Age, sex, disease severity, and disease duration difference in placebo response: implications from a meta-analysis of diabetes mellitus

Abstract

Background The placebo response in patients with diabetes mellitus is very common. A systematic evaluation needs to be updated with the current evidence about the placebo response in diabetes mellitus and the associated factors in clinical trials of anti-diabetic medicine. Methods Literature research was conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for studies published between the date of inception and June 2019. Randomized placebo-controlled trials conducted in type 1and type 2 diabetes mellitus (T1DM/T2DM) were included. Random-effects model and meta-regression analysis were accordingly used. This meta-analysis was registered in PROSPERO as CRD42014009373. Results Significantly weight elevation (effect size (ES) = 0.33 kg, 95% CI, 0.03 to 0.61 kg) was observed in patients with placebo treatments in T1DM subgroup while significantly HbA1c reduction (ES = − 0.12%, 95% CI, − 0.16 to − 0.07%) and weight reduction (ES = − 0.40 kg, 95% CI, − 0.50 to − 0.29 kg) were observed in patients with placebo treatments in T2DM subgroup. Greater HbA1c reduction was observed in patients with injectable placebo treatments (ES = − 0.22%, 95% CI, − 0.32 to − 0.11%) versus oral types (ES = − 0.09%, 95% CI, − 0.14 to − 0.04%) in T2DM (P = 0.03). Older age (β = − 0.01, 95% CI, − 0.02 to − 0.01, P < 0.01) and longer diabetes duration (β = − 0.02, 95% CI, − 0.03 to − 0.21 × 10−2, P = 0.03) was significantly associated with more HbA1c reduction by placebo in T1DM. However, younger age (β = 0.02, 95% CI, 0.01 to 0.03, P = 0.01), lower male percentage (β = 0.01, 95% CI, 0.22 × 10−2, 0.01, P < 0.01), higher baseline BMI (β = − 0.02, 95% CI, − 0.04 to − 0.26 × 10−2, P = 0.02), and higher baseline HbA1c (β = − 0.09, 95% CI, − 0.16 to − 0.01, P = 0.02) were significantly associated with more HbA1c reduction by placebo in T2DM. Shorter diabetes duration (β = 0.06, 95% CI, 0.06 to 0.10, P < 0.01) was significantly associated with more weight reduction by placebo in T2DM. However, the associations between baseline BMI, baseline HbA1c, and placebo response were insignificant after the adjusted analyses. Conclusion The placebo response in diabetes mellitus was systematically outlined. Age, sex, disease severity (indirectly reflected by baseline BMI and baseline HbA1c), and disease duration were associated with placebo response in diabetes mellitus. The association between baseline BMI, baseline HbA1c, and placebo response may be the result of regression to the mean.

Predictors of placebo response in three large clinical trials of the V1a receptor antagonist balovaptan in autism spectrum disorder

“…Placebo response is a ubiquitous challenge in medicine. Though reported symptoms (e.g., pain, fatigue, and psychiatric symptoms) may be particularly vulnerable to expectancy bias and other forms of bias [15][16][17], placebo response has also been demonstrated in studies investigating more "objective" disease markers such as glycosylated hemoglobin in diabetes, hepatocyte histology in non-alcoholic steatohepatitis, body mass index (BMI), and blood pressure [18][19][20][21]. Unsurprisingly, high rates of placebo response have been observed across several ASD randomized controlled trials for multiple symptoms and endpoints [5,7,[22][23][24].…”

Disease‐ and treatment‐related expectations, attitudes, and beliefs among adult patients initiating or switching biological therapies for psoriasis

“…Previous studies suggest that a reduction in PASI correlates with quality of life benefits 38,39 . Baseline disease severity has previously been identified as an independent predictor of placebo response in other clinical conditions 40,41 . In this study, high baseline PASI and high DLQI scores were associated with high overall expectations and high expectations towards effect on socializing/work/partner interaction, respectively.…”

“…38,39 Baseline disease severity has previously been identified as an independent predictor of placebo response in other clinical conditions. 40,41 In this study, high baseline PASI and high DLQI scores were associated with high overall expectations and high expectations towards effect on socializing/work/partner interaction, respectively. This association was also found in a similar study exploring patients' future expectations regarding health-related quality of life.…”

Placebo: a brief updated review

“…A placebo effect has also been observed on blood glucose levels (Lin et al 2020 ), on immune response (Hadamitzky et al 2018 ) and in the treatment of addiction to pharmaceuticals and drugs of abuse, legal or illicit (Evers et al 2018 ; Galindo et al 2020 ). Finally, in Sports Medicine, the use of placebo during training improves performance in a low percentage of athletes in a moderate and significant way (Hurst et al 2020 ).…”