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Terry A. Jacobson - One of the best experts on this subject based on the ideXlab platform.
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Safety and Efficacy of Statin Therapy
Nature reviews. Cardiology, 2018Co-Authors: Bhavin B. Adhyaru, Terry A. JacobsonAbstract:The 2013 ACC/AHA guidelines on blood cholesterol management were a major shift in the delineation of the main patient groups that could benefit from Statin therapy and emphasized the use of higher-intensity Statin therapies. In 2016, an expert consensus panel from the ACC recommended the use of nonStatin therapies (ezetimibe and PCSK9 inhibitors) in addition to maximally tolerated Statin therapy in individuals whose LDL-cholesterol and non-HDL-cholesterol levels remained above certain thresholds after Statin treatment. Given the substantial benefits of Statin therapies in both primary and secondary prevention of cardiovascular disease, their long-term safety has become a concern. The potential harmful effects of Statin therapy on muscle and liver have been known for some time, but new concerns have emerged regarding the risk of new-onset diabetes mellitus, cognitive impairment and haemorrhagic stroke associated with the use of Statins and the risks of achieving very low levels of LDL cholesterol. The increased media attention on the adverse events associated with Statins has unfortunately led to Statin therapy discontinuation, nonadherence to therapy or concerns about initiating Statin therapy. In this Review, we explore the safety of Statin therapy in light of the latest evidence and provide clinicians with reassurance about the safety of Statins. Overwhelming evidence suggests that the benefits of Statin therapy far outweigh any real or perceived risks.
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Evidence-Based Management of Statin Myopathy
Current Atherosclerosis Reports, 2010Co-Authors: Charles R. Harper, Terry A. JacobsonAbstract:Statin-associated muscle symptoms are a relatively common condition that may affect 10% to 15% of Statin users. Statin myopathy includes a wide spectrum of clinical conditions, ranging from mild myalgia to rhabdomyolysis. The etiology of myopathy is multifactorial. Recent studies suggest that Statins may cause myopathy by depleting isoprenoids and interfering with intracellular calcium signaling. Certain patient and drug characteristics increase risk for Statin myopathy, including higher Statin doses, Statin cytochrome metabolism, and polypharmacy. Genetic risk factors have been identified, including a single nucleotide polymorphism of SLCO1B1 . Coenzyme Q10 and vitamin D have been used to prevent and treat Statin myopathy; however, clinical trial evidence demonstrating their efficacy is limited. Statin-intolerant patients may be successfully treated with either low-dose Statins, alternate-day dosing, or using twice-weekly dosing with longer half-life Statins. An algorithm is presented to assist the clinician in managing myopathy in patients with dyslipidemia.
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toward pain free Statin prescribing clinical algorithm for diagnosis and management of myalgia
Mayo Clinic Proceedings, 2008Co-Authors: Terry A. JacobsonAbstract:Myalgia, which often manifests as pain or soreness in skeletal muscles, is among the most salient adverse events associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (Statins). Clinical issues related to Statin-associated myotoxicity include (1) incidence in randomized controlled trials and occurrence in postmarketing surveillance databases; (2) potential differences between Statins in their associations with such adverse events; and (3) diagnostic and treatment strategies to prevent, recognize, and manage these events. Data from systematic reviews, meta-analyses, clinical and observational trials, and postmarketing surveillance indicate that Statin-associated myalgia typically affects approximately 5.0% of patients, as myopathy in 0.1% and as rhabdomyolysis in 0.01%. However, studies also suggest that myalgia is among the leading reasons patients discontinue Statins (particularly high-dose Statin monotherapy) and that treatment with certain Statins (eg, fluvaStatin) is unlikely to result in such adverse events. This review presents a clinical algorithm for monitoring and managing Statin-associated myotoxicity. The algorithm highlights risk factors for muscle toxicity and provides recommendations for (1) creatine kinase measurements and monitoring; (2) Statin dosage reduction, discontinuation, and rechallenge; and (3) treatment alternatives, such as extended-release fluvaStatin with or without ezetimibe, low-dose or alternate-day rosuvaStatin, or ezetimibe with or without colesevelam. The algorithm should help to inform and enhance patient care and reduce the risk of myalgia and other potentially treatment-limiting muscle effects that might undermine patient adherence and compromise the overall cardioprotective benefits of Statins.
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Statin safety: lessons from new drug applications for marketed Statins.
The American journal of cardiology, 2006Co-Authors: Terry A. JacobsonAbstract:Safety has become a central issue in the management of dyslipidemia with Statins. A review of New Drug Applications (NDAs) and the US Food and Drug Administration (FDA) Web site was conducted for all 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or Statins, with a major focus on cerivaStatin and rosuvaStatin. The findings provide insight into the incidence of adverse events for this class of drugs and support the significant benefits of Statins relative to associated risks. These data delineate the nature of Statin associated liver, muscle, and renal adverse events. Although transaminase levels increase in a dose-related fashion with Statins, a definitive correlation between Statin therapy and hepatotoxicity is not supported by Statin NDA data. Statin-induced myopathy is a relatively rare event (1 in 1,000) and rhabdomyolysis is even rarer (1 in 10,000). The cerivaStatin NDA, along with its supplementary NDA, was the first to demonstrate a clear Statin dose-response relation with myopathy and a threshold effect above which myotoxicity increases significantly. Proteinuria was identified as a consequence of Statin therapy with data from the rosuvaStatin NDA, and subsequent analysis suggests a class effect that is dose related but transient. Studies in cell culture suggest the mechanism is a pharmacologic effect on the proximal renal tubule. The available evidence suggests no clear renal toxicity with currently approved Statins, because no declines in renal function or glomerular filtration rate have been documented over time. Overall, currently marketed Statins have a very favorable benefit-to-risk relation with respect to liver, muscle, and renal issues.
George D. Giannoglou - One of the best experts on this subject based on the ideXlab platform.
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Risk Factors and Drug Interactions Predisposing to Statin-Induced Myopathy
Drug Safety, 2010Co-Authors: Yiannis S. Chatzizisis, Konstantinos C. Koskinas, Gesthimani Misirli, Chris Vaklavas, Apostolos Hatzitolios, George D. GiannoglouAbstract:HMG-CoA reductase inhibitors (‘Statins’) represent the most effective and widely prescribed drugs currently available for the reduction of low-density lipoprotein cholesterol, a critical therapeutic target for primary and secondary prevention of cardiovascular atherosclerotic disease. In the face of the established lipid lowering and the emerging pleiotropic properties of Statins, the patient population suitable for long-term Statin treatment is expected to further expand. An overall positive safety and tolerability profile of Statins has been established, although adverse events have been reported. Skeletal muscle-related events are the most common adverse events of Statin treatment. Statin-induced myopathy can (rarely) manifest with severe and potentially fatal cases of rhabdomyolysis, thus rendering the identification of the underlying predisposing factors critical. The purpose of this review is to summarize the factors that increase the risk of Statin-related myopathy. Data from published clinical trials, meta-analyses, postmarketing studies, spontaneous report systems and case reports for rare effects were reviewed. Briefly, the epidemiology, clinical spectrum and molecular mechanisms of Statin-associated myopathy are discussed. We further analyse in detail the risk factors that precipitate or increase the likelihood of Statin-related myopathy. Individual demographic features, genetic factors and co-morbidities that may account for the significant inter-individual variability in the myopathic risk are presented. Physicochemical properties of Statins have been implicated in the differential risk of currently marketed Statins. Pharmacokinetic interactions with concomitant medications that interfere with Statin metabolism and alter their systemic bioavailability are reviewed. Of particular clinical interest in cases of resistant dyslipidaemia is the interaction of Statins with other classes of lipid-lowering agents; current data on the relative safety of available combinations are summarized. Finally, we provide an update of current guidelines for the prevention and management of Statin myopathy. The identification of patients with an increased proclivity to Statin-induced myopathy could allow more cost-effective approaches of monitoring and screening, facilitate targeted prevention of potential complications, and further improve the already overwhelmingly positive benefit-risk ratio of Statins.
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risk factors and drug interactions predisposing to Statin induced myopathy implications for risk assessment prevention and treatment
Drug Safety, 2010Co-Authors: Yiannis S. Chatzizisis, Konstantinos C. Koskinas, Gesthimani Misirli, Chris Vaklavas, Apostolos Hatzitolios, George D. GiannoglouAbstract:HMG-CoA reductase inhibitors (‘Statins’) represent the most effective and widely prescribed drugs currently available for the reduction of low-density lipoprotein cholesterol, a critical therapeutic target for primary and secondary prevention of cardiovascular atherosclerotic disease. In the face of the established lipid lowering and the emerging pleiotropic properties of Statins, the patient population suitable for long-term Statin treatment is expected to further expand. An overall positive safety and tolerability profile of Statins has been established, although adverse events have been reported. Skeletal muscle-related events are the most common adverse events of Statin treatment. Statin-induced myopathy can (rarely) manifest with severe and potentially fatal cases of rhabdomyolysis, thus rendering the identification of the underlying predisposing factors critical.
Marcella A Evans - One of the best experts on this subject based on the ideXlab platform.
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Statin Adverse Effects
American Journal of Cardiovascular Drugs, 2008Co-Authors: Beatrice A Golomb, Marcella A EvansAbstract:HMG-CoA reductase inhibitors (Statins) are a widely used class of drug, and like all medications, have potential for adverse effects (AEs). Here we review the Statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the Statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with Statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with Statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase Statin potency, often through inhibition of the cytochrome P450 3A4 system. An array of additional risk factors for Statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with Statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many nonmuscle Statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional Statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of Statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.
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Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism.
American journal of cardiovascular drugs : drugs devices and other interventions, 2008Co-Authors: Beatrice A Golomb, Marcella A EvansAbstract:HMG-CoA reductase inhibitors (Statins) are a widely used class of drug, and like all medications, have potential for adverse effects (AEs). Here we review the Statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the Statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with Statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with Statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase Statin potency, often through inhibition of the cytochrome P450 3A4 system. An array of additional risk factors for Statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with Statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many nonmuscle Statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional Statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of Statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.
Paul D. Thompson - One of the best experts on this subject based on the ideXlab platform.
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Statin-Associated Side Effects
Journal of the American College of Cardiology, 2016Co-Authors: Paul D. Thompson, Gregory A. Panza, Amanda L. Zaleski, Beth A. TaylorAbstract:Hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors or Statins are well tolerated, but associated with various Statin-associated symptoms (SAS), including Statin-associated muscle symptoms (SAMS), diabetes mellitus (DM), and central nervous system complaints. These are "Statin-associated symptoms" because they are rare in clinical trials, making their causative relationship to Statins unclear. SAS are, nevertheless, important because they prompt dose reduction or discontinuation of these life-saving mediations. SAMS is the most frequent SAS, and mild myalgia may affect 5% to 10% of Statin users. Clinically important muscle symptoms, including rhabdomyolysis and Statin-induced necrotizing autoimmune myopathy (SINAM), are rare. Antibodies against HMG-CoA reductase apparently provoke SINAM. Good evidence links Statins to DM, but evidence linking Statins to other SAS is largely anecdotal. Management of SAS requires making the possible diagnosis, altering or discontinuing the Statin treatment, and using alternative lipid-lowering therapy.
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Statin associated muscle symptoms impact on Statin therapy european atherosclerosis society consensus panel statement on assessment aetiology and management
European Heart Journal, 2015Co-Authors: E S G Stroes, Paul D. Thompson, Alberto Corsini, Georgirene D Vladutiu, Frederick J Raal, Michael Roden, Evan A Stein, Lale Tokgozoglu, Borge G Nordestgaard, Eric BruckertAbstract:Statin-associated muscle symptoms (SAMS) are one of the principal reasons for Statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of Statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of Statins, affecting 1 per 1000 to 1 per 10 000 people on standard Statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7–29% in registries and observational studies. Preclinical studies show that Statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between Statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of Statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive Statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated Statin dose combined with non-Statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different Statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.
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Statin and exercise prescription
Lancet (London England), 2013Co-Authors: Thijs M.h. Eijsvogels, Beth A. Parker, Paul D. ThompsonAbstract:Peter Kokkinos and colleagues (Feb 2, p 394) describe the interactive eff ects of fi tness and Statins on mortality risk in veterans with dyslipidaemia. They report that increasing physical activity and Statins independently lowers lipid levels and total mortality, but that the combination of these interventions is superior to either alone. The authors conclude that prescription of physical activity is as important as prescribing Statins in groups with increased cardiovascular risk. Physically active individuals might have the best cardiovascular risk profi le, but they might be more vulnerable to the skeletal muscle side-eff ects of Statins. Sinzinger and O’Grady reported Statin intolerance in elite soccer players, and the PRIMO study reported a higher incidence of Statin induced myalgia in subjects performing intense sports. We have reported previously that Statins magnify the increase in serum creatine kinase produced by exercise. Consequently physicians must weight relative benefi ts of physical activity and Statins in active individuals. Physical activity could produce greater risk reduction than Statins. The signifi cant eff ect of physical activity and Statins on cardiovascular risk reduction emphasises the importance of determination of the causes and treatment of Statin-induced myopathy, and the need for lipidlowering agents that do not aff ect skeletal muscle.
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Statin associated myopathy
JAMA, 2003Co-Authors: Paul D. Thompson, Priscilla M Clarkson, Richard H KarasAbstract:Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are associated with skeletal muscle complaints, including clinically important myositis and rhabdomyolysis, mild serum creatine kinase (CK) elevations, myalgia with and without elevated CK levels, muscle weakness, muscle cramps, and persistent myalgia and CK elevations after Statin withdrawal. We performed a literature review to provide a clinical summary of Statin-associated myopathy and discuss possible mediating mechanisms. We also update the US Food and Drug Administration (FDA) reports on Statin-associated rhabdomyolysis. Articles on Statin myopathy were identified via a PubMed search through November 2002 and articles on Statin clinical trials, case series, and review articles were identified via a PubMed search through January 2003. Adverse event reports of Statin-associated rhabdomyolysis were also collected from the FDA MEDWATCH database. The literature review found that reports of muscle problems during Statin clinical trials are extremely rare. The FDA MEDWATCH Reporting System lists 3339 cases of Statin-associated rhabdomyolysis reported between January 1, 1990, and March 31, 2002. CerivaStatin was the most commonly implicated Statin. Few data are available regarding the frequency of less-serious events such as muscle pain and weakness, which may affect 1% to 5% of patients. The risk of rhabdomyolysis and other adverse effects with Statin use can be exacerbated by several factors, including compromised hepatic and renal function, hypothyroidism, diabetes, and concomitant medications. Medications such as the fibrate gemfibrozil alter Statin metabolism and increase Statin plasma concentration. How Statins injure skeletal muscle is not clear, although recent evidence suggests that Statins reduce the production of small regulatory proteins that are important for myocyte maintenance.
Yiannis S. Chatzizisis - One of the best experts on this subject based on the ideXlab platform.
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Risk Factors and Drug Interactions Predisposing to Statin-Induced Myopathy
Drug Safety, 2010Co-Authors: Yiannis S. Chatzizisis, Konstantinos C. Koskinas, Gesthimani Misirli, Chris Vaklavas, Apostolos Hatzitolios, George D. GiannoglouAbstract:HMG-CoA reductase inhibitors (‘Statins’) represent the most effective and widely prescribed drugs currently available for the reduction of low-density lipoprotein cholesterol, a critical therapeutic target for primary and secondary prevention of cardiovascular atherosclerotic disease. In the face of the established lipid lowering and the emerging pleiotropic properties of Statins, the patient population suitable for long-term Statin treatment is expected to further expand. An overall positive safety and tolerability profile of Statins has been established, although adverse events have been reported. Skeletal muscle-related events are the most common adverse events of Statin treatment. Statin-induced myopathy can (rarely) manifest with severe and potentially fatal cases of rhabdomyolysis, thus rendering the identification of the underlying predisposing factors critical. The purpose of this review is to summarize the factors that increase the risk of Statin-related myopathy. Data from published clinical trials, meta-analyses, postmarketing studies, spontaneous report systems and case reports for rare effects were reviewed. Briefly, the epidemiology, clinical spectrum and molecular mechanisms of Statin-associated myopathy are discussed. We further analyse in detail the risk factors that precipitate or increase the likelihood of Statin-related myopathy. Individual demographic features, genetic factors and co-morbidities that may account for the significant inter-individual variability in the myopathic risk are presented. Physicochemical properties of Statins have been implicated in the differential risk of currently marketed Statins. Pharmacokinetic interactions with concomitant medications that interfere with Statin metabolism and alter their systemic bioavailability are reviewed. Of particular clinical interest in cases of resistant dyslipidaemia is the interaction of Statins with other classes of lipid-lowering agents; current data on the relative safety of available combinations are summarized. Finally, we provide an update of current guidelines for the prevention and management of Statin myopathy. The identification of patients with an increased proclivity to Statin-induced myopathy could allow more cost-effective approaches of monitoring and screening, facilitate targeted prevention of potential complications, and further improve the already overwhelmingly positive benefit-risk ratio of Statins.
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risk factors and drug interactions predisposing to Statin induced myopathy implications for risk assessment prevention and treatment
Drug Safety, 2010Co-Authors: Yiannis S. Chatzizisis, Konstantinos C. Koskinas, Gesthimani Misirli, Chris Vaklavas, Apostolos Hatzitolios, George D. GiannoglouAbstract:HMG-CoA reductase inhibitors (‘Statins’) represent the most effective and widely prescribed drugs currently available for the reduction of low-density lipoprotein cholesterol, a critical therapeutic target for primary and secondary prevention of cardiovascular atherosclerotic disease. In the face of the established lipid lowering and the emerging pleiotropic properties of Statins, the patient population suitable for long-term Statin treatment is expected to further expand. An overall positive safety and tolerability profile of Statins has been established, although adverse events have been reported. Skeletal muscle-related events are the most common adverse events of Statin treatment. Statin-induced myopathy can (rarely) manifest with severe and potentially fatal cases of rhabdomyolysis, thus rendering the identification of the underlying predisposing factors critical.
