Nonalcoholic fatty liver disease (NAFLD) is considered a highly prevalent disease associated with various co-morbidities that lead to socioeconomic burden. Despite large-scale investigation, no pharmacological treatment has been approved specifically for NAFLD to date. Lifestyle modifications and diet are regarded as highly beneficial for the management of NAFLD, albeit with poor compliance, thus rendering pharmacological treatment highly important. Based on the current failure to discover a “magic bullet” to treat all patients with NAFLD and considering the multifaceted pathophysiology of the disease, combination therapies may be considered to be a rational alternative approach. In this regard, several drug categories have been considered, including, but not limited to, lipid-lowering, anti-hypertensive, glucose-lowering, anti-obesity, anti-oxidant, anti-inflammatory and anti-fibrotic medications. The aim of this review is, in addition to summarizing some of the multiple factors contributing to the pathophysiology of NAFLD, to focus on the efficacy of pharmacological combinations on the management of NAFLD. This may provide evidence for a more personalized treatment of patients with NAFLD in the future.

Empagliflozin is a sodium–glucose co-transporter inhibitor approved for the treatment of type 2 diabetes mellitus. The aim of this study was the 6-month effect of empagliflozin on serum and liver lipidome in C57BL/6J mice fed on a fast food diet (FFD). Three groups were studied; two of them fed on FFD, one with empagliflozin (EMPA group), and another without empagliflozin (FFD group); the third group fed on a chow diet and served as the control group (CD group). Following untargeted lipidomic analysis, the FFD and EMPA groups displayed largely similar serum lipid profiles, characterized by elevated levels in the majority of identified lipids, compared with the CD group, particularly glycerophospholipids. For instance, phosphatidylcholine (PC) 34:1 and phosphatidylinositol (PI) 38:3 increased in the FFD compared with the CD group (both p < 0.001, fold change 2.4 and 17.6, respectively) with comparable increases observed in the EMPA group. Hepatic lipid profiles varied more significantly between groups. For example, PC 34:1 was increased in the FFD and in the EMPA compared with the CD group (both p < 0.001, fold change 1.7 and 1.6, respectively), whereas PC 32:0 was decreased in the FFD group and in the EMPA group compared with the CD group (both p < 0.001, fold change 0.6 and 0.5, respectively). FFD appears to have a more substantial impact on lipidomic profiles compared with the preventive empagliflozin effect. Notably, the concentration of lysophosphatidylcholine (LPC) 22:6 was significantly reduced in the EMPA compared with the FFD group (p < 0.001, fold change 1.4). Interestingly, several glycerophospholipids, including PC 34:1, PC 35:1, PC 36:3, PC 38:4, PI 34:2 and PI 38:3, increased in both serum and hepatic tissues of the FFD and EMPA groups compared with the CD group. In conclusion, limited differences in the lipidomic profile were observed in the EMPA compared with the FFD group (e.g., LPC 22:6). However, both the EMPA and FFD groups showed distinct lipidomic profiles compared with the CD group.