NAFLD in the 21st Century: Current Knowledge Regarding Its Pathogenesis, Diagnosis and Therapeutics

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a major public health issue worldwide. It is the most common liver disease in Western countries, andits global prevalence is estimated to be up to 35%. However, its diagnosis may be elusive, because liver biopsy is relatively rarely performed and usually only in advanced stages of the disease. Therefore, several non-invasive scores may be applied to more easily diagnose and monitor NAFLD. In this review, we discuss the various biomarkers and imaging scores that could be useful in diagnosing and managing NAFLD. Despite the fact that general measures, such as abstinence from alcohol and modulation of other cardiovascular disease risk factors, should be applied, the mainstay of prevention and management is weight loss. Bariatric surgery may be suggested as a means to confront NAFLD. In addition, pharmacological treatment with GLP-1 analogues or the GIP agonist tirzepatide may be advisable. In this review, we focus on the utility of GLP-1 analogues and GIP agonists in lowering body weight, their pharmaceutical potential, and their safety profile, as already evidenced inanimal and human studies. We also elaborate on other options, such as the use of vitamin E, probiotics, especially next-generation probiotics, and prebiotics in this context. Finally, we explore future perspectives regarding the administration of GLP-1 analogues, GIP agonists, and probiotics/prebiotics as a means to prevent and combat NAFLD. The newest drugs pegozafermin and resmetiron, which seem to be very promising, arealso discussed.

MAFLD Pandemic: Updates in Pharmacotherapeutic Approach Development

“…Due to the short half-life of human FGF-21, the development of FGF-21 analogs requires structural modifications to increase stability and avoid rapid elimination from the body [46]. An FGF-21 analog, pegozafermin (BIO89-100), was developed as subcutaneous injection for the therapy of MASH as well as severe hypertriglyceridemia [47]. Being pegylated, pegozafermin has a prolonged half-life compared to FGF-21, so it only needs to be administered once every 14 days [45].…”

“…Based on these encouraging results, pegozafermin entered phase 3 clinical trials (NCT06318169) in March 2024 to evaluate the safety and efficacy of pegozafermin in patients with MASH and fibrosis. A total of 1050 patients will be enrolled in the study, which is expected to be completed in 2029 [47]. Efruxifermin, which exerts an agonistic effect on FGF-21, is another promising drug from this group.…”