Hormone-based pharmacotherapy for metabolic dysfunction-associated fatty liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has reached epidemic proportions globally in parallel to the rising prevalence of obesity. Despite its significant burden, there is no approved pharmacotherapy specifically tailored for this disease. Many potential drug candidates for MAFLD have encountered setbacks in clinical trials, due to safety concerns or/and insufficient therapeutic efficacy. Nonetheless, several investigational drugs that mimic the actions of endogenous metabolic hormones, including thyroid hormone receptor ß (THRß) agonists, fibroblast growth factor 21 (FGF21) analogues, and glucagon-like peptide-1 receptor agonists (GLP-1RAs), showed promising therapeutic efficacy and excellent safety profiles. Among them, resmetirom, a liver-targeted THRß-selective agonist, has met the primary outcomes in alleviation of metabolic dysfunction-associated steatohepatitis (MASH), the advanced form of MAFLD, and liver fibrosis in phase-3 clinical trials. These hormone-based pharmacotherapies not only exhibit varied degrees of therapeutic efficacy in mitigating hepatic steatosis, inflammation and fibrosis, but also improve metabolic profiles. Furthermore, these three hormonal agonists/analogues act in a complementary manner to exert their pharmacological effects, suggesting their combined therapies may yield synergistic therapeutic benefits. Further in-depth studies on the intricate interplay among these metabolic hormones are imperative for the development of more efficacious combination therapies, enabling precision management of MAFLD and its associated comorbidities.

Effects of microbiome-based interventions on neurodegenerative diseases: a systematic review and meta-analysis.

Neurodegenerative diseases (NDDs) are characterized by neuronal damage and progressive loss of neuron function. Microbiome-based interventions, such as dietary interventions, biotics, and fecal microbiome transplant, have been proposed as a novel approach to managing symptoms and modulating disease progression. Emerging clinical trials have investigated the efficacy of interventions modulating the GM in alleviating or reversing disease progression, yet no comprehensive synthesis have been done. A systematic review of the literature was therefore conducted to investigate the efficacy of microbiome-modulating methods. The search yielded 4051 articles, with 15 clinical trials included. The overall risk of bias was moderate in most studies. Most microbiome-modulating interventions changed the GM composition. Despite inconsistent changes in GM composition, the meta-analysis showed that microbiome-modulating interventions improved disease burden (SMD, - 0.57; 95% CI - 0.93 to - 0.21; I2 = 42%; P = 0.002) with a qualitative trend of improvement in constipation. However, current studies have high methodological heterogeneity and small sample sizes, requiring more well-designed and controlled studies to elucidate the complex linkage between microbiome, microbiome-modulating interventions, and NDDs.

Current status and future perspectives of FGF21 analogues in clinical trials.

Recent advances in fibroblast growth factor 21 (FGF21) biology and pharmacology have led to the development of several long-acting FGF21 analogues and antibody-based mimetics now in various phases of clinical trials for the treatment of obesity-related metabolic comorbidities. The efficacy of these FGF21 analogues/mimetics on glycaemic control and weight loss is rather mild and inconsistent; nevertheless, several promising therapeutic benefits have been reproducibly observed in most clinical studies, including amelioration of dyslipidaemia (particularly hypertriglyceridaemia) and hepatic steatosis, reduction of biomarkers of liver fibrosis and injury, and resolution of metabolic dysfunction-associated steatohepatitis (MASH). Evidence is emerging that combination therapy with FGF21 analogues and other hormones (such as glucagon-like peptide 1; GLP-1) can synergise their pharmacological benefits, thus maximising the therapeutic efficacy for obesity and its comorbidities.