Clinical and laboratory phenotype of patients experiencing statin intolerance attributable to myalgia

Harris, L. Jeff; Thapa, Rashmi; Brown, Michael J.; Pabbathi, Sabitha; Childress, Richard Dale; Heimberg, Murray; Braden, Ron; Elam, Marshall B.

doi:10.1016/j.jacl.2011.05.005

Cited by 30 publications

(17 citation statements)

References 30 publications

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“…However, the inhibition of cholesterol synthesis by statins leads to the activation of the SREBP pathway and a rise of fatty acid biosynthetic enzymes in liver, which leads to other metabolic syndrome risk factors characterized by dyslipidemia and insulin resistance, also in part due to statin intolerance (Vladutiu, 2008;Vandenberg and Robinson, 2010;Mancini et al, 2011). The noncompliance of statin is often related to statin-induced myalgia (Harris et al, 2011). Furthermore, recent evidence suggests that high-dose statins may increase the risk of developing type 2 diabetes (Culver et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Andrographolide Prevents High-Fat Diet–Induced Obesity in C57BL/6 Mice by Suppressing the Sterol Regulatory Element-Binding Protein Pathway

Ding

Song

et al. 2014

J Pharmacol Exp Ther

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Sterol regulatory element-binding proteins (SREBPs) are major transcription factors regulating the expression of genes involved in biosynthesis of cholesterol, fatty acids, and triglycerides. We investigated the effect of the specific SREBP suppressor andrographolide, a natural compound isolated from Andrographis paniculata, on the regulation of SREBP signaling by use of Western blot, reporter gene assay, and quantitative real-time polymerase chain reaction analysis. In addition, the antiobesity effects of andrographolide were evaluated in C57BL/6 mice with high-fat diet (HFD)-induced obesity. Our results showed that andrographolide downregulated the expressions of SREBPs target genes and decreased cellular lipid accumulation in vitro. Further, andrographolide (100 mg/kg per day) attenuated HFD-induced body weight gain and fat accumulation in liver or adipose tissues, and improved serum lipid levels and insulin or glucose sensitivity in HFD-induced obese mice. Andrographolide effectively suppressed the respiratory quotient, energy expenditure, and oxygen consumption, which may have contributed to the decreased body-weight gain of the obese mice fed with a HFD. Consistently, andrographolide regulated SREBP target genes and metabolism-associated genes in liver or brown adipose tissue, which may have directly contributed to the lower lipid levels and enhanced insulin sensitivity. Taken together, our results indicated that andrographolide ameliorated lipid metabolism and improved glucose use in mice with HFD-induced obesity. Andrographolide has potential as a leading compound in the prevention or treatment of obesity and insulin resistance.

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Section: Discussionmentioning

confidence: 99%

Andrographolide Prevents High-Fat Diet–Induced Obesity in C57BL/6 Mice by Suppressing the Sterol Regulatory Element-Binding Protein Pathway

Ding

Song

et al. 2014

J Pharmacol Exp Ther

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“…Patients experiencing statin myalgia report symptoms that interfere with their normal daily activity with over half totally precluding moderate exertion [6]. Inability to tolerate statin due to myalgia has emerged as a significant barrier to effective control of LDL cholesterol, thereby exposing these individuals to increased risk of cardiovascular disease [6, 7]. Whereas some risk factors for the rare, more serious syndromes such as myositis and rhabdomyolysis have been identified, information regarding the underlying pathogenesis and predisposing factors for statin-induced myalgia remains limited [2, 3, 8].…”

Section: Introductionmentioning

confidence: 99%

“…Whereas some risk factors for the rare, more serious syndromes such as myositis and rhabdomyolysis have been identified, information regarding the underlying pathogenesis and predisposing factors for statin-induced myalgia remains limited [2, 3, 8]. Conventional risk factors for myositis are noticeably absent in the majority of cases of statin-related myalgia [7]. These observations suggest the presence of an underlying, perhaps genetic susceptibility in patients with statin myalgia that elicits a unique pathophysiological response to statins.…”

Section: Introductionmentioning

confidence: 99%

Patients experiencing statin-induced myalgia exhibit a unique program of skeletal muscle gene expression following statin re-challenge

et al. 2017

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Statins, the 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors, are widely prescribed for treatment of hypercholesterolemia. Although statins are generally well tolerated, up to ten percent of statin-treated patients experience myalgia symptoms, defined as muscle pain without elevated creatinine phosphokinase (CPK) levels. Myalgia is the most frequent reason for discontinuation of statin therapy. The mechanisms underlying statin myalgia are not clearly understood. To elucidate changes in gene expression associated with statin myalgia, we compared profiles of gene expression in skeletal muscle biopsies from patients with statin myalgia who were undergoing statin re-challenge (cases) versus those of statin-tolerant controls. A robust separation of case and control cohorts was revealed by Principal Component Analysis of differentially expressed genes (DEGs). To identify putative gene expression and metabolic pathways that may be perturbed in skeletal muscles of patients with statin myalgia, we subjected DEGs to Ingenuity Pathways (IPA) and DAVID (Database for Annotation, Visualization and Integrated Discovery) analyses. The most prominent pathways altered by statins included cellular stress, apoptosis, cell senescence and DNA repair (TP53, BARD1, Mre11 and RAD51); activation of pro-inflammatory immune response (CXCL12, CST5, POU2F1); protein catabolism, cholesterol biosynthesis, protein prenylation and RAS-GTPase activation (FDFT1, LSS, TP53, UBD, ATF2, H-ras). Based on these data we tentatively conclude that persistent myalgia in response to statins may emanate from cellular stress underpinned by mechanisms of post-inflammatory repair and regeneration. We also posit that this subset of individuals is genetically predisposed to eliciting altered statin metabolism and/or increased end-organ susceptibility that lead to a range of statin-induced myopathies. This mechanistic scenario is further bolstered by the discovery that a number of single nucleotide polymorphisms (e.g., SLCO1B1, SLCO2B1 and RYR2) associated with statin myalgia and myositis were observed with increased frequency among patients with statin myalgia.

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“…95 % confident interval (95 % CI) was reported with significant statistic at p value \0.01 or p value \0.05. Concomitant medications were determined for potential drug interactions that might increased risks of muscle-or liverrelated injuries by using Drug information handbook (2011-2012) [22], and previous reports [23,24] (Appendix 2 of ESM).…”

Section: Discussionmentioning

confidence: 99%

Statin adverse effects: patients’ experiences and laboratory monitoring of muscle and liver injuries

et al. 2015

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Clinical and laboratory phenotype of patients experiencing statin intolerance attributable to myalgia

Cited by 30 publications

References 30 publications

Andrographolide Prevents High-Fat Diet–Induced Obesity in C57BL/6 Mice by Suppressing the Sterol Regulatory Element-Binding Protein Pathway

Andrographolide Prevents High-Fat Diet–Induced Obesity in C57BL/6 Mice by Suppressing the Sterol Regulatory Element-Binding Protein Pathway

Patients experiencing statin-induced myalgia exhibit a unique program of skeletal muscle gene expression following statin re-challenge

Statin adverse effects: patients’ experiences and laboratory monitoring of muscle and liver injuries

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