Substantial placebo, nocebo response seen in obesity trials

In pharmacotherapy trials for obesity, there appears to be strong placebo and nocebo effects, according to a recent Singapore study. These should be taken into consideration for designing future studies.

Sixty-three papers retrieved from the databases of Medline, Embase, and Cochrane CENTRAL were included in the analysis. This analytic sample corresponded to 69 trials with 20,454 placebo patients overall, of whom 18,886 were assessed for the ≥5-percent weight loss threshold. More than a fifth (20.4 percent) achieved this bar. [EClinicalMedicine 2022;54:101685]

Of note, the researchers reported an important effect of study duration. The proportion of patients reaching ≥5 percent weight loss increased progressively as the study grew longer.

A similar effect was reported for the 18,495 placebo-treated patients in whom ≥10-percent weight loss was assessed. In this group, 8.3 percent satisfied the threshold, a proportion that likewise grew in a stepwise manner with increasing study duration.

Meta-regression analysis revealed that participants with diabetes were significantly less likely to experience a placebo effect and show a ≥5-percent (β, –0.85, 95 percent confidence interval [CI], 1.54 to –0.16; p=0.016) and ≥10-percent (β, –1.14, 95 percent CI, 1.81 to –0.48; p=0.00073) weight loss.

Age also emerged as a negative predictor, such that older patients were less likely to achieve both weight loss thresholds (≥5 percent: β, –0.06, 95 percent CI, –0.12 to –0.00; p=0.02; ≥10 percent: β, –0.086, 95 percent CI, –0.13 to –0.01; p=0.015).

Extending the analysis to ≥15-percent weight loss included 3,343 placebo participants, of whom 6.2 percent met the threshold. While there were insufficient studies for a robust meta-regression analysis, such an effect also appeared to be stronger among participants without diabetes.

Similar findings were reported for key secondary outcomes. Placebo participants saw significant reductions in body mass index and average weight, along with marginal improvements in blood markers such as low-density lipoprotein cholesterol, triglycerides, and total cholesterol.

“The observed findings in primary weight-loss outcomes and improvements in the secondary ancillary weight-loss and metabolic markers show that placebo effects can lead to improvements in the overall metabolic milieu of participants with overweight or obesity in these placebo-controlled trials,” the researchers said.

These findings may be attributed to lifestyle programs that these trials often advocate for or to the patients’ increased adherence to healthier behaviours driven by consistent contact with physicians, they added.

Nocebo effects

Aside from placebo effects, the meta-analysis also assessed potential nocebo effects in pharmacological obesity trials, as manifested through adverse events. The researchers found that in 9,408 placebo-treated participants, 73.7 percent developed such side effects, while serious adverse events and discontinuations had corresponding rates of 3.4 percent and 5.2 percent.

Upper respiratory tract infection was the most common systemic adverse event, detected in 13.3 percent of participants.

Of note, 10.3 percent developed injection-site reactions despite receiving placebo. Anxiety and depression were also notable, arising in 2.7 percent and 2.5 percent of participants, respectively.

“We showed and quantified the presence of significant nocebo effects, with up to 74 percent of study subjects experiencing adverse events while taking pharmacologically inert pills,” the researchers said. “These findings may inform the design of future randomized controlled trials examining weight loss medications.”