GLP-1-based drugs are approved for the treatment of type 2 diabetes mellitus (T2DM) and obesity. Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than 60% of patients with T2DM, and the gut microbiome plays a critical role in its pathogenesis. The gut–liver axis represents a key mechanistic link between dysbiosis and hepatic steatosis. A narrative literature review was conducted using PubMed, Scopus, and ClinicalTrials.gov (2015–2026). Search terms included “GLP-1 receptor agonist,” “microbiome,” “MASLD,” “MASH,” “NAFLD,” “NASH,” “liraglutide,” “semaglutide,” “tirzepatide,” “dulaglutide,” and “exenatide.” Of 363 identified articles, 330 were excluded due to duplication or non-relevant study design; 33 studies (18 preclinical, 15 clinical) were included. In preclinical models, liraglutide demonstrated normalization of the Firmicutes/Bacteroidetes ratio and increased Bifidobacterium and Lactobacillus spp., while tirzepatide significantly reduced hepatic steatosis and increased Akkermansia abundance in diabetic mice. Semaglutide improved gut barrier integrity, increased Alloprevotella and Alistipes, and ameliorated MASLD in murine models. In clinical studies, tirzepatide achieved MASH resolution in 44–62% of patients in the phase 2 SYNERGY-NASH trial. In August 2025, the FDA approved semaglutide for MASH with fibrosis based on the Phase 3 ESSENCE trial. A recent longitudinal study in T2DM patients showed that baseline microbiome composition predicted glycemic response to semaglutide, without significant changes in microbiome diversity. In conclusion, GLP-1-based therapies demonstrate consistent preclinical associations with gut microbiome modulation and reduction in hepatic steatosis. Baseline microbiome composition has been suggested as a potential predictor of treatment response, supporting a personalized approach to MASLD management and warranting future clinical studies.

The global burden of type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise at an alarming pace, with substantial pathophysiological overlap driven by insulin resistance, visceral obesity, and chronic low-grade inflammation. MASLD may progress to metabolic dysfunction-associated steatohepatitis (MASH), with increased risk of cirrhosis and hepatocellular carcinoma. Glucagon-like peptide 1 (GLP-1)-based therapies have transformed the management of T2DM and obesity. They exert pleiotropic effects whose basis remains incompletely understood. Concurrently, Akkermansia muciniphila has emerged as a keystone gut microbiota species with demonstrated hepatoprotective potential in preclinical models of MASLD/MASH. This narrative review positions A. muciniphila simultaneously as a target of GLP-1-mediated microbiome remodeling and as an independent modulator of hepatoprotection in MASLD/MASH. A structured search of PubMed, Scopus, and Web of Science (last searched: 12 April 2026) was conducted using terms related to Akkermansia muciniphila, GLP-1 receptor agonists, MASLD/MASH and T2DM. A total of 174 records were identified. Of these, 148 were excluded due to duplication or non-relevant study design. 26 studies (23 preclinical, 3 clinical) were included in the synthesis, directly addressing A. muciniphila. Preclinical evidence demonstrates that liraglutide, semaglutide, exenatide, and tirzepatide increase A. muciniphila abundance, while A. muciniphila in turn enhances endogenous GLP-1 secretion via the P9/ICAM-2 axis, forming a hypothetical positive feedback loop. A working mechanistic model integrating these bidirectional interactions is proposed, alongside a discussion of current limitations and future research priorities, including microbiome-guided clinical trials in MASLD/MASH populations.

This study investigated changes in serum levels of protein glycation products, specifically fructosamine, methylglyoxal, and advanced glycation end products (AGEs), in rats with a chronic experimental model of type 2 diabetes induced by a high-fat diet and low-dose streptozotocin. Anthropometric, metabolic, and biochemical parameters were monitored. We observed an early and sustained increase in fructosamine and methylglyoxal, followed by a progressive accumulation of AGEs over the 28-week follow-up period. This experimental model enables the investigation of glycation products not only as biomarkers of disease development, severity, and complications but also as potential therapeutic targets through inhibition of their formation, enhancement of their clearance, or modulation of their receptor actions.

Background: Cardiovascular complications are a leading cause of death in patients with type 2 diabetes (T2D). The GLP-1 receptor agonist (GLP-1RA) semaglutide has shown cardiometabolic benefits in individual studies, but a comprehensive analysis of its effects in both oral and subcutaneous formulations is lacking. Objective: This study aimed to systematically evaluate the impact of semaglutide, in oral and subcutaneous formulations, on major adverse cardiovascular events (MACE) in patients with T2D. Methods: This review adhered to the PRISMA guidelines and included a comprehensive search of PubMed, MEDLINE, and Google Scholar from November 2016 to June 2025. High-quality randomized controlled trials (RCTs) comparing semaglutide with placebo in patients with T2D were included. The primary endpoint was MACE, defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Hazard ratio (HR) and 95% confidence intervals (CIs) were pooled using a random-effects model. Results: Of the 127 articles screened, 3 trials involving 16,130 participants met the inclusion criteria. The pooled HR for MACE across the SOUL, SUSTAIN-6, and PIONEER-6 trials was 0.83 (95% CI: 0.76–0.92; I² = 25%), indicating a 17% relative risk reduction with low heterogeneity. Adverse event profiles were comparable between the semaglutide and placebo groups. Conclusions: Semaglutide use was associated with a significant and consistent reduction in MACE in patients with T2D, supporting its role as a valuable therapeutic option for combined glycemic control and cardiovascular risk reduction.

Mylin is a peptide hormone co-synthesized with insulin in pancreatic beta cells at a ratio of 1:100. Notably, amylin has a pronounced tendency to form toxic amyloid fibrils, a characteristic relevant to its pathological role. Purpose: This study aims to review both approved amylin analogs (AAs) and those currently in preclinical and clinical development, with a focus on their molecular structure, pharmacokinetics, receptor activity, and metabolic outcomes. Methods: A comprehensive literature review was conducted using PubMed and clinical trial databases. The analysis focused on structure-function relationships of AAs, biotechnological modifications influencing pharmacokinetics, receptor pharmacology (AMY 1-3), and their effects on glycemic control and appetite. Results: Pramlintide, approved by the FDA in 2005, delays gastric emptying, suppresses postprandial glucagon secretion, improves HbA1c, and induces modest weight loss. Dual amylin-calcitonin receptor agonists (DACRAs) represent next-generation drugs. Davalintide, in phase II trials, has demonstrated reductions in food intake, body weight, and HbA1c. It was ultimately discontinued due to insufficient efficacy and an unfavorable tolerability profile. KBP-089 and KBP-088 have shown favorable metabolic and hepatic effects in preclinical studies. Cagrilintide, a long-acting amylin analog combined with semaglutide (CagriSema), is currently in phase III clinical trials, showing significantly greater weight loss and improved glycemic control compared to monotherapy. Novel investigational agents, including NN1213, eloralintide, petrelintide, MET-233i, and amycretin, have demonstrated substantial weight loss, signaling a new era in amylin-based obesity pharmacotherapy. Conclusion: Amylin analogs present a compelling dual-targeted approach for managing T2D and obesity by improving both glycemic control and weight outcomes. Ongoing clinical trials will further define their long-term therapeutic role.

Oral absorption remains challenging for peptides, proteins, and other drug substances with limited stability or permeability. Sodium N-(8-[2-hydroxybenzoyl]amino)caprylate (SNAC), also known as salcaprozate sodium, is an oral permeation enhancer used in approved drug products. This review summarizes the physicochemical properties and mechanisms of action of SNAC and evaluates its clinical and emerging preclinical applications. A structured literature search was conducted in PubMed and Scopus, supplemented as needed with ClinicalTrials.gov and regulatory documents. The search covered 2015–2026, with earlier key publications included where necessary for historical context. After screening, 71 sources were included in the narrative synthesis. The review examines the proposed mechanisms of SNAC-mediated permeation enhancement, including local pH modulation, membrane-mediated effects, peptide self-association, and context-dependent effects on epithelial permeability. Clinical evidence is summarized for oral semaglutide, cyanocobalamin, unfractionated heparin, ibandronate, and investigational peptide products. Emerging applications beyond metabolic diseases are discussed together with formulation strategies and safety considerations. Recent preclinical findings suggesting changes in gut microbiota and inflammatory markers are critically evaluated in the context of the available clinical safety experience, while their relevance to humans remains unconfirmed. Overall, SNAC reliably enhances permeation in vitro and in vivo, yet the resulting oral bioavailability remains low and variable and is strongly dependent on payload, formulation, and gastrointestinal conditions. Long-term safety and the clinical relevance of recent preclinical microbiome findings remain important areas for future investigation.