Lobeglitazone, a Novel Thiazolidinedione, Improves Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: Its Efficacy and Predictive Factors Related to Responsiveness

Lee, Yong-ho; Kim, Jae Hyeon; Kim, So Ra; Jin, Heung Yong; Rhee, Eun-Jung; Cho, Young Min; Lee, Byung-Wan

In this study, we identified predictive factors that were associated with lobeglitazone responsiveness, and found that individuals with higher values of CAP, WBC, and ALT, and lower values of LSM and γGTP at baseline showed greater reductions in hepatic fat following lobeglitazone treatment. Although most previous trials with TZDs did not analyze predictors of responsiveness, a trial with rosiglitazone showed that responders have lower baseline γGTP levels and higher baseline amounts of steatosis than non-responders (22) , which is consistent with our findings. Similar to previous studies (22, 25) , we also observed greater reductions in the ALT levels of responders, compared with those observed in non-responders, following treatment. Previous studies have also shown that responders show greater increments in serum adiponectin levels after TZD treatment than non-responders (22, 23) . Furthermore, Ratziu et al. (22) reported greater reductions in insulin levels in responders to rosiglitazone than in non-responders, which we did not observe in our trial. Such difference was likely due to the fact that 100% of patients in our study had diabetes, whereas only 32% of the patients in the Ratziu et al. (22) study had diabetes. Moreover, our multiple regression analysis demonstrated that patients treated with metformin and lobeglitazone showed a greater reduction in hepatic steatosis than patients treated with lobeglitazone alone. Previous RCTs have shown inconsistent effects using metformin alone to treat NAFLD (5, 33) ; thus, the combination of metformin and lobeglitazone may synergistically act to reduce hepatic fat. One plausible explanation could be that they act together on the pathogenic heterogeneities in NAFLD. For example, lobeglitazone may play a role in decreasing the availability of plasma fatty acids arising from adipose tissue through abated lipolysis and the positive distribution of fat mass; on the other hand, metformin may activate either fatty acid oxidation or lipophagy, as well as mitophagy, via upregulation of the adenosine monophosphate kinase and/or sirtuin 1 pathways (34, 35) . In addition, metformin may ameliorate the adverse effects of weight gain caused by TZD treatment.