Magnitude and Pattern of Placebo Response in Clinical Trials of Oral Antihyperglycemic Agents: Data From the U.S. Food and Drug Administration, 1999-2015

To evaluate the magnitude of placebo response and treatment response patterns in clinical trials of investigational oral antihyperglycemics over time.

We examined the U.S. Food and Drug Administration medical and statistical reviews for 19 oral antihyperglycemic agents (23,438 patients, 50 trials, and 96 treatment arms) approved between 1999 and 2015. Placebo and medication treatment response (HbA_1c reduction) and effect sizes were examined over time (year of approval). Exclusively placebo-controlled and augmented/adjunctive placebo-controlled trials were analyzed separately, and differences were compared. Potential effects of trial and patient characteristics were explored.

In more recent trials, augmented placebo-controlled arms reduced HbA_1c by 0.2% on average and more frequently lowered HbA_1c from baseline compared with exclusively placebo-controlled arms (63 vs. 18%; ² = 9.93; P = 0.002). In exclusively placebo-controlled trials, placebo response increased significantly over time (β = 0.035; R² = 0.31; P = 0.0013), reaching ~0% average change in HbA_1c, whereas drug response also increased significantly (β = 0.017; R² = 0.076; P = 0.0498). In augmented placebo-controlled trials, placebo response (β = 0.33; R² = 0.407; P < 0.001) showed the same pattern, whereas the growth in drug response was not significant (R² = 0.031; P = 0.207). Placebo response in both groups increased by 0.5% HbA_1c reduction over time, whereas effect sizes remained stable with high success rates (100%; 96 out of 96). Drug response and effect size were not significantly predicted by patient or trial characteristics, but follow-up analysis suggested an inverse relationship of placebo baseline HbA_1c with placebo response.

Remarkably, placebo-treated patients with diabetes commonly experienced reduction in HbA_1c, more markedly in augmented compared with exclusively placebo-controlled treatment arms. Placebo response increased significantly over time without impacting efficacy outcomes. Nonpharmacologic effects measured in the placebo response appear stronger when used with active medication than when implemented in isolation and may be related to the level of HbA_1c at baseline.