Combination Therapies for Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is considered a highly prevalent disease associated with various co-morbidities that lead to socioeconomic burden. Despite large-scale investigation, no pharmacological treatment has been approved specifically for NAFLD to date. Lifestyle modifications and diet are regarded as highly beneficial for the management of NAFLD, albeit with poor compliance, thus rendering pharmacological treatment highly important. Based on the current failure to discover a “magic bullet” to treat all patients with NAFLD and considering the multifaceted pathophysiology of the disease, combination therapies may be considered to be a rational alternative approach. In this regard, several drug categories have been considered, including, but not limited to, lipid-lowering, anti-hypertensive, glucose-lowering, anti-obesity, anti-oxidant, anti-inflammatory and anti-fibrotic medications. The aim of this review is, in addition to summarizing some of the multiple factors contributing to the pathophysiology of NAFLD, to focus on the efficacy of pharmacological combinations on the management of NAFLD. This may provide evidence for a more personalized treatment of patients with NAFLD in the future.

To Do One and To Get More: Part II. Diabetes and metabolic dysfunction-associated fatty liver diseases

“…2), although some arguments are present to show a significantly different prognosis between uncomplicated MAFLD and MASH. [96][97][98] A normal healthy hepatocyte plays a major role in the maintenance of general homeostasis, including nutrition, energy, metabolism and detoxication or clearance of debris, and removal of wastes in human body. Hepatocyte also possesses the capacity to store fat in the form of lipids as energy storage.…”

“…13,65–89 In brief, MAFLD, characterized by the fat accumulation >5% (by histological examination) or >5.6% (by magnetic resonance imaging (MRI)-derived proton density fat fraction [MRI-PDFF]) of hepatocytes (presence of steatosis) without excessive alcohol consumption or secondary causes of hepatic steatosis, presents a biggest health hazard globally, based on its potential continuous progression to advanced liver fibrosis (liver cirrhosis) and finally the development of hepatocellular carcinoma (HCC), contributing to the heavy economic and social burdens worldwide. 65–67,88,90–100…”

“…115 So far, evidence, including randomized controlled trials (RCTs), review, and meta-analyses shows at least three classes of ADA, such as insulin sensitizers (metformin and thiazolidinediones), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), glucagon-like peptide-1 receptor agonist (GLP-1R agonist), and so on that may have favorable effects on the spectrum of MAFLD (Table 1). 27,28,30,63,65,67,69,71–84,87,96–98,101,102,108–110,112–114,116,117…”

“…15,65,86,[96][97][98][99] All, augmented by each other for figuring out a vicious cycle play a critical pathogenesis of MAFLD. 15,65,86,[96][97][98][99] The clinical course of FLD is slowly progressed, and initiated from MAFLD, nonalcoholic steatosis (metabolic dysfunctionassociated liver steatosis), MASH, hepatic fibrosis to hepatic cirrhosis (Fig. 2), although some arguments are present to show a significantly different prognosis between uncomplicated MAFLD and MASH.…”

“…The American Association of the Study of Liver Disease (AASLD) recommends using the noninvasive tests, such as biochemistry and image, or an invasive procedure, suchas liver biopsy, to evaluate the NAFLD. [96][97][98]101,[103][104][105] Blood test for biochemistry evaluation is the most convenient and frequently used tool to evaluate the severity of MAFLD, but the abnormality is seldom found at the initial stage of MAFLD or mild MAFLD. These blood tests include basic liver function test, serum iron contents (ferritin, iron, and iron saturation), infection (hepatitis B or hepatitis C), and certain-type of autoimmune antibodies (antinuclear antibody [ANA], antimitochondrial antibody, and antismooth muscular atrophy) and others by indication.…”