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    Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Cannon Christopher P,Cariou Bertrand,Blom Dirk,McKenney James M,Lorenzato Christelle,Pordy Robert,Chaudhari Umesh,Colhoun Helen M, European heart journal AIMS:To compare the efficacy [low-density lipoprotein cholesterol (LDL-C) lowering] and safety of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin 9, compared with ezetimibe, as add-on therapy to maximally tolerated statin therapy in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia. METHODS AND RESULTS:COMBO II is a double-blind, double-dummy, active-controlled, parallel-group, 104-week study of alirocumab vs. ezetimibe. Patients (n = 720) with high cardiovascular risk and elevated LDL-C despite maximal doses of statins were enrolled (August 2012-May 2013). This pre-specified analysis was conducted after the last patient completed 52 weeks. Patients were randomized to subcutaneous alirocumab 75 mg every 2 weeks (plus oral placebo) or oral ezetimibe 10 mg daily (plus subcutaneous placebo) on a background of statin therapy. At Week 24, mean ± SE reductions in LDL-C from baseline were 50.6 ± 1.4% for alirocumab vs. 20.7 ± 1.9% for ezetimibe (difference 29.8 ± 2.3%; P < 0.0001); 77.0% of alirocumab and 45.6% of ezetimibe patients achieved LDL-C <1.8 mmol/L (P < 0.0001). Mean achieved LDL-C at Week 24 was 1.3 ± 0.04 mmol/L with alirocumab and 2.1 ± 0.05 mmol/L with ezetimibe, and were maintained to Week 52. Alirocumab was generally well tolerated, with no evidence of an excess of treatment-emergent adverse events. CONCLUSION:In patients at high cardiovascular risk with inadequately controlled LDL-C, alirocumab achieved significantly greater reductions in LDL-C compared with ezetimibe, with a similar safety profile. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT01644188. 10.1093/eurheartj/ehv028
    ACP Journal Club. Review: Statins do not increase adverse cognitive effects in patients with or without initial cognitive impairment. Belknap Steven M Annals of internal medicine 10.7326/ACPJC-2015-162-10-006
    Muscular adverse effects are common with statins. Gøtzsche Peter C BMJ (Clinical research ed.) 10.1136/bmj.g3724
    (Mis)interpreting studies on the adverse effects of statins. Zhang Huabing,Plutzky Jorge,Turchin Alexander BMJ (Clinical research ed.) 10.1136/bmj.g3652
    Adverse Effects of Statins. Goldstein Larry B JAMA 10.1001/jama.2017.0142
    Adverse Effects of Statins-Reply. Thompson Paul D JAMA 10.1001/jama.2017.0154
    Adverse Effects of Statins. Malachowski Stephen J,Quattlebaum Alexander M,Miladinovic Branko JAMA 10.1001/jama.2017.0148
    Results of investigation into statin side effects due by end of year. Hawkes Nigel BMJ (Clinical research ed.) 10.1136/bmj.h957
    Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. Sullivan David,Olsson Anders G,Scott Rob,Kim Jae B,Xue Allen,Gebski Val,Wasserman Scott M,Stein Evan A JAMA CONTEXT:An estimated 10% to 20% of patients cannot tolerate statins or adequate doses to achieve treatment goals. Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, promoting their degradation and increasing LDL cholesterol levels. In phase 1 studies, a human monoclonal antibody to PCSK9, AMG145, was well tolerated and reduced LDL cholesterol levels. OBJECTIVE:To assess the efficacy and tolerability of AMG145 in patients with statin intolerance due to muscle-related side effects. DESIGN, SETTING, AND PATIENTS:A 12-week, randomized, double-blind, placebo- and ezetimibe-controlled, dose-ranging study conducted between July 2011 and May 2012 in statin-intolerant adult patients at 33 international sites. INTERVENTION:Patients were randomized equally to 1 of 5 groups: AMG145 alone at doses of 280 mg, 350 mg, or 420 mg; AMG145 at 420 mg plus 10 mg of ezetimibe; or 10 mg of ezetimibe plus placebo. AMG145 or placebo was administered subcutaneously every 4 weeks. MAIN OUTCOME MEASURES:The primary end point was percentage change from baseline to week 12 in ultracentrifugation-measured LDL cholesterol. Other end points included measures of safety and tolerability of different doses of AMG145 and AMG145 plus ezetimibe. RESULTS:Of 236 patients screened, 160 were randomized (mean age, 62 years; 64% female; mean baseline LDL cholesterol, 193 mg/dL); all patients had intolerance to 1 or more statins because of muscle-related events. At week 12, mean changes in LDL cholesterol levels were -67 mg/dL (-41%; 95% CI, -49% to -33%) for the AMG145, 280-mg, group; -70 mg/dL (-43%; 95% CI, -51% to -35%) for the 350-mg group; -91 mg/dL (-51%; 95% CI, -59% to -43%) for the 420-mg group; and -110 mg/dL (-63%; 95% CI, -71% to -55%) for the 420-mg/ezetimibe group compared with -14 mg/dL (-15%; 95% CI, -23% to -7.0%) for the placebo/ezetimibe group (P < .001). Four serious adverse events were reported with AMG145 (coronary artery disease, acute pancreatitis, hip fracture, syncope). Myalgia was the most common treatment-emergent adverse event during the study, occurring in 5 patients (15.6%) in the 280-mg group (n = 32); 1 patient (3.2%) in the 350-mg group (n = 31), 1 patient (3.1%) in the 420-mg group (n = 32), 6 patients (20.0%) receiving 420-mg AMG145/ezetimibe, and 1 patient (3.1%) receiving placebo/ezetimibe. CONCLUSION:In this phase 2 study in statin-intolerant patients, subcutaneous administration of a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels and was associated with short-term tolerability. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01375764. 10.1001/jama.2012.25790
    Effect of Loading Dose of Atorvastatin Prior to Planned Percutaneous Coronary Intervention on Major Adverse Cardiovascular Events in Acute Coronary Syndrome: The SECURE-PCI Randomized Clinical Trial. Berwanger Otavio,Santucci Eliana Vieira,de Barros E Silva Pedro Gabriel Melo,Jesuíno Isabella de Andrade,Damiani Lucas Petri,Barbosa Lilian Mazza,Santos Renato Hideo Nakagawa,Laranjeira Ligia Nasi,Egydio Flávia de Mattos,Borges de Oliveira Juliana Aparecida,Dall Orto Frederico Toledo Campo,Beraldo de Andrade Pedro,Bienert Igor Ribeiro de Castro,Bosso Carlos Eduardo,Mangione José Armando,Polanczyk Carisi Anne,Sousa Amanda Guerra de Moraes Rego,Kalil Renato Abdala Karam,Santos Luciano de Moura,Sposito Andrei Carvalho,Rech Rafael Luiz,Sousa Antônio Carlos Sobral,Baldissera Felipe,Nascimento Bruno Ramos,Giraldez Roberto Rocha Corrêa Veiga,Cavalcanti Alexandre Biasi,Pereira Sabrina Bernardez,Mattos Luiz Alberto,Armaganijan Luciana Vidal,Guimarães Hélio Penna,Sousa José Eduardo Moraes Rego,Alexander John Hunter,Granger Christopher Bull,Lopes Renato Delascio, JAMA Importance:The effects of loading doses of statins on clinical outcomes in patients with acute coronary syndrome (ACS) and planned invasive management remain uncertain. Objective:To determine if periprocedural loading doses of atorvastatin decrease 30-day major adverse cardiovascular events (MACE) in patients with ACS and planned invasive management. Design, Setting, and Participants:Multicenter, double-blind, placebo-controlled, randomized clinical trial conducted at 53 sites in Brazil among 4191 patients with ACS evaluated with coronary angiography to proceed with a percutaneous coronary intervention (PCI) if anatomically feasible. Enrollment occurred between April 18, 2012, and October 6, 2017. Final follow-up for 30-day outcomes was on November 6, 2017. Interventions:Patients were randomized to receive 2 loading doses of 80 mg of atorvastatin (n = 2087) or matching placebo (n = 2104) before and 24 hours after a planned PCI. All patients received 40 mg of atorvastatin for 30 days starting 24 hours after the second dose of study medication. Main Outcomes and Measures:The primary outcome was MACE, defined as a composite of all-cause mortality, myocardial infarction, stroke, and unplanned coronary revascularization through 30 days. Results:Among the 4191 patients (mean age, 61.8 [SD, 11.5] years; 1085 women [25.9%]) enrolled, 4163 (99.3%) completed 30-day follow-up. A total of 2710 (64.7%) underwent PCI, 333 (8%) underwent coronary artery bypass graft surgery, and 1144 (27.3%) had exclusively medical management. At 30 days, 130 patients in the atorvastatin group (6.2%) and 149 in the placebo group (7.1%) had a MACE (absolute difference, 0.85% [95% CI, -0.70% to 2.41%]; hazard ratio, 0.88; 95% CI, 0.69-1.11; P = .27). No cases of hepatic failure were reported; 3 cases of rhabdomyolysis were reported in the placebo group (0.1%) and 0 in the atorvastatin group. Conclusions and Relevance:Among patients with ACS and planned invasive management with PCI, periprocedural loading doses of atorvastatin did not reduce the rate of MACE at 30 days. These findings do not support the routine use of loading doses of atorvastatin among unselected patients with ACS and intended invasive management. Trial Registration:clinicaltrials.gov Identifier: NCT01448642. 10.1001/jama.2018.2444
    Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network. Russo Mark W,Hoofnagle Jay H,Gu Jiezhun,Fontana Robert J,Barnhart Huiman,Kleiner David E,Chalasani Naga,Bonkovsky Herbert L Hepatology (Baltimore, Md.) UNLABELLED:The HMG-CoA reductase inhibitors (statins) are widely prescribed for patients with hyperlipidemia and are generally well tolerated. Mild elevations in serum aminotransferases arise in up to 3% of treated patients, but clinically apparent drug-induced liver injury is rare. The aim of this study is to report the presenting features and outcomes of 22 patients with clinically apparent liver injury due to statins. Among 1,188 cases of drug-induced liver injury enrolled between 2004 and 2012 in a prospective registry by the U.S. Drug Induced Liver Injury Network, 22 were attributed to a statin. All patients were evaluated in a standard fashion and followed for at least 6 months after onset. The median age was 60 years (range 41-80), and 15 (68%) were female. The latency to onset of liver injury ranged from 34 days to 10 years (median = 155 days). Median peak levels were alanine aminotransferase 892 U/L, alkaline phosphatase 358 U/L, and total bilirubin 6.1 mg/dL. Nine patients presented with cholestatic hepatitis and 12 patients presented with hepatocellular injury, of which six had an autoimmune phenotype. Nine patients were hospitalized, four developed evidence of hepatic failure, and one died. All commonly used statins were implicated. Four patients developed chronic liver injury, of which three had an autoimmune phenotype of liver injury. CONCLUSION:Drug-induced liver injury from statins is rare and characterized by variable patterns of injury, a range of latencies to onset, autoimmune features in some cases, and persistent or chronic injury in 18% of patients, most of whom have an autoimmune phenotype. 10.1002/hep.27157
    Synergistic interaction between genetics and disease on pravastatin disposition. Clarke John D,Hardwick Rhiannon N,Lake April D,Lickteig Andrew J,Goedken Michael J,Klaassen Curtis D,Cherrington Nathan J Journal of hepatology BACKGROUND & AIMS:A genome wide association study and multiple pharmacogenetic studies have implicated the hepatic uptake transporter organic anion transporting polypeptide-1B1 (OATP1B1) in the pharmacokinetics and musculoskeletal toxicity of statin drugs. Other OATP uptake transporters can participate in the transport of pravastatin, partially compensating for the loss of OATP1B1 in patients carrying the polymorphism. Non-alcoholic steatohepatitis (NASH) in humans and in a diet-induced rodent model alter the expression of multiple OATP transporters. METHODS:To determine how genetic alteration in one Oatp transporter can interact with NASH-associated changes in Oatp expression we measured the disposition of intravenously administered pravastatin in Slco1b2 knockout (Slco1b2(-/-)) and wild-type (WT) mice fed either a control or a methionine and choline deficient (MCD) diet to induce NASH. RESULTS:Genetic loss of Oatp1b2, the rodent ortholog of human OATP1B transporters, caused a modest increase in pravastatin plasma concentrations in mice with healthy livers. Although a diet-induced model of NASH decreased the expression of multiple hepatic Oatp transporters, it did not alter the disposition of pravastatin compared to WT control mice. In contrast, the combination of NASH-associated decrease in compensatory Oatp transporters and Oatp1b2 genetic loss caused a synergistic increase in plasma area under the curve (AUC) and tissue concentrations in kidney and muscle. CONCLUSIONS:Our data show that NASH alters the expression of multiple hepatic uptake transporters which, due to overlapping substrate specificity among the OATP transporters, may combine with the pharmacogenetic loss of OATP1B1 to increase the risk of statin-induced adverse drug reactions. 10.1016/j.jhep.2014.02.021
    Statin-associated muscle symptoms: beware of the nocebo effect. Pedro-Botet Juan,Rubiés-Prat Juan Lancet (London, England) 10.1016/S0140-6736(17)31163-7
    HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Swerdlow Daniel I,Preiss David,Kuchenbaecker Karoline B,Holmes Michael V,Engmann Jorgen E L,Shah Tina,Sofat Reecha,Stender Stefan,Johnson Paul C D,Scott Robert A,Leusink Maarten,Verweij Niek,Sharp Stephen J,Guo Yiran,Giambartolomei Claudia,Chung Christina,Peasey Anne,Amuzu Antoinette,Li KaWah,Palmen Jutta,Howard Philip,Cooper Jackie A,Drenos Fotios,Li Yun R,Lowe Gordon,Gallacher John,Stewart Marlene C W,Tzoulaki Ioanna,Buxbaum Sarah G,van der A Daphne L,Forouhi Nita G,Onland-Moret N Charlotte,van der Schouw Yvonne T,Schnabel Renate B,Hubacek Jaroslav A,Kubinova Ruzena,Baceviciene Migle,Tamosiunas Abdonas,Pajak Andrzej,Topor-Madry Roman,Stepaniak Urszula,Malyutina Sofia,Baldassarre Damiano,Sennblad Bengt,Tremoli Elena,de Faire Ulf,Veglia Fabrizio,Ford Ian,Jukema J Wouter,Westendorp Rudi G J,de Borst Gert Jan,de Jong Pim A,Algra Ale,Spiering Wilko,Maitland-van der Zee Anke H,Klungel Olaf H,de Boer Anthonius,Doevendans Pieter A,Eaton Charles B,Robinson Jennifer G,Duggan David, , , ,Kjekshus John,Downs John R,Gotto Antonio M,Keech Anthony C,Marchioli Roberto,Tognoni Gianni,Sever Peter S,Poulter Neil R,Waters David D,Pedersen Terje R,Amarenco Pierre,Nakamura Haruo,McMurray John J V,Lewsey James D,Chasman Daniel I,Ridker Paul M,Maggioni Aldo P,Tavazzi Luigi,Ray Kausik K,Seshasai Sreenivasa Rao Kondapally,Manson JoAnn E,Price Jackie F,Whincup Peter H,Morris Richard W,Lawlor Debbie A,Smith George Davey,Ben-Shlomo Yoav,Schreiner Pamela J,Fornage Myriam,Siscovick David S,Cushman Mary,Kumari Meena,Wareham Nick J,Verschuren W M Monique,Redline Susan,Patel Sanjay R,Whittaker John C,Hamsten Anders,Delaney Joseph A,Dale Caroline,Gaunt Tom R,Wong Andrew,Kuh Diana,Hardy Rebecca,Kathiresan Sekar,Castillo Berta A,van der Harst Pim,Brunner Eric J,Tybjaerg-Hansen Anne,Marmot Michael G,Krauss Ronald M,Tsai Michael,Coresh Josef,Hoogeveen Ronald C,Psaty Bruce M,Lange Leslie A,Hakonarson Hakon,Dudbridge Frank,Humphries Steve E,Talmud Philippa J,Kivimäki Mika,Timpson Nicholas J,Langenberg Claudia,Asselbergs Folkert W,Voevoda Mikhail,Bobak Martin,Pikhart Hynek,Wilson James G,Reiner Alex P,Keating Brendan J,Hingorani Aroon D,Sattar Naveed Lancet (London, England) BACKGROUND:Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target. METHODS:We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis. FINDINGS:Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials). INTERPRETATION:The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition. FUNDING:The funding sources are cited at the end of the paper. 10.1016/S0140-6736(14)61183-1
    Is this muscle pain caused by my statin? Shun-Shin Matthew J,Francis Darrel P BMJ (Clinical research ed.) 10.1136/bmj.j3030
    Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study. Nicoletti Paola,Aithal Guruprasad P,Bjornsson Einar S,Andrade Raul J,Sawle Ashley,Arrese Marco,Barnhart Huiman X,Bondon-Guitton Emmanuelle,Hayashi Paul H,Bessone Fernando,Carvajal Alfonso,Cascorbi Ingolf,Cirulli Elizabeth T,Chalasani Naga,Conforti Anita,Coulthard Sally A,Daly Mark J,Day Christopher P,Dillon John F,Fontana Robert J,Grove Jane I,Hallberg Pär,Hernández Nelia,Ibáñez Luisa,Kullak-Ublick Gerd A,Laitinen Tarja,Larrey Dominique,Lucena M Isabel,Maitland-van der Zee Anke H,Martin Jennifer H,Molokhia Mariam,Pirmohamed Munir,Powell Elizabeth E,Qin Shengying,Serrano Jose,Stephens Camilla,Stolz Andrew,Wadelius Mia,Watkins Paul B,Floratos Aris,Shen Yufeng,Nelson Matthew R,Urban Thomas J,Daly Ann K, Gastroenterology BACKGROUND & AIMS:We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS:We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS:We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9-3.8; P = 2.4 × 10) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P = 9.7 × 10). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P = 4.8 × 10). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0-9.5; P = 7.1 × 10). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS:In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors. 10.1053/j.gastro.2016.12.016
    Giant cell arteritis and polymyalgia rheumatica after reexposure to a statin: a case report. de Jong Hilda J I,Meyboom Ronald H B,Helle Markku J,Klungel Olaf H,Niskanen Leo,Cohen Tervaert Jan Willem Annals of internal medicine 10.7326/L14-5020-6
    N-of-1 (single-patient) trials for statin-related myalgia. Akinboro Oladimeji,Williams Linda,Pomerantz Daniel Annals of internal medicine 10.7326/L14-5019
    GATM polymorphism associated with the risk for statin-induced myopathy does not replicate in case-control analysis of 715 dyslipidemic individuals. Luzum Jasmine A,Kitzmiller Joseph P,Isackson Paul J,Ma Changxing,Medina Marisa W,Dauki Anees M,Mikulik Eduard B,Ochs-Balcom Heather M,Vladutiu Georgirene D Cell metabolism Statin-induced myopathy (SIM) is the most common reason for discontinuation of statin therapy. A polymorphism affecting the gene encoding glycine amidinotransferase (GATM rs9806699 G > A) was previously associated with reduced risk for SIM. Our objective was to replicate the GATM association in a large, multicenter SIM case-control study. Mild and severe SIM cases and age- and gender-matched controls were enrolled. Participants were genotyped, and associations were tested (n = 715) using chi-square and logistic regression with consideration for SIM severity and exclusion of subjects with potentially confounding comedications. The minor allele (A) frequencies of GATM rs9806699 in the controls (n = 106), mild SIM (n = 324), and severe SIM (n = 285) cases were 0.26, 0.28, and 0.29, respectively (p = 0.447). The unadjusted odds ratio for the A allele for any SIM (mild or severe) was 1.14 (0.82-1.61; p = 0.437), which remained nonsignificant in all models. Our results do not replicate the association between GATM rs9806699 and SIM. 10.1016/j.cmet.2015.03.003
    The diabetogenic action of statins - mechanisms and clinical implications. Betteridge D John,Carmena Rafael Nature reviews. Endocrinology Treatment with statins has transformed primary and secondary prevention of cardiovascular disease (CVD), including thrombotic stroke. Evidence-based data demonstrate the benefits and safety of statin therapy and help to guide clinicians in the management of populations at high risk of CVD. Nevertheless, clinical trials, meta-analyses and observational studies highlight a 10-12% increase in new-onset diabetes mellitus (NODM) among patients receiving statins. The risk further increases with intensive therapy and among individuals with known risk factors for NODM. Mechanisms underpinning this effect are not yet fully understood; however, Mendelian randomization studies suggest that they are related to lowered activity of HMG-CoA reductase, the target of statin therapy. In vitro research indicates that statins potentially impair β-cell function and decrease insulin sensitivity but how these findings relate to patients is unknown. In the clinic, statins should be prescribed on the basis of CVD risk and individual patient characteristics. In addition, diet and lifestyle interventions should be emphasized to help mitigate the risk of NODM. Individuals who develop NODM while taking statins do not exhibit increased microvascular disease, which is reassuring. In diabetes mellitus of long duration, the effect of statins on glycaemic control is small and unlikely to be clinically important. 10.1038/nrendo.2015.194
    Impact of Statins on Cardiovascular Outcomes Following Coronary Artery Calcium Scoring. Mitchell Joshua D,Fergestrom Nicole,Gage Brian F,Paisley Robert,Moon Patrick,Novak Eric,Cheezum Michael,Shaw Leslee J,Villines Todd C Journal of the American College of Cardiology BACKGROUND:Compared with traditional risk factors, coronary artery calcium (CAC) scores improve prognostic accuracy for atherosclerotic cardiovascular disease (ASCVD) outcomes. However, the relative impact of statins on ASCVD outcomes stratified by CAC scores is unknown. OBJECTIVES:The authors sought to determine whether CAC can identify patients most likely to benefit from statin treatment. METHODS:The authors identified consecutive subjects without pre-existing ASCVD or malignancy who underwent CAC scoring from 2002 to 2009 at Walter Reed Army Medical Center. The primary outcome was first major adverse cardiovascular event (MACE), a composite of acute myocardial infarction, stroke, and cardiovascular death. The effect of statin therapy on outcomes was analyzed stratified by CAC presence and severity, after adjusting for baseline comorbidities with inverse probability of treatment weights based on propensity scores. RESULTS:A total of 13,644 patients (mean age 50 years; 71% men) were followed for a median of 9.4 years. Comparing patients with and without statin exposure, statin therapy was associated with reduced risk of MACE in patients with CAC (adjusted subhazard ratio: 0.76; 95% confidence interval: 0.60 to 0.95; p = 0.015), but not in patients without CAC (adjusted subhazard ratio: 1.00; 95% confidence interval: 0.79 to 1.27; p = 0.99). The effect of statin use on MACE was significantly related to the severity of CAC (p < 0.0001 for interaction), with the number needed to treat to prevent 1 initial MACE outcome over 10 years ranging from 100 (CAC 1 to 100) to 12 (CAC >100). CONCLUSIONS:In a largescale cohort without baseline ASCVD, the presence and severity of CAC identified patients most likely to benefit from statins for the primary prevention of cardiovascular diseases. 10.1016/j.jacc.2018.09.051
    The SLCO1B1*5 genetic variant is associated with statin-induced side effects. Voora Deepak,Shah Svati H,Spasojevic Ivan,Ali Shazia,Reed Carol R,Salisbury Benjamin A,Ginsburg Geoffrey S Journal of the American College of Cardiology OBJECTIVES:We sought to identify single nucleotide polymorphisms associated with mild statin-induced side effects. BACKGROUND:Statin-induced side effects can interfere with therapy. Single nucleotide polymorphisms in cytochrome P450 enzymes impair statin metabolism; the reduced function SLCO1B1*5 allele impairs statin clearance and is associated with simvastatin-induced myopathy with creatine kinase (CK) elevation. METHODS:The STRENGTH (Statin Response Examined by Genetic Haplotype Markers) study was a pharmacogenetics study of statin efficacy and safety. Subjects (n = 509) were randomized to atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 10 mg followed by 80 mg, 80 mg, and 40 mg, respectively. We defined a composite adverse event (CAE) as discontinuation for any side effect, myalgia, or CK >3x upper limit of normal during follow-up. We sequenced CYP2D6, CYP2C8, CYP2C9, CYP3A4, and SLCO1B1 and tested 7 reduced function alleles for association with the CAE. RESULTS:The CAE occurred in 99 subjects (54 discontinuations, 49 myalgias, and 9 CK elevations). Sex was associated with CAE (percent female in CAE vs. no CAE groups, 66% vs. 50%, p < 0.01). SLCO1B1*5 was associated with CAE (percent with > or = 1 allele in CAE vs. no CAE groups, 37% vs. 25%, p = 0.03) and those with CAE with no significant CK elevation (p < or = 0.03). Furthermore, there was evidence for a gene-dose effect (percent with CAE in those with 0, 1, or 2 alleles: 19%, 27%, and 50%, trend p = 0.01). Finally, the CAE risk appeared to be greatest in those carriers assigned to simvastatin. CONCLUSIONS:SLCO1B1*5 genotype and female sex were associated mild statin-induced side effects. These findings expand the results of a recent genome-wide association study of statin myopathy with CK >3x normal to milder, statin-induced, muscle side effects. 10.1016/j.jacc.2009.04.053
    Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial. Nissen Steven E,Stroes Erik,Dent-Acosta Ricardo E,Rosenson Robert S,Lehman Sam J,Sattar Naveed,Preiss David,Bruckert Eric,Ceška Richard,Lepor Norman,Ballantyne Christie M,Gouni-Berthold Ioanna,Elliott Mary,Brennan Danielle M,Wasserman Scott M,Somaratne Ransi,Scott Rob,Stein Evan A, JAMA IMPORTANCE:Muscle-related statin intolerance is reported by 5% to 20% of patients. OBJECTIVE:To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. DESIGN, SETTING, AND PARTICIPANTS:Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. INTERVENTIONS:Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). MAIN OUTCOME AND MEASURES:Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels. RESULTS:Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, -16.7% (95% CI, -20.5% to -12.9%), absolute change, -31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, -54.5% (95% CI, -57.2% to -51.8%); absolute change, -106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, -16.7% (95% CI, -20.8% to -12.5%); absolute change, -31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, -52.8% (95% CI, -55.8% to -49.8%); absolute change, -102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was -37.8%; absolute difference, -75.8 mg/dL. For week 24, between-group difference in LDL-C was -36.1%; absolute difference, -71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). CONCLUSIONS AND RELEVANCE:Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT01984424. 10.1001/jama.2016.3608
    Statin Therapy and Risk of Acute Memory Impairment. Strom Brian L,Schinnar Rita,Karlawish Jason,Hennessy Sean,Teal Valerie,Bilker Warren B JAMA internal medicine IMPORTANCE:Reports on the association between statins and memory impairment are inconsistent. OBJECTIVE:To assess whether statin users show acute decline in memory compared with nonusers and with users of nonstatin lipid-lowering drugs (LLDs). DESIGN, SETTING, AND PARTICIPANTS:Using The Health Improvement Network database during January 13, 1987, through December 16, 2013, a retrospective cohort study compared 482,543 statin users with 2 control groups: 482,543 matched nonusers of any LLDs and all 26,484 users of nonstatin LLDs. A case-crossover study of 68,028 patients with incident acute memory loss evaluated exposure to statins during the period immediately before the outcome vs 3 earlier periods. Analysis was conducted from July 7, 2013, through January 15, 2015. RESULTS:When compared with matched nonusers of any LLDs (using odds ratio [95% CI]), a strong association was present between first exposure to statins and incident acute memory loss diagnosed within 30 days immediately following exposure (fully adjusted, 4.40; 3.01-6.41). This association was not reproduced in the comparison of statins vs nonstatin LLDs (fully adjusted, 1.03; 0.63-1.66) but was also present when comparing nonstatin LLDs with matched nonuser controls (adjusted, 3.60; 1.34-9.70). The case-crossover analysis showed little association. CONCLUSIONS AND RELEVANCE:Both statin and nonstatin LLDs were strongly associated with acute memory loss in the first 30 days following exposure in users compared with nonusers but not when compared with each other. Thus, either all LLDs cause acute memory loss regardless of drug class or the association is the result of detection bias rather than a causal association. 10.1001/jamainternmed.2015.2092
    A statin-dependent QTL for GATM expression is associated with statin-induced myopathy. Mangravite Lara M,Engelhardt Barbara E,Medina Marisa W,Smith Joshua D,Brown Christopher D,Chasman Daniel I,Mecham Brigham H,Howie Bryan,Shim Heejung,Naidoo Devesh,Feng QiPing,Rieder Mark J,Chen Yii-Der I,Rotter Jerome I,Ridker Paul M,Hopewell Jemma C,Parish Sarah,Armitage Jane,Collins Rory,Wilke Russell A,Nickerson Deborah A,Stephens Matthew,Krauss Ronald M Nature Statins are prescribed widely to lower plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk and have been shown to have beneficial effects in a broad range of patients. However, statins are associated with an increased risk, albeit small, of clinical myopathy and type 2 diabetes. Despite evidence for substantial genetic influence on LDL concentrations, pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy or toxicity, and have produced little information regarding mechanisms that modulate statin response. Here we identify a downstream target of statin treatment by screening for the effects of in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment. This analysis identified six expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure, including rs9806699, a cis-eQTL for the gene glycine amidinotransferase (GATM) that encodes the rate-limiting enzyme in creatine synthesis. We found this locus to be associated with incidence of statin-induced myotoxicity in two separate populations (meta-analysis odds ratio = 0.60). Furthermore, we found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated lowering of cholesterol and susceptibility to statin-induced myopathy. 10.1038/nature12508
    Statin toxicity from macrolide antibiotic coprescription: a population-based cohort study. Patel Amit M,Shariff Salimah,Bailey David G,Juurlink David N,Gandhi Sonja,Mamdani Muhammad,Gomes Tara,Fleet Jamie,Hwang Y Joseph,Garg Amit X Annals of internal medicine BACKGROUND:Clarithromycin and erythromycin, but not azithromycin, inhibit cytochrome P450 isoenzyme 3A4 (CYP3A4), and inhibition increases blood concentrations of statins that are metabolized by CYP3A4. OBJECTIVE:To measure the frequency of statin toxicity after coprescription of a statin with clarithromycin or erythromycin. DESIGN:Population-based cohort study. SETTING:Ontario, Canada, from 2003 to 2010. PATIENTS:Continuous statin users older than 65 years who were prescribed clarithromycin (n = 72,591) or erythromycin (n = 3267) compared with those prescribed azithromycin (n = 68,478). MEASUREMENTS:The primary outcome was hospitalization with rhabdomyolysis within 30 days of the antibiotic prescription. RESULTS:Atorvastatin was the most commonly prescribed statin (73%) followed by simvastatin and lovastatin. Compared with azithromycin, coprescription of a statin with clarithromycin or erythromycin was associated with a higher risk for hospitalization with rhabdomyolysis (absolute risk increase, 0.02% [95% CI, 0.01% to 0.03%]; relative risk [RR], 2.17 [CI, 1.04 to 4.53]) or with acute kidney injury (absolute risk increase, 1.26% [CI, 0.58% to 1.95%]; RR, 1.78 [CI, 1.49 to 2.14]) and for all-cause mortality (absolute risk increase, 0.25% [CI, 0.17% to 0.33%]; RR, 1.56 [CI, 1.36 to 1.80]). LIMITATIONS:Only older adults were included in the study. The absolute risk increase for rhabdomyolysis may be underestimated because the codes used to identify it were insensitive. CONCLUSION:In older adults, coprescription of clarithromycin or erythromycin with a statin that is metabolized by CYP3A4 increases the risk for statin toxicity. PRIMARY FUNDING SOURCE:Academic Medical Organization of Southwestern Ontario. 10.7326/0003-4819-158-12-201306180-00004
    Long-Term Safety and Efficacy of Lowering Low-Density Lipoprotein Cholesterol With Statin Therapy: 20-Year Follow-Up of West of Scotland Coronary Prevention Study. Ford Ian,Murray Heather,McCowan Colin,Packard Chris J Circulation BACKGROUND:Extended follow-up of statin-based low-density lipoprotein cholesterol lowering trials improves the understanding of statin safety and efficacy. Examining cumulative cardiovascular events (total burden of disease) gives a better appreciation of the clinical value of statins. This article evaluates the long-term impact of therapy on mortality and cumulative morbidity in a high-risk cohort of men. METHODS AND RESULTS:The West of Scotland Coronary Prevention Study was a primary prevention trial in 45- to 64-year-old men with high low-density lipoprotein cholesterol. A total of 6595 men were randomized to receive pravastatin 40 mg once daily or placebo for an average of 4.9 years. Subsequent linkage to electronic health records permitted analysis of major incident events over 20 years. Post trial statin use was recorded for 5 years after the trial but not for the last 10 years. Men allocated to pravastatin had reduced all-cause mortality (hazard ratio, 0.87; 95% confidence interval, 0.80-0.94; P=0.0007), attributable mainly to a 21% decrease in cardiovascular death (hazard ratio, 0.79; 95% confidence interval, 0.69-0.90; P=0.0004). There was no difference in noncardiovascular or cancer death rates between groups. Cumulative hospitalization event rates were lower in the statin-treated arm: by 18% for any coronary event (P=0.002), by 24% for myocardial infarction (P=0.01), and by 35% for heart failure (P=0.002). There were no significant differences between groups in hospitalization for noncardiovascular causes. CONCLUSION:Statin treatment for 5 years was associated with a legacy benefit, with improved survival and a substantial reduction in cardiovascular disease outcomes over a 20-year period, supporting the wider adoption of primary prevention strategies. 10.1161/CIRCULATIONAHA.115.019014
    Trust the Blinded Randomized Evidence That Statin Therapy Rarely Causes Symptomatic Side Effects. Peto Richard,Collins Rory Circulation 10.1161/CIRCULATIONAHA.118.036846
    N-of-1 (single-patient) trials for statin-related myalgia. Joy Tisha R,Monjed Alaa,Zou Guang Yong,Hegele Robert A,McDonald Charlotte G,Mahon Jeffrey L Annals of internal medicine BACKGROUND:Statin-related myalgia is difficult to distinguish from other conditions causing myalgia and may often lead to statin discontinuation. OBJECTIVE:To compare the effect of statin rechallenge with placebo in patients with prior statin-related myalgia and to determine whether patients resumed statin therapy after evaluating the results. DESIGN:N-of-1 trial with 3 double-blind, crossover comparisons separated by 3-week washout periods. (Clinicaltrials.gov: NCT01259791) SETTING: Tertiary care lipid clinic. PATIENTS:Patients with prior statin-related myalgia with or without mild elevation of creatine kinase levels. INTERVENTION:Rechallenge with the statin that was previously associated with myalgia within 3 weeks of open-label use versus matching placebo. MEASUREMENTS:Weekly visual analogue scale (VAS) scores for myalgia and specific symptoms (VAS myalgia score and symptom-specific VAS score, respectively), pain interference scores, and pain severity scores were recorded during the 3-week periods when patients were receiving placebo or statin. The primary outcome was the VAS myalgia score (range, 0 to 100 mm). RESULTS:Eight patients (mean age, 66 years [SD, 8 years]; 88% women, all with high 10-year Framingham cardiovascular risk) participated in n-of-1 trials. Seven patients completed 3 treatment pairs, and 1 completed 2 treatment pairs. For each n-of-1 trial, no statistically significant differences were seen between statin and placebo in the VAS myalgia score, symptom-specific VAS score, pain interference score, and pain severity score. Five patients resumed open-label statin treatment, with a median posttrial follow-up of 10 months. LIMITATION:Results are limited by the small sample size and cannot be extended to patients with longer onset of myalgia after statin initiation. CONCLUSION:In selected patients with a history of statin-related myalgia whose symptoms are difficult to evaluate, n-of-1 trials may be a useful method for determining statin tolerability. PRIMARY FUNDING SOURCE:Western University, London, Ontario, Canada. 10.7326/M13-1921
    Residual Inflammatory Risk on Treatment With PCSK9 Inhibition and Statin Therapy. Pradhan Aruna D,Aday Aaron W,Rose Lynda M,Ridker Paul M Circulation BACKGROUND:The combination of statin therapy and PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition markedly lowers low-density lipoprotein cholesterol (LDL-C) and reduces cardiovascular event rates. Whether residual inflammatory risk as measured by on-treatment high sensitivity C-reactive protein (hsCRP) remains an important clinical issue in such patients is uncertain. METHODS:We evaluated residual inflammatory risk among 9738 patients participating in the SPIRE-1 and SPIRE-2 cardiovascular outcomes trials (Studies of PCSK9 Inhibition and the Reduction in Vascular Events), who were receiving both statin therapy and bococizumab, according to on-treatment levels of hsCRP (hsCRP) and LDL-C measured 14 weeks after drug initiation. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death. RESULTS:At 14 weeks, the mean percentage change in LDL-C among statin-treated patients who additionally received bococizumab was -60.5% (95% confidence interval [CI], -61.2 to -59.8; <0.001; median change, -65.4%) as compared to 6.6% (95% CI, -1.0 to 14.1; =0.09; median change, 0.0%) for hsCRP. Incidence rates for future cardiovascular events for patients treated with both statin therapy and bococizumab according to hsCRP <1, 1 to 3, and >3 mg/L were 1.96, 2.50, and 3.59 events per 100 person-years, respectively, corresponding to multivariable adjusted hazard ratios of 1.0, 1.16 (95% CI, 0.81-1.66), and 1.62 (95% CI, 1.14-2.30) (-trend=0.001) after adjustment for traditional cardiovascular risk factors and LDL-C. Comparable adjusted hazard ratios for LDL-C (<30, 30-50, >50 mg/dL) were 1.0, 0.87, and 1.21, respectively (-trend=0.16). Relative risk reductions with bococizumab were similar across hsCRP groups (-interaction=0.87). CONCLUSIONS:In this post hoc analysis of the SPIRE trials of bococizumab in a stable outpatient population, evidence of residual inflammatory risk persisted among patients treated with both statin therapy and proprotein convertase subtilisin-kexin type 9 inhibition. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01975376, NCT01975389. 10.1161/CIRCULATIONAHA.118.034645
    Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With Versus Without Diabetes Mellitus: Results From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Giugliano Robert P,Cannon Christopher P,Blazing Michael A,Nicolau José C,Corbalán Ramón,Špinar Jindřich,Park Jeong-Gun,White Jennifer A,Bohula Erin A,Braunwald Eugene, Circulation BACKGROUND:Ezetimibe, when added to simvastatin, reduces cardiovascular events after acute coronary syndrome. We explored outcomes stratified by diabetes mellitus (DM). METHODS:In IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), 18 144 patients after acute coronary syndrome with low-density lipoprotein cholesterol 50 to 125 mg/dL were randomized to 40 mg ezetimibe/simvastatin (E/S) or 40 mg placebo/simvastatin. The primary composite end point was cardiovascular death, major coronary events, and stroke. DM was a prespecified subgroup. RESULTS:The 4933 (27%) patients with DM were more often older and female, had had a prior myocardial infarction and revascularization, and presented more frequently with non-ST segment elevation acute coronary syndrome compared with patients without DM (each <0.001). The median admission low-density lipoprotein cholesterol was lower among patients with DM (89 versus 97 mg/dL, <0.001). E/S achieved a significantly lower median time-weighted average low-density lipoprotein cholesterol compared with placebo/simvastatin, irrespective of DM (DM: 49 versus 67 mg/dL; no DM: 55 versus 71 mg/dL; both <0.001). In patients with DM, E/S reduced the 7-year Kaplan-Meier primary end point event rate by 5.5% absolute (hazard ratio, 0.85; 95% confidence interval, 0.78-0.94); in patients without DM, the absolute difference was 0.7% (hazard ratio, 0.98; 95% confidence interval, 0.91-1.04; =0.02). The largest relative reductions in patients with DM were in myocardial infarction (24%) and ischemic stroke (39%). No differences in safety outcomes by treatment were present regardless of DM. When stratified further by age, patients ≥75 years of age had a 20% relative reduction in the primary end point regardless of DM (=0.91), whereas patients <75 years of age with DM had greater benefit than those without (=0.011). When stratified by the TIMI (Thrombolysis in Myocardial Infarction) Risk Score for Secondary Prevention, all patients with DM demonstrated benefit with E/S regardless of risk. In contrast, among patients without DM, those with a high risk score experienced a significant (18%) relative reduction in the composite of cardiovascular death, myocardial infarction, and ischemic stroke with E/S compared with placebo/simvastatin, whereas patients without DM at low or moderate risk demonstrated no benefit with the addition of ezetimibe to simvastatin ( =0.034). CONCLUSIONS:In IMPROVE-IT, the benefit of adding ezetimibe to statin was enhanced in patients with DM and in high-risk patients without DM. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00202878. 10.1161/CIRCULATIONAHA.117.030950
    Risk of Intracranial Hemorrhage From Statin Use in Asians: A Nationwide Cohort Study. Chang Chia-Hsuin,Lin Chin-Hsien,Caffrey James L,Lee Yen-Chieh,Liu Ying-Chun,Lin Jou-Wei,Lai Mei-Shu Circulation BACKGROUND:Reports of statin usage and increased risk of intracranial hemorrhage (ICH) have been inconsistent. This study examined potential associations between statin usage and the risk of ICH in subjects without a previous history of stroke. METHODS AND RESULTS:Patients initiating statin therapy between 2005 and 2009 without a previous history of ischemic or hemorrhagic stroke were identified from Taiwan's National Health Insurance database. Participants were stratified by advanced age (≥70 years), sex, and diagnosed hypertension. The outcome of interest was hospital admission for ICH (International Classification of Diseases, Ninth Revision, Clinical Modification codes 430, 431, 432). Cox regression models were applied to estimate the hazard ratio of ICH. The cumulative statin dosage stratified by quartile and adjusted for baseline disease risk score served as the primary variable using the lowest quartile of cumulative dosage as a reference. There were 1 096 547 statin initiators with an average follow-up of 3.3 years. The adjusted hazard ratio for ICH between the highest and the lowest quartile was nonsignificant at 1.06 with a 95% confidence interval spanning 1.00 (0.94-1.19). Similar nonsignificant results were found in sensitivity analyses using different outcome definitions or model adjustments, reinforcing the robustness of the study findings. Subgroup analysis identified an excess of ICH frequency in patients without diagnosed hypertension (adjusted hazard ratio 1.36 [1.11-1.67]). CONCLUSIONS:In general, no association was observed between cumulative statin use and the risk of ICH among subjects without a previous history of stroke. An increased risk was identified among the nonhypertensive cohort, but this finding should be interpreted with caution. 10.1161/CIRCULATIONAHA.114.013046
    Association Between Achieved Low-Density Lipoprotein Levels and Major Adverse Cardiac Events in Patients With Stable Ischemic Heart Disease Taking Statin Treatment. Leibowitz Morton,Karpati Tomas,Cohen-Stavi Chandra J,Feldman Becca S,Hoshen Moshe,Bitterman Haim,Suissa Samy,Balicer Ran D JAMA internal medicine IMPORTANCE:International guidelines recommend treatment with statins for patients with preexisting ischemic heart disease to prevent additional cardiovascular events but differ regarding target levels of low-density lipoprotein cholesterol (LDL-C). Trial data on this question are inconclusive and observational data are lacking. OBJECTIVE:To assess the relationship between levels of LDL-C achieved with statin treatment and cardiovascular events in adherent patients with preexisting ischemic heart disease. DESIGN, SETTING, AND PARTICIPANTS:Population-based observational cohort study from 2009 to 2013 using data from a health care organization in Israel covering more than 4.3 million members. Included patients had ischemic heart disease, were aged 30 to 84 years, were treated with statins, and were at least 80% adherent to treatment or, in a sensitivity analysis, at least 50% adherent. Patients with active cancer or metabolic abnormalities were excluded. EXPOSURES:Index LDL-C was defined as the first achieved serum LDL-C measure after at least 1 year of statin treatment, grouped as low (≤70.0 mg/dL), moderate (70.1-100.0 mg/dL), or high (100.1-130.0 mg/dL). MAIN OUTCOMES AND MEASURES:Major adverse cardiac events included acute myocardial infarction, unstable angina, stroke, angioplasty, bypass surgery, or all-cause mortality. The hazard ratio of adverse outcomes was estimated using 2 Cox proportional hazards models with low vs moderate and moderate vs high LDL-C, adjusted for confounders and further tested using propensity score matching analysis. RESULTS:The cohort with at least 80% adherence included 31 619 patients, for whom the mean (SD) age was 67.3 (9.8) years. Of this population, 27% were female and 29% had low, 53% moderate, and 18% high LDL-C when taking statin treatment. Overall, there were 9035 patients who had an adverse outcome during a mean 1.6 years of follow-up (6.7 per 1000 persons per year). The adjusted incidence of adverse outcomes was not different between low and moderate LDL-C (hazard ratio [HR], 1.02; 95% CI, 0.97-1.07; P = .54), but it was lower with moderate vs high LDL-C (HR, 0.89; 95% CI, 0.84-0.94; P < .001). Among 54 884 patients with at least 50% statin adherence, the adjusted HR was 1.06 (95% CI, 1.02-1.10; P = .001) in the low vs moderate groups and 0.87 (95% CI, 0.84-0.91; P = .001) in the moderate vs high groups. CONCLUSIONS AND RELEVANCE:Patients with LDL-C levels of 70 to 100 mg/dL taking statins had lower risk of adverse cardiac outcomes compared with those with LDL-C levels between 100 and 130 mg/dL, but no additional benefit was gained by achieving LDL-C of 70 mg/dL or less. These population-based data do not support treatment guidelines recommending very low target LDL-C levels for all patients with preexisting heart disease. 10.1001/jamainternmed.2016.2751
    Clinical Effectiveness of Statin Therapy After Ischemic Stroke: Primary Results From the Statin Therapeutic Area of the Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) Study. O'Brien Emily C,Greiner Melissa A,Xian Ying,Fonarow Gregg C,Olson DaiWai M,Schwamm Lee H,Bhatt Deepak L,Smith Eric E,Maisch Lesley,Hannah Deidre,Lindholm Brianna,Peterson Eric D,Pencina Michael J,Hernandez Adrian F Circulation BACKGROUND:In patients with ischemic stroke, data on the real-world effectiveness of statin therapy for clinical and patient-centered outcomes are needed to better inform shared decision making. METHODS AND RESULTS:Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) is a Patient-Centered Outcomes Research Institute-funded research program designed with stroke survivors to evaluate the effectiveness of poststroke therapies. We linked data on patients ≥65 years of age enrolled in the Get With The Guidelines-Stroke Registry to Medicare claims. Two-year to postdischarge outcomes of those discharged on a statin versus not on a statin were adjusted through inverse probability weighting. Our coprimary outcomes were major adverse cardiovascular events and home time (days alive and out of a hospital or skilled nursing facility). Secondary outcomes included all-cause mortality, all-cause readmission, cardiovascular readmission, and hemorrhagic stroke. From 2007 to 2011, 77 468 patients who were not taking statins at the time of admission were hospitalized with ischemic stroke; of these, 71% were discharged on statin therapy. After adjustment, statin therapy at discharge was associated with a lower hazard of major adverse cardiovascular events (hazard ratio, 0.91; 95% confidence interval, 0.87-0.94), 28 more home-time days after discharge (P<0.001), and lower all-cause mortality and readmission. Statin therapy at discharge was not associated with increased risk of hemorrhagic stroke (hazard ratio, 0.94; 95% confidence interval, 0.72-1.23). Among statin-treated patients, 31% received a high-intensity dose; after risk adjustment, these patients had outcomes similar to those of recipients of moderate-intensity statin. CONCLUSION:In older ischemic stroke patients who were not taking statins at the time of admission, discharge statin therapy was associated with lower risk of major adverse cardiovascular events and nearly 1 month more home time during the 2-year period after hospitalization. 10.1161/CIRCULATIONAHA.115.016183
    Diagnosis of osteoporosis in statin-treated patients is dose-dependent. Leutner Michael,Matzhold Caspar,Bellach Luise,Deischinger Carola,Harreiter Jürgen,Thurner Stefan,Klimek Peter,Kautzky-Willer Alexandra Annals of the rheumatic diseases OBJECTIVE:Whether HMG-CoA-reductase inhibition, the main mechanism of statins, plays a role in the pathogenesis of osteoporosis, is not entirely known so far. Consequently, this study was set out to investigate the relationship of different kinds and dosages of statins with osteoporosis, hypothesising that the inhibition of the synthesis of cholesterol could influence sex-hormones and therefore the diagnosis of osteoporosis. METHODS:Medical claims data of all Austrians from 2006 to 2007 was used to identify all patients treated with statins to compute their daily defined dose averages of six different types of statins. We applied multiple logistic regression to analyse the dose-dependent risks of being diagnosed with osteoporosis for each statin individually. RESULTS:In the general study population, statin treatment was associated with an overrepresentation of diagnosed osteoporosis compared with controls (OR: 3.62, 95% CI 3.55 to 3.69, p<0.01). There was a highly non-trivial dependence of statin dosage with the ORs of osteoporosis. Osteoporosis was underrepresented in low-dose statin treatment (0-10 mg per day), including lovastatin (OR: 0.39, CI 0.18 to 0.84, p<0.05), pravastatin (OR: 0.68, 95% CI 0.52 to 0.89, p<0.01), simvastatin (OR: 0.70, 95% CI 0.56 to 0.86, p<0.01) and rosuvastatin (OR: 0.69, 95% CI 0.55 to 0.87, p<0.01). However, the exceeding of the 40 mg threshold for simvastatin (OR: 1.64, 95% CI 1.31 to 2.07, p<0.01), and the exceeding of a 20 mg threshold for atorvastatin (OR: 1.78, 95% CI 1.41 to 2.23, p<0.01) and for rosuvastatin (OR: 2.04, 95% CI 1.31 to 3.18, p<0.01) was related to an overrepresentation of osteoporosis. CONCLUSION:Our results show that the diagnosis of osteoporosis in statin-treated patients is dose-dependent. Thus, osteoporosis is underrepresented in low-dose and overrepresented in high-dose statin treatment, demonstrating the importance of future studies' taking dose-dependency into account when investigating the relationship between statins and osteoporosis. 10.1136/annrheumdis-2019-215714
    Application of the Statin-Associated Muscle Symptoms-Clinical Index to a Randomized Trial on Statin Myopathy. Taylor Beth A,Sanchez Robert J,Jacobson Terry A,Chibedi-De-Roche Daniela,Manvelian Garen,Baccara-Dinet Marie T,Khan Irfan,Rosenson Robert S Journal of the American College of Cardiology 10.1016/j.jacc.2017.07.767
    Statin-Induced Anti-HMGCR-Associated Myopathy. Basharat Pari,Lahouti Arash H,Paik Julie J,Albayda Jemima,Pinal-Fernandez Iago,Bichile Tanmayee,Lloyd Thomas E,Danoff Sonye K,Casciola-Rosen Livia,Mammen Andrew L,Christopher-Stine Lisa Journal of the American College of Cardiology 10.1016/j.jacc.2016.04.037
    Association of Statin Use With Risk of Back Disorder Diagnoses. Makris Una E,Alvarez Carlos A,Wei Wei,Mortensen Eric M,Mansi Ishak A JAMA internal medicine 10.1001/jamainternmed.2017.1068
    LPA Variants Are Associated With Residual Cardiovascular Risk in Patients Receiving Statins. Wei Wei-Qi,Li Xiaohui,Feng Qiping,Kubo Michiaki,Kullo Iftikhar J,Peissig Peggy L,Karlson Elizabeth W,Jarvik Gail P,Lee Ming Ta Michael,Shang Ning,Larson Eric A,Edwards Todd,Shaffer Christian M,Mosley Jonathan D,Maeda Shiro,Horikoshi Momoko,Ritchie Marylyn,Williams Marc S,Larson Eric B,Crosslin David R,Bland Sarah T,Pacheco Jennifer A,Rasmussen-Torvik Laura J,Cronkite David,Hripcsak George,Cox Nancy J,Wilke Russell A,Stein C Michael,Rotter Jerome I,Momozawa Yukihide,Roden Dan M,Krauss Ronald M,Denny Joshua C Circulation BACKGROUND:Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with statins decreases circulating levels of low-density lipoprotein cholesterol and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown. METHODS:We performed a 2-stage genome-wide association study of CHD events during statin therapy. We first identified 3099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7681 controls without CHD events during comparable intensity and duration of statin therapy from 4 sites in the Electronic Medical Records and Genomics Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth Electronic Medical Records and Genomics site, which joined the network after the initial genome-wide association study. Finally, we performed a phenome-wide association study for other traits linked to the most significant locus. RESULTS:The meta-analysis identified 7 single nucleotide polymorphisms at a genome-wide level of significance within the LPA/PLG locus associated with CHD events on statin treatment. The most significant association was for an intronic single nucleotide polymorphism within LPA/PLG (rs10455872; minor allele frequency, 0.069; odds ratio, 1.58; 95% confidence interval, 1.35-1.86; P=2.6×10). In the replication cohort, rs10455872 was also associated with CHD events (odds ratio, 1.71; 95% confidence interval, 1.14-2.57; P=0.009). The association of this single nucleotide polymorphism with CHD events was independent of statin-induced change in low-density lipoprotein cholesterol (odds ratio, 1.62; 95% confidence interval, 1.17-2.24; P=0.004) and persisted in individuals with low-density lipoprotein cholesterol ≤70 mg/dL (odds ratio, 2.43; 95% confidence interval, 1.18-4.75; P=0.015). A phenome-wide association study supported the effect of this region on coronary heart disease and did not identify noncardiovascular phenotypes. CONCLUSIONS:Genetic variations at the LPA locus are associated with CHD events during statin therapy independently of the extent of low-density lipoprotein cholesterol lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins. 10.1161/CIRCULATIONAHA.117.031356
    Triglyceride-Rich Lipoprotein Cholesterol and Risk of Cardiovascular Events Among Patients Receiving Statin Therapy in the TNT Trial. Vallejo-Vaz Antonio J,Fayyad Rana,Boekholdt S Matthijs,Hovingh G Kees,Kastelein John J,Melamed Shari,Barter Philip,Waters David D,Ray Kausik K Circulation BACKGROUND:Mendelian randomization data suggest that the genetic determinants of lifetime higher triglyceride-rich lipoprotein-cholesterol (TRL-C) are causally related to cardiovascular disease and therefore a potential therapeutic target. The relevance of TRL-C among patients receiving statins is unknown. We assessed the relationship between TRL-C and cardiovascular risk, and whether this risk was modifiable among patients receiving statins in the TNT trial (Treating to New Targets). METHODS:Patients with coronary heart disease and low-density lipoprotein cholesterol (LDL-C) 130 to 250 mg/dL entered an 8-week run-in phase with atorvastatin 10 mg/d (ATV10). After this period, participants with LDL-C <130 mg/dL entered the randomized phase with ATV10 (n=5006) versus atorvastatin 80 mg/d (ATV80, n=4995). The primary end point was coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke (major adverse cardiovascular events [MACE]). TRL-C was calculated as total cholesterol minus high-density lipoprotein cholesterol minus LDL-C. The effect of atorvastatin on TRL-C was assessed during the run-in phase (ATV10) and randomized phase (ATV80 versus ATV10). The risk of MACE was assessed across quintiles (Q) of baseline TRL-C (and, for comparison, by baseline triglycerides and non-high-density lipoprotein cholesterol) during the randomized period. Last, the association between TRL-C changes with atorvastatin and cardiovascular risk was assessed by multivariate Cox regression. RESULTS:ATV10 reduced TRL-C 10.7% from an initial TRL-C of 33.9±16.6 mg/dL. ATV80 led to an additional 15.4% reduction. Cardiovascular risk factors positively correlated with TRL-C. Among patients receiving ATV10, higher TRL-C was associated with higher 5-year MACE rates (Q1=9.7%, Q5=13.8%; hazard ratio Q5-versus-Q1, 1.48; 95% confidence interval, 1.15-1.92; P-trend<0.0001). ATV80 (versus ATV10) did not significantly alter the risk of MACE in Q1-Q2, but significantly reduced risk in Q3-Q5 (relative risk reduction, 29%-41%; all P<0.0250), with evidence of effect modification ( P-homogeneity=0.0053); results were consistent for triglycerides ( P-homogeneity=0.0101) and directionally similar for non-high-density lipoprotein cholesterol ( P-homogeneity=0.1387). Last, in adjusted analyses, a 1 SD percentage reduction in TRL-C with atorvastatin resulted in a significant lower risk of MACE (hazard ratio, 0.93; 95% confidence interval, 0.86-1.00; P=0.0482) independent of the reduction in LDL-C and of similar magnitude to that per 1 SD lowering in LDL-C (hazard ratio, 0.89; 95% confidence interval, 0.83-0.95; P=0.0008). CONCLUSIONS:The present post hoc analysis from TNT shows that increased TRL-C levels are associated with an increased cardiovascular risk and provides evidence for the cardiovascular benefit of lipid lowering with statins among patients who have coronary heart disease with high TRL-C. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov . Unique identifier: NCT00327691. 10.1161/CIRCULATIONAHA.117.032318
    Interpretation of the evidence for the efficacy and safety of statin therapy. Collins Rory,Reith Christina,Emberson Jonathan,Armitage Jane,Baigent Colin,Blackwell Lisa,Blumenthal Roger,Danesh John,Smith George Davey,DeMets David,Evans Stephen,Law Malcolm,MacMahon Stephen,Martin Seth,Neal Bruce,Poulter Neil,Preiss David,Ridker Paul,Roberts Ian,Rodgers Anthony,Sandercock Peter,Schulz Kenneth,Sever Peter,Simes John,Smeeth Liam,Wald Nicholas,Yusuf Salim,Peto Richard Lancet (London, England) This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes. It explains how the evidence that is available from randomised controlled trials yields reliable information about both the efficacy and safety of statin therapy. In addition, it discusses how claims that statins commonly cause adverse effects reflect a failure to recognise the limitations of other sources of evidence about the effects of treatment. Large-scale evidence from randomised trials shows that statin therapy reduces the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. The absolute benefits of statin therapy depend on an individual's absolute risk of occlusive vascular events and the absolute reduction in LDL cholesterol that is achieved. For example, lowering LDL cholesterol by 2 mmol/L (77 mg/dL) with an effective low-cost statin regimen (eg, atorvastatin 40 mg daily, costing about £2 per month) for 5 years in 10 000 patients would typically prevent major vascular events from occurring in about 1000 patients (ie, 10% absolute benefit) with pre-existing occlusive vascular disease (secondary prevention) and in 500 patients (ie, 5% absolute benefit) who are at increased risk but have not yet had a vascular event (primary prevention). Statin therapy has been shown to reduce vascular disease risk during each year it continues to be taken, so larger absolute benefits would accrue with more prolonged therapy, and these benefits persist long term. The only serious adverse events that have been shown to be caused by long-term statin therapy-ie, adverse effects of the statin-are myopathy (defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase), new-onset diabetes mellitus, and, probably, haemorrhagic stroke. Typically, treatment of 10 000 patients for 5 years with an effective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of myopathy (one of which might progress, if the statin therapy is not stopped, to the more severe condition of rhabdomyolysis), 50-100 new cases of diabetes, and 5-10 haemorrhagic strokes. However, any adverse impact of these side-effects on major vascular events has already been taken into account in the estimates of the absolute benefits. Statin therapy may cause symptomatic adverse events (eg, muscle pain or weakness) in up to about 50-100 patients (ie, 0·5-1·0% absolute harm) per 10 000 treated for 5 years. However, placebo-controlled randomised trials have shown definitively that almost all of the symptomatic adverse events that are attributed to statin therapy in routine practice are not actually caused by it (ie, they represent misattribution). The large-scale evidence available from randomised trials also indicates that it is unlikely that large absolute excesses in other serious adverse events still await discovery. Consequently, any further findings that emerge about the effects of statin therapy would not be expected to alter materially the balance of benefits and harms. It is, therefore, of concern that exaggerated claims about side-effect rates with statin therapy may be responsible for its under-use among individuals at increased risk of cardiovascular events. For, whereas the rare cases of myopathy and any muscle-related symptoms that are attributed to statin therapy generally resolve rapidly when treatment is stopped, the heart attacks or strokes that may occur if statin therapy is stopped unnecessarily can be devastating. 10.1016/S0140-6736(16)31357-5
    Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Stroes Erik S,Thompson Paul D,Corsini Alberto,Vladutiu Georgirene D,Raal Frederick J,Ray Kausik K,Roden Michael,Stein Evan,Tokgözoğlu Lale,Nordestgaard Børge G,Bruckert Eric,De Backer Guy,Krauss Ronald M,Laufs Ulrich,Santos Raul D,Hegele Robert A,Hovingh G Kees,Leiter Lawrence A,Mach Francois,März Winfried,Newman Connie B,Wiklund Olov,Jacobson Terry A,Catapano Alberico L,Chapman M John,Ginsberg Henry N, European heart journal 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. 10.1093/eurheartj/ehv043
    Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition. Schirris Tom J J,Renkema G Herma,Ritschel Tina,Voermans Nicol C,Bilos Albert,van Engelen Baziel G M,Brandt Ulrich,Koopman Werner J H,Beyrath Julien D,Rodenburg Richard J,Willems Peter H G M,Smeitink Jan A M,Russel Frans G M Cell metabolism Cholesterol-lowering statins effectively reduce the risk of major cardiovascular events. Myopathy is the most important adverse effect, but its underlying mechanism remains enigmatic. In C2C12 myoblasts, several statin lactones reduced respiratory capacity and appeared to be strong inhibitors of mitochondrial complex III (CIII) activity, up to 84% inhibition. The lactones were in general three times more potent inducers of cytotoxicity than their corresponding acid forms. The Qo binding site of CIII was identified as off-target of the statin lactones. These findings could be confirmed in muscle tissue of patients suffering from statin-induced myopathies, in which CIII enzyme activity was reduced by 18%. Respiratory inhibition in C2C12 myoblasts could be attenuated by convergent electron flow into CIII, restoring respiration up to 89% of control. In conclusion, CIII inhibition was identified as a potential off-target mechanism associated with statin-induced myopathies. 10.1016/j.cmet.2015.08.002
    Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Gupta Ajay,Thompson David,Whitehouse Andrew,Collier Tim,Dahlof Bjorn,Poulter Neil,Collins Rory,Sever Peter, Lancet (London, England) BACKGROUND:In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials. METHODS:In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40-79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6·5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest-muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment-and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum. RESULTS:The blinded randomised phase was done between February, 1998, and December, 2002; we included 101 80 patients in this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo group), with a median follow-up of 3·3 years (IQR 2·7-3·7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] non-users), with a median follow-up of 2·3 years (2·2-2·4). During the blinded phase, muscle-related AEs (298 [2·03% per annum] vs 283 [2·00% per annum]; hazard ratio 1·03 [95% CI 0·88-1·21]; p=0·72) and erectile dysfunction (272 [1·86% per annum] vs 302 [2·14% per annum]; 0·88 [0·75-1·04]; p=0·13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 [1·00% per annum] vs 210 [1·46% per annum]; 0·69 [0·56-0·85]; p=0·0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 [0·20% per annum] vs 32 [0·22% per annum]; 0·94 [0·57-1·54]; p=0·81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 [1·87%] per annum vs 392 [1·51%] per annum; 1·23 [1·08-1·41]; p=0·002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1·26% per annum] vs 124 [1·00% per annum]; 1·41 [1·10-1·79]; p=0·006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 [8·69% per annum] vs 831 [7·45% per annum]; 1·17 [1·06-1·29]; p=0·001) and blood and lymphatic system disorders (114 [0·88% per annum] vs 80 [0·64% per annum]; 1·40 [1·04-1·88]; p=0·03), which were reported more commonly by statin users than by non-users. INTERPRETATION:These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects. FUNDING:Pfizer, Servier Research Group, and Leo Laboratories. 10.1016/S0140-6736(17)31075-9
    High-Quality Statin Trials Support the 2013 American College of Cardiology/American Heart Association Cholesterol Guidelines After the HOPE-3 Trial (Heart Outcomes Prevention Evaluation-3): MESA (The Multiethnic Study of Atherosclerosis). Mortensen Martin Bødtker,Budoff Matthew,Li Dong,Nasir Khurram,Blaha Michael J,Sandfort Veit,Jose Rodriguez Carlos,Ouyang Pamela,Falk Erling Circulation 10.1161/CIRCULATIONAHA.117.029381
    Impact of Heart Outcomes Prevention Evaluation Trial on Statin Eligibility for the Primary Prevention of Cardiovascular Disease: Insights from the National Health and Nutrition Examination Survey. Burstein Barry,Altobelli Kathleen K,Williams Ken,Cannon Christopher P,Pencina Michael J,Sniderman Allan D,Thanassoulis George Circulation 10.1161/CIRCULATIONAHA.117.029102
    A common missense variant of LILRB5 is associated with statin intolerance and myalgia. K Siddiqui Moneeza,Maroteau Cyrielle,Veluchamy Abirami,Tornio Aleksi,Tavendale Roger,Carr Fiona,Abelega Ngu-Uma,Carr Dan,Bloch Katyrzyna,Hallberg Par,Yue Qun-Ying,Pearson Ewan R,Colhoun Helen M,Morris Andrew D,Dow Eleanor,George Jacob,Pirmohamed Munir,Ridker Paul M,Doney Alex S F,Alfirevic Ana,Wadelius Mia,Maitland-van der Zee Anke-Hilse,Chasman Daniel I,Palmer Colin N A, European heart journal Aims:A genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366: T > C: Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility to muscle-related symptoms. We examined the association of this variant with statin intolerance ascertained from electronic medical records in the GoDARTS study. Methods and results:In the GoDARTS cohort, the LILRB5 Asp247 variant was associated with statin intolerance (SI) phenotypes; one defined as having raised CK and being non-adherent to therapy [odds ratio (OR) 1.81; 95% confidence interval (CI): 1.34-2.45] and the other as being intolerant to the lowest approved dose of a statin before being switched to two or more other statins (OR 1.36; 95% CI: 1.07-1.73). Those homozygous for Asp247 had increased odds of developing both definitions of intolerance. Importantly the second definition did not rely on CK elevations. These results were replicated in adjudicated cases of statin-induced myopathy in the PREDICTION-ADR consortium (OR1.48; 95% CI: 1.05-2.10) and for the development of myalgia in the JUPITER randomized clinical trial of rosuvastatin (OR1.35, 95% CI: 1.10-1.68). A meta-analysis across the studies showed a consistent association between Asp247Gly and outcomes associated with SI (OR1.34; 95% CI: 1.16-1.54). Conclusion:This study presents a novel immunogenetic factor associated with statin intolerance, an important risk factor for cardiovascular outcomes. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a potential role for the immune system in their development. We identify a genetic group that is more likely to be intolerant to their statins. 10.1093/eurheartj/ehx467
    Statin Toxicity. Ward Natalie C,Watts Gerald F,Eckel Robert H Circulation research There is now overwhelming evidence to support lowering LDL-c (low-density lipoprotein cholesterol) to reduce cardiovascular morbidity and mortality. Statins are a class of drugs frequently prescribed to lower cholesterol. However, in spite of their wide-spread use, discontinuation and nonadherence remains a major gap in both the primary and secondary prevention of atherosclerotic cardiovascular disease. The major reason for statin discontinuation is because of the development of statin-associated muscle symptoms, but a range of other statin-induced side effects also exist. Although the mechanisms behind these side effects have not been fully elucidated, there is an urgent need to identify those at increased risk of developing side effects as well as provide alternative treatment strategies. In this article, we review the mechanisms and clinical importance of statin toxicity and focus on the evaluation and management of statin-associated muscle symptoms. 10.1161/CIRCRESAHA.118.312782
    Association of Statin Exposure With Histologically Confirmed Idiopathic Inflammatory Myositis in an Australian Population. Caughey Gillian E,Gabb Genevieve M,Ronson Saffron,Ward Michael,Beukelman Timothy,Hill Catherine L,Limaye Vidya JAMA internal medicine Importance:Statin medications are widely prescribed for cardiovascular risk reduction. Myalgia and rhabdomyolysis are well-recognized adverse effects of statins, and they resolve with the cessation of statin therapy. Idiopathic inflammatory myositis (IIM) is a heterogeneous group of autoimmune myopathies that may also be associated with statin use. Recently, statin-associated autoimmune myopathy has been recognized as a distinct entity with the presence of specific autoantibodies against hydroxymethylglutaryl-coenzyme A reductase, which results in a necrotizing myositis that does not resolve with cessation of statin therapy and requires treatment with immunosuppressive agents. Objective:To examine the association between histologically confirmed IIM and current exposure to statin medications. Design, Setting, and Participants:Population-based case-control study using the South Australian Myositis Database of all histologically confirmed cases of IIM diagnosed between 1990 and 2014 in patients 40 years or older (n = 221) and population-based controls from the North West Adelaide Health Study (n = 662), matched by age and sex in a 3:1 ratio of controls to cases. Data analysis using conditional logistic regression was performed from June 1, 2016, to July 14, 2017. Exposures:Current statin medication use. Main Outcomes and Measures:Unadjusted and adjusted (for diabetes and cardiovascular disease) odds ratios and 95% CIs for likelihood of inflammatory myositis. Results:A total of 221 IIM cases met the inclusion criteria with a mean (SD) age of 62.2 (10.8) years, and 132 (59.7%) were female. Statin exposure at the time of IIM diagnosis was 68 of 221 patients (30.8%) and 142 of 662 matched controls (21.5%) (P = .005). There was an almost 2-fold increased likelihood of statin exposure in patients with IIM compared with controls (adjusted odds ratio, 1.79; 95% CI, 1.23-2.60; P = .001). Similar results were observed when patients with necrotizing myositis were excluded from the analysis (adjusted odds ratio, 1.92; 95% CI, 1.29-2.86; P = .001). Conclusions and Relevance:In this large population-based study, statin exposure was significantly associated with histologically confirmed IIM. Given the increased use of statins worldwide and the severity of IIM, increased awareness and recognition of this potentially rare adverse effect of statin exposure is needed. 10.1001/jamainternmed.2018.2859
    Statin-Associated Side Effects. Thompson Paul D,Panza Gregory,Zaleski Amanda,Taylor Beth Journal of the American College of Cardiology 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. 10.1016/j.jacc.2016.02.071
    What to Believe and Do About Statin-Associated Adverse Effects. Thompson Paul D JAMA 10.1001/jama.2016.16557
    Continued Statin Prescriptions After Adverse Reactions and Patient Outcomes: A Cohort Study. Zhang Huabing,Plutzky Jorge,Shubina Maria,Turchin Alexander Annals of internal medicine BACKGROUND:Many patients discontinue statin treatment, often after having a possible adverse reaction. The risks and benefits of continued statin therapy after an adverse reaction are not known. OBJECTIVE:To examine the relationship between continuation of statin therapy (any prescription within 12 months after an adverse reaction) and clinical outcomes. DESIGN:Retrospective cohort study. SETTING:Primary care practices affiliated with 2 academic medical centers. PARTICIPANTS:Patients with a presumed adverse reaction to a statin between 2000 and 2011. MEASUREMENTS:Information on adverse reactions to statins was obtained from structured electronic medical record data or natural-language processing of narrative provider notes. The primary composite outcome was time to a cardiovascular event (myocardial infarction or stroke) or death. RESULTS:Most (81%) of the adverse reactions to statins were identified from the text of electronic provider notes. Among 28 266 study patients, 19 989 (70.7%) continued receiving statin prescriptions after the adverse reaction. Four years after the presumed adverse event, the cumulative incidence of the composite primary outcome was 12.2% for patients with continued statin prescriptions, compared with 13.9% for those without them (difference, 1.7% [95% CI, 0.8% to 2.7%]; P < 0.001). In a secondary analysis of 7604 patients for whom a different statin was prescribed after the adverse reaction, 2014 (26.5%) had a documented adverse reaction to the second statin, but 1696 (84.2%) of those patients continued receiving statin prescriptions. LIMITATIONS:The risk for recurrent adverse reactions to statins could not be established for the entire sample. It was also not possible to determine whether patients actually took the statins. CONCLUSION:Continued statin prescriptions after an adverse reaction were associated with a lower incidence of death and cardiovascular events. PRIMARY FUNDING SOURCE:Chinese National Key Program of Clinical Science, National Natural Science Foundation of China, and Young Scientific Research Fund of Peking Union Medical College Hospital. 10.7326/M16-0838
    Safety and efficacy of statin therapy. Adhyaru Bhavin B,Jacobson Terry A Nature reviews. Cardiology 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. 10.1038/s41569-018-0098-5
    Adverse effects of statin therapy: perception vs. the evidence - focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract. Mach François,Ray Kausik K,Wiklund Olov,Corsini Alberto,Catapano Alberico L,Bruckert Eric,De Backer Guy,Hegele Robert A,Hovingh G Kees,Jacobson Terry A,Krauss Ronald M,Laufs Ulrich,Leiter Lawrence A,März Winfried,Nordestgaard Børge G,Raal Frederick J,Roden Michael,Santos Raul D,Stein Evan A,Stroes Erik S,Thompson Paul D,Tokgözoglu Lale,Vladutiu Georgirene D,Gencer Baris,Stock Jane K,Ginsberg Henry N,Chapman M John, European heart journal Aims:To objectively appraise evidence for possible adverse effects of long-term statin therapy on glucose homeostasis, cognitive, renal and hepatic function, and risk for haemorrhagic stroke or cataract. Methods and results:A literature search covering 2000-2017 was performed. The Panel critically appraised the data and agreed by consensus on the categorization of reported adverse effects. Randomized controlled trials (RCTs) and genetic studies show that statin therapy is associated with a modest increase in the risk of new-onset diabetes mellitus (about one per thousand patient-years), generally defined by laboratory findings (glycated haemoglobin ≥6.5); this risk is significantly higher in the metabolic syndrome or prediabetes. Statin treatment does not adversely affect cognitive function, even at very low levels of low-density lipoprotein cholesterol and is not associated with clinically significant deterioration of renal function, or development of cataract. Transient increases in liver enzymes occur in 0.5-2% of patients taking statins but are not clinically relevant; idiosyncratic liver injury due to statins is very rare and causality difficult to prove. The evidence base does not support an increased risk of haemorrhagic stroke in individuals without cerebrovascular disease; a small increase in risk was suggested by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels study in subjects with prior stroke but has not been confirmed in the substantive evidence base of RCTs, cohort studies and case-control studies. Conclusion:Long-term statin treatment is remarkably safe with a low risk of clinically relevant adverse effects as defined above; statin-associated muscle symptoms were discussed in a previous Consensus Statement. Importantly, the established cardiovascular benefits of statin therapy far outweigh the risk of adverse effects. 10.1093/eurheartj/ehy182