Pattern of Placebo Response in Oral Antihyperglycemic Agent Drug Trials

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Placebo-treated patients with diabetes commonly experienced a reduction in HbA1c, more markedly in augmented vs exclusively placebo-controlled treatment arms.

Placebo response in individuals participating in efficacy trials of oral antihyperglycemic agents may be increasing over time, more markedly in individuals treated in augmented placebo groups, while simultaneously not having a significant impact on efficacy outcomes in the treatment arms of studies, according to a study published in Diabetes Care.

Researchers examined a total of 51 clinical trials that included 23,438 individuals in 96 treatment arms studying the efficacy of 19 oral antihyperglycemic agents over the course of 16 years (1999 to 2015).

Studies included were gleaned from the US Food and Drug Administration (FDA) database that studied oral antihyperglycemic agents at approved doses intended to lower hemoglobin A1c (HbA1c) levels in adults diagnosed with type 2 diabetes.

The study included 2 different placebo arms: placebo alone; or augmented placebo, in which individuals stabilized on a background medication in addition to placebo in the control group. Individuals in the treatment arm received the background medication in addition to the trial medication. The purpose of the study was to determine whether the placebo response to treatment increased over time.  In addition, if such an increase was found in the placebo arm, researchers examined whether trial efficacy outcomes were affected.

Study results demonstrated an increase in placebo-alone response by 0.035 per year since 1999 with a positive predictive value of R2 0.076 (P =.0498) and an increase in augmented placebo response of 0.33 per year with a positive predictive value of R2 0.407 (P <.001). In the placebo-alone group, drug response increased by 0.017 every year but time was not predictive of any increase or decrease in effect size (R2 0.003, P =.725). In the augmented placebo group, while response increased by 0.33 the increase did not reach statistical significance (R2 0.031, P =.207). Both groups had 100% success rates that did not change over time.

The researchers noted that there was a higher placebo response in the augmented placebo-controlled arms of the studies compared with studies with strictly placebo-controlled arms (0.05 ± 0.23% and –0.19 ± 0.35%, respectively; t=2.8; df=47; P =.008), while the mean drug responses did not differ significantly between groups (0.75 ± 0.35% and 0.72 ± 0.19%, respectively; t = –0.67; df=94; P = .504).  This may contribute to the finding that studies controlled with placebo exclusively had a lower placebo response and a higher mean size effect compared with studies controlled with an augmented placebo group (0.96 ± 0.36 and 0.68 ± 0.20, respectively; t= –4.7; df=94; P <.001). 

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Investigators found that HbA1c levels were reduced from baseline 63% and 18% in the augmented-placebo and placebo-alone control groups, respectively (X2=9.93; df=1; P =.002).  Also of note is the relationship between baseline HbA1c and the subsequent predictable reduction, (exclusive placebo control: β = –0.411, P < .001; augmented placebo control: β = –0.199, P = .008).  Upon closer examination, an inverse relationship was found between baseline and subsequent HbA1c in both placebo-controlled groups: the higher the baseline HbA1c, the smaller the reduction in HbA1c in the placebo-treatment group (R2 0.566; β = –0.32; P <.001) and augmented-placebo controlled group (R2 = 0.454; β = –0.297; P <.001).

Researchers concluded that the effect size and success rates of treatment groups have remained unaffected despite the observed increase in placebo response over time. A higher response observed in the augmented-placebo group suggests a potentially greater nonpharmacologic benefit in patients currently on medication. The placebo responses in both groups compared with treatment arms were found to be nontrivial overall, demonstrating the need for more research regarding nonpharmacologic and pharmacologic elements in research designs.


Khan A, Fahl Mar K, Schilling J, Brown WA. Magnitude and pattern of placebo response in clinical trials of oral antihyperglycemic agents: data from the Food and Drug Administration 1999-2015 [published online January 23, 2018]. Diabetes Care. doi:10.2337/dc17-1316