Review

. 2022 Jun;13(3):1596-1622.

doi: 10.1002/jcsm.12960. Epub 2022 Mar 10.

Step-by-step diagnosis and management of the nocebo/drucebo effect in statin-associated muscle symptoms patients: a position paper from the International Lipid Expert Panel (ILEP)

Peter E Penson^{1

2}, Eric Bruckert³, David Marais⁴, Željko Reiner⁵, Matteo Pirro⁶, Amirhossein Sahebkar^{7

8

9}, Gani Bajraktari^{10

11}, Erkin Mirrakhimov¹², Manfredi Rizzo^{13

14}, Dimitri P Mikhailidis¹⁵, Alexandros Sachinidis^{13

16}, Dan Gaita^{17

18}, Gustavs Latkovskis^{19

20}, Mohsen Mazidi^{21

22}, Peter P Toth^{23

24}, Daniel Pella²⁵, Fahad Alnouri²⁶, Arman Postadzhiyan²⁷, Hung-I Yeh²⁸, G B John Mancini²⁷, Stephan von Haehling^{29

30}, Maciej Banach^{31

32

33}; International Lipid Expert Panel (ILEP)

Collaborators, Affiliations

Collaborators

International Lipid Expert Panel (ILEP):
Julio Acosta, Mutaz Al-Khnifsawi, Fahad Alnouri, Fahma Amar, Atanas G Atanasov, Gani Bajraktari, Maciej Banach, Sonu Bhaskar, Ibadete Bytyçi, Bojko Bjelakovic, Eric Bruckert, Alberto Cafferata, Richard Ceska, Arrigo F G Cicero, Xavier Collet, Magdalena Daccord, Olivier Descamps, Dragan Djuric, Ronen Durst, Marat V Ezhov, Zlatko Fras, Dan Gaita, Adrian V Hernandez, Steven R Jones, Jacek Jozwiak, Nona Kakauridze, Amani Kallel, Niki Katsiki, Amit Khera, Karam Kostner, Raimondas Kubilius, Gustavs Latkovskis, G B John Mancini, A David Marais, Seth S Martin, Julio Acosta Martinez, Mohsen Mazidi, Dimitri P Mikhailidis, Erkin Mirrakhimov, Andre R Miserez, Olena Mitchenko, Natalya P Mitkovskaya, Patrick M Moriarty, Seyed Mohammad Nabavi, Devaki Nair, Demosthenes B Panagiotakos, György Paragh, Daniel Pella, Peter E Penson, Zaneta Petrulioniene, Matteo Pirro, Arman Postadzhiyan, Raman Puri, Ashraf Reda, Željko Reiner, Dina Radenkovic, Michał Rakowski, Jemaa Riadh, Dimitri Richter, Manfredi Rizzo, Massimiliano Ruscica, Amirhossein Sahebkar, Naveed Sattar, Maria-Corina Serban, Abdullah M A Shehab, Aleksandr B Shek, Cesare R Sirtori, Claudia Stefanutti, Tomasz Tomasik, Peter P Toth, Margus Viigimaa, Pedro Valdivielso, Dragos Vinereanu, Branislav Vohnout, Stephan von Haehling, Michal Vrablik, Nathan D Wong, Hung-I Yeh, Jiang Zhisheng, Andreas Zirlik

Affiliations

¹ School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK.
² Liverpool Centre for Cardiovascular Science, Liverpool, UK.
³ Pitié-Salpetrière Hospital and Sorbonne University, Cardio metabolic Institute, Paris, France.
⁴ Chemical Pathology Division of the Department of Pathology, University of Cape Town Health Science Faculty, Cape Town, South Africa.
⁵ Department of Internal Medicine, University Hospital Centre Zagreb, School of Medicine University of Zagreb, Zagreb, Croatia.
⁶ Department of Medicine, University of Perugia, Perugia, Italy.
⁷ Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
⁸ Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
⁹ Clinic of Cardiology, University Clinical Centre of Kosova, Medical Faculty, University of Prishtina, Prishtina, Kosovo.
¹⁰ Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
¹¹ Department of Internal Disease, Kyrgyz State Medical Academy, Bishkek, Kyrgyzstan.
¹² Department of Atherosclerosis and Coronary Heart Disease, National Center of Cardiology and Internal Diseases, Bishkek, Kyrgyzstan.
¹³ Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy.
¹⁴ Division of Endocrinology, Diabetes and Metabolism, School of Medicine, University of South Carolina, Columbia, SC, USA.
¹⁵ Department of Clinical Biochemistry, University College London Medical School, University College London (UCL), London, UK.
¹⁶ 2nd Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
¹⁷ Universitatea de Medicina si Farmacie Victor Babes, Timisoara, Romania.
¹⁸ Clinica de Cardiologie, Institutul de Boli Cardiovasculare Timisoara, Timisoara, Romania.
¹⁹ Pauls Stradins Clinical University Hospital, Riga, Latvia.
²⁰ University of Latvia, Riga, Latvia.
²¹ Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK.
²² Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
²³ CGH Medical Center, Sterling, IL, USA.
²⁴ Cicarrone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁵ 2nd Department of Cardiology of the East Slovak Institute of Cardiovascular Disease and Faculty of Medicine, PJ Safarik University, Kosice, Slovak Republic.
²⁶ Cardiovascular Prevention Unit, Adult Cardiology Department, Prince Sultan Cardiac Centre Riyadh, Riyadh, Saudi Arabia.
²⁷ Department of General Medicine, Emergency University Hospital 'St. Anna', Medical University of Sofia, Sofia, Bulgaria.
²⁸ Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.
²⁹ Department of Cardiology and Pneumology, Heart Center, University of Göttingen Medical Center, Göttingen, Germany.
³⁰ German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany.
³¹ Polish Moother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland.
³² Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Lodz, Poland.
³³ Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland.

PMID: 35969116
PMCID: PMC9178378
DOI: 10.1002/jcsm.12960

Review

Step-by-step diagnosis and management of the nocebo/drucebo effect in statin-associated muscle symptoms patients: a position paper from the International Lipid Expert Panel (ILEP)

Peter E Penson et al. J Cachexia Sarcopenia Muscle. 2022 Jun.

. 2022 Jun;13(3):1596-1622.

doi: 10.1002/jcsm.12960. Epub 2022 Mar 10.

Authors

Collaborators

International Lipid Expert Panel (ILEP):
Julio Acosta, Mutaz Al-Khnifsawi, Fahad Alnouri, Fahma Amar, Atanas G Atanasov, Gani Bajraktari, Maciej Banach, Sonu Bhaskar, Ibadete Bytyçi, Bojko Bjelakovic, Eric Bruckert, Alberto Cafferata, Richard Ceska, Arrigo F G Cicero, Xavier Collet, Magdalena Daccord, Olivier Descamps, Dragan Djuric, Ronen Durst, Marat V Ezhov, Zlatko Fras, Dan Gaita, Adrian V Hernandez, Steven R Jones, Jacek Jozwiak, Nona Kakauridze, Amani Kallel, Niki Katsiki, Amit Khera, Karam Kostner, Raimondas Kubilius, Gustavs Latkovskis, G B John Mancini, A David Marais, Seth S Martin, Julio Acosta Martinez, Mohsen Mazidi, Dimitri P Mikhailidis, Erkin Mirrakhimov, Andre R Miserez, Olena Mitchenko, Natalya P Mitkovskaya, Patrick M Moriarty, Seyed Mohammad Nabavi, Devaki Nair, Demosthenes B Panagiotakos, György Paragh, Daniel Pella, Peter E Penson, Zaneta Petrulioniene, Matteo Pirro, Arman Postadzhiyan, Raman Puri, Ashraf Reda, Željko Reiner, Dina Radenkovic, Michał Rakowski, Jemaa Riadh, Dimitri Richter, Manfredi Rizzo, Massimiliano Ruscica, Amirhossein Sahebkar, Naveed Sattar, Maria-Corina Serban, Abdullah M A Shehab, Aleksandr B Shek, Cesare R Sirtori, Claudia Stefanutti, Tomasz Tomasik, Peter P Toth, Margus Viigimaa, Pedro Valdivielso, Dragos Vinereanu, Branislav Vohnout, Stephan von Haehling, Michal Vrablik, Nathan D Wong, Hung-I Yeh, Jiang Zhisheng, Andreas Zirlik

Affiliations

¹ School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK.
² Liverpool Centre for Cardiovascular Science, Liverpool, UK.
³ Pitié-Salpetrière Hospital and Sorbonne University, Cardio metabolic Institute, Paris, France.
⁴ Chemical Pathology Division of the Department of Pathology, University of Cape Town Health Science Faculty, Cape Town, South Africa.
⁵ Department of Internal Medicine, University Hospital Centre Zagreb, School of Medicine University of Zagreb, Zagreb, Croatia.
⁶ Department of Medicine, University of Perugia, Perugia, Italy.
⁷ Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
⁸ Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
⁹ Clinic of Cardiology, University Clinical Centre of Kosova, Medical Faculty, University of Prishtina, Prishtina, Kosovo.
¹⁰ Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
¹¹ Department of Internal Disease, Kyrgyz State Medical Academy, Bishkek, Kyrgyzstan.
¹² Department of Atherosclerosis and Coronary Heart Disease, National Center of Cardiology and Internal Diseases, Bishkek, Kyrgyzstan.
¹³ Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy.
¹⁴ Division of Endocrinology, Diabetes and Metabolism, School of Medicine, University of South Carolina, Columbia, SC, USA.
¹⁵ Department of Clinical Biochemistry, University College London Medical School, University College London (UCL), London, UK.
¹⁶ 2nd Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
¹⁷ Universitatea de Medicina si Farmacie Victor Babes, Timisoara, Romania.
¹⁸ Clinica de Cardiologie, Institutul de Boli Cardiovasculare Timisoara, Timisoara, Romania.
¹⁹ Pauls Stradins Clinical University Hospital, Riga, Latvia.
²⁰ University of Latvia, Riga, Latvia.
²¹ Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK.
²² Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
²³ CGH Medical Center, Sterling, IL, USA.
²⁴ Cicarrone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁵ 2nd Department of Cardiology of the East Slovak Institute of Cardiovascular Disease and Faculty of Medicine, PJ Safarik University, Kosice, Slovak Republic.
²⁶ Cardiovascular Prevention Unit, Adult Cardiology Department, Prince Sultan Cardiac Centre Riyadh, Riyadh, Saudi Arabia.
²⁷ Department of General Medicine, Emergency University Hospital 'St. Anna', Medical University of Sofia, Sofia, Bulgaria.
²⁸ Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.
²⁹ Department of Cardiology and Pneumology, Heart Center, University of Göttingen Medical Center, Göttingen, Germany.
³⁰ German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany.
³¹ Polish Moother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland.
³² Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Lodz, Poland.
³³ Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland.

PMID: 35969116
PMCID: PMC9178378
DOI: 10.1002/jcsm.12960

Abstract

Statin intolerance is a clinical syndrome whereby adverse effects (AEs) associated with statin therapy [most commonly statin-associated muscle symptoms (SAMS)] result in the discontinuation of therapy and consequently increase the risk of adverse cardiovascular outcomes. However, complete statin intolerance occurs in only a small minority of treated patients (estimated prevalence of only 3-5%). Many perceived AEs are misattributed (e.g. physical musculoskeletal injury and inflammatory myopathies), and subjective symptoms occur as a result of the fact that patients expect them to do so when taking medicines (the nocebo/drucebo effect)-what might be truth even for over 50% of all patients with muscle weakness/pain. Clear guidance is necessary to enable the optimal management of plasma in real-world clinical practice in patients who experience subjective AEs. In this Position Paper of the International Lipid Expert Panel (ILEP), we present a step-by-step patient-centred approach to the identification and management of SAMS with a particular focus on strategies to prevent and manage the nocebo/drucebo effect and to improve long-term compliance with lipid-lowering therapy.

Keywords: Drucebo effect; Nocebo effect; SAMS; Statin intolerance.

PubMed Disclaimer

Conflict of interest statement

Peter E. Penson has received honoraria and/or travel reimbursement for events sponsored by AKCEA, Amgen, AMRYT, Link Medical, Mylan, Napp, Sanofi; Eric Bruckert: speakers bureau: Servier, Mylan, Sanofi, Amgen, Akcea; consultant to Amgen, MSD, Sanofi, Novartis, Danone, Aegerion, Ionis Pharmaceuticals, Amarin, Akcea, Servier, Mylan, Silence Therpautic; Zeljko Reiner: speakers bureau: Sanofi, Novartis; Gani Bajraktari: speakers bureau: KRKA; Manfredi Rizzo: speakers bureau: Amgen, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Meda, Mylan, Merck Sharp & Dohme, Novo Nordisk, Roche Diagnostics, Sanofi, and Servier; consultant to Amgen, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Meda, Mylan, Merck Sharp & Dohme, Novo Nordisk, Roche Diagnostics, Sanofi, and Servier; Medical and Scientific Advisor, Europe East and South at Novo Nordisk; Dimitri P. Mikhailidis has given talks, acted as a consultant or attended conferences sponsored by Amgen and Novo Nordisk; Gustavs Latkovskis: speakers bureau: Abbott Laboratories, Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Grindex, Medtronic, Mylan, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Servier, Siemens Laboratories, Zentiva; consultant to Amgen, Bayer, Boehringer Ingelheim, Grindex, Novartis, Novo Nordisk, Sanofi, Servier; Peter P. Toth: speakers bureau: Amgen, Esperion, Kowa, Merck, Novo‐Nordisk; consultant to Amarin, bio89, Kowa, Merck, Resverlogix, Theravance; Daniel Pella: received honoraria for events sponsored by Amgen, Jamieson, Novartis, MSD, Pfizer, Servier; Fahad Alnouri is in advisory board and giving lectures supported by Amgen, AMRYT Pharma and Novartis; Stephan von Haehling: has been a paid consultant for and/or received honoraria payments from AstraZeneca, Bayer, Boehringer Ingelheim, BRAHMS, Chugai, Grünenthal, Helsinn, Hexal, Novartis, Pharmacosmos, Respicardia, Roche, Servier, Sorin, and Vifor. SvH reports research support from Amgen, Boehringer Ingelheim, IMI, and the German Center for Cardiovascular Research (DZHK); Maciej Banach: speakers bureau: Amgen, Herbapol, Kogen, KRKA, Polpharma, Mylan/Viatris, Novartis, Novo‐Nordisk, Sanofi‐Aventis, Teva, Zentiva; consultant to Amgen, Daichii Sankyo, Esperion, Freia Pharmaceuticals, Novartis, Novo‐Nordisk, Polfarmex, Sanofi‐Aventis; Grants from Amgen, Mylan/Viatris, Sanofi and Valeant; CMO at Nomi Biotech Corporation Ltd; all other authors have no conflict of interest.

Figures

**Figure 1**
Nocebo, drucebo, and pharmacological effects explained. The nocebo effect refers to adverse effects experienced when taking an inert substance (i.e. the difference in symptom intensity between no treatment, and an inert tablet), and is analogous to the placebo effect (albeit with adverse rather than desired symptoms). The drucebo effect is defined as the difference in the frequency or intensity of symptoms between blinded and open‐label use of a drug. The difference between symptoms experienced with an inert tablet and an apparently identically drug‐containing tablet represents the true pharmacological effect of the drug. Image created using Biorender.com and originally published in *European Heart Journal* ¹⁹ (reused with permission—Licence No. 5203820225699).

**Figure 2**
International Lipid Expert Panel (ILEP) algorithm for the management of the nocebo/drucebo effect in statin‐intolerant patients. Note that SLAP proposes a range of options to be considered in a patient‐centred manner, rather than a set of actions which should be enacted in a particular order. Abbreviations: AE, adverse effects; ALT alanine aminotransferase; CK, creatine kinase; PCSK9I, proprotein convertase subtilisin kexin type 9 inhibitors; SAMS, statin‐associated muscle symptoms; MoAb, monoclonal antibody; SAMS‐CI, statin‐associated muscle symptoms–clinical index; ULN, upper limit of normal.

**Figure 3**
Proposed template for the personal lipid intervention plan (PLIP).

See this image and copyright information in PMC

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References

1. Ference BA, Cannon CP, Landmesser U, Luscher TF, Catapano AL, Ray KK. Reduction of low density lipoprotein‐cholesterol and cardiovascular events with proprotein convertase subtilisin‐kexin type 9 (PCSK9) inhibitors and statins: an analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration. Eur Heart J 2018;39:2540–2545. - PMC - PubMed
1. Reiner Z. Statins in the primary prevention of cardiovascular disease. Nat Rev Cardiol 2013;10:453–464. - PubMed
1. Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532–2561. - PubMed
1. Thompson PD, Panza G, Zaleski A, Taylor B. Statin‐sssociated side effects. J Am Coll Cardiol 2016;67:2395–2410. - PubMed
1. Simic I, Reiner Z. Adverse effects of statins—myths and reality. Curr Pharm Des 2015;21:1220–1226. - PubMed

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Step-by-step diagnosis and management of the nocebo/drucebo effect in statin-associated muscle symptoms patients: a position paper from the International Lipid Expert Panel (ILEP)

Collaborators

Affiliations

Step-by-step diagnosis and management of the nocebo/drucebo effect in statin-associated muscle symptoms patients: a position paper from the International Lipid Expert Panel (ILEP)

Authors

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Abstract

Conflict of interest statement

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