Comparative Clinical Study to Evaluate the Possible Beneficial Effect of Empagliflozin Versus Pioglitazone on Non-diabetic Patients With Non-Alcoholic Steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is a condition of fat accumulation in the liver in the absence of alcohol consumption. Dyslipidemia predominantly hypertriglyceridemia, oxidative stress and insulin resistance play crucial roles in the pathogenesis of NASH. Non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) are the two major subtypes of NAFLD. The patients diagnosed with NASH can subsequently progress to liver fibrosis, which increases the risks of cirrhosis and liver cancer. In Egypt, the prevalence of NAFLD is rising owing to rising prevalence of obesity whereas NAFLD was diagnosed in 57.65% of a cohort of obese Egyptian adolescents. Furthermore, around 1 in 3 had steatosis, and 1 in 20 had moderate-to-advanced fibrosis in Egypt.

NASH is also associated with production of various atherogenic factors including pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) which has been proposed to be the key link between obesity and insulin resistance during NASH. Current guidelines recommend changing lifestyle patterns as first-line therapy strategy for NAFLD. However, there is no defined treatment for NAFLD, previous studies aimed at discovering new treatments for NAFLD and several treatment approaches have been proposed, such as insulin-sensitizers, lipid-lowering drugs, antioxidants, L-carnitine, pentoxifylline, probiotics, ezetimibe, sitagliptin, empagliflozin, pentoxifylline, dapagliflozin, pioglitazone, and lobeglitazone which were reported to reduce liver fat and improve ALT levels in patients with NASH and NAFLD through their anti-inflammatory, antioxidant, and antifibrogenic effects.

Cytokeratin 18 (CK18) is an intermediate filament protein expressed by hepatocytes. Cytokeratin 18 is released into the blood by cell death and hepatocyte apoptosis. Transforming growth factor beta-1 (TGF-β1) cytokine mediates the transformation of quiescent hepatic stellate cells (HSCs) into myofibroblast-like cells with an increased production of extra cellular matrix proteins. TGF-β1 concentration is elevated in patients with NASH as compared to patients with hepatic steatosis, suggesting that this cytokine is involved in the fibrogenesis during NASH.

Although pioglitazone has been proven to enhance metabolism and liver histology among patients with NAFLD, it has limitations in clinical use due to significant adverse events including weight gain, lower extremity edema and risk for heart failure. Pioglitazone is a peroxisome proliferator activated receptor γ (PPARγ) agonist which can protect the liver by improving insulin resistance in patients with NAFLD and T2DM. It has been shown that pioglitazone could improve biochemical and histological parameters in non-diabetic patients with NASH. Previous trial revealed that, pioglitazone improved hepatic fibrosis in patients with NAFLD.

Sodium-glucose co-transporter type-2 inhibitors (SGLT2i) are glucose-lowering agents that improve glucose panel, promote weight loss and reduce serum uric acid level. There is increasing interest regarding the implication of SGLT2i in the treatment of NAFLD, regardless of the co-existence of T2DM. The beneficial effects of SGLT2i on NAFLD appear to be mediated directly through regulation of Endoplasmic Reticulum stress, oxidative stress, low-grade inflammation, autophagy and apoptosis. Empagliflozin (SGLT2i) was reported to decrease the expression of pro-fibrotic genes such as alpha smooth muscle actin (α-SMA), collagen, type I, alpha 1(collagen1α1), Matrix Metalloproteinase -2 (MMP2), and Transforming growth factor beta (TGF-β).