Background: Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction–Associated Steatohepatitis (MASH) are closely linked to obesity, insulin resistance, metabolic syndrome, and Type 2 Diabetes Mellitus (T2DM), all of which contribute to fibrosis progression and liver-related complications.

Objective: To systematically review the association of metabolic syndrome and T2DM with progression of MASLD/MASH to advanced fibrosis and cirrhosis, and to evaluate the effects of metabolic pharmacotherapies on hepatic and clinical outcomes.

Methods: This systematic review was registered in PROSPERO (CRD420261322056) and conducted according to PRISMA 2020 guidelines. PubMed/MEDLINE, Embase, and Cochrane Library were searched for studies published between January 2016 and September 2025. Randomized controlled trials and prospective controlled studies involving adults with MASLD/MASH, liver fibrosis, or cirrhosis associated with metabolic syndrome and/or T2DM were included. Risk of bias was assessed using RoB 2.0 and certainty of evidence was evaluated using GRADE.

Results: Twenty-six studies were included in the qualitative synthesis. Metabolic dysfunction and insulin resistance were consistently associated with worsening liver disease severity. GLP-1 receptor agonists, dual incretin agonists, and SGLT2 inhibitors were associated with reductions in hepatic steatosis, improvements in liver enzyme levels, better glycemic control, and weight loss. Resolution of MASH and improvement in fibrosis were reported mainly with semaglutide, liraglutide, tirzepatide, and pegozafermin, although evidence for advanced fibrosis regression remained limited and heterogeneous. Lifestyle interventions and sustained weight loss also showed clinically relevant histological benefits. However, evidence for long-term outcomes, including prevention of cirrhosis, hepatocellular carcinoma, hepatic decompensation, and liver-related mortality, remains insufficient.

Conclusion: Metabolic syndrome and T2DM play a central role in the progression of MASLD/MASH toward advanced fibrosis and cirrhosis. Pharmacological strategies targeting metabolic dysfunction, particularly GLP-1 receptor agonists, dual incretin agonists, and SGLT2 inhibitors; appear promising for improving hepatic and metabolic surrogate outcomes, but robust evidence for long-term cirrhosis-related clinical benefit is still lacking.

MASLD/MASH, Type 2 diabetes mellitus, Metabolic syndrome, Liver fibrosis, Cirrhosis, GLP-1 receptor agonists, SGLT2 inhibitors, Fibrosis progression