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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 Bruckert  3 , David Marais  4 , Željko Reiner  5 , Matteo Pirro  6 , Amirhossein Sahebkar  7   8   9 , Gani Bajraktari  10   11 , Erkin Mirrakhimov  12 , Manfredi Rizzo  13   14 , Dimitri P Mikhailidis  15 , Alexandros Sachinidis  13   16 , Dan Gaita  17   18 , Gustavs Latkovskis  19   20 , Mohsen Mazidi  21   22 , Peter P Toth  23   24 , Daniel Pella  25 , Fahad Alnouri  26 , Arman Postadzhiyan  27 , Hung-I Yeh  28 , G B John Mancini  27 , Stephan von Haehling  29   30 , Maciej Banach  31   32   33 ; International Lipid Expert Panel (ILEP)
Collaborators, Affiliations
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.

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.

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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
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
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
Figure 3
Proposed template for the personal lipid intervention plan (PLIP).
See this image and copyright information in PMC

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