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

Authors:

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 | https://doi.org/10.1002/jcsm.12344

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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ACKNOWLEDGEMENTS

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.

Funding

This work was conducted without any specific funding.

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