Statin-associated Myopathy Research Articles

Statin-Associated Myalgia, Myopathy, and Myositis

Statin-Associated Myalgia, Myopathy, and Myositis

A Possible Solution to Statin Noncompliance

Dear Sir/Madam Pakistan is one of the top six countries for Cardiovascular deaths and it is estimated that 4.7 million people will die from Cardiovascular deaths between 2005-2027[1]. Considering the burden of cardiovascular disease, it is imperative that we focus our efforts on preventing and addressing risk factors while simultaneously ensuring that the goals of our preventive strategies are met. One such issue arises with statins. Statin drugs are the first line drug therapy for dyslipidemia (a significant risk factor for CVDs) and the most widely prescribed drugs for dyslipidemia treatment as per both the American and European guidelines [2]. Statin drugs are essential for improving cardiovascular outcomes [2]. However, a challenge with statin therapy is nonadherence to the drug as shown by various studies. The percentage of patients taking statin dropped to 60.3% in one year and 48.8% in five years as shown by a cohort study on 1221 patients [3]. Statin associated muscle symptoms are the most common side effect implicated in patients discontinuing therapy. A meta-analysis showed that patients with statin-associated myopathy had significantly lower vitamin D levels than non-myopathy patients. This study pooled the results of four studies to show a significant increase in tolerance rate after vitamin D supplementation [4]. A randomized control trial showed a decrease in cardiorespiratory fitness with statin drugs, significantly reduced in the group of statins plus vitamin D supplementation [5]. These studies show the positive results of vitamin D supplementation when given with statin. It is, thus, possible for us to increase compliance with statin therapy and improve patients' exercise performance on statin drugs. Considering the impact of CVDs on our population and the pivotal part of Statin therapy, any related development can have a vast clinical impact and should be welcomed. We believe that general physicians should be made aware of such discoveries. Further, guidelines could be updated with inclusions of Vitamin D with high intensity Statin therapy. Finally, the importance of these drugs warrants further clinical trials to assess the feasibility of their use with vitamin D.

Effects of HMGCR deficiency on skeletal muscle development.

Pathogenic variants in HMGCR were recently linked to a limb-girdle muscular dystrophy (LGMD) phenotype. The protein product HMG CoA reductase (HMGCR) catalyzes a key component of the cholesterol synthesis pathway. The two other muscle diseases associated with HMGCR, statin-associated myopathy (SAM) and autoimmune anti-HMGCR myopathy, are not inherited in a Mendelian pattern. The mechanism linking pathogenic variants in HMGCR with skeletal muscle dysfunction is unclear. We knocked down Hmgcr in mouse skeletal myoblasts, knocked down hmgcr in Drosophila, and expressed three pathogenic HMGCR variants (c.1327C>T, p.Arg443Trp; c.1522_1524delTCT, p.Ser508del; and c.1621G>A, p.Ala541Thr) in Hmgcr knockdown mouse myoblasts. Hmgcr deficiency was associated with decreased proliferation, increased apoptosis, and impaired myotube fusion. Transcriptome sequencing of Hmgcr knockdown versus control myoblasts revealed differential expression involving mitochondrial function, with corresponding differences in cellular oxygen consumption rates. Both ubiquitous and muscle-specific knockdown of hmgcr in Drosophila led to lethality. Overexpression of reference HMGCR cDNA rescued myotube fusion in knockdown cells, whereas overexpression of the pathogenic variants of HMGCR cDNA did not. These results suggest that the three HMGCR-related muscle diseases share disease mechanisms related to skeletal muscle development.

44124 Nonspecific cutaneous eruption in a patient with statin-associated autoimmune myopathy

44124 Nonspecific cutaneous eruption in a patient with statin-associated autoimmune myopathy

The frequency of major ABCG2, SLCO1B1 and CYP2C9 variants in Asian, Native Hawaiian and Pacific Islander women subgroups: implications for personalized statins dosing.

Aim: The frequencies of SLCO1B1*5 and CYP2C9*2 and *3 in specific Asian, Native Hawaiian and Pacific Islander (NHPI) subgroups are unknown. Patients & methods: Repository DNA samples from 1064 women self-identifying as Filipino, Korean, Japanese, Native Hawaiian, Marshallese or Samoan and aged 18years or older were used for targeted sequencing of three genetic variants (rs4149056, rs1799853 and rs1057910). Results: SLCO1B1*5 was significantly less frequent in NHPI women (0.5-6%) than in Europeans (16%). Except for Koreans, CYP2C9*2 (0-1.4%) and *3 (0.5-3%) were significantly less frequent in all subgroups than in Europeans (8 and 12.7%, respectively). Prior reports showed that Asian and NHPI individuals have significantly higher ABCG2 Q141K allele frequency (13-46%) than Europeans (9.4%). Combined phenotype rates for rosuvastatin and fluvastatin revealed that Filipinos and Koreans had the highest frequencies of statin-associated myopathy symptoms risk alleles. Conclusion: Differences in ABCG2, SLCO1B1 and CYP2C9 allele frequencies among different racial and ethnic subgroups highlight the need for increased diversity in pharmacogenetic research. Risk alleles for statin-associated myopathy symptoms are more prevalent in Filipinos, underscoring the importance of genotype-based statin dosing.

Camptocormia, a late complication of statin-associated autoimmune myopathy. (SAM) (P9-8.011)

Camptocormia, a late complication of statin-associated autoimmune myopathy. (SAM) (P9-8.011)

Cardiolipin-Mediated Alleviation of Mitochondrial Dysfunction Is a Neuroprotective Effect of Statin in Animal Model of Ischemic Stroke.

In clinical settings, the benefit of statin for stroke is debatable as regular statin users may suffer from myalgia, statin-associated myopathy (SAM), and rarely rhabdomyolysis. Studies suggest that patients on statin therapy show lesser vulnerability toward ischemic stroke and post-stroke frailty. Both pre- and post-treatment benefits of statin have been reported as evident by its neuroprotective effects in both cases. As mitochondrial dysfunction following stroke is the fulcrum for neuronal death, we hereby explore the role of statin in alleviating mitochondrial dysfunction by regulating the mitochondrial dynamics. In the present study, we intend to evaluate the role of statin in modulating cardiolipin-mediated mitochondrial functionality and further providing a therapeutic rationale for repurposing statins either as preventive or an adjunctive therapy for stroke.

Safety and efficacy of short-term dual antiplatelet therapy combined with intensive rosuvastatin in acute ischemic stroke

To investigate the safety and efficacy of short-term (7-day) Dual Antiplatelet Therapy (DAPT) with intensive rosuvastatin in Acute Ischemic Stroke (AIS). In this study, patients with AIS in the emergency department of the hospital from October2016 to December2019 were registered and divided into the control group (Single Antiplatelet Therapy [SAPT]+ rosuvastatin) and the study group (7-day DAPT+intensive rosuvastatin) according to the therapy regimens. The generalized linear model was used to compare the National Institute of Health Stroke Scale (NIHSS) scores between the two groups during the21-day treatment. A Cox regression model was used to compare recurrent ischemic stroke, bleeding events, Statin-Induced Liver Injury (SILI), and Statin-Associated Myopathy (SAM) between the two groups during the90-day follow-up. Comparison of NIHSS scores after21-day treatment: NIHSS scores in the study group decreased significantly, 0.273-times as much as that in the control group (Odds Ratio [OR]0.273; 95%Confidence Interval [95%CI]0.208-0.359; p < 0.001). Comparison of recurrent ischemic stroke during the90-day follow-up: The therapy of the study group reduced the risk of recurrent stroke by 65% (7.76%vs.22.82%, Hazard Ratio [HR]0.350; 95%CI0.167-0.730; p=0.005). Comparison of bleeding events: There was no statistical difference between the two groups (7.79%vs.6.71%, HR=1.076; 95%CI0.424-2.732; p=0.878). No cases of SILI and SAM were found. Short-term DAPT with intensive rosuvastatin effectively relieved the clinical symptoms and significantly reduced the recurrent stroke for patients with mild-to-moderate AIS within90 days, without increasing bleeding events, SILI and SAM.

Evaluation and subgroup analysis of the efficacy and safety of intensive rosuvastatin therapy combined with dual antiplatelet therapy in patients with acute ischemic stroke

ObjectivesWe investigated the efficacy of intensive rosuvastatin therapy plus 7-day dual antiplatelet therapy (DAPT) in reducing stroke recurrence for patients with acute ischemic stroke (AIS) and compared subgroups of patients.MethodsWe enrolled patients with AIS whose time of onset to medication was ≤ 72 h, and the baseline scores of NIHSS (bNIHSS) were 0–10. The patients received intensive rosuvastatin therapy plus 7-day DAPT with aspirin and clopidogrel (study group) or rosuvastatin plus single antiplatelet therapy (SAPT, control group). The primary outcomes were recurrence of ischemic stroke, bleeding, statin-induced liver injury, and statin-associated myopathy (SAM) within 90 days. We also performed a subgroup analysis to assess the heterogeneity of the two therapy regimens in reducing recurrent stroke.ResultsRecurrent stroke occurred in 10 patients in the study group and 42 patients in the control group (hazard ratio [HR], 0.373, 95% confidence interval [CI], 0.178–0.780; P = 0.009). Bleeding events occurred in 9 patients in the study group and 14 patients in the control group (HR, 1.019; 95%CI, 0.441–2.353; P = 0.966). Statin-induced liver injury and SAM were not recorded. Intensive rosuvastatin plus 7-day DAPT was generally effective in reducing the risk of recurrent stroke, except in the subgroup with bNIHSS ≤ 2. The therapy was particularly efficient in the elderly, male, high-bNIHSS, and hypertension, diabetes, and hyperlipidemia subgroups, with P < 0.02.ConclusionsWithout increasing bleeding and statin-associated adverse events, intensive rosuvastatin therapy plus 7-day DAPT significantly reduced the risk of recurrent stroke, especially for subgroups with high-risk factors. Clinical trial registration. China Clinical Trial Registration Center (ChiCTR1800017809).

PSUN63 Approach to hyperlipidemia management in Carnitine Palmitoyltransferase II deficiency

Abstract Background Carnitine Palmitoyltransferase II deficiency (CPT II) is a disorder of long-chain fatty-acid oxidation. Clinical presentations include a lethal neonatal form, severe infantile hepatocardiomuscular form, and myopathic form. The myopathic form is the most common disorder of lipid metabolism affecting skeletal muscle. Individuals with CPT II deficiency are unable to metabolize long-chain fatty acids and can have myalgia. The incidence of statin-induced muscle symptoms is 1.5% to 5%. Individuals with CPT II deficiency have been reported to have an increased incidence of statin-associated myopathy. Yet, it remains crucial to place patients with high ASCVD risk on the appropriate statin therapy. Case Presentation We present a 70-year-old male with medical history of CPT II deficiency (myopathic form), hyperlipidemia with significant hypertriglyceridemia, hypertension, type 2 diabetes mellitus, carotid artery stenosis, atrial fibrillation, and recurrent pancreatitis. Family history was positive for hyperlipidemia and premature coronary artery disease. After history of recurrent pancreatitis and severe myalgias, patient was diagnosed with CPT II deficiency at the age of 30 years. The myalgias were managed by increased carbohydrates intake for many years. Multiple low potency statins, and fenofibrate were attempted but he developed severe myalgia with elevated CPK levels. Eventually he was started on ezetimibe 10 mg daily with fish oil 2000 mg twice daily but his LDL-C continued to rise. CMP and TSH were within normal limits. Nuclear stress test was normal but his ASCVD risk score was 39%. Given the patient's CPT II deficiency and high risk for ASCVD score, statin was recommended for primary prevention. After a thorough discussion of risks and benefits of lipid-lowering therapy, the patient was started on pitavastatin 2 mg twice-weekly regimen and ezetimibe 10mg was continued. Eight weeks later, his LDL-C reduced from 132 mg/dl to 94 mg/dl (n &amp;lt;129mg/dl), TG from 449 mg/dl to 307 mg/dl (n 0-149 mg/dl). As he experienced no myalgias, an extra tablet of pitavastatin a week was added until he reached a daily regimen. He continued to tolerate this treatment and his LDL-C improved to 66 mg/dl with normal CPK levels. Clinical Lesson: We present a case of CPT II deficiency and significant hyperlipidemia successfully managed with pitavastatin and ezetimibe, which helped to achieve a desirable LDL-C. Pitavastatin is not metabolized by hepatic CYP3A4 isoenzyme as other statins and is minimally metabolized by CYP2C9. In addition, patients with CPT II deficiency may benefit from avoiding extended episodes of exertion and high-fat diet. When treating patients with CPT II deficiency and hyperlipidemia, close follow-up and laboratory monitoring will be needed. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Abstract 141: African American Women With Cyp3a4/5 Polymorphisms Have Increased Statin Intolerance.

Background: Approximately 3 million Americans have ill managed lipidemia due to statin intolerance (SI) or statin-associated myopathy (SAM). Atorvastatin and simvastatin are the most prescribed statins which are transported into the liver by SLCO1B1 and metabolized by cytochrome P450 (CYP) 3A4 and 3A5. CYP3A4*22 and CYP3A5*3 are two polymorphisms known to decrease their activity; thus, increasing the systemic daily exposure (AUC) and serum concentration (C max ) of unmetabolized statin. In Caucasian (CAU) populations the prevalence [5-7% CYP3A4*22 and 90% CYP3A5*3] and effect of these polymorphisms is well characterized but not in African American (AA) populations. We hypothesize that the prevalence of SI and SAM are correlated with CYP3A4/5 polymorphisms in AA populations. Methods: After IRB approval, saliva samples were collected from patients currently prescribed atorvastatin or simvastatin at The Ohio State University Medical for genotyping. SLCO1B1 status was assessed to control for its confounding effect. Participants with polymorphic results were contacted to complete 8 blood draws over 13hrs for pharmacokinetic analysis. Electronic medical records were utilized to collect demographic information, medical histories, risk factors, and concomitant medications. Results: Preliminary analysis of 502 participants (395 AA, 104 CAU, and 3 others) shows racially different polymorphic prevalence. Reduced activity of CYP3A4 was present in 5.8% CAU vs 0.51% AA. Notably, CYP3A5*3 is inactive in 73% and reduced in 20.3% of CAU compared to 41.7% and 40.7% respectively in AA. A statistically significant increase in SI in AA women vs CAU women (p=0.0032) was observed. In combined analysis, atorvastatin has reduced odds of intolerance compared to simvastatin (OR=0.463; p &lt;0.05). However, the odds of SAM is higher in patients with no history of cardiovascular disease (OR=6.137; p &lt;0.01) and those with chronic kidney disease (OR=1.269; p &lt;0.05). Clinical significance: Considering, the CYP3A5 is fully active in 18.5% of the AA population compared to 6.8% CAU, the characterization of this metabolic enzyme is of clinical significance in minority populations to better manage lipidemia, assess the safety profile of current therapeutic doses, and reduce SAM.

Statin-Associated Myopathy: Emphasis on Mechanisms and Targeted Therapy.

Hyperlipidemia is a major risk factor for cardiovascular morbidity and mortality. Statins are the first-choice therapy for dyslipidemias and are considered the cornerstone of atherosclerotic cardiovascular disease (ASCVD) in both primary and secondary prevention. Despite the statin-therapy-mediated positive effects on cardiovascular events, patient compliance is often poor. Statin-associated muscle symptoms (SAMS) are the most common side effect associated with treatment discontinuation. SAMS, which range from mild-to-moderate muscle pain, weakness, or fatigue to potentially life-threatening rhabdomyolysis, are reported by 10% to 25% of patients receiving statin therapy. There are many risk factors associated with patient features and hypolipidemic agents that seem to increase the risk of developing SAMS. Due to the lack of a “gold standard”, the diagnostic test for SAMS is based on a clinical criteria score, which is independent of creatine kinase (CK) elevation. Mechanisms that underlie the pathogenesis of SAMS remain almost unclear, though a high number of risk factors may increase the probability of myotoxicity induced by statin therapy. Some of these, related to pharmacokinetic properties of statins and to concomitant therapies or patient characteristics, may affect statin bioavailability and increase vulnerability to high-dose statins.

Statin-associated anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) myopathy: Imaging findings on thigh-muscle magnetic resonance imaging (MRI) in six patients.

Anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) myopathy is a rare but serious complication of statin use. The aim of this study was to describe the imaging features of statin-associated anti-HMGCR myopathy on thigh muscle magnetic resonance imaging (MRI). Thigh muscle MRI images of six patients with statin-associated anti-HMGCR myopathy were reviewed for muscle edema, fatty replacement, and fascial edema in four compartments of each thigh: gluteal, anterior, medial, and posterior. Signal intensity ratio (SIR) was calculated in 17 muscles in both thighs on T2-weighted fat-suppressed images. Intracompartmental comparison of T2 SIRs of different muscles were performed. All patients demonstrated bilateral symmetrical pan-compartmental muscle edema. Three patients had fatty infiltration, involving gluteal and/or posterior compartments. In the anterior compartment, rectus femoris and vastus lateralis most frequently demonstrated the highest T2 SIR. In the posterior compartment, semimembranosus most frequently demonstrated the highest T2 SIR. The long head of the biceps femoris always had a higher T2 SIR than the short head. Statin-associated anti-HMGCR myopathy commonly demonstrates bilateral symmetrical pan-compartmental edema on thigh muscle MRI, with anterolateral predilection in the anterior compartment, and greater involvement of the semimembranosus with relative sparing of the short head of the biceps femoris in the posterior compartment. These observations can contribute to the diagnosis of statin-associated anti-HMGCR myopathy.

Modulation of Phospholipid Bilayer Properties by Simvastatin

Simvastatin (Zocor) is one of the most prescribed drugs for reducing high cholesterol. Although simvastatin is ingested in its inactive lactone form, it is converted to its active dihydroxyheptanoate form by carboxylesterases in the liver. The dihydroxyheptanoate form can also be converted back to its original lactone form. Unfortunately, some of the side effects associated with the intake of simvastatin and other lipophilic statins at higher doses include statin-associated myopathy (SAM) and, in more severe cases, kidney failure. While the cause of SAM is unknown, it is hypothesized that these side effects are dependent on the localization of statins in lipid bilayers and their impact on bilayer properties. In this work, we carry out all-atom molecular dynamics simulations on both the lactone and dihydroxyheptanoate forms of simvastatin (termed "SN" and "SA", respectively) with a pure 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer and a POPC/cholesterol (30 mol %) binary mixture as membrane models. Additional simulations were carried out with multiple simvastatin molecules to mimic in vitro conditions that produced pleiotropic effects. Both SN and SA spontaneously diffused into the lipid bilayer, and a longer simulation time of 4 μs was needed for the complete incorporation of multiple SAs into the bilayer. By constructing potential mean force and electron density profiles, we find that SN localizes deeper within the hydrophobic interior of the bilayer and that SA has a greater tendency to form hydrogen-bonding interactions with neighboring water molecules and lipid headgroups. For the pure POPC bilayer, both SN and SA increase membrane order, while membrane fluidity increases for the POPC/cholesterol bilayer.

New experimental possibilities for statin myopathy diagnosing

Aim. To identify the relationships between structural proteins of myocytes, as well as indicators of antioxidant defense and metabolites of glycolysis against the background of using statins in animals in the experiment for clarifying the diagnosis of statin-associated myopathy. Materials and methods . The study was conducted on outbred male rats, which were divided into 3 groups. The control group consisted of intact animals, and there were two experimental groups: group 1 – animals with induced hypercholesterolemia, group 2 – animals with induced hypercholesterolemia treated with simvastatin. In the muscles of animals from the studied groups, the content of structural proteins of the sarcomere, titin and nebulin, was analyzed, and the concentration of glycolysis metabolites (pyruvic acid and lactate) and the activity of antioxidant defense enzymes (superoxide dismutase (SOD) and catalase) were determined. Results and discussion. The use of simvastatin in the animals led to a decrease in the content of NT- and N2Atitin isoforms and an increase in the content of the T2-proteolytic fragment. Complete absence of nebulin was also noted, which reflects the presence of dystrophic changes in the muscle tissue. Long-term administration of simvastatin caused metabolic changes in the rats, characterized by impaired supply of cells with molecular oxygen. However, as opposed to the animals with hypercholesterolemia that were not given statins, a decrease in hypoxia-induced shifts was observed. Abnormalities in the performance of the antioxidant defense (AOD) system and multidirectional changes in the activity of the antioxidant pair “SOD – catalase” were noted. The correlation analysis revealed a positive relationship between the content of the NT-titin isoform and the SOD activity and negative correlations between the content of the N2A-titin isoform and the level of lactate, as well as between the T2-proteolytic fragment of titin and the level of lactate. Conclusion. The study revealed a complex set of biochemical changes in the muscles that underlie myotoxicity of statins during their long-term use. Additional biochemical parameters were found – SOD activity and lactate concentration, changes in which, along with the determination of titin and nebulin concentrations, indicating tissue hypoxia, will make it possible to more accurately diagnose statin-associated myopathy.

Efficacy and Safety of Statin for Hepatocellular Carcinoma Prevention Among Chronic Liver Disease Patients: A Systematic Review and Meta-analysis.

Hepatocellular carcinoma (HCC) is a deadly complication among patients with chronic liver disease (CLD). Controversies on the efficacy and safety of statin to prevent HCC among patients with CLD remain despite the growing evidences. We aim to investigate the efficacy and safety of using statin for HCC prevention among adult with CLD. We performed a systematic search of 4 electronic databases (PubMed/MEDLINE, EMBASE, Cochrane library, and ClinicalTrial.gov) up to April 15, 2020. We selected all types of studies evaluating the statin use and the risk of HCC among CLD patients, regardless of language, region, publication date, or status. The primary endpoint was the pooled risk of HCC. The secondary endpoint was the risk of statin-associated myopathy. From 583 citations, we included a total of 13 studies (1,742,260 subjects, 7 types of statins), fulfilling the inclusion criteria, evaluating efficacy and safety of statin in CLD patients for HCC prevention. All studies were observational (2 nested case-control studies, 11 cohort studies), and no randomised trial was identified. We found that statin user has a lower pooled risk of HCC development (hazard ratio=0.57, 95% confidence interval: 0.52-0.62, I2=42%). HCC reduction was consistent among statin users in cirrhosis, hepatitis B virus, and hepatitis C virus infections. The risk of statin-associated myopathy was similar between statin user and nonuser (hazard ratio=1.07, 95% confidence interval=0.91-1.27). Statin use was safe and associated with a lower pooled risk of HCC development among adults with CLD. Given the bias with observation studies, prospective randomised trial is needed to confirm this finding.

A case of statin-associated immune-mediated necrotizing myopathy with atypical biopsy features.

Statin-associated immune-mediated necrotizing myopathy (IMNM) is a rare presentation of a statin-associated myopathy. Patients usually present with muscle weakness and pain in the setting of statin use with elevated creatine kinase (CK) levels and a positive anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibody. Muscle biopsies typically show necrosis, CD68+ macrophages, and minimal lymphocytes. We present a case of a 67-year-old woman who had 2 months of progressive weakness and bilateral lower extremity pain after initiating atorvastatin therapy with symptoms persisting after statin cessation. She was found to have high anti-HMGCR antibody titers, and the biopsy of the rectus femoris muscle showed a prominent endomysial inflammatory cell infiltrate with necrotic and regenerative fibers and an atypical extensive inflammatory infiltrate composed of both CD4+ helper T cells and CD8+ cytotoxic T cells. She showed symptom resolution and normalization of CK levels and inflammatory markers with treatment involving a prolonged prednisone taper and a brief course of azathioprine, which was stopped because of the adverse effects.

Simvastatin Enhances Muscle Regeneration Through Autophagic Defect-Mediated Inflammation and mTOR Activation in G93ASOD1 Mice.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterised by the selective loss of motor neurons, muscular atrophy, and degeneration. Statins, as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are the most widely prescribed drugs to lower cholesterol levels and used for the treatment of cardiovascular and cerebrovascular diseases. However, statins are seldom used in muscular diseases, primarily because of their rare statin-associated myopathy. Recently, statins have been shown to reduce muscular damage and improve its function. Here, we investigated the role of statins in myopathy using G93ASOD1 mice. Our results indicated that simvastatin significantly increased the autophagic flux defect and increased inflammation in the skeletal muscles of G93ASOD1 mice. We also found that increased inflammation correlated with aggravated muscle atrophy and fibrosis. Nevertheless, long-term simvastatin treatment promoted the regeneration of damaged muscle by activating the mammalian target of rapamycin pathway. However, administration of simvastatin did not impede vast muscle degeneration and movement dysfunction resulting from the enhanced progressive impairment of the neuromuscular junction. Together, our findings highlighted that simvastatin exacerbated skeletal muscle atrophy and denervation in spite of promoting myogenesis in damaged muscle, providing new insights into the selective use of statin-induced myopathy in ALS.

Efficacy and Safety of High-Dose Immunoglobulin-Based Regimen in Statin-Associated Autoimmune Myopathy: A Multi-Center and Multi-Disciplinary Retrospective Study.

Statin-associated autoimmune myopathy is a rare muscle disorder, characterized by autoantibodies against HMGCR. The anti-HMGCR myopathy persists after statin, and often requires immunosuppressive therapy. However, there is not a standardized therapeutic approach. The purpose of this study is to report the effectiveness of the immunosuppressive treatment employed in a multi-center and multi-disciplinary cohort of patients affected by anti-HMGCR myopathy, in which an immunoglobulin (IVIG)-based treatment strategy was applied. We collected 16 consecutive patients with a diagnosis of anti-HMGCR myopathy, between 2012 and 2019, and recorded data on clinical and laboratory presentation (i.e., muscle strength, serum CK levels, and anti-HMGCR antibody titer) and treatment strategies. Our results highlight the safety and efficacy of an induction therapy combining IVIG with GCs and/or methotrexate to achieve persistent remission of the disease and steroid-free maintenance. Under IVIG-based regimens, clinical improvement and CK normalization occurred in more than two thirds of patients by six months. Relapse rate was low (3/16) and 2/3 relapses occurred after treatment suspension. Nearly 90% of the patients who successfully discontinued GCs were treated with a triple immunosuppressive regimen. In conclusion, an IVIG-based regimen, which particularly includes high-dose immunoglobulin, GCs and methotrexate, can provide a fast remission achievement with GC saving.

Simvastatin improves mitochondrial respiration in peripheral blood cells

Statins are prescribed to treat hypercholesterolemia and to reduce the risk of cardiovascular disease. However, statin users frequently report myalgia, which can discourage physical activity or cause patients to discontinue statin use, negating the potential benefit of the treatment. Although a proposed mechanism responsible for Statin-Associated Myopathy (SAM) suggests a correlation with impairment of mitochondrial function, the relationship is still poorly understood. Here, we provide evidence that long-term treatment of hypercholesterolemic patients with Simvastatin at a therapeutic dose significantly display increased mitochondrial respiration in peripheral blood mononuclear cells (PBMCs), and platelets compared to untreated controls. Furthermore, the amount of superoxide is higher in mitochondria in PBMCs, and platelets from Simvastatin-treated patients than in untreated controls, and the abundance of mitochondrial superoxide, but not mitochondrial respiration trends with patient-reported myalgia. Ubiquinone (also known as coenzyme Q10) has been suggested as a potential treatment for SAM; however, an 8-week course of oral ubiquinone had no impact on mitochondrial functions or the abundance of superoxide in mitochondria from PBMCs, and platelets. These results demonstrate that long-term treatment with Simvastatin increases respiration and the production of superoxide in mitochondria of PBMCs and platelets.