Disease-modifying combination of Dapagliflozin plus Pioglitazone in the Management of Metabolic Dysfunction-associated Fatty Liver Disease in Type 2 Diabetes

Abstract The burden of metabolic dysfunction-associated fatty liver disease (MAFLD) is significantly increasing in individuals with type 2 diabetes (T2D), primarily due to shared metabolic drivers like insulin resistance and adipose tissue dysfunction. Despite its high prevalence in T2D populations, MAFLD often remains underdiagnosed until advanced stages of liver fibrosis have developed. The combination of dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, with pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, as an early intervention strategy has been studied recently. Evidence suggests this combination not only enhances glycemic control but also exerts complementary benefits on hepatic steatosis, inflammation, and fibrosis, potentially modifying disease progression. The weight-lowering and natriuretic effects of dapagliflozin may counterbalance the fluid retention and weight gain effects of pioglitazone, providing a balanced therapeutic profile. Clinical studies show superior improvements in non-invasive liver fibrosis markers with combination therapy compared to monotherapy. Given the pathophysiological overlap between MAFLD and T2D, initiating dual therapy early may offer a strategic advantage in limiting disease advancement. These findings support dapagliflozin and pioglitazone as a promising, synergistic treatment option for MAFLD in T2D, warranting broader clinical adoption. This paper underlines the therapeutic role of dapagliflozin plus pioglitazone for MAFLD in T2D, shedding light on the pathophysiological aspects and clinical significance of the combination.