Systematic review and synthesis without meta-analysis (SWiM) reveals lack of clinical studies and weak preclinical evidence for interaction between glucose regulating drugs and environmental contaminant exposure

Environmental chemical exposure is associated with T2D incidence and may underly some of the large observed variation in therapeutic responses. Clinical and applicable preclinical studies could help reveal whether environmental chemicals interact with the action of drugs used for glucose management. We systematically searched for studies testing the interaction between environmental contaminants and T2D drug action on glucose regulation outcomes. We found no clinical studies that examined chemical exposure interaction with T2D drug action. Nine of 458 papers were eligible, all of which were preclinical. Four contained in vivo studies, four contained in vitro work and one contained both approaches. Bisphenols were the main focus (n = 4). Inhaled particulates (PM_2.5), polychlorinated biphenyls (PCBs), cadmium, arsenic, and per-and-poly-fluorinated-alkalated substances (PFAS) were each examined once. Metformin and rosiglitazone were the most frequently examined drugs (n = 4). Exendin-4 was investigated twice and glibenclamide once. Lack of study design comparability precluded meta-analysis. Instead, we calculated effect sizes and differences in outcome values (mean ± 95 % CI) for synthesis without meta-analysis (SWiM). Five studies reported impairment of drug action. Our analysis shows support for this conclusion was only present in two papers. Small sample sizes, short duration exposures, unrealistic chemical levels, lack of full factorial analysis and absence of testing in suitable T2D models restrict the applicability of the current, limited preclinical evidence for translation to clinical practice. The potential for chemical exposure to impact T2D medication effects on glucose control needs to be addressed with dedicated clinical studies in patients with T2D.