SGLT2 Inhibitors as the Most Promising Influencers on the Outcome of Non-Alcoholic Fatty Liver Disease

Abstract

Non-alcoholic fatty liver disease (NAFLD), the most frequent liver disease in the Western world, is a common hepatic manifestation of metabolic syndrome (MetS). A specific cure has not yet been identified, and its treatment is currently based on risk factor therapy. Given that the initial accumulation of triglycerides in the liver parenchyma, in the presence of inflammatory processes, mitochondrial dysfunction, lipotoxicity, glucotoxicity, and oxidative stress, can evolve into non-alcoholic steatohepatitis (NASH). The main goal is to identify the factors contributing to this evolution because, once established, untreated NASH can progress through fibrosis to cirrhosis and, ultimately, be complicated by hepatocellular carcinoma (HCC). Several drugs have been tested in clinical trials for use as specific therapy for NAFLD; most of them are molecules used to cure type 2 diabetes mellitus (T2DM), which is one of the main risk factors for NAFLD. Among the most studied is pioglitazone, either alone or in combination with vitamin E, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors. Actually, the most promising category seems to be sodium-glucose cotransporter (SGLT2) inhibitors. Their action is carried out by inhibiting glucose reabsorption in the proximal renal tubule, leading to its increased excretion in urine and decreased levels in plasma. Experimental studies in animal models have suggested that SGLT2 inhibitors may have beneficial modulatory effects on NAFLD/NASH, and several trials in patients have proven their beneficial effects on liver enzymes, BMI, blood lipids, blood glucose, and insulin resistance in NAFLD patients, thus creating strong expectations for their possible use in preventing the evolution of liver damage in these patients. We will review the main pathogenetic mechanisms, diagnostic modalities, and recent therapies of NAFLD, with particular attention to the use of SGLT2 inhibitors.

Relationship of liver fat content with systemic metabolism and chronic complications in patients with type 2 diabetes mellitus

“…NAFLD is closely associated with T2DM, and some studies believe that insulin resistance may serve as a bridge between the etiology and clinical features LDL-C (mmol/L) 3.3 ± 0.9 3.1 ± 1.0 3.4 ± 0.9 2.9 ± 0.9 0.359 of NAFLD and may attribute to the main risk factors for the development of NAFLD [27]. Visceral obesity, T2DM, dyslipidemia, and arterial hypertension are the phenotypic expression of NAFLD, and the presence of one or more of these conditions increases the risk of developing NAFLD [28].…”

No evidence of compensatory changes in energy balance, despite reductions in body weight and liver fat, during dapagliflozin treatment in type 2 diabetes mellitus: A randomized, double‐blind, placebo‐controlled, cross‐over trial (ENERGIZE)

“…[33][34][35][36] However, their potential impact in patients with non-alcoholic fatty liver disease, with or without T2D, is increasingly being recognized. 37 It will be interesting to observe the impact of the combination of SGLT2is and GLP-1 analogues on appetite responses, energy expenditure and body composition, including liver fat/fibrosis in future mechanistic studies. 38 Both classes of drug cause weight loss, albeit through different mechanisms.…”

EVOO’s Effects on Incretin Production: Is There a Rationale for a Combination in T2DM Therapy?

“…The phenolic content of EVOO consists of: phenolic acids (e.g., caffeic, vanillic, coumaric, ferulic and sinapic acids), phenolic alcohols (e.g., tyrosol and hydroxytyrosol), secoiridoids (e.g., oleuropein), lignans (e.g., pinoresinol) and flavones (e.g., luteolin and apigenin) [ 59 , 60 ].…”