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


Peter E. Penson | G. B. John Mancini | Peter P. Toth | Seth S. Martin | Gerald F. Watts | Amirhossein Sahebkar | Dimitri P. Mikhailidis | Maciej Banach | on behalf of Lipid and Blood Pressure Meta-Analysis Collaboration (LBPMC) Group & International Lipid Expert Panel (ILEP)
First published: 11 October 2018 |



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.


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.


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.


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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The authors certify that they comply with the ethical guidelines for publishing in the Journal of Cachexia, Sarcopenia and Muscle: update 2017.40

Conflict of interest

Dr Penson owns four shares in Astra Zeneca PLC and has received travel/speaker’s fees from Amgen Inc. Dr Banach—speakers bureau: Abbott/Mylan, Abbott Vascular, Actavis, Akcea, Amgen, Biofarm, KRKA, MSD, Sanofi-Aventis and Valeant; consultant to Abbott Vascular, Akcea, Amgen, Daichii Sankyo, Esperion, Lilly, MSD, Resverlogix, Sanofi-Aventis; Grants from Sanofi and Valeant. Dr Mikhailidis has given talks and attended conferences sponsored by MSD, AstraZeneca, and Libytec. Dr Toth has previously received consulting fees and/or honoraria from AbbVie, Amarin, Amgen, Gemphire, Kowa, Merck, Regeneron, and Sanofi and payment for lectures from Amarin, Amgen, Kowa, Merck, Regeneron, and Sanofi. Dr Martin reports receiving personal fees for serving on scientific advisory boards for Amgen, Sanofi/Regeneron, Quest Diagnostics, and Akcea Therapeutics, as well as grants and research support from the PJ Schafer Cardiovascular Research Fund, the David and June Trone Family Foundation, American Heart Association, Aetna Foundation, Maryland Innovation Initiative, Nokia, Google, and Apple outside the submitted work; in addition, he reports having patent applications pending. Dr Mancini has received consulting fees and/or honoraria from Astra Zeneca, Amgen, Sanofi, Esperion; grants from Amgen, Sanofi. Dr Sahebkar has no declarations.


This work was conducted without any specific funding.

  1. Kennedy WPThe nocebo reactionMed World 196195203205.
  2. Tobert JANewman CBThe nocebo effect in the context of statin intoleranceJ Clin Lipidol 201610739747
  3. Manchikanti LBoswell MVKaye ADHelm Ii SHirsch JATherapeutic role of placebo: evolution of a new paradigm in understanding research and clinical practicePain Physician 201720363386.
  4. Collins RReith CEmberson JArmitage JBaigent CBlackwell L, et al. Interpretation of the evidence for the efficacy and safety of statin therapyLancet 201638825322561.
  5. Thompson PDPanza GZaleski ATaylor BStatin-associated side effectsJ Am Coll Cardiol 20166723952410.
  6. Thompson PDClarkson PKaras RHStatin-associated myopathyJAMA 200328916811690.
  7. Toth PPPatti AMGiglio RVNikolic DCastellino GRizzo M, et al. Management of statin intolerance in 2018: still more questions than answersAm J Cardiovasc Drugs 201818157173.
  8. Rosenson RSBaker SBanach MBorow KMBraun LTBruckert E, et al. Optimizing cholesterol treatment in patients with muscle complaintsJ Am Coll Cardiol 20177012901301.
  9. Banach MStulc TDent RToth PPStatin non-adherence and residual cardiovascular risk: there is need for substantial improvementInt J Cardiol 2016225184196.
  10. Banach MSerban MCDiscussion around statin discontinuation in older adults and patients with wasting diseasesJ Cachexia Sarcopenia Muscle 20167396399.
  11. Serban MCColantonio LDManthripragada ADMonda KLBittner VABanach M, et al. Statin intolerance and risk of coronary heart events and all-cause mortality following myocardial infarctionJ Am Coll Cardiol 20176913861395.
  12. Zhang HPlutzky JShubina MTurchin AContinued statin prescriptions after adverse reactions and patient outcomes: a cohort studyAnn Intern Med 2017167221227.
  13. Heller MKChapman SCHorne RBeliefs about medication predict the misattribution of a common symptom as a medication side effect—evidence from an analogue online studyJ Psychosom Res 201579519529.
  14. Nissen SEStatin denial: an internet-driven cult with deadly consequencesAnn Intern Med 2017167281282.
  15. Pasternak RCSmith SC JrBairey-Merz CNGrundy SMCleeman JILenfant CAmerican College of Cardiology; American Heart Association; National Heart, Lung and Blood Institute. ACC/AHA/NHLBI Advisory on the use and safety of statinsJ Am Coll Cardiol 200240567572.
  16. Mancini GBTashakkor AYBaker SBergeron JFitchett DFrohlich J, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus updateCan J Cardiol 20132915531568.
  17. Rosenson RSBaker SKJacobson TAKopecky SLParker BAThe National Lipid Association’s Muscle Safety Expert P. An assessment by the statin muscle safety task force: 2014 updateJ Clin Lipidol 20148S58S71.
  18. Banach MRizzo MToth PPFarnier MDavidson MHAl-Rasadi K, et al. Statin intolerance—an attempt at a unified definition. Position paper from an International Lipid Expert PanelExpert Opin Drug Saf 201514935955.
  19. Banach MRizzo MToth PPFarnier MDavidson MHAl-Rasadi K, et al. Statin intolerance—an attempt at a unified definition. Position paper from an International Lipid Expert PanelArch Med Sci 201511(1):1–231.
  20. Ganga HVSlim HBThompson PDA systematic review of statin-induced muscle problems in clinical trialsAm Heart J 2014168615.
  21. Kashani APhillips COFoody JMWang YMangalmurti SKo DT, et al. Risks associated with statin therapy: a systematic overview of randomized clinical trialsCirculation 200611427882797.
  22. Finegold JAManisty CHGoldacre BBarron AJFrancis DPWhat proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choiceEur J Prev Cardiol 201421464474.
  23. Riaz HKhan ARKhan MSRehman KAAlansari SARGheyath B, et al. Meta-analysis of placebo-controlled randomized controlled trials on the prevalence of statin intoleranceAm J Cardiol 2017120774781.
  24. Gupta AThompson DWhitehouse ACollier TDahlof BPoulter N, et al. 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 phaseLancet 201738924732481.
  25. Rojas-Mirquez JCRodriguez-Zuniga MJBonilla-Escobar FJGarcia-Perdomo HAPetkov MBecerra L, et al. Nocebo effect in randomized clinical trials of antidepressants in children and adolescents: systematic review and meta-analysisFront Behav Neurosci 20148375.
  26. Hrobjartsson AGotzsche PCPlacebo interventions for all clinical conditionsCochrane Database Syst Rev 20043CD003974.
  27. Moher DLiberati ATetzlaff JAltman DGGroup PPreferred reporting items for systematic reviews and meta-analyses: the PRISMA statementBMJ 2009339b2535.
  28. Higgins JPTSterne JACSavović JPage MJHróbjartsson ABoutron I, et al. A revised tool for assessing risk of bias in randomized trials. In: Chandler JMcKenzie JBoutron I, V W, editors. Cochrane Methods. 10 (Suppl 1). Cochrane Database of Systematic Reviews 2016.
  29. Sever PSDahlof BPoulter NRWedel HBeevers GCaulfield M, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trialLancet 200336111491158.
  30. Nissen SEStroes EDent-Acosta RERosenson RSLehman SJSattar N, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trialJAMA 201631515801590.
  31. Moriarty PMThompson PDCannon CPGuyton JRBergeron JZieve FJ, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trialJ Clin Lipidol 20159758769.
  32. Taylor BALorson LWhite CMThompson PDA randomized trial of coenzyme Q10 in patients with confirmed statin myopathyAtherosclerosis 2015238329335.
  33. Joy TRMonjed AZou GYHegele RAMcDonald CGMahon JLN-of-1 (single-patient) trials for statin-related myalgiaAnn Intern Med 2014160301310.
  34. Pravastatin Multicenter Study Group IIComparative efficacy and safety of pravastatin and cholestyramine alone and combined in patients with hypercholesterolemiaArch Intern Med 199315313211329.
  35. LaRosa JCGrundy SMWaters DDShear CBarter PFruchart JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary diseaseN Engl J Med 200535214251435.
  36. National Institute for Health and Care ExcellenceCG181 Cardiovascular disease: risk assessment and reduction, including lipid modification. 2014. In updated2016.
  37. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experienceEur Heart J 199920725741.
  38. Patel JMartin SSBanach MExpert opinion: the therapeutic challenges faced by statin intoleranceExpert Opin Pharmacother 20161714971507.
  39. Hall KTLoscalzo JKaptchuk TJGenetics and the placebo effect: the placebomeTrends Mol Med 201521285294.
  40. von Haehling SMorley JECoats AJSAnker, SDEthical guidelines for publishing in the Journal of Cachexia, Sarcopenia and Muscle: update 2017J Cachexia Sarcopenia Muscle 2017810811083.