Assessing Scientific Soundness and Translational Value of Animal Studies on DPP4 Inhibitors for Treating Type 2 Diabetes Mellitus

SIMPLE SUMMARY: The value of animal models to predict human outcomes has been increasingly challenged due to a low rate of translation between preclinical and clinical trials. However, translational failure has been proposed to be at least partly explained by the poor methodological quality of animal studies. We thus retrospectively assessed the predictive value of animal models in Type-2-diabetes research, comparing the same outcome measure (glycaemia) in response to a currently available class of antidiabetic drugs between published clinical trials and animal studies, and assessed methodological quality of the latter. In our sample, both mice and rats performed similarly to humans in response to dipeptidyl peptidase-4 (DPP4) inhibitors. These results, while on animal models of just one disease treated with one drug class, suggest current criticism of animal models may not be entirely warranted, though we found a margin for improvement in the research quality of animal studies. ABSTRACT: Although there is a wide range of animal models of type 2 diabetes mellitus (T2DM) used in research; we have limited evidence on their translation value. This paper provides a) a comparison of preclinical animal and clinical results on the effect of five dipeptidyl peptidase-4 (DPP4) inhibitors by comparing the pharmaceutical caused glucose changes, and b) an evaluation of methodological and reporting standards in T2DM preclinical animal studies. DPP4 inhibitors play an important role in the clinical management of T2DM: if metformin alone is not sufficient enough to control the blood sugar levels, DPP4 inhibitors are often used as second-line therapy; additionally, DPP-4 inhibitors are also used in triple therapies with metformin and sodium-glucose co-transporter-2 (SGLT-2) inhibitors or with metformin and insulin. In our analysis of 124 preclinical studies and 47 clinical trials, (1) we found no evidence of species differences in glucose change response to DPP4 inhibitors, which may suggest that, for this drug class, studies in mice and rats may be equally predictive of how well a drug will work in humans; and (2) there is good reporting of group size, sex, age, euthanasia method and self-reported compliance with animal welfare regulations in animal studies but poor reporting of justification of group size, along with a strong bias towards the use of male animals and young animals. Instead of the common non-transparent model selection, we call for a reflective and evidenced-based assessment of predictive validity of the animal models currently available.