Effect of SGLT-2 Inhibitors in Patients With T2DM and Moderate to Severe Liver Fibrosis

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease worldwide. Type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) commonly exist together. The presentations of NAFLD range from simple steatosis (NAFL), nonalcoholic steatohepatitis (NASH), and cirrhosis. NAFLD has a prevalence of 70% among T2DM patients. This results in adverse outcomes such as higher rates of mortality due to cirrhosis. Cirrhosis and liver failure occurs in 11%-20% in NASH patients. Overweight/obesity and insulin resistance (IR) have been strongly linked with NAFLD. Patients with diabetes or prediabetes had progressive fibrosis when their serial biopsies were studied. Those patients with worsening metabolic risk factors tend to have increased progression from NAFL to NASH and fibrosis.

Non-invasive assessment of disease are based on clinical parameters such as age, sex, liver function test, platelet count, lipid profile, body mass index (BMI), and imaging modalities such as ultrasound (USG), transient Elastography (TE), and magnetic resonance imaging (MRI) mass spectroscopy. Fibrosis stage is recognized as the most objective indicator of liver damage and is the best prognostic marker for morbidity and mortality in liver disease of various etiologies. The rise in the incidence of nonalcoholic steatohepatitis (NASH) has necessitated the development of an effective prevention methodology.

Sodium-glucose cotransporter type-2 (SGLT2) inhibitors are glucose-lowering agents that improve glucose control while promoting weight loss and lowering serum uric acid levels. These agents may exert cardiovascular and renal protection in T2DM patients with established cardiovascular disease. Recent findings from both randomized controlled trials and open-label studies have also shown that SGLT2 inhibitors are able to reduce fatty liver content, as assessed by different imaging techniques, and improve biological markers of NAFLD, especially serum liver enzymes, in patients with T2DM. In addition, there are emerging data to suggest a mechanism beyond the reduction of hyperglycaemia and body weight, and a potential role for the decrease in low-grade inflammation and oxidative stress associated with SGLT2 inhibitor therapy. This positive effect of SGLT2 inhibitors on NAFLD complements their already well-known effects on cardiovascular and chronic kidney diseases.

SGLT2 inhibitors significantly reduced liver fat when added to the standard treatment for T2DM. There are very few studies which have examined the effects of SGLT2 inhibitors in patients with F3 fibrosis. In a randomized controlled trail addition of 5mg/d dapagliflozin(SGLT2 inhibitor) for 24 weeks decreased liver stiffness measure from 14.7 to 11 kPa and also reduced visceral fat. In a prospective non-randomized study 100mg canagliflozin (SGLT-2 inhibitor) administered once daily for 12 months significantly reduced hepatic fat 17.6 to 12 after 6 months measured by magnetic resonance imaging. It also reduced body fat and improved liver enzymes. Another study showed reduction in patients with F4 fibrosis with exenatide once weekly and dapagliflozin once daily at 28 weeks.