Meta-analysis of the Placebo and Nocebo effects associated with Placebo treatment in randomized trials of lipid-lowering therapies.

Yip H Chin, Oliver Lim, Chaoxing Lin, Yu Y Chan, Gwyneth Kong, Cheng H Ng, Bryan Chong, Nicholas Syn, Kai E Chan, Mark D Muthiah, Mohammad S Siddiqui, Jiong-Wei Wang, Gemma Figtree, Mark Y Chan, Nicholas W S Chew

Journal: European heart journal. Quality of care & clinical outcomes 2023;9(5):511-519

PMID: 36107462

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Abstract

BACKGROUND

Randomized controlled trials (RCTs) of lipid-lowering therapy (LLT) in which the control groups received placebo without background LLT offer unique insights into the placebo and nocebo effects of lipid-lowering RCTs.

METHODS AND RESULTS

Embase and Medline were searched for hyperlipidaemia RCTs with placebo-controlled arms. Placebo arms with background LLT were excluded. A single arm meta-analysis of proportions was used to estimate major adverse cardiovascular events (MACE) and adverse events (AE). A meta-analysis of means was used to estimate the pooled mean differences of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoproteins (HDL) and triglycerides (TG).A total of 40 RCTs and 37 668 placebo-treated participants were included. The pooled mean changes for TC, LDL, HDL, and TG were -0.019 mmol/L, -0.028 mmol/L, 0.013 mmol/L, and 0.062 mmol/L respectively among placebo-treated participants, indicating a modest placebo effect. The pooled average nocebo effect among placebo-treated participants was 42.62% for all AEs and 3.38% for musculoskeletal-related AEs, 11.36% for gastrointestinal-related AEs, and 6.62% for headaches. Placebo-treated participants in secondary prevention RCTs had a far higher incidence of these nocebo effects than primary prevention RCTs: any AEs (OR 6.76, 95% CI: 5.56-8.24, P < 0.001), and gastrointestinal-related AE (OR 1.23, 95% CI: 1.00-1.51, P = 0.049). No differences in nocebo effects were found between the placebo arms of statin and non-statin trials.

CONCLUSION

Our meta-analysis of placebo-treated participants in RCTs with no background LLT indicate a modest placebo effect but prominent nocebo effect of musculoskeletal, headache, and gastrointestinal symptoms that was greatest among secondary prevention RCTs. These findings may inform the design of future LLT RCTs.

Address: Yong Loo Lin School of Medicine, National University of Singapore, 119077, Singapore.; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, 119074Singapore.; National University Centre for Organ Transplantation, National University Health System, 119074Singapore.; Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, 23284USA.; Department of Surgery, Cardiovascular Research Institute, National University of Singapore, 117599 Singapore.; Nanomedicine Translational Research Program, Centre for NanoMedicine, Yong Loo Lin School of Medicine, National University of Singapore, 117600 Singapore.; Northern Clinical School, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, 2065, Australia.; Department of Cardiology, Royal North Shore Hospital, Sydney, NSW, 2065, Australia.; Department of Cardiology, National University Heart Centre, 119074Singapore.

DOI: 10.1093/ehjqcco/qcac060

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MeSH Terms: Humans, Nocebo Effect, Randomized Controlled Trials as Topic, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipids