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      Introducing the ‘Drucebo’ effect in statin therapy: a systematic review of studies comparing reported rates of statin‐associated muscle symptoms, under blinded and open‐label conditions

      1 , 2 , 3 , 3 , 4 , 5 , 6 , 7 , 8 , , 9 , 10 , 11 , on behalf of Lipid and Blood Pressure Meta‐Analysis Collaboration (LBPMC) Group & International Lipid Expert Panel (ILEP)

      Journal of Cachexia, Sarcopenia and Muscle

      John Wiley and Sons Inc.

      Statins, Nocebo, Placebo, Drucebo

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          Abstract

          Background

          The ‘placebo effect’ and ‘nocebo effect’ are phenomena whereby beneficial (placebo) or adverse (nocebo) effects result from the expectation that an inert substance will relieve or cause a particular symptom. These terms are often inappropriately applied to effects experienced on drug therapy. Quantifying the magnitude of placebo and nocebo effects in clinical trials is problematic because it requires a ‘no treatment’ arm. To overcome the difficulties associated with measuring the nocebo effect, and the fact that its definition refers to inert compounds, rather than drugs, we introduce the concept of ‘drucebo’ (a combination of DRUg and plaCEBO or noCEBO) to relate to beneficial or adverse effects of a drug, which result from expectation and are not pharmacologically caused by the drug. As an initial application of the concept, we have estimated the contribution of the drucebo effect to statin discontinuation and statin‐induced muscle symptoms by performing a systematic review of randomized controlled trial of statin therapy.

          Methods

          This preferred reporting items for systematic reviews and meta‐analysis‐compliant systematic review was prospectively registered in PROSPERO (CRD42017082700). We searched PubMed and Cochrane Central from inception until 3 January 2018 using a search strategy designed to detect studies including the concepts (Statins AND Placebo AND muscle pain). We included studies that allowed us to quantify the drucebo effect for adverse muscle symptoms of statins by (i) comparing reported rates of muscle symptoms in blinded and unblinded phases of randomized controlled trials and (ii) comparing rates of muscle symptoms at baseline and during blinded therapy in trials that included patients with objectively confirmed statin intolerance at baseline. Extraction was performed by two researchers with disagreements settled by a third reviewer.

          Results

          Five studies allowed the estimation of the drucebo effect. All trials demonstrated an excess of side effects under open‐label conditions. The contribution of the drucebo effect to statin‐associated muscle pain ranged between 38% and 78%. The heterogeneity of study methods, outcomes, and reporting did not allow for quantitative synthesis (meta‐analysis) of the results.

          Conclusions

          The drucebo effect may be useful in evaluating the safety and efficacy of medicines. Diagnosis of the drucebo effect in patients presenting with statin intolerance will allow restoration of life‐prolonging lipid‐lowering therapy. Our study was limited by heterogeneity of included studies and lack of access to individual patient data. Further studies are necessary to better understand risk factors for and clinical management of the drucebo effect.

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          Most cited references 26

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          Ethical guidelines for publishing in the journal of cachexia, sarcopenia and muscle: update 2017

          Abstract This article details an updated version of the principles of ethical authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle (JCSM). At the time of submission to JCSM, the corresponding author, on behalf of all co‐authors, needs to certify adherence to these principles. The principles are as follows: All authors listed on a manuscript considered for publication have approved its submission and (if accepted) publication as provided to JCSM. No person who has a right to be recognized as author has been omitted from the list of authors on the submitted manuscript. Each author has made a material and independent contribution to the work submitted for publication. The submitted work is original and is neither under consideration elsewhere nor that it has been published previously in whole or in part other than in abstract form. All authors certify that the work is original and does not contain excessive overlap with prior or contemporaneous publication elsewhere, and where the publication reports on cohorts, trials, or data that have been reported on before these other publications must be referenced. All original research work has been approved by the relevant bodies such as institutional review boards or ethics committees. All conflicts of interest, financial or otherwise, that may affect the authors' ability to present data objectively, and relevant sources of funding have been duly declared in the manuscript. The manuscript in its published form will be maintained on the servers of JCSM as a valid publication only as long as all statements in the guidelines on ethical publishing remain true. If any of the aforementioned statements ceases to be true, the authors have a duty to notify the Editors of JCSM as soon as possible so that the available information regarding the published article can be updated and/or the manuscript can be withdrawn.
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            Statin-associated myopathy.

            Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are associated with skeletal muscle complaints, including clinically important myositis and rhabdomyolysis, mild serum creatine kinase (CK) elevations, myalgia with and without elevated CK levels, muscle weakness, muscle cramps, and persistent myalgia and CK elevations after statin withdrawal. We performed a literature review to provide a clinical summary of statin-associated myopathy and discuss possible mediating mechanisms. We also update the US Food and Drug Administration (FDA) reports on statin-associated rhabdomyolysis. Articles on statin myopathy were identified via a PubMed search through November 2002 and articles on statin clinical trials, case series, and review articles were identified via a PubMed search through January 2003. Adverse event reports of statin-associated rhabdomyolysis were also collected from the FDA MEDWATCH database. The literature review found that reports of muscle problems during statin clinical trials are extremely rare. The FDA MEDWATCH Reporting System lists 3339 cases of statin-associated rhabdomyolysis reported between January 1, 1990, and March 31, 2002. Cerivastatin was the most commonly implicated statin. Few data are available regarding the frequency of less-serious events such as muscle pain and weakness, which may affect 1% to 5% of patients. The risk of rhabdomyolysis and other adverse effects with statin use can be exacerbated by several factors, including compromised hepatic and renal function, hypothyroidism, diabetes, and concomitant medications. Medications such as the fibrate gemfibrozil alter statin metabolism and increase statin plasma concentration. How statins injure skeletal muscle is not clear, although recent evidence suggests that statins reduce the production of small regulatory proteins that are important for myocyte maintenance.
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              Risks associated with statin therapy: a systematic overview of randomized clinical trials.

              Although statins reduce the risk of cardiovascular events, concerns about adverse effects may deter physicians from prescribing these agents. We performed a systematic overview of randomized statin trials to quantify the risks of musculoskeletal, renal, and hepatic complications associated with therapy. Major statin trials were identified by electronic search of the MEDLINE database from 1966 to December 2005. We included English language reports of adults with documented hyperlipidemia; double-blind, random allocation of > or = 100 patients to statin monotherapy versus placebo; and reports of myalgia, creatine kinase elevations, rhabdomyolysis, transaminase elevations, and discontinuation due to adverse events. Among 74,102 subjects enrolled in 35 trials (follow-up range, 1 to 65 months), statin therapy (excluding cerivastatin) did not result in significant absolute increases in risks of myalgias (risk difference/1000 patients [RD], 2.7; 95% CI, -3.2 to 8.7), creatine kinase elevations (RD, 0.2; 95% CI, -0.6 to 0.9), rhabdomyolysis (RD, 0.4; 95% CI, -0.1 to 0.9), or discontinuation due to any adverse event (RD, -0.5; 95% CI, -4.3 to 3.3). The absolute risk of transaminase elevations was significantly higher with statin therapy (RD, 4.2; 95% CI, 1.5 to 6.9). On the basis of data available from published clinical trials, statin therapy is associated with a small excess risk of transaminase elevations, but not of myalgias, creatine kinase elevations, rhabdomyolysis, or withdrawal of therapy compared with placebo. Further study is necessary to determine whether the results from these published clinical trials are similar to what occurs in routine practice, particularly among patients who are older, have more severe comorbid conditions, or receive higher statin doses than most patients in these clinical trials.
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                Author and article information

                Contributors
                maciejbanach77@gmail.com
                Journal
                J Cachexia Sarcopenia Muscle
                J Cachexia Sarcopenia Muscle
                10.1007/13539.2190-6009
                JCSM
                Journal of Cachexia, Sarcopenia and Muscle
                John Wiley and Sons Inc. (Hoboken )
                2190-5991
                2190-6009
                11 October 2018
                December 2018
                : 9
                : 6 ( doiID: 10.1002/jcsm.v9.6 )
                : 1023-1033
                Affiliations
                [ 1 ] School of Pharmacy and Biomolecular Sciences Liverpool John Moores University Liverpool UK
                [ 2 ] Division of Cardiology, Department of Medicine University of British Columbia Vancouver BC Canada
                [ 3 ] Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Division of Cardiology, Department of Medicine Johns Hopkins University Baltimore MD USA
                [ 4 ] Lipid Disorders Clinic, Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology The University of Western Australia Perth WA Australia
                [ 5 ] Biotechnology Research Center, Pharmaceutical Technology Institute Mashhad University of Medical Sciences Mashhad Iran
                [ 6 ] Neurogenic Inflammation Research Center Mashhad University of Medical Sciences Mashhad Iran
                [ 7 ] School of Pharmacy Mashhad University of Medical Sciences Mashhad Iran
                [ 8 ] Department of Clinical Biochemistry, Royal Free Hospital Campus University College London London UK
                [ 9 ] Department of Hypertension, Chair of Nephrology and Hypertension Medical University of Lodz Lodz Poland
                [ 10 ] Polish Mother's Memorial Hospital Research Institute (PMMHRI) Lodz Poland
                [ 11 ] Cardiovascular Research Centre University of Zielona Gora Zielona Gora Poland
                Author notes
                [* ] Correspondence to: Prof. Maciej Banach, MD, PhD, FNLA, FAHA, FESC, FASA, Head, Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, Lodz 90‐549, Poland . Email: maciejbanach77@ 123456gmail.com
                Article
                JCSM12344 JCSM-D-18-00247
                10.1002/jcsm.12344
                6240752
                30311434
                © 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                Page count
                Figures: 0, Tables: 3, Pages: 11, Words: 5145
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                Original Article
                Original Articles
                Custom metadata
                2.0
                jcsm12344
                December 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.3 mode:remove_FC converted:19.11.2018

                Orthopedics

                nocebo, statins, placebo, drucebo

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