Pioglitazone with SGLT2 inhibitors or GLP-1 receptor agonists in patients with type 2 diabetes and non-alcoholic fatty liver disease: could the combinations of an old friend with new players yield better outcomes?

More than 25% of the adult population worldwide and approximately 50-75% of patients with type 2 diabetes are diagnosed with non-alcoholic fatty liver disease. Insulin resistance is one of the most crucial factors underlying its pathogenesis and a significant determinant of its progression to non-alcoholic steatohepatitis. The complex pathophysiology of non-alcoholic fatty liver disease emphasizes the need for combination treatment strategies with drug classes that target different cellular pathways, since no single agent can control all the mechanisms contributing to its development and evolution. Pioglitazone, the main thiazolidinedione in clinical practice, is the only true insulin sensitizing antidiabetic drug in our therapeutic armamentarium for the treatment of patients with type 2 diabetes. Current international practice guidelines recommend PIO as a promising therapy for patients who experience NASH and type 2 diabetes. GLP-1 receptor agonists and SGLT2 inhibitors have shown salutary cardiometabolic and renal effects in patients with type 2 diabetes, as well as beneficial liver activities in those with non-alcoholic fatty liver disease. This review discusses the pathophysiological background for the use of these three drug categories in patients with type 2 diabetes and non-alcoholic fatty liver disease. It also explores thoroughly the combinations of pioglitazone with either GLP-1 receptor agonists or SGLT2 inhibitors, as well as their future role in this setting.