SGLT2 Inhibitor Applications in Metabolic Liver Disease

Sodium–glucose cotransporter 2 (SGLT2) inhibitors, originally developed to lower blood glucose by promoting renal glucose excretion, have emerged as versatile agents in the management of metabolic liver disease. Beyond glycaemic control, these compounds modulate hepatic lipid handling, attenuate inflammation, reduce fibrotic progression and influence systemic energy balance. In preclinical models, SGLT2 inhibition shifts fat deposition away from the liver, ameliorates steatosis and blunts pro-inflammatory cytokine expression. Clinically, treatment is associated with reductions in liver enzymes and imaging markers of steatosis, with accumulating evidence for benefits in non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and even in preventing the transition to cirrhosis or hepatocellular carcinoma (HCC). Mechanistic studies highlight roles for improved insulin sensitivity, adipose tissue remodelling, activation of autophagy and mitigation of endoplasmic reticulum stress. Collectively, SGLT2 inhibitors represent a promising pharmacological strategy to address the global burden of metabolic liver disorders.

Research from Nature Portfolio

Recent studies in genetically susceptible mouse models have demonstrated that selective SGLT2 inhibition can impede the progression of NASH to HCC. In a melanocortin 4 receptor-deficient model fed a Western diet, chronic treatment with an SGLT2 inhibitor reduced hepatic steatosis, suppressed fibrogenic gene expression and cut tumour incidence by more than half. This effect was linked to ‘healthy’ expansion of adipose tissue and lowered oxidative stress within fat depots, suggesting a systemic redistribution of lipids away from the liver. In a related investigation using a diabetic, NASH-prone mouse strain, non-selective SGLT inhibition via phlorizin improved gut barrier integrity, restored microbial balance and prevented hepatocarcinogenesis when intestinal insulin signalling was intact. These findings underscore the interplay between renal glucose handling, intestinal health and liver cancer risk, and reveal novel axes of SGLT2-mediated protection in metabolic liver disease.

SGLT2 Inhibitor Applications in Metabolic Liver Disease publication trend

The graph below shows the total number of articles in sglt2 inhibitor applications in metabolic liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

SGLT2 inhibitor: A class of oral agents that block renal sodium–glucose cotransporter 2, increasing urinary glucose excretion and lowering blood glucose.

Non-alcoholic fatty liver disease (NAFLD): A spectrum of liver conditions characterised by excess fat accumulation in hepatocytes, not due to alcohol intake.

Non-alcoholic steatohepatitis (NASH): A progressive form of NAFLD marked by hepatocellular injury, inflammation and varying degrees of fibrosis.

Hepatocellular carcinoma (HCC): The most common primary liver cancer, often arising in the context of chronic liver injury and cirrhosis.

Autophagy: A cellular degradation pathway that clears damaged organelles and proteins, important in maintaining hepatic metabolic homeostasis.

References

1. Gut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis. Nature Communications (2023).
2. Non-alcoholic fatty liver disease risk with GLP-1 receptor agonists and SGLT-2 inhibitors in type 2 diabetes: a nationwide nested case–control study. Cardiovascular Diabetology (2024).
3. Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study. Diabetologia (2018).
4. Ipragliflozin Improves Hepatic Steatosis in Obese Mice and Liver Dysfunction in Type 2 Diabetic Patients Irrespective of Body Weight Reduction. PLOS ONE (2016).