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.

Long-Term Prognosis of Patients With Coexisting Obesity and Malnutrition After Acute Myocardial Infarction: A Cohort Study

“…Although not evaluated in the present study due to the lack of data, individuals with lipid-lowering therapies at baseline may present with lower serum cholesterol, yet they represent a potentially high-risk group. 47 Thus, one must be cognizant of the influence that the underlying disease and baseline medications have on the individual components of the nutritional scores that utilize albumin, lymphocyte, and cholesterol levels (used in the CONUT scoring), as well as anthropometric variables (used in the NRI scoring).…”

Hepatic steatosis and advanced hepatic fibrosis are independent predictors of long‐term mortality in acute myocardial infarction

“…This disruption of metabolic homeostasis contributes to accelerated atherosclerosis and cardiovascular risk 41‐43 . Moreover, standard cardiovascular risk scoring measures may be potentially inaccurate in hepatic steatosis as the alterations of hepatic architecture can impair lipid production 44,45 . Integration of hepatic steatosis screening in CVD risk stratification appears promising pending further independent corroboration.…”

A two‐decade population‐based study on the effect of hypertension in the general population with obesity in the United States

“…Both the path mechanisms of poorly controlled hypertension and the underuse of cardioprotective antihypertensive medications may explain the excess mortality observed in the uncontrolled hypertension group. Other guideline‐directed medical therapies such as antiplatelets [33] and statins [34] have also been shown to improve metabolic profile and cardiovascular outcomes. Beyond biological and lifestyle factors, socioeconomic status (SES) has been shown to be an important social determinant of health and obesity, with individuals of lower SES exposed to poverty, inequitable access to health care [35], increased cigarette smoking exposure [36], and stress exposure [37].…”