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Objective: To evaluate the impact of coadministering statins with direct oral anticoagulants (DOACs) on the risk of major bleeding events in patients with venous thromboembolism (VTE)., Design: Observational cohort analysis based on a multicentre international registry., Setting: Data were extracted from the Registro Informatizado de Enfermedad TromboEmbolica Registry, which involves 205 centres across 27 countries., Participants: A total of 73 659 patients diagnosed with VTE were classified based on their anticoagulant therapy (DOACs) versus low-molecular-weight heparin (LMWH) or vitamin K antagonists (VKAs) and concurrent use of statins., Methods: Multivariable Cox proportional hazards models adjusted for confounding variables to assess the risk of major bleeding events stratified by the type of anticoagulant use and statin use., Results: From October 2013 to February 2023, 73 659 patients were recruited: 2573 were statin users on DOACs, 14 090 were statin users on LMWH or VKA therapy, 10 088 were non-statin users on DOACs and 46 908 were non-statin users on LMWH or VKA therapy. Statin users were 10 years older and more likely to have hypertension, diabetes, renal failure or prior artery disease. During anticoagulation (median, 187 days), 1917 patients (2.6%) suffered major bleeding. Rates of major bleeding per 100 patient-years were 2.33 (95% CI 1.72 to 3.09), 3.75 (95% CI 3.43 to 4.10), 1.39 (95% CI 1.13 to 1.69) and 3.10 (95% CI 2.93 to 3.27), respectively. On multivariable analysis, patients treated with DOACs had a significantly lower risk of major bleeding compared with those on LMWH or VKA therapy (adjusted HR 0.59; 95% CI 0.48 to 0.74). The adjusted HR in statin users versus non-users was 1.03 (95% CI 0.92 to 1.14), while in statin users on DOACs versus the rest of patients, it was 1.18 (95% CI 0.79 to 1.76)., Conclusions: In patients with VTE receiving statins, long-term anticoagulation with DOACs was associated with a reduced risk of major bleeding, regardless of the statin use. These findings support the safety profile of DOACs over VKAs or LMWH in the management of VTE in patients requiring statins., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The use of statins for the primary prevention of cardiovascular diseases (CVD) is associated with various beneficial outcomes, alongside certain undesirable effects. This study aims to determine optimal risk thresholds above which statin therapy yields a net benefit, considering both the positive effects and potential adverse effects, as well as their probabilities and patient preferences., Methods: Quantitative benefit-harm balance modeling was applied to the Iranian general population aged 40 to 75 years with no history of CVD. The analysis utilized data from prior studies, including statin effect estimates for different outcomes from a meta-analysis, patient preferences obtained from an Iranian survey, and baseline incidence rates of adverse outcomes sourced from the Global Burden of Disease study for Iran. Outcomes were defined as angina, myocardial infarction, fatal coronary heart disease, fatal or non-fatal stroke, and heart failure. Benefit-harm balance indices were calculated for various combinations of age, sex, and 10-year CVD risk., Results: Statin therapy was found to be advantageous at a lower 10-year CVD risk threshold in men (18-23%) compared to women (24-28%). Furthermore, individuals aged 40-45 years exhibited a lower risk threshold (18% in men, 24% in women) than those aged 70-75 years (23% in men, 28% in women)., Conclusion: The desirable 10-year risk thresholds for statin prescription in the primary prevention of CVD vary by age and gender, ranging from 18 to 28%, encompassing a spectrum of outcomes from angina to CVD mortality. These results suggest hard-CVD risk thresholds of 7.5% to 10% for both sexes., (© 2024. The Author(s).)

Background: Although the relation between statin use and liver cancer risk has been extensively examined, few studies have examined other cholesterol-lowering medications in relation to liver cancer risk. The authors examined five classes of nonstatin medications and liver cancer risk., Methods: A nested case-control including 3719 cases and 14,876 matched controls was conducted within the Clinical Practice Research Datalink. Additional matches on type 2 diabetes and chronic liver disease were also implemented. The medications examined included cholesterol absorption inhibitors, bile acid sequestrants, fibrates, niacin, and omega-3 fatty acids. Conditional logistic regression estimated odds ratios and 95% confidence intervals., Results: Cholesterol absorption inhibitor use was associated with reduced liver cancer risk in the overall analysis (odds ratio, 0.69; 95% confidence interval, 0.50-0.96) and in analyses based on type 2 diabetes and chronic liver disease status. Although bile acid sequestrant use was associated with increased liver cancer risk in the overall analysis (odds ratio, 5.31; 95% confidence interval, 3.53-7.97), the results of the analyses based on type 2 diabetes and chronic liver disease status were inconsistent. [Correction added on 19 August 2024, after first online publication: In the preceding sentence, the value '3.534' has been changed to '3.54'.]. No associations were observed for the other medications., Conclusions: Cholesterol absorption inhibitors may be associated with reduced liver cancer risk. Whether bile acid sequestrant use was associated with increased risk was only partially supported in the current study., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Understanding the risk relationship between statin use and immune-related adverse events (irAEs) in patients undergoing immune checkpoint inhibitors (ICIs) therapy is crucial for optimizing oncological management., Objective: This study aimed to investigate whether the use of statins increases the risk of irAEs in patients receiving ICI therapy., Methods: This study primarily utilized data from FAERS database. Multivariable logistic regression was the principal method of analysis, and the Benjamini-Hochberg procedure was employed to adjust for multiple hypothesis testing., Results: In a group of 145,214 patients undergoing ICI therapy, 9,339 reported using statin medications. Multivariable analysis indicated an increased risk of irAEs among statin users (OR 1.199, 95% CI: 1.141-1.261; FDR p < 0.001) in comparison to those not using statins. Notably, increased risks were observed particularly in patients diagnosed with lung, pancreatic, and renal cancers. The link between statin usage and increased irAEs risk remained consistent across various ICIs treatments., Conclusions: Statin medication usage is linked to an elevated probability of experiencing irAEs in patients enrolled in ICI therapy. In cancer patients receiving immune checkpoint inhibitors, careful consideration of statin use is essential to avoid potentially increased irAEs risk. These findings provide critical guidance for clinicians in developing treatment strategies that balance therapeutic efficacy and safety in oncological management., Competing Interests: Author RH was employed by Hangzhou Linan Guorui Health Industry Investment Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Huang, Zhang, Liu, Liu, He and Peng.)

Hormone therapy, especially androgen deprivation therapy (ADT), is effective against prostate cancer (PC), whereas long-term ADT is a risk for metabolic/cardiovascular disorders including diabetes (DM), hypertension (HT) and dyslipidemia (DL), and might result in progression to castration-resistant prostate cancer (CRPC). We thus conducted a multicenter retrospective cohort study to ask whether CRPC progression would be associated positively with HT, DM or DL and negatively with statins prescribed for treatment of DL. In this study, 1,112 nonmetastatic PC patients undergoing ADT were enrolled. Univariate statistical analyses clearly showed significant association of HT or DM developing after ADT onset, though not preexisting HT or DM, with early CRPC progression. On the other hand, preexisting DL or statin use, but not newly developed DL or started statin prescriptions following ADT, was negatively associated with CRPC progression. Multivariate analysis revealed significant independent association of the newly developed DM or HT, or preexisting statin use with CRPC progression [adjusted hazard ratios (95% confidence intervals): 3.85 (1.65-8.98), p = 0.002; 2.75 (1.36-5.59), p = 0.005; 0.25 (0.09-0.72), p = 0.010, respectively]. Together, ADT-related development of HT or DM and preexisting statin use are considered to have positive and negative impact on CRPC progression, respectively., (© 2024. The Author(s).)

Statins use is linked to side effects, notably muscular ones, known as Statin-Associated Muscle Symptoms (SAMS). These can include a pain, an increased sensitivity to palpation, aches, and cramps. SAMS are a real problem in the clinical management of patients, as it is difficult to causally link these complaints with drug use, and they may lead to a reduction in statin intake, or even to the patient -discontinuing their use. The absence of objective markers and the -variety of possible clinical manifestations of these muscular -complaints impede a full understanding of the objective and -subjective impacts of these symptoms on the everyday life of sympto-matic patients. This article assess the current state of knowledge on the impact of SAMS on performance and health--related quality of life., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Statin-associated muscle symptoms are frequently reported and often lead to discontinuation of statin therapy with an increased risk of cardiovascular events. In vitro studies suggest that statin-mediated inhibition of the mevalonate pathway leads to muscle cell toxicity. We aimed to determine the relationship between mevalonate, LDL-cholesterol, and atorvastatin metabolites in patients with coronary heart disease and self-perceived muscle side effects. Furthermore, we assessed the correlation between mevalonate in blood and muscle and the relationship to statin intolerance due to muscle symptoms. We used blood plasma from a randomized crossover trial (n = 70) and muscle biopsies and plasma from a subgroup in a subsequent open intervention study (n = 26). Both studies tested atorvastatin 40 mg/day. Seven patients did not tolerate ≥3 statins throughout the follow-up and were classified as statin-intolerant. Mevalonate in blood plasma decreased during atorvastatin treatment (median difference -38%, range -77% to 43%, p < 0.001), whereas mevalonate in muscle tissue was not lowered (0.05%, range -47% to 145%). Mevalonate correlated poorly with LDL-cholesterol and atorvastatin metabolites (Spearman's rho -0.28 to 0.10). The statin-intolerant patients had a smaller reduction in circulating mevalonate compared with the tolerant patients; median difference -8.1 (-22 to 3.5) nmol/L versus -25 (-93 to 12) nmol/L, p = 0.028. A similar observation was made for LDL-cholesterol. Cutoffs based on these biomarkers classified >50% correctly as tolerant. Inhibition of the mevalonate pathway does not appear to be the mechanism underlying statin intolerance in the present study. Further studies of mevalonate as a biomarker for statin tolerance are needed to clarify the potential., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Higher serum cholesterol levels have been associated with an increased risk of dry eye disease (DED). The relationship between statin (HMG-CoA reductase inhibitor) use and DED in patients with hyperlipidemia remains unclear. To investigate the association between statin use and the risk of DED in patients with hyperlipidemia, we conducted a population-based retrospective cohort study utilizing data from Taiwan's Longitudinal Generation Tracking Database. Patients were categorized into statin users and nonusers, with a 5-year follow-up period. The study identified patients with newly diagnosed hyperlipidemia, excluding those with prior DED diagnoses. Matching and adjustments for covariates resulted in 41,931 individuals in each group. Patients receiving statin therapy were compared with those unexposed. Cumulative exposure doses were also evaluated to assess dose-response relationships. The primary outcome was the incidence of DED diagnosed during the follow-up period. Cox proportional hazards regression models estimated the risk of DED, and conditional logistic regression analyzed the dose-response effect of statin exposure. Among 41,931 matched pairs, statin users exhibited a slightly increased risk of developing DED compared with nonusers (adjusted hazard ratio, 1.06; 95% CI, 1.02-1.11; p < 0.01). However, no dose-response relationship was observed between statin exposure and DED risk. Statin use among patients with hyperlipidemia is associated with a marginally higher risk of DED. These findings underscore the importance of regular eye examinations in this patient population to facilitate early detection and management of DED., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Recent insights suggest that lipids and statin medication play a role in the development of sensorineural hearing loss (SNHL), yet the exact role remains controversial. This research applied Mendelian randomization (MR) to assess whether lipids and statin medication are associated with an increased risk of SNHL., Methods: A two-sample MR was used in this study. Genetic instruments were constructed from variants associated with risk factors. Data for lipids and statin medication were obtained from the IEU OpenGWAS project, and for SNHL from the Finngen research project, which comprises 32,487 individuals with SNHL and 331,736 control individuals., Results: Genetically predicted higher levels of triglycerides were associated with an increased risk of SNHL. The use of genetically predicted atorvastatin was associated with a lower risk of SNHL. Rosuvastatin has demonstrated potential in treating SNHL, yet further investigations are warranted to elucidate its relationship with SNHL. Insufficient evidence was available to suggest that the genetically predicted level of high-density lipoprotein cholesterol or low-density lipoprotein cholesterol or the use of simvastatin were associated with SNHL., Conclusions: The study provides genetic evidence suggesting that increased levels of triglycerides in the blood could be a risk factor for SNHL and that the use of certain statin medications, including atorvastatin and rosuvastatin, could reduce the risk of SNHL. These results align with findings from previous observational studies that have linked hyperlipidemia with the risk of SNHL., Level of Evidence: According to the Oxford Centre for Evidence-Based Medicine 2011 levels of Evidence, the study has a third level of Evidence Laryngoscope, 134:4366-4373, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Statins are one of the most important classes of drugs. In this analytical review, we elucidate the intricate molecular mechanisms and toxicological rationale regarding both the on- (targeting 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMGCR]) and off-target effects of statins. Statins interact with a number of membrane kinases, such as epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (HER2) and MET proto-oncogene, receptor tyrosine kinase (MET), as well as cytosolic kinases, such as SRC proto-oncogene, non-receptor tyrosine kinase (Src) and show inhibitory activity at nanomolar concentrations. In addition, they interact with calcium ATPases and peroxisome proliferator-activated receptor α (PPARα/NR1C1) at higher concentrations. Statins interact with mitochondrial complexes III and IV, and their inhibition of coenzyme Q10 synthesis also impairs the functioning of complexes I and II. Statins act as inhibitors of kinases, calcium ATPases and mitochondrial complexes, while activating PPARα. These off-target effects likely contribute to the side effects observed in patients undergoing statin therapy, including musculoskeletal symptoms and hepatic effects. Interestingly, some off-target effects of statins could also be the cause of favourable outcomes, relating to repurposing statins in conditions such as inflammatory disorders and cancer., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background and Aims: Half of dyslipidemic patients sometimes discontinue statin medication. It is unclear if blood atherogenic risk increases right after statin discontinuation or if there is a lingering protective effect. We sought to determine if a legacy effect prevented blood lipid increases during the first stages of statin cessation., Methods and Results: Atherogenic blood lipid profile was measured in 10 overweight (BMI 31 ± 3 kg m -2 ) middle-aged males (62 ± 7 years old), statin users, while fasted and postprandially. Trials were conducted before (i.e., Day 0) and after 4, 7, 15, and 30 days of statin withdrawal and 20 days after statins reloading (Day 50). Four days after statin discontinuation, blood fasting LDL-c, total cholesterol (CHOL), and triglyceride (TG) concentrations increased by 30%, 18%, and 17%, respectively (P < 0.05). The increases in LDL-c, CHOL, and TG peaked after 7-15 days at 79%, 48%, and 34% of basal levels (P < 0.001), respectively. There were no significant correlations between the increases in blood lipids and the dose or years under statin treatment (P = 0.156-0.575). Twenty days after resuming statins, blood LDL-c (2.79 ± 1.06 vs 2.20 ± 0.50 mmol L -1 ; P = 0.568), CHOL (4.85 ± 1.41 vs 4.25 ± 0.83 mmol L -1 ; P = 0.747), and TG (1.47 ± 0.60 vs 1.50 ± 0.68 mmol L -1 ; P = 0.782), returned to basal levels., Conclusions: Our data does not support a statin lingering/legacy effect in blood lipids since they dangerously increased after only 4 days of statin withdrawal in every patient, regardless of dose and years under treatment. Reloading statins restored blood lipids, evidencing a reproducible biological effect at the whole-body level., Competing Interests: Declaration of competing interest The authors have no conflicts of interest. ClinicalTrials.gov identifier: NCT04477590. The authors state that the results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Statins are widely used crucial drugs for the primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD). Although generally well tolerated, statin intolerance can unfortunately limit statin use, with statin-associated muscle symptoms (SAMS) being the most common side effect associated with its discontinuation. Statin intolerance is an inability to tolerate a dose of statin required to sufficiently reduce an individual's cardiovascular risk, limiting the effective treatment of patients at risk of or with cardiovascular disease (CVD). Statin myopathy is a broad entity encompassing self-limited/toxic and autoimmune aetiologies. As statins are a mainstay of therapy in those with or at risk for CVD and offer a mortality benefit, it is critical to determine whether one's symptoms are truly statin-associated before discontinuing the drug. This review article aims to provide an update on the epidemiology, pathophysiology, clinical features, diagnosis, evaluation and management of statin myopathy and to elucidate key differences between autoimmune and self-limited types., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose of Review: The aim of this review is two-fold: (1) To examine the mechanisms by which statins may protect from anthracycline-induced cardiotoxicity and (2) To provide a comprehensive overview of the existing clinical literature investigating the role of statins for the primary prevention of anthracycline-induced cardiotoxicity., Recent Findings: The underlying cardioprotective mechanisms associated with statins have not been fully elucidated. Key mechanisms related to the inhibition of Ras homologous (Rho) GTPases have been proposed. Data from observational studies has supported the beneficial role of statins for the primary prevention of anthracycline-induced cardiotoxicity. Recently, several randomized controlled trials investigating the role of statins for the primary prevention of anthracycline-induced cardiotoxicity have produced contrasting results. Statins have been associated with a lower risk of cardiac dysfunction in cancer patients receiving anthracyclines. Further investigation with larger randomized control trials and longer follow-up periods are needed to better evaluate the long-term role of statin therapy and identify the subgroups who benefit most from statin therapy., (© 2024. The Author(s).)

Circulating lipoproteins may interact with platelets, increasing platelet sensitivity to aggregating agonists and their tendency towards activation and thrombus formation. In particular, patients with hypercholesterolemia exhibit a higher degree of platelet reactivity compared to normolipidemic. Moreover, accruing evidence report that lipid-lowering therapies can reduce thrombus formation, particularly in the absence of concomitant antiplatelet therapy. However, the underlying biological mechanism(s) explaining these clinical observations are not completely understood. Baseline platelet reactivity and high on-treatment platelet reactivity while on antiplatelet therapy (e.g., aspirin and clopidogrel) are associated with poor clinical outcomes. Therefore, strategies to reduce baseline platelet reactivity or improve the pharmacodynamic profile of antiplatelet therapies are an unmet clinical need. The potential use of lipid-lowering therapies for optimizing platelet reactivity provides several advantages as there is strong evidence that reducing circulating lipoproteins can improve clinical outcomes, and they may avoid the need for potent antiplatelet therapies that, although more effective, are associated with increased bleeding risk. This review will provide a systematic overview of the effects of lipid-lowering therapy on platelet reactivity in patients treated with and without antiplatelet therapy. We will focus on the potential biological mechanism(s) of action and the effect of statins, ezetimibe, proprotein convertase subtilisin/kexin 9 inhibitors, omega-3 fatty acids, and recombinant high-density lipoprotein on platelet reactivity. Ultimately, we will assess the current gaps in the literature and future perspective in the field.

Schwartz Jampel syndrome (SJS) is a genetic disorder characterized by myotonia and chondrodysplasia. Mutations of the Perlecan gene (HSPG2), which encodes a key component of the extracellular matrix of muscle, bone, and cartilage is cause for the characteristic dysmorphisms of SJS. Clinically remarkable creatinine phosphokinase (CPK) levels are typical and can be associated with myotonia as an underlying cause in SJS patients. We report a unique case of a symptomatic adverse event of statin use in a SJS patient who demonstrated heightened levels of CPK to baseline following a statin induced myopathy. Discontinuation of the statin and administration of a PCSK-9 inhibitor revealed a return to baseline CPK. This case challenges the current lipid treatment algorithm as it pertains to SJS patients. Further investigation into treatment is required in this special population., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: The Medication Review in the Pharmacotherapeutic Follow-up Service (PFS) seems to be an effective method to study long-term drug safety in the outpatient setting. The adverse drug reactions (ADRs) that are not immediately obvious are difficult to identify and sometimes can be confused with a more common condition. Misdiagnosis by not associating the symptoms of AMR to its pharmacological cause causes its masking and hinders its detection., Objective: Detect in the SFT service the diagnostic errors related to the non-detection of adverse reactions to statins., Material and Methods: The data obtained from the medication review at the Pharmacotherapeutic Follow-up Service (PFS) were pooled for analysis. The patients who received the service were selected with the "DLGM screening" tool, an acronym "Diagnosis load Generated by Medications", that allows us to describe adverse drug reactions (ADRs), when their symptoms are attributed to a pathology, without considering medication as a possible underlying cause.Only the results of patients over 60 years of age, who after a prolonged period of statin use gradually presented musculoskeletal disorders (MSD) and other symptoms theoretically described as possible ADRs, are shown., Results: In 66 % of the cases, corresponding to 14 patients out of a total of 21 studied, the physician modified the treatment and in 92% of these cases there was improvement and a decrease of the consumption of analgesics drug, anti-inflammatory and other drugs used to treat ADR symptoms., Conclusion: DLGM screening identified hidden AMRs in 62 % of patients., (Copyright SEFAC. Sociedad Española de Farmacia Clínica, Familiar y Comunitaria. This article is available from url https://www.farmaceuticoscomunitarios.org/.)

Introduction/aims: The common presentations of statin intolerance are muscle-specific symptoms. Although statins are one type of drug reported to cause myasthenic worsening, myasthenic worsening has not been recognized as statin intolerance. The purpose of the present study is to investigate in a large cohort the safety profiles of statins in patients with myasthenia gravis (MG)., Methods: A total of 1710 consecutive patients with MG who visited sites associated with the Japan MG registry 2021 group between April and October 2021 were reviewed. Statin-associated myasthenic worsening was defined as worsening of any myasthenic symptoms on statin use and improvement of the symptom by stopping the statin or by undertaking additional treatment with patient and doctor confirmation., Results: Among the 400 patients who used statins, 8 (2%) patients experienced statin intolerance and 6 (1.5%) patients experienced myasthenic worsening. No patients developed MG on the statin. Ptosis was a main symptom of myasthenic worsening in 4 (67%) patients. Atorvastatin was used in all patients with statin-associated myasthenic worsening. The symptoms of statin intolerance and statin-associated myasthenic worsening were improved within 2 months and 3 months, respectively, in all patients by cessation of statin use., Discussion: Regarding statin-associated myasthenic worsening, prevalence was low, and severity was mild; with cessation of statin use, symptoms improved within a few months, and outcomes were generally good. Although statins can be used in MG patients with little concern, statin-associated myasthenic worsening should be noted in addition to the classical statin intolerance associated with statin use., Competing Interests: Declaration of competing interest T. Sugimoto declares no potential conflicts of interest related to this article. S. Suzuki received speakers' fees from Alexion Pharmaceuticals, the Japan Blood Products Organization, Asahi Kasei Medical, and Argenx and participated in advisory board meetings of Alexion Pharmaceuticals and Argenx. A. Uzawa has received honoraria from Alexion Pharmaceuticals and Argenx. T. Yamawaki declares no potential conflicts of interest related to this article. M, Masuda declares no potential conflicts of interest related to this article. N. Minami declares no potential conflicts of interest related to this article. N. Kawaguchi declare no financial or other conflicts of interest. T. Kubota reports honoraria for lectures from Alexon Pharmaceuticals. M. P. Takahashi reports unrestricted research grants from Japan Blood Products Organization, Astellas Pharma, Mitsubishi Tanabe Pharma and Pfizer, outside the submitted work, and has served as a paid Consultant for Alexion, Argenx, Sanofi, and UCB Pharma and received honoraria for lectures from Argenx, Alexion Pharmaceuticals and UCB Pharma. Y. Suzuki declares no potential conflicts of interest related to this article. G Watanabe declares no potential conflicts of interest related to this article. S. Konno declares no potential conflicts of interest related to this article. T. Kimura declares no potential conflicts of interest related to this article. M. Samukawa declares no potential conflicts of interest related to this article. K. Ishizuchi declares no potential conflicts of interest related to this article. H. Akamine declares no potential conflicts of interest related to this article. Y. Onishi declares no potential conflicts of interest related to this article. M. Yasuda declares no potential conflicts of interest related to this article. Y. Nagane has received honoraria from Alexion Pharmaceuticals, Argenx, the Japan Blood Products Organization, and UCB Pharma. H. Maruyama declares no potential conflicts of interest related to this article. H. Murai has served as a paid consultant for UCB Pharma, Argenx, Janssen Pharma, Viela Bio, Chugai Pharma, Hanall BioPharma, and Mitsubishi Tanabe Pharma, and has received speaker honoraria from Argenx, Alexion Pharmaceuticals, and the Japan Blood Products Organization. K. Utsugisawa has served as a paid consultant for UCB Pharma, Argenx, Janssen Pharma, Viela Bio, Chugai Pharma, Hanall BioPharma, Merck and Mitsubishi Tanabe Pharma, and has received speaker honoraria from Argenx, Alexion Pharmaceuticals, UCB Pharma and the Japan Blood Products Organization., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: This study aims to systematically evaluate the clinical efficacy and safety of acupuncture in combination with statin therapy compared to statin monotherapy for the treatment of dyslipidemia., Methods: A comprehensive search for relevant randomized controlled trials assessing the clinical efficacy of acupuncture and statin combination in the treatment of dyslipidemia was conducted. Databases including PubMed, EMbase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine disc, Wanfang database, and China Science and Technology Journal Database were searched up to October 27, 2023., Results: Sixteen Chinese-language studies involving a total of 1333 subjects were included for analysis. The meta-analysis revealed that the total effective rate of acupuncture combined with statin was significantly higher than that of statin alone (odds ratios = 3.32, 95% confidence intervals [CI] = 2.33 to 4.72). Furthermore, the combination of acupuncture with statin treatment resulted in a significant reduction in triglyceride levels (mean differences [MD] = -0.72 mmol/L, 95% CI = -1.05 to -0.4), total cholesterol levels (MD = -0.79 mmol/L, 95% CI = -1.07 to -0.51), low-density lipoprotein cholesterol levels (MD = -0.61 mmol/L, 95% CI = -0.95 to -0.27) and traditional Chinese medicine syndrome integral (MD = -1.32, 95% CI = -1.75 to -0.89), compared to statin treatment alone. Additionally, the high-density lipoprotein cholesterol level was higher in the combined acupuncture and statin treatment group than in the statin treatment alone group (MD = 0.44 mmol/L, 95% CI = 0.09 to 0.79). Notably, the rate of adverse reactions reported with combined acupuncture and statin treatment was lower than that with statin therapy alone., Conclusion: Our findings support the potential of acupuncture combined with statin as a viable clinical treatment option for dyslipidemia. However, it is important to note that current research on the mechanism of acupuncture for lipid-lowering has not yielded definitive results, and there are inherent biases in the conducted clinical studies., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Dyslipidemia represents an important risk factor for cardiovascular diseases, although its optimal management after kidney transplantation remains unclear. The present meta-analysis aimed to shed light on the efficacy and safety of statins among kidney transplant recipients, evaluating their potential effects on the risk of cardiovascular events, mortality and graft survival., Methods: Medline, Scopus, Web of Science, CENTRAL, Clinicaltrials.gov and Google Scholar were systematically searched from their inception through April 20, 2024. Both randomized controlled trials and observational studies evaluating the effects of statin administration after kidney transplantation were held eligible. Random-effects models were fitted using the maximum likelihood method, while the certainty of evidence was appraised following the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach., Results: Overall, 27 studies (10 randomized controlled trials and 17 observational studies) were included. Statin use compared to no use was associated with a lower risk of major adverse cardiovascular events [Relative risk (RR): 0.87, 95% confidence interval (CI): 0.67-0.96, moderate certainty] and overall mortality (RR: 0.84, 95% CI: 0.74-0.94, low certainty). The risk of graft loss did not differ between the compared groups (RR: 0.72, 95% CI: 0.48-1.08, very low certainty). Regarding safety endpoints, statin use was associated with a lower risk of hepatotoxicity (RR: 0.81, 95% CI: 0.70-0.93, moderate certainty), but with a greater risk of rhabdomyolysis (RR: 1.37, 95% CI: 1.10-1.70, low certainty) and cataract (RR: 1.22, 95% CI: 1.14-1.31, moderate certainty). No statistically significant differences between the compared groups with and without statin use were observed concerning the risk of creatine kinase elevation, post-transplant diabetes mellitus, hip fracture, venous thromboembolism, or cancer., Conclusions: Among kidney transplant recipients, statin use is associated with a lower risk of cardiovascular events and better patient survival, presenting an acceptable safety profile. Further large-scale studies are needed to determine the optimal statin dosing strategy and lipid-lowering goals, depending on comorbidities and immunosuppression regimens., Registration: https://doi.org/10.17504/protocols.io.5qpvok3yzl4o/v1 ., (© 2024. The Author(s).)

Backgrounds and Objective: Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, are pivotal in managing hypercholesterolemia and reducing cardiovascular risk. While rosuvastatin demonstrates superior efficacy and tolerability compared to other statins, its safety profile in elderly patients older than 75 years old with acute coronary syndrome (ACS) remains underexplored. So, the objective of this study is to evaluate the frequency of adverse reactions and investigate the efficacy of high-dose rosuvastatin on lipid profiles in elderly patients aged over 75 with ACS., Methods: In this observational study, 110 consecutive elderly ACS patients attending Modarres Hospital in Tehran, Iran, in 2019 were enrolled. The effects of high-dose rosuvastatin were assessed in elderly patients older than 75 years old by comparison of the adverse effects, lipid profile, cardiac function, and other biomarkers at the baseline and after 6 weeks of rosuvastatin therapy with a dose of 40 mg., Results: Following 6 weeks of treatment, there was a significant reduction in total cholesterol (136.2 ± 24.3 to 115.5 ± 24.0, p = 0.001) and LDL levels (72.6 ± 17.5 to 50.9 ± 18.9, p = 0.001), accompanied by a notable increase in HDL levels (38.3 ± 7.1 to 47.2 ± 7.4, p = 0.001). Cardiac function, as measured by ejection fraction (EF), significantly improved from 43.4 ± 8.8 to 48.5 ± 8.5 (p = 0.001). Adverse effects such as cramps (N = 12, p = 0.001), weakness (N = 28, p = 0.001), and anorexia (N = 12, p = 0.001) were reported but did not warrant discontinuation of therapy. Notably, no cases of jaundice were observed. Two deaths occurred due to major adverse cardiac events (MACE) during the study period, unrelated to stroke or recurrent myocardial infarction., Conclusion: Totally, high-dose rosuvastatin therapy effectively improved lipid profiles, cardiac function, and liver enzyme levels in elderly ACS patients, with manageable adverse effects. These findings underscore the importance of rosuvastatin in optimizing cardiovascular health in this vulnerable population., (© 2024. The Author(s).)

Background: Lowering LDL-cholesterol is a fundamental goal for both primary and secondary prevention of atherosclerotic cardiovascular diseases. Our study aims to analyse potential sex disparities regarding the tolerability and effectiveness of lipid-lowering therapy in patients with and without reported statin intolerance who are being treated at a lipid-outpatient clinic., Methods: From 2017 to 2022, n = 1062 patients (n = 612 men, n = 450 women) at high-risk were referred to our lipid-outpatient clinic because of difficulties in lipid control by primary healthcare providers. The main therapeutic objective was to optimize lipid-lowering therapy according to current treatment guidelines., Results: Patients presented with high LDL-C baseline levels (4.97 ± 1.81 mmol/l (192 ± 70 mg/dL) in men and 5.46 ± 2.04 mmol/l (211 ± 79 mg/dL) in women). Intolerance towards statins was reported more frequently by women (48.2%) than by men (38.9%, p = 0.004). LDL-C continuously decreased with individual treatment adjustments across follow-up visits. In total, treatment goals (LDL < 1.4 mmol/l (< 55 mg/dl) or < 1.8 mmol/l (< 70 mg/dl)) were accomplished in 75.8% of men and 55.5% of women after the last follow-up visit (p < 0.0001). In men, these data are almost identical in subjects with statin intolerance. In contrast, treatment goals were reached less frequently in women with statin intolerance compared to women tolerant to statin therapy., Conclusion: Even if treated in a specialized lipid clinic, women are less likely to reach their target LDL-C than men, particularly when statin intolerant. Nevertheless, many patients with statin intolerance can be successfully treated using oral combination and PCSK9 inhibitor therapy. However, ongoing follow-up care to monitor progress and to adjust treatment plans is necessary to reach this goal., (© 2024. The Author(s).)

BACKGROUND Statin-induced myopathy can present with symptoms ranging from mild myalgia to significant muscle weakness. Muscle-related adverse effects of statins have been very challenging in clinical practice and they necessitate high clinical suspicion. This case report highlights how statin-induced autoimmune myopathy often goes undiagnosed. CASE REPORT We present a 69-year-old man with a past medical history of coronary artery disease who presented with myalgia and progressive proximal muscle weakness for 2 months, with a creatinine kinase of 8323 U/L. Atorvastatin was held on admission and the patient received intravenous (IV) fluid as treatment for presumed rhabdomyolysis. Although CK was trending down, he did not show significant improvement in muscle weakness or myalgia. At this point, myositis was suspected, so a myositis panel including anti-HMG Co-A reductase antibody was ordered and he was started on IV steroids. Anti-HMG Co-A reductase antibody was positive, and the rest of myopathy workup was negative. Meanwhile, the patient's muscle weakness significantly improved with IV steroid. He was discharged on methylprednisolone with close outpatient rheumatology follow-up. CONCLUSIONS Muscle-related adverse effects of statins, including rhabdomyolysis and myopathy, can fail to respond to conservative management. It is crucial to identify and manage statin-induced autoimmune myopathy as a possible differential diagnosis in patients with muscle weakness and elevated CK while on statin therapy who do not respond to intravenous fluid alone.

Statins are the first line of treatment for both primary and secondary prevention of atherosclerotic cardiovascular disease. Despite the positive effects of statins on cardiovascular events, not all patients can use them at an optimized dose. The reason for this is the skeletal muscle side effects, termed statin-associated muscle symptoms (SAMS). Despite extensive research, the precise pathophysiology of SAMS remains unclear and multiple mechanisms may contribute to this phenomenon. Various therapeutic options are available for the management of SAMS, ranging from rechallenging with the same or a different statin to utilizing non-statin therapeutic alternatives in patients intolerant to statins. However, the lack of consensus on the definition of SAMS, the absence of a definitive diagnostic test, and lack of a universally accepted management algorithm pose a great challenge in dealing with this entity. This review aims to explore the various pathophysiological mechanisms involved in SAMS and understand the difference between self-limited toxic myopathy and immune-mediated myopathy requiring immunomodulatory therapy. The conundrum of statin withdrawal, tapering, and rechallenge in SAMS will also be explored in detail along with the newer non-statin therapies that are available., (© 2024 The Author(s). International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Competing Interests: We declare no competing interests.

Background and Objectives: Immune-mediated necrotizing myopathy (IMNM) caused by antibodies against 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is an inflammatory myopathy that has been epidemiologically correlated with previous statin exposure. We characterized in detail a series of 11 young statin-naïve patients experiencing a chronic disease course mimicking a limb-girdle muscular dystrophy. With the hypothesis that HMGCR upregulation may increase immunogenicity and trigger the production of autoantibodies, our aim was to expand pathophysiologic knowledge of this distinct phenotype., Methods: Clinical and epidemiologic data, autoantibody titers, creatine kinase (CK) levels, response to treatment, muscle imaging, and muscle biopsies were assessed. HMGCR expression in patients' muscle was assessed by incubating sections of affected patients with purified anti-HMGCR+ serum. Whole-exome sequencing (WES) with a special focus on cholesterol biosynthesis-related genes and high-resolution human leukocyte antigen (HLA) typing were performed., Results: Patients, aged 3-25 years and mostly female (90.9%), presented with subacute proximal weakness progressing over many years and high CK levels (>1,000 U/L). Diagnostic delay ranged from 3 to 27 years. WES did not reveal any pathogenic variants. HLA-DRB1*11:01 carrier frequency was 60%, a significantly higher proportion than in the control population. No upregulation or mislocalization of the enzyme in statin-exposed or statin-naïve anti-HMGCR+ patients was observed, compared with controls., Discussion: WES of a cohort of patients with dystrophy-like anti-HMGCR IMNM did not reveal any common rare variants of any gene, including cholesterol biosynthesis-related genes. HLA analysis showed a strong association with HLA-DRB1*11:01, previously mostly described in statin-exposed adult patients; consequently, a common immunogenic predisposition should be suspected, irrespective of statin exposure. Moreover, we were unable to conclusively demonstrate muscle upregulation/mislocalization of HMGCR in IMNM, whether or not driven by statins.

Background: Antiplatelets and statins therapies are associated with improved cardiovascular outcomes following major vascular intervention. Many vascular surgery institutions are reporting improved prescribing rates for aspirin (ASA), P2Y12 antagonists, and statins. Nevertheless, there remains limited publication describing rates and patient-perceived barriers for postoperative adherence. The purpose of this study is to investigate patient nonadherence to antiplatelet and statin therapies following major vascular intervention., Methods: A retrospective review of patients who underwent major vascular intervention at a single academic center was performed. The prescribing rates of ASA, P2Y12 antagonists, and statins were reviewed. Postoperative adherence, defined as consistent intake as prescribed, was evaluated at 1, 3, 6, 9, and 12 months using electronic documentation of both follow-up clinic appointments and phone call assessments, then corroborated with pharmacy fulfilment records. Patient-reported barriers to medication adherence were also examined., Results: A total of 101 subjects underwent major vascular intervention between January 2020 and July 2020, 98% of whom were discharged on at least 1 antiplatelet or statin agent. Approximately 90% of patients were discharged with ASA, 32% with a P2Y12 antagonist, and 96% with a statin. All patients who maintained adherence up to 6 months continued to report adherence at 9 and 12 months. Consistent adherence at 12 months was documented in 76% of patients on ASA, 81% on P2Y12 antagonism therapy, and 73% on statins. New adverse drug reactions represented the most common barrier to achieving adherence (37% [n = 20]). Preoperative therapy with ASA, P2Y12 antagonists, and statins were all independently predictive of postoperative adherence to the same regimen (P ≤ 0.001). The female gender was also associated with higher rates of adherence to postoperative P2Y12 antagonism therapy (P ≤ 0.05)., Conclusions: The current prescribing rates for antiplatelet and statin agents are promising, but postoperative nonadherence remains a multifaceted issue., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Statin is crucial for acute myocardial infarction (AMI) patients. However, the risk of new-onset diabetes mellitus (NODM) associated with statin is a concern. This study aimed to determine the incremental diabetogenic effects of statins according to their intensity and dose in AMI patients undergoing percutaneous coronary intervention (PCI). Among 13,104 patients enrolled in the Korea AMI Registry between 2011 and 2015, 6152 patients without diabetes mellitus (DM) who underwent PCI and received moderate-to-high-intensity atorvastatin and rosuvastatin were selected for the study. The endpoints were NODM and major adverse cardiovascular events (MACE), composite of all-cause mortality, recurrent MI, and revascularization up to 3 years. Among the participants, 3747 and 2405 received moderate- and high-intensity statins, respectively. The Kaplan-Meier curves demonstrated a higher incidence of NODM in patients with high-intensity statins than those with moderate-intensity. High-intensity statin was a significant predictor of NODM after adjusting for other co-variables (HR = 1.316, 95% CI 1.024-1.692; P < 0.032). Higher dose of rosuvastatin was associated with a higher cumulative incidence of NODM, but this dose-dependency was not apparent with atorvastatin. Cumulative incidence of MACE decreased dose-dependently only with atorvastatin. High-intensity statin was associated with a higher cumulative incidence of NODM in AMI patients, and this association was more evident in rosuvastatin. The different diabetogenic effects of the two statins provide supporting evidence for understanding the nuanced nature of statin treatment in relation to NODM., (© 2024. The Author(s).)

Expression of Concern: I. Ramesh, J. C. Campos, P. Lee, Y. Song, G. Hernandez, J. Sin, K. C. Tucker, H. Saadaeijahromi, M. Gurney, J. C. B. Ferreira, and A. M. Andres, "Mitophagy Protects Against Statin-Mediated Skeletal Muscle Toxicity," The FASEB Journal 33, no. 11 (2019): 11857-11869, https://doi.org/10.1096/fj.201900807RR. This Expression of Concern is for the above article, published online on August 23, 2019, in Wiley Online Library (wileyonlinelibrary.com) and has been published by agreement between the journal Editor-in-Chief, Loren E. Wold; the Federation of American Societies for Experimental Biology; and Wiley Periodicals LLC. The Expression of Concern has been published due to concerns raised by a third party regarding a duplication between the COX-IV panel of Figure 3C and the COX-IV panel of Figure 5D. The authors have been informed about the concerns, but due to the time elapsed since publication, they could not provide the original raw data. Consequently, the journal team could not verify the validity of these figures describing different experimental conditions and could not exclude that these image duplications affect the overall conclusions of the article. Therefore, the journal has decided to issue an Expression of Concern to inform and alert the readers., (© 2024 Federation of American Societies for Experimental Biology.)

This study utilized Mendelian randomization (MR) analysis and genome-wide association study (GWAS) data to investigate the association between commonly prescribed drugs and bladder cancer (BLCA) risk. Our results revealed that HMG CoA reductase (HMGCR) inhibitors, specifically simvastatin, are significantly associated with reduced BLCA risk. We further showed that simvastatin could significantly inhibit BLCA proliferation and epithelial-mesenchymal transition in animal models, with transcriptomic data identifying several pathways associated with these processes. Higher expression of HMGCR were linked with BLCA development and progression, and certain blood lipids, such as lipoprotein particles and very low density lipoprotein (VLDL) cholesterol, might influence BLCA risk. These findings suggested that HMGCR inhibitors, particularly simvastatin, could be potential treatment options or adjuvant therapies for BLCA., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The impact of rosuvastatin versus atorvastatin on new-onset diabetes mellitus (NODM) among patients treated with high-intensity statin therapy for coronary artery disease (CAD) remains to be clarified. This study aimed to evaluate the risk of NODM in patients with CAD treated with rosuvastatin compared to atorvastatin in the randomized LODESTAR trial., Methods: In the LODESTAR trial, patients with CAD were randomly assigned to receive either rosuvastatin or atorvastatin using a 2-by-2 factorial randomization. In this post-hoc analysis, the 3-year incidence of NODM was compared between rosuvastatin and atorvastatin treatment in the as-treated population with high-intensity statin therapy as the principal population of interest., Results: Among 2932 patients without diabetes mellitus at baseline, 2377 were included in the as-treated population analysis. In the as-treated population with high-intensity statin therapy, the incidence of NODM was not significantly different between the rosuvastatin and atorvastatin groups (11.4% [106/948] versus 8.8% [73/856], hazard ratio [HR] = 1.32, 95% confidence interval [CI] = 0.98 to 1.77, P = 0.071). When the risk of NODM with rosuvastatin versus atorvastatin was assessed according to the achieved low-density lipoprotein cholesterol (LDL-C) level, the risk of NODM began to increase at a LDL-C level below 70 mg/dL. The incidence of NODM was significantly greater in the rosuvastatin group than it was in the atorvastatin group when the achieved LDL-C level was < 70 mg/dL (13.9% versus 8.0%; HR = 1.79, 95% CI 1.18 to 2.73, P = 0.007)., Conclusions: Among CAD patients receiving high-intensity statin therapy, the incidence of NODM was not significantly different between rosuvastatin and atorvastatin. However, a drug effect of the statin type on NODM was observed when the achieved LDL-C level was < 70 mg/dL., Trial Registration: ClinicalTrials.gov, Identifier: NCT02579499., (© 2024. The Author(s).)

Purpose: Statins are widely prescribed for cardiovascular diseases (CVD) prevention; however, a significant proportion of users discontinue the medication for various reasons. This review aimed to determine the prevalence of statin therapy discontinuation, its associated factors, and adverse cardiovascular outcomes within the first year of discontinuation., Methods: The PubMed, EMBASE, ScienceDirect, SCOPUS, and Google Scholar databases were systematically searched from their inception to December 2022. Manual searches were also conducted on the bibliographies of relevant articles. Studies were included for qualitative data synthesis and assessed for methodological quality., Results: Fifty-two studies, predominantly cohort studies (n = 38), involving 4 277 061 participants were included. The prevalence of statin discontinuation within the first year of statin initiation ranged from 0.8% to 70.5%, which was higher for primary prevention indications. Factors frequently associated with an increased likelihood of statin discontinuation included male sex, nonWhite ethnicity, smoking status, and being uninsured. Conversely, discontinuation was less likely in patients with CVD who received secondary prevention statin therapy and in patients with polypharmacy. Furthermore, age showed diverse and inconsistent relationships with statin discontinuation among various age categories. Five studies that reported the cardiovascular risk of statin discontinuation within the first year of initiation showed significantly increased risk of discontinuation, including all-cause mortality (hazard ratio: 1.36-3.65)., Conclusion: Our findings indicate a high prevalence of statin discontinuation and an increased likelihood of adverse cardiovascular outcomes within the first year of discontinuation, despite wide variability across published studies. This review highlights the importance of addressing the modifiable risk factors associated with statin discontinuation, such as smoking and lack of insurance coverage., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Introduction: Several interventions have been tested for cardio-protection against anthracycline-induced cancer therapy-related cardiovascular dysfunction (CTRCD). The role of statins in this setting remains unclear., Methods: We systematically searched PubMed, Embase, Cochrane Library, Clinicaltrials.gov, and Web of Science for randomized controlled trials (RCTs) comparing statins versus control (placebo or no intervention) for preventing anthracycline-induced CTRCD. We applied a random-effects model to pool risk ratios (RR) and mean differences (MD) with 95 % confidence intervals (CI)., Results: We included seven RCTs comprising 887 patients with planned chemotherapy with anthracycline-based regimens, of whom 49.8 % were randomized to statins. Relative to placebo, statins significantly reduced the incidence of cardiotoxicity/CTRCD (RR 0.46; 95 % CI 0.29 to 0.72; p < 0.001). The left ventricular end-systolic volume was also lower in patients treated with statin (MD -3.12 mL; 95 % CI -6.13 to -0.12 mL; p = 0.042). There was no significant difference between groups in post-anthracycline left ventricular ejection fraction (LVEF) overall., Conclusion: In this meta-analysis of RCTs, statins were significantly associated with a lower incidence of anthracycline-induced CTRCD and attenuated changes in the left ventricular end-systolic volume. Thus, our findings suggest that statins should be considered as a cardio-protection strategy for patients with planned anthracycline-based chemotherapy., (Copyright © 2024 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

The combined cilostazol and rosuvastatin therapy is frequently used for coronary artery disease treatment. This open-label, 3 × 3 crossover clinical trial evaluated the pharmacokinetics and safety of a fixed-dose combination (FDC) of cilostazol/rosuvastatin (200 + 20 mg) versus a concurrent administration of the separate components (SCs) under both fasted and fed conditions. Among 48 enrolled healthy adults, 38 completed the study. Participants were administered a single oral dose of cilostazol/rosuvastatin (200 + 20 mg), either as an FDC or SCs in a fasted state, or FDC in a fed state, in each period of the trial. Blood samples were taken up to 48 hours after dosing, and plasma concentrations were analyzed using validated liquid chromatography-tandem mass spectrometry. The geometric mean ratios of FDC to SCs for area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUC last ) and maximum plasma concentration (C max ) were 0.94/1.05 and 1.06/1.15 for cilostazol and rosuvastatin, respectively (AUC last /C max ). Compared with that during fasting, fed-state administration increased the AUC last and C max for cilostazol by approximately 72% and 160% and decreased these parameters for rosuvastatin by approximately 39% and 43%, respectively. To conclude, the FDC is bioequivalent to the SCs, with notable differences in pharmacokinetics when administered in a fed state. No significant safety differences were observed between the treatments., (© 2024, The American College of Clinical Pharmacology.)

Background and Objectives: Controversy exists regarding potential cancer risks associated with long-term statin use. This study aimed to use real-world data to investigate the association between cancer incidence and sustained statin use over a 10-year period., Methods: Using territory-wide public electronic medical records in Hong Kong, we emulated a sequence of nested target trials on patients who met indications for statin initiation in each calendar month from January 2009 to December 2011. Statin initiators and noninitiators were matched in a 1:1 ratio to mimic the randomization of eligible person-trials at baseline. Pooled logistic regression was applied to obtain the hazard ratios for the cancer incidence of statin initiation in intention-to-treat analysis, with the adjustment of baseline confounders and the inverse probability weighting accounting for the postbaseline confounders in per-protocol analysis., Results: Among 8,560,051 eligible person-trials, 119,715 noninitiators were matched to 119,715 initiators for analysis. Over the 10-year study period, the estimated hazard ratio of overall cancer incidence was 0.96 (0.87, 1.05), and the standardized 10-year risk difference was -0.4% (-1.3%, 0.4%) in the per-protocol analysis. For the cancer subtypes of interest (ie, breast cancer, colorectal cancer, hematological cancer, pancreatic cancer, prostate cancer, urothelial carcinoma, and lung cancer), the 10-year risk differences ranged from -0.3% to 0.2% in the per-protocol analysis. No observable risk change for cancer was found in all patient subgroups with regards to their sex, age (<70/≥70 years), Charlson Comorbidity Index (≤4/>4), and statin indication., Conclusion: Statin use has no impact on cancer incidence over a 10-year follow-up period, including all cancer subtypes of interest and patient subgroups with regards to sex, age, comorbidities, and statin indications., Competing Interests: Declaration of competing interest Eric Wan has received research grants from the Health Bureau of the Government of the Hong Kong SAR, the Hong Kong Research Grant Council, National Natural Science Foundation of China, outside the submitted work. Linda Chan has received research grants from the Health Bureau of the Government of the Hong Kong SAR and The University of Hong Kong. Wanchun Xu, Yuan Lu, and Goodarz Danaei report no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: In vitro investigations have established metformin's capacity to downregulate proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, suggesting a potential beneficial effect on atherogenic lipoprotein particles when combined with metformin therapy. Our objective was to assess whether metformin could mitigate statin-induced adverse effects on PCSK9, thereby improving lipid profiles in patients with coronary artery disease (CAD) but without diabetes. Employing an open-label, placebo-controlled, randomized trial, we randomized patients with CAD but without diabetes into CLA (cholesterol-lowering agents alone: atorvastatin ± ezetimibe, n = 38) and Met + CLA groups (metformin plus CLA, n = 33) in a 1:1 ratio. The primary end point was the therapeutic impact of 1-month metformin combination treatment on low-density lipoprotein cholesterol (LDL-C) and PCSK9 levels. Baseline LDL-C and PCSK9 levels were 76.18 mg·dL -1 and 80.54 ng·mL -1 , respectively. After 1 month, metformin significantly reduced LDL-C (-20.81%, P < 0.001), enabling 72% of patients to attain guideline-recommended LDL-C goals. Noteworthy reductions in PCSK9 levels (-15.03%, P < 0.001) were observed. Moreover, Met + CLA markedly reduced LDL particle number more than CLA alone (-10.65% vs. 1.45%, P = 0.009), primarily due to diminished small-dense LDL particle count. Mechanistically, our study demonstrated metformin's inhibition of statin-induced PCSK9 expression in human hepatocellular cells. In summary, a 1-month metformin combination regimen reduced LDL-C levels in patients with CAD but without diabetes by inhibiting PCSK9 expression., Trial Registration: Chinese Clinical Trial Registry identifier: ChiCTR1900026925 (26/10/2019)., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Hyperlipidemia is not uncommon in patients with hereditary myopathies who get older and also in several conditions in which it is frequently observed. Thus, using the common cholesterol reducing medications of the stains group could be considered. However, the side effects of these drugs include myalgia, myopathy and rhabdomyolysis typically associated with high serum creatine kinase (CK). Because high CK levels are very frequently found in hereditary myopathies, physicians are reluctant to use statins in such patients. Reviewing the literature about statin side effects in hereditary myopathies does not provide a clear evidence about the true risk of these drugs. This review critically describes the reported cases of statin side effects in several genetic myopathies and suggests some guidelines for conditions that are contra indicated for statin usage (particularly in mitochondrial disorders, metabolic myopathies, myotonic dystrophy type 2). Possible solutions to the dilemma of whether to use statins in hereditary myopathies are discussed (prescribing other cholesterol lowering agents and a carefully monitored treatment initiation of statins)., Competing Interests: Declaration of competing interest The Author has no conflict of interests to declare, (Copyright © 2024. Published by Elsevier B.V.)

Background: It remains controversial whether adding ezetimibe to low/moderate-intensity statins has a more beneficial impact on the treatment efficacy and safety of patients with existing atherosclerotic cardiovascular disease (ASCVD) compared to high-intensity statin regimens., Hypothesis: A combination of low/moderate-intensity statins plus ezetimibe might be more effective and safer than high-intensity statin monotherapy., Methods: We searched databases for randomized controlled trials comparing lipid profile alterations, drug-related adverse events, and MACE components between high-intensity statin monotherapy and low/moderate-intensity statin plus ezetimibe combination therapy. Pooled risk ratios (RR), mean differences (MD), and 95% confidence intervals (95% CI) were estimated using a random-effects model., Results: Our comprehensive search resulted in 32 studies comprising 6162 patients treated with monotherapy against 5880 patients on combination therapy. Combination therapy was more effective in reducing low-density lipoprotein cholesterol (LDL-C) levels compared to monotherapy (MD = -6.6, 95% CI: -10.6 to -2.5); however, no significant differences were observed in other lipid parameters. Furthermore, the combination therapy group experienced a lower risk of myalgia (RR = 0.27, 95% CI: 0.13-0.57) and discontinuation due to adverse events (RR = 0.61, 95% CI: 0.51-0.74). The occurrence of MACE was similar between the two treatment groups., Conclusions: Adding ezetimibe to low/moderate-intensity statins resulted in a greater reduction in LDL-C levels, a lower rate of myalgia, and less drug discontinuation compared to high-intensity statin monotherapy in patients with existing cardiovascular disease. However, according to our meta-analysis, the observed reduction in LDL-C levels in the combination group did not correlate with a reduction in MACE compared to the high-intensity statin group., (© 2024 The Author(s). Clinical Cardiology published by Wiley Periodicals, LLC.)

Statins were reported to have a potential effect of primary prevention of venous thromboembolism (VTE), although that of secondary prevention remains uncertain. To investigate the association between statins use and recurrent VTE in the current era. The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive VTE patients among 31 centers in Japan between January 2015 and August 2020. We divided the entire cohort into 2 groups according to statins use at the time of discharge; the statins (N = 865) and no statins groups (N = 4332). The statins group was older (72.9 vs. 66.7 years, P < 0.001), and less often had active cancer (22.0% vs. 30.4%, P < 0.001). The cumulative incidence of discontinuation of anticoagulation was significantly lower in the statins group (60.3% vs. 52.6%, Log-rank P < 0.001). The cumulative 5-year incidence of recurrent VTE was significantly lower in the statins group (6.8% vs. 10.1%, Log-rank P = 0.01). Even after adjusting for the confounders, the lower risk of the statins group relative to the no statins group remained significant for recurrent VTE (HR 0.65, 95% CI 0.45-0.91, P = 0.01). The cumulative 5-year incidence of major bleeding was significantly lower in the statins group (12.2% vs. 14.1%, Log-rank P = 0.04), although, after adjusting for the confounders, the risk of the statins group relative to the no statins group turned to be insignificant (HR 0.77, 95% CI 0.59-1.00, P = 0.054). In this large real-world VTE registry, statins use was significantly associated with a lower risk for the recurrent VTE in the current era., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Statin agents play a major role in secondary prevention after acute cerebral ischemia (ACI) events but are not indicated in all patients with ischemic stroke and transient ischemic attack. National guidelines recommend statins for patients with ACI of large or small vessel atherosclerotic origin and without these stroke mechanisms but coexisting coronary artery disease or primary prevention indications. The potential adverse effect burden of statin overuse in the remaining ACI patients have not been well delineated., Methods: Per Preferred Reporting Items of Systematic Reviews and Meta-Analyses guidelines, we performed systematic meta-analyses of: (1) statin randomized clinical trials to determine absolute risk increases for 6 major adverse events; (2) large clinical series to determine the proportion of ACI events due to large or small vessel atherosclerotic disease; and (3) the proportion of remaining patients with coronary artery disease/primary prevention statin indications., Results: For adverse effects, data were available from 63 randomized clinical trials enrolling 155 107 patients. Statin therapy was associated with an increased risk of the occurrence of 6 conditions: diabetes, myalgia or muscle weakness, myopathy, liver disease, renal insufficiency, and eye disease. Across 55 large series enrolling 53 501 patients, the rate of ACI due to large and small artery atherosclerosis was 45.0% (large artery atherosclerosis 21.6%, small vessel disease 23.4%), the rate of remaining patients with coronary artery disease/primary prevention statin indications was 31.8%, and the rate of patients without statin indications was 23.2%. Data synthesis indicated that, in the United States, were all patients with ACI without statin indications treated with statins, a total of 5601 patients would develop needless adverse events each year, most commonly diabetes, myopathy, and eye disease., Conclusions: More than one-fifth of patients with ACI do not have an indication for statins, and statin overuse in these patients could annually lead to over 5600 adverse events each year in the United States, including diabetes, myopathy, and eye disease. These findings emphasize the importance of adhering to guideline indications for the start of statin therapy in ACI., Competing Interests: Dr Saver reports receiving research support from the National Institutes of Health and the American Heart Association; receives contracted hourly payments from Medtronic, Stryker, Cerenovus, Boehringer Ingelheim, Roche, Genentech, Bayer, CSL Behring, Phillips Medical, and stock options or stock from Rapid Medical, MindRhythm, Argenx, Let’s Get Proof, NeuroMerit, and Neuronics for service on clinical trial steering, Data Safety and Monitoring Board, and other committees advising on rigorous trial design and conduct. The other author reports no conflict.

Elevated triglyceride levels are associated with an increased risk of cardiovascular events despite guideline-based statin treatment of low-density lipoprotein cholesterol. Peroxisome proliferator-activated receptor α (PPARα) agonists exert a significant triglyceride-lowering effect. However, combination therapy of PPARα agonists with statins poses an increased risk of rhabdomyolysis, which is rare but a major concern of the combination therapy. Pharmacokinetic interaction is suspected to be a contributing factor to the risk. To examine the potential for combination therapy with the selective PPARα modulator (SPPARMα) pemafibrate and statins, drug-drug interaction studies were conducted with open-label, randomized, 6-sequence, 3-period crossover designs for the combination of pemafibrate 0.2 mg twice daily and each of 6 statins once daily: pitavastatin 4 mg/day (n = 18), atorvastatin 20 mg/day (n = 18), rosuvastatin 20 mg/day (n = 29), pravastatin 20 mg/day (n = 18), simvastatin 20 mg/day (n = 20), and fluvastatin 60 mg/day (n = 19), involving healthy male volunteers. The pharmacokinetic parameters of pemafibrate and each of the statins were similar regardless of coadministration. There was neither an effect on the systemic exposure of pemafibrate nor a clinically important increase in the systemic exposure of any of the statins on the coadministration although the systemic exposure of simvastatin was reduced by about 15% and its open acid form by about 60%. The HMG-CoA reductase inhibitory activity in plasma samples from the simvastatin and pemafibrate combination group was about 70% of that in the simvastatin alone group. In conclusion, pemafibrate did not increase the systemic exposure of statins, and vice versa, in healthy male volunteers., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: High-intensity statin therapy is currently recommended initial guideline therapy in ACS treatment. However, only a minority of patients are achieving LDL-C attainment goal at 6 months. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are on recommended guideline therapy post-ACS if LDL-C goal attainment is not achieved after high-intensity statin (4-6 weeks) and after the addition of ezetimibe if guideline goal attainment is not achieved after an additional 4-6 weeks. Thus, it has been recommended that PCSK9 inhibitors be considered earlier post-ACS. However, the efficacy of early PCSK9 inhibitors initiation in ACS patients remains uncertain., Methods: This systematic review and meta-analysis was conducted following PRISMA guidelines. Randomized controlled trials (RCTs) and observational studies involving ACS patients who received PCSK9 inhibitors within 48 h of hospitalization were included. Common and random effects models were used to evaluate the pooled effect of early PCSK9 inhibitor administration. Nine RCTs and three cohort studies were included., Results: Early PCSK9 inhibitor administration reduced the incidence of MI, ACS hospitalization, and revascularization at 6-18 months post-ACS. Although there was a drift towards reduced stroke, all-cause mortality, and cardiovascular death, no statistically significant reduction was observed. Additionally, PCSK9 inhibitors significantly enhanced lipid control at 4-12 weeks after index hospitalization., Conclusion: Early PCSK9 inhibitors initiation in ACS patients reduces MACE and improves lipid profiles. While the results propose promising benefits in terms of stroke and mortality, further research with longer follow-up is required for more decisive evidence., (© 2024. The Author(s).)

Objective: Statins have anti-inflammatory and immune-modulatory effects which could alter the risk of rheumatoid arthritis (RA). We reviewed published literature and conducted a meta-analysis to examine if statins have an impact on the risk of RA., Methods: Case-control studies, cohort studies, or randomized controlled trials (RCT) published on the PubMed, Scopus, and EMBASE databases up to 30th October 2023 were searched. The association between statin use and risk of RA was pooled in a random-effects meta-analysis., Results: Nine studies (four cohort, four case-control, and one RCT) were included. Overall, the analysis failed to note an association between the use of statins and the risk of RA with the pooled OR being 0.93 (95% CI 0.82, 1.06). High heterogeneity was noted with I2 = 75%. Results were consistent across study types with no association noted between prior statin use and risk of RA in case-control studies (OR: 0.88 95% CI: 0.69, 1.13), cohort studies (OR: 1.01 95% CI: 0.92, 1.10), and the lone RCT (OR: 1.40 95% CI: 0.50, 3.92)., Conclusion: Current literature shows that there is no association between the use of statins and the risk of RA. Further rigorous studies taking into account patient factors, duration of statin exposure, and other confounders are needed to generate better evidence., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Pan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)