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

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.

Keywords: Hyperlipidaemia; Nocebo effect; Placebo effect; Primary prevention; Secondary prevention.