Semaglutide

BackgroundWith the increasing use of GLP-1 receptor agonists and dual GIP/GLP-1 agonists for managing obesity and type 2 diabetes, understanding their real-world effectiveness and safety is essential. This TriNetX analysis directly compares clinical outcomes among patients treated with tirzepatide vs semaglutide.MethodWe utilized data from the TriNetX Research Network, identifying patients aged > 40 years or with obesity ("BMI ≥ 30 kg/m2") and type 2 diabetes (HbA1c ≥ 6.5% or fasting glucose.≥ 125 mg/dL). Qualifying events were restricted to May 1, 2022, through November 21, 2024. We established two cohorts: one initiating tirzepatide and another semaglutide, ensuring each patient had at least three prescriptions and no prior exposure to the comparator drug or other GLP-1 receptor agonists. The index date was defined as the first co-occurrence of the obesity/diabetes criteria and the respective drug prescription. To ensure comparability, we performed 1:1 propensity matching, resulting in 47,804 patients in each cohort. Outcomes, including all-cause mortality, MACE, heart failure exacerbation, ischemic stroke/TIA, hospitalization/ED use, dementia, UTI, adverse Gastrointestinal (GI) effects, and changes in HbA1c, were assessed within a 1-year window after the index date.ResultsOur matched cohort had a mean age of 75 years, with 45% male patients and 74% identified as white. Patients treated with tirzepatide experienced a significantly lower incidence of MACE at "("3.7% vs 4.1% (RR 0.918, 95% CI 0.862-0.978). All-cause mortality was also lower with tirzepatide (0.2% vs. 0.4%; Risk Ratio 0.436, 95% CI 0.338-0.562). The tirzapetide group achieved better glycemic control with a lower mean HbA1c (6.565% vs. 6.848%; p < 0.001) during the follow-up. There was no significant difference in heart failure exacerbation or UTI incidence. GI side effects were slightly less frequent in the tirzepatide cohort (9.8% vs. 10.2%; Risk Ratio 0.959, 95% CI 0.924-0.997), while hospitalization or emergency visits were comparable between the two groups.ConclusionIn this propensity matched cohort of patients with obesity and type 2 diabetes, tirzepatide demonstrated improved cardiometabolic outcomes compared to semaglutide, including lower all-cause mortality and lower HbA1c. These findings support the cardiovascular safety and efficacy of tirzapetide and highlight the need for further studies to evaluate its effectiveness in broader clinical populations.

BACKGROUND: Metabolic-associated fatty liver disease (MAFLD) is a leading cause of chronic liver disease and is closely linked to type 2 diabetes mellitus (T2DM). The pathogenesis of MAFLD involves complex metabolic imbalances, including impaired fatty acid β-oxidation and chronic inflammation. GLP-1 receptor agonists (GLP-1 RAs) have shown promise in improving metabolic outcomes, but their specific effects on MAFLD remain unclear. This study aims to investigate the molecular mechanisms underlying the hepatic benefits of semaglutide, a GLP-1 RA, in T2DM patients with MAFLD using serum proteomics and metabolomics. METHODS: We conducted a single-centre, longitudinal, data-driven study involving 75 T2DM patients with MAFLD (pre-treatment, PT) and 100 healthy controls (health control, HC). Patients received semaglutide treatment (0.25 mg/week initially, escalated to 0.5 mg/week) for 12 weeks. Serum proteomic and metabolomic profiles were analyzed using 4D-DIA proteomics and LC-MS before and after treatment. Biomarker discovery involved the identification of differential metabolites and proteins, pathway analysis, and integration of proteomic and metabolomic data. Clinical and biochemical parameters were also assessed. RESULTS: Semaglutide significantly improved metabolic and liver parameters, including HbA1c, BMI, HOMA-IR, liver function, IL-6, and liver stiffness (p < 0.01). Multivariate analysis revealed distinct proteomic and metabolomic profiles between baseline and post-treatment groups. A total of 203 differential metabolites and 61 proteins were identified, with key changes including reductions in long-chain fatty acids and inflammatory mediators, alongside increases in carnitine derivatives and anti-inflammatory proteins. Pathway analysis highlighted effects on fatty acid metabolism, PPAR signaling, and NAFLD-related pathways. CONCLUSION: Our study provides a comprehensive multi-omics analysis revealing that semaglutide modulates serum proteomic and metabolomic profiles in T2DM-MAFLD patients, potentially through enhancing mitochondrial β-oxidation, reducing lipid toxicity, and suppressing inflammation. These findings offer mechanistic insights into the hepatic benefits of semaglutide and support its potential as a therapeutic agent for MAFLD. This innovative approach advances our understanding of GLP-1 RAs' multi-organ protective effects and provides a foundation for developing precision medicine strategies for MAFLD.

OBJECTIVE: We aimed to compare the effectiveness and safety of semaglutide 1.0 mg versus dulaglutide 1.5 mg and liraglutide 1.8 mg in patients with type 2 diabetes mellitus (T2DM) under routine clinical care. METHODS: This multicenter, retrospective, real-world study enrolled Chinese adults with T2DM who initiated GLP-1 receptor agonist therapy in endocrinology clinics between January 1, 2022, and August 31, 2024. We compared the effectiveness of these agents on HbA1c and weight loss, with safety as a key exploratory endpoint. Additionally, the UK Prospective Diabetes Study Outcomes Model 2.1 was utilized to project long-term health outcomes. RESULTS: This multicenter retrospective study included 111, 74, and 107 patients treated with semaglutide 1.0 mg, dulaglutide 1.5 mg, and liraglutide 1.8 mg, respectively. After 1:1 propensity score matching, semaglutide demonstrated significantly greater HbA1c reduction compared to both dulaglutide (-0.27% ± 0.70%, p = 0.008) and liraglutide (-0.39% ± 0.87%, p < 0.001), along with higher glycemic target achievement rates. Semaglutide was associated with improved outcomes in all death, cardiovascular death, and other death endpoints. No significant differences in safety profiles were observed among the three treatment groups. CONCLUSIONS: Semaglutide demonstrated superior glycemic control and weight loss compared to both dulaglutide and liraglutide, whereas dulaglutide and liraglutide exhibited comparable clinical efficacy.

Subcutaneous glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to reduce risk of major adverse cardiac events (MACE) for patients with type 2 diabetes (T2DM) who have or are at high risk of cardiovascular disease, but the evaluation of cardiovascular efficacy of oral GLP-1 RAs has yet to be performed. This article reviews results from the SOUL (Semaglutide Cardiovascular Outcomes) trial, whose aim was to assess the cardiovascular benefit in oral semaglutide in high-risk individuals. SOUL was a randomized, double blind, parallel-group, placebo-controlled superiority trial that enrolled 9,650 adults with T2DM who had established atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or both, to receive a maximum daily dose of 14 mg oral semaglutide or placebo. The primary outcome in this study was a composite of time to first CV death, non-fatal MI, or non-fatal stroke. In prespecified secondary analyses, treatment groups were analyzed for an expanded list of CV, CKD, PAD, and HF outcomes. Over a median follow-up of 49.5 months, the risk for MACE was significantly lower in the oral semaglutide compared with the placebo group (HR 0.86; 95% CI, 0.77; 0.96; p = 0.006), and these results were consistent across subgroup analysis, including by sodium glucose co-transporter 2 inhibitor (SGLT2i) drug use. Oral semaglutide reduces the risk of MACE in high-risk patients with T2DM.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) significantly impacts the patients' quality of life due to chronic complications and associated comorbidities. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated benefits in glycemic control. This study evaluates the effect of oral semaglutide on quality of life, metabolic parameters, and treatment adherence of T2DM patients. PATIENTS AND METHODS: We conducted a multicenter prospective observational study Galicia (Spain). A total of 43 adult T2DM patients on oral semaglutide were evaluated at baseline and 3-6 months later using validated questionnaires (DTSQ and EuroQol), anthropometric measures, and metabolic parameters. Changes in quality of life, HbA1c, weight, lipid profile, and insulin dose were analyzed. RESULTS: Oral semaglutide significantly improved quality of life according to the visual analog scale (from 62.8 to 72.6 points; p < 0.001) and DTSQ questionnaire (from 28.2 to 33.0 points; p < 0.001). Significant reductions were observed in HbA1c (8.3% to 7.2%; p < 0.001) and body weight (-4.9%; p = 0.018). The most common adverse effects were nausea and vomiting, reported by 39.5% of patients, with no impact on the overall quality of life. CONCLUSION: Oral semaglutide significantly improves quality of life and metabolic parameters in T2DM patients, with good tolerance and low discontinuation rates. These findings support its utility in the comprehensive management of T2DM.

Bimagrumab is an investigational antibody targeting type II activin receptors, intended to reduce total body and visceral fat mass and promote muscle growth. In this double-blind, placebo-controlled phase 2, trial, 507 adults with obesity (body mass index ≥30 kg m-2 or ≥27 kg m-2 with at least one obesity-associated complication (excluding diabetes) were randomized to nine groups (1:1:1:1:1:1:1:1:1 ratio) to receive treatment for 48 weeks: placebo, bimagrumab (10 mg kg-1 or 30 mg kg-1 intravenously every 12 weeks), semaglutide (1.0 mg or 2.4 mg subcutaneously once a week) and combinations thereof. An open-label treatment extension to week 72 followed. Randomization was stratified by sex across the treatment groups. The primary and secondary endpoints were absolute change from baseline in body weight at week 48 and week 72, respectively. The least squares mean absolute changes in body weight at week 48 were -9.3 kg (bimagrumab 30 mg kg-1), -14.2 kg (semaglutide 2.4 mg) and -17.8 kg (bimagrumab 30 mg kg-1 plus semaglutide 2.4 mg-that is, high-dose combination) versus -3.3 kg (placebo) (all P < 0.001 versus placebo). Continued improvements were observed through week 72. Common adverse events for bimagrumab included muscle spasms, diarrhea and acne, and semaglutide was associated with nausea, diarrhea, constipation and fatigue. Bimagrumab plus semaglutide resulted in substantial reductions in body weight, and safety was consistent with the known safety profiles of both drugs. ClinicalTrials.gov identifier: NCT05616013 .