clinical data as well as SBT bolus dosage and infusion duration were collected, and outcomes were compared with an unmatched consecutive cohort of patients with potential indications for SBT but who did not receive SBT. The primary outcome was the occurrence of ACVE, and secondary outcomes were delayed QTc (Bazett) prolongation (DQTP), and death. Propensity score and multivariable adjusted analyses were conducted to evaluate associations between adverse outcomes and SBT administration. Planned subgroup analysis was performed for salicylates, wide QRS (> 100 ms), and acidosis (pH < 7.2).ResultsOut of 2365 patients screened, 369 patients had potential indications for SBT, of whom 31 (8.4%) actually received SBT. In adjusted analyses, SBT was found to be a significant predictor of ACVE (aOR 9.35, CI 3.6–24.1), DQTP (aOR 126.7, CI 9.8–1646.2), and death (aOR 11.9, CI 2.4–58.9). Using a propensity score model, SBT administration was associated with ACVE (OR 5.07, CI 1.8–14.0). Associations between SBT and ACVE were maintained in subgroup analyses of specific indications for sodium channel blockade (OR 21.03, CI 7.16–61.77) and metabolic acidosis (OR: 6.42, 95% CI: 1.20, 34.19).ConclusionIn ED patients with acute drug overdose and potential indications for SBT, administration of SBT as part of routine clinical care was an independent, dose-dependent, predictor of ACVE, DQTP, and death. This study was not designed to determine whether the SBT or acute overdose itself was causative of ACVE; however, these data suggest that poisoned patients receiving antidotal SBT require close cardiovascular monitoring.     

Effects of an ethanol extract and the diterpene,xylopic acid,of Xylopia aethiopica fruits in murine models of musculoskeletal pain

Context: Fruits of Xylopia aethiopica (Dunal) A. Rich. (Annonaceae) are used traditionally to manage arthritis, headache and other pain disorders.

Objective: The analgesic properties of the X. aethiopica ethanol fruit extract (XAE) and xylopic acid (XA) were evaluated in musculoskeletal pain models.

Materials and methods: Acute muscle pain was induced in gastrocnemius muscle of Sprague–Dawley rats with 3% carrageenan (i.m.). Rats received XAE (30–300?mg/kg), XA (10–100?mg/kg) or morphine (1–10?mg/kg) after 12?h. Effects of XAE and XA on muscle pain were assessed by measuring post-treatment grip strength of the rats. Chronic muscle pain was similarly induced, but drug treatment was on the eighth day and effects of XAE and XA assessed with Randall–Selitto test for hyperlagesia. Acute-skeletal pain was induced in knee joints of rats with 3% carrageenan-kaolin mixture and effects determined 12-h later. Similar induction protocol was used for chronic knee pain with treatment and measurement as done for chronic muscle pain.

Results: XAE and XA significantly and dose-dependently ameliorated both acute muscle (ED₅₀ mg/kg: XAE?=?22.9; XA?=?6.2) and skeletal hyperalgesia (XAE?=?39.9; XA?=?17.7) induced by 3% carrageenan. Similarly, chronic skeletal hyperalgesia was reduced by XAE and XA treatment similar to morphine (ED₅₀: XAE?=?13.0; XA?=?4.6). This reduction was also seen in chronic muscle hyperalgesia (ED₅₀: XAE?=?79.1; XA?=?42.7). XAE and XA significantly reduced the spread of hyperalgesia to contralateral limbs in both models of chronic hyperalgesia.

Conclusion: These findings establish analgesic properties of the ethanol fruit extract of X. aethiopica and xylopic acid in musculoskeletal pain.     

Muscle and statins: from toxicity to the nocebo effect

Introduction: Although statins have a satisfactory safety profile and are well tolerated, many statin-treated patients report muscle symptoms in clinical practice which contribute to drug discontinuation and, consequently, adverse cardiovascular outcomes.

Areas covered: This narrative review will cover the definition and prevalence of statin intolerance, the clinical spectrum of statin-associated muscle symptoms (SAMS) with special focus on patients with only mild myalgias, the complexity of statin muscle intolerance diagnosis and provide an overview on the nocebo effect of particular importance for physicians.

Expert opinion: Many patients are unable to tolerate statin therapy, with SAMS being the most common cause of statin intolerance. The reported incidence of SAMS was consistently lower in randomized placebo-controlled trials than in observational studies. These results strongly suggested that SAMS were not always due to by the pharmacologic effects of statin therapy. Convincing patients that their muscle symptoms might be due to causes other than statin treatment is sometimes difficult. Furthermore, clinicians should not prematurely discontinue statin therapy before considering other possible causes, including the nocebo effect.     

长效酸甲孕酮治疗子宫内膜异位症术后疼痛复发的疗效和安全性评价

目的 :评价长效醋酸甲孕酮 (depotmedroxypro gesteroneacetate ,DMPA)治疗子宫内膜异位症术后疼痛复发的有效性和安全性。方法 :选择因子宫内膜异位症行保守手术后疼痛复发的患者 4 8例 ,随机分为长效醋酸甲孕酮组及达那唑组。长效醋酸甲孕酮组 2 5例 ,月经来潮 5d内深部肌肉注射DMPA15 0mg ,2 8～ 30d注射 1次 ,共 6次 ;达那唑组 2 3例 ,于月经周期d 1开始口服达那唑 4 0 0mg·d-1,如无明显副反应增至 6 0 0mg·d-1,连续 2 4周。观察治疗前后症状、体征、肝、肾功能、血性激素变化及月经变化、体重改变等副反应。结果 :DMPA组总主观症状评分于治疗 3个月后下降了 82 .5 % ,6个月后下降了 92 .5 % ,卵巢异位囊肿于 3个月后缩小了4 1.5 % ,6个月后缩小了 5 6 .2 % (P <0 .0 5 )。达那唑组总主观症状评分于 3、6个月后分别下降了84 .1%和 95 .1% ,卵巢异位囊肿分别缩小了 34.4 %与 5 2 .2 % (P <0 .0 5 )。两组雌激素 (E2 )维持在卵泡早期水平。DMPA主要副作用为阴道点滴状出血或突破性出血、排卵恢复延迟及体重增加 ,随用药时间延长闭经增加。达那唑主要副作用为肝功能损害、痤疮等雄性素作用及体重增加。结论 :长效醋酸甲孕酮可有效治疗子宫内膜异位症术后疼痛复发 ,因用药方便、价廉、副作用少等优点     

Statins and telomere length: risk assessment and management for coronary heart disease

Cornoary heart disease (CHD) is identified as one of the diseases characterised by biological ageing as one of the important risk factors in several epidemiological studies. Premature biological ageing is distinct from chronological ageing and may predispose the individual to myocardial infarction, atherosclerosis and CHD in particular. The mean telomere length serves as a marker for the biological age at the cellular level, with shorter telomeres defining the increased biological age. Telomere length, therefore, correlates with the risk of CHD and atherosclerosis. Statins serve as the drugs of obvious choice based on their well established efficacy and safety profiles for the treatment of CHD and associated atherosclerosis. A present clinical study states that the treatment with a statin is associated with a reduction in the number of clinical events but only in individuals with increased risk based on their telomere length. This suggests a positive relationship of telomere length with the risk of CHD and, therefore, would help clinicians to categorise the patient populations based on their leucocyte telomere length for treatment with statins.     

Cardiovascular adverse events by non-steroidal anti-inflammatory drugs: when the benefits outweigh the risks

Introduction: Therapeutic efficiency of NSAID is handicapped by ongoing discussion of cardiovascular (CV) safety.

Areas covered: We update meta-analyses on NSAIDs in patients with and without cardiovascular (CV) diseases and analyse the association between NSAIDs and cardiovascular events in patients with inflammation. We demonstrate the substantial influence of an indication bias and confounding, which falsely increase the CV risk. We demonstrate protective cardiovascular effects of NSAIDs due to their anti-inflammatory activity, in particular in patients with rheumatoid arthritis, osteoarthritis or inflammatory pain.

Expert commentary: t-NSAIDs and Coxibes drugs resemble in their observed CV risk which, in contrast, reflects the intrinsic risk of patients with pain and inflammation. The anti-inflammatory NSAIDs reduce the risk of first myocardial infarction in patients with inflammation and elevated CRP. The extended use of NSAIDs is not associated with an increased CV risk in patients with pain and inflammation but with reduction in all-cause mortality.     

秋水仙碱与他汀类潜在药物相互作用处方风险分析

目的 分析秋水仙碱与他汀类潜在药物相互作用（potential drug-drug interactions,pDDIS）处方,进行风险评估并制定预防措施。方法 检索知网、维普、万方、PubMed和Elsevier数据库关于秋水仙碱与他汀类相互作用致不良反应的个案和研究报道,进行文献分析;通过医院合理用药软件抽取2020年1月—2022年10月秋水仙碱联合他汀类药物的所有门诊处方,鉴别出潜在药物相互作用并进行严重性分级。结果 检索到该药物相互作用致不良反应个案报道22例,病例对照研究1篇,观察性队列研究2篇;不良反应以老年人居多,男性多于女性;发生时间集中在联合用药21 d内,3例患者死亡;高剂量、高龄、男性和肝/肾功能不全可能增加该pDDIS发生风险;遵义医科大学附属医院共收集到秋水仙碱联合他汀类药物处方72张,其中阿托伐他汀65张,瑞舒伐他汀6张,辛伐他汀1张,危险程度分级均为严重;1例患者联合使用秋水仙碱和阿托伐他汀4个月后出现肌病,1个月后好转;临床药师制定了7项预防措施。结论 遵义医科大学附属医院秋水仙碱与他汀类处方存在pDDIS,需积极实施预防措施并加强监测,尤其是联合用药早期的老年男性及肝肾功能不全患者。     

紫杉醇引起关节肌肉痛及消炎痛栓缓解其疼痛的疗效观察

目的观察紫杉醇(paclitaxel,PTX)化疗所致的关节、肌肉痛的不良反应及消炎痛栓缓解其疼痛的临床疗效。方法本组随机选取使用紫杉醇辅助化疗50例非小细胞肺癌患者,观察每周期化疗过程中出现关节、肌肉痛的不良反应,以及使用消炎痛栓后疼痛控制情况。结果 34例患者在化疗中出现不同程度的关节、肌肉痛。19例为轻度疼痛,未镇痛处理;14例出现中度疼痛,予消炎痛栓纳肛后,12例疼痛缓解,另外2例缓解不理想,予口服吗啡后缓解;1例出现较严重的关节、肌肉痛,口服吗啡后缓解。结论应用紫杉醇化疗后,关节、肌肉痛症状常见,消炎痛栓纳肛可以缓解其疼痛。     

Risk of adverse cardiovascular events with use of inhaled long-acting bronchodilators in management of chronic obstructive pulmonary disease

Inhaled long-acting bronchodilators, including long-acting β₂ agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are the mainstay therapy in the treatment of chronic obstructive pulmonary disease (COPD), a disease that poses a heavy burden on morbidity and mortality worldwide. Use of LABAs and LAMAs in patients with COPD, however, has been concerned about an increased risk of adverse cardiovascular events, despite inconsistent findings reported from randomized controlled trials (RCTs) and observational studies. In this review, we detailed the relevant evidence generated from RCTs and observational studies with respect to the risk of cardiovascular disease with use of LABAs and LAMAs in management of COPD, and analyzed the contradictory findings in the literature, as well as recommended future research directions to clear the air regarding the cardiovascular safety of inhaled long-acting bronchodilators.