Additive effects of evogliptin in combination with pioglitazone on fasting glucose control through direct and indirect hepatic effects in diabetic mice

Due to very limited preclinical reports, pharmacodynamic interactions between dipeptidyl peptidase 4 (DPP4) inhibitors and peroxisome proliferator-activated receptor γ (PPARγ) agonists are not conclusive yet. This study aimed to evaluate the pharmacological responses from adding evogliptin, a DPP4 inhibitor, to pioglitazone, a PPARγ agonist, in diabetic db/db mice after a 2-week treatment. This combination led to further decrease in both fasting and fed blood glucose levels compared to evogliptin alone (P < 0.05), but combination effects were more dramatic in fasting glucose levels (P < 0.05 vs. each treatment alone). Of note, plasma glucagon and high-molecular-weight (HMW) form of adiponectin were also further altered by the combination (P < 0.05 vs. each treatment alone). In line with these results, hepatic gluconeogenic gene expression was normalized by this combination. However, although evogliptin or pioglitazone directly suppressed glucose output in HepG2 hepatocytes, their combination did not further reduce hepatic glucose output. By contrast, glucose utilization of HepG2 cells was synergistically enhanced by this combination regardless of insulin presence (P < 0.05 vs. each treatment alone). These results suggest that the combination of evogliptin and pioglitazone is more efficacious in fasting glucose control through systemic alterations such as decreasing glucagon and increasing adiponectin, and through enhancing glucose utilization. To our knowledge, this is the first report regarding the significant combination effects of DPP4 inhibitors plus PPARγ agonists on plasma HMW adiponectin and hepatic glucose utilization. Our findings provide insight that the evogliptin and pioglitazone combination therapy may be more beneficial in type 2 diabetic patients characterized by exaggerated glucagon dysregulation.