Semaglutide is a potent GLP-1 receptor agonist used in the treatment of type 2 diabetes mellitus due to its ability to regulate blood glucose levels and promote weight loss. On July 26, 2021, with a manually defined set of computational structural and biophysical analysis, a simple Val27-Arg28 exchange was for the first time introduced in the backbone of semaglutide to strengthen the semaglutide-GLP-1R binding affinity. In this article, a comprehensive structural and biophysical analysis approach is for the first time proposed towards an exhaustive exploration of the semaglutide-GLP-1R sequence space for the design of semaglutide analogues with elevated binding affinity to GLP-1R, thereby potentially enhancing therapeutic efficacy of structurally conceivable semaglutide analogues. Through structure biophysics-based rational design and computational modeling, this article puts forward a set of semaglutide analogues and calculated their binding affinities to GLP-1R, with one particular semaglutide analogue-GLP-1R structural model reaching a K_d of 3.0 × 10^-8 M, while the K_d is 3.4 × 10^-6 M for the binding of native semaglutide to GLP-1. Overall, the computationally designed semaglutide analogues here constitute a hopeful approach for developing GLP-1 receptor agonists with improved efficacy for the treatment of diabetes and weight management in future.

With more than half of U.S. adults reporting alcohol consumption the last 30 days and nearly 6% reporting heavy drinking, alcohol imposes a significant socioeconomic burden. While there are a host of current medications approved to treat alcoholism, they have limited effectiveness and lack support from both providers and patients. Semaglutide, a medication originally developed for obese type 2 diabetics, may offer a distinctly new approach. A survey to assess the impact of semaglutide on alcohol consumption and desire was designed and distributed in semaglutide-user Facebook and Reddit groups. Of those who had reported drinking before starting semaglutide, 21% of respondents (N= 121) ceased drinking altogether, and 88·4% of respondents (N=538) reported a reduction in their desire to consume alcohol after commencing their medication. Respondents also shared further personal accounts of decreased occurrences of compulsive or "addictive" behaviors beyond a reduction in the desire to consume alcohol. Considering the growing number of reports detailing experiences such as these, combined with our survey results indicating a reduction in both frequency and quantity of alcohol consumption, we strongly recommend conducting scientifically rigorous investigations and clinical trials to explore the potential of semaglutide for addressing conditions associated with alcohol use.

Semaglutide is a glucagon-like peptide 1 analog used for the treatment of patients with type 2 diabetes mellitus. With 94% sequence similarity to human GLP-1, semaglutide is a glucagon-like peptide-1 receptor (GLP-1R) agonist, which binds directly to GLP-1R, causing various beneficial downstream effects that reduce blood glucose. Practically, it is favourable for semaglutide to bind not just directly, but also tighter, to its receptor GLP-1R. Therefore, incorporating currently available experimental structural data of semaglutide-GLP-1R, this short article reports for the first time that biophysically, semaglutide is able to bind tighter to GLP-1R with just a simple Val27-Arg28 exchange in its peptide backbone.

Background: The number of people with type 2 diabetes is increasing daily, and therefore effective therapy is needed to successfully regulate glycemia and reduce the risk of associated complications. Recently, an oral formulation of the glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide has become available. Therefore, the aim of our study was to compare the effectiveness of the new oral formulation and the existing injectable formulation of semaglutide in terms of glycemic and body weight control in a real-world setting. Patients and methods: This was a single-center retrospective observational study conducted at the Rijeka Clinical Hospital Centre. A total of 106 patients with inadequately controlled type 2 diabetes (HbA1 ≥ 7%) on different oral or basal insulin supported oral therapy were recruited from the diabetes outpatient clinic, and data from electronic medical records were retrospectively collected and analyzed from May 2021 to November 2022. All subjects were GLP-1 RA naive and consequently prescribed 0.5 or 1.0 mg once weekly injectable semaglutide (IS) or 7 mg or 14 mg once daily oral semaglutide (OS) for at least 6 months. Glycated hemoglo-bin (HbA1c), body weight, and body mass index (BMI) were assessed prior to semaglutide administration and after a 6-month follow-up period. The primary endpoint was the change from baseline in HbA1c, and sec-ondary endpoints were the change in body weight and the proportion of participants with a reduction in body weight of ≥ 5% and ≥ 10%, respectively, 6 months after the initiation of semaglutide treatment. Results: At 6-month follow-up, no significant difference was observed between the two formulations in terms of HbA1c reduction (IS -1.1% vs OS -1.4%, p=0.126) and weight loss (IS -6.50 kg vs OS -5.90 kg, p=0.714). Exactly the same proportion of participants in both groups achieved a weight loss of ≥ 5% (56.7%, n=30). A weight loss ≥ 10% was observed in 20.7% (n=11) of participants administered IS and 15.1% (n=8) of participants adminis-tered OS, respectively (p=0.454). Conclusion: In a real-world setting, oral semaglutide as add-on therapy to ongoing antihyperglycemic treatment in patients with inadequately controlled type 2 diabetes who had not previously received GLP-1 RA demonstrated the same effectiveness as injectable semaglutide in terms of gly-cemic control and weight loss after 6 months of treatment.

Drug-target binding is a crucial parameter in drug discovery and design, ensuring drug efficacy and specificity. Semaglutide, a potent GLP-1 receptor agonist, is widely used to treat type 2 diabetes mellitus by regulating blood glucose levels and promoting weight loss. This study introduces a novel approach utilizing the concept of a general intermolecular binding affinity calculator (GIBAC) for designing semaglutide analogues with enhanced binding affinity to GLP-1R. For the first time, a Val27-Arg28 exchange was manually introduced to strengthen the semaglutide-GLP-1R binding affinity. A comprehensive structural and biophysical analysis was conducted to explore the semaglutide-GLP-1R sequence space, leading to the identification of promising analogues. Among these, one semaglutide analogue demonstrated a binding affinity to GLP-1R that is more than two orders of magnitude (113.3 times) higher than native semaglutide, achieving a Kd of 3.0 x 10^-8 M compared to the Kd of 3.4 x 10^-6 M for native semaglutide. This article proposes a promising structural biophysical approach for developing GLP-1 receptor agonists with improved efficacy. The prototype GIBAC, termed semaGIBAC, represents a paradigm shift in precise drug discovery and design, advocating for the construction of a full-scale GIBAC to be prioritized within the drug discovery and design community.

Some glucagon-like peptide-1 receptor agonists (GLP-1 RAs), first used in the treat-ment of type 2 diabetes mellitus (T2DM), have been approved for the treatment of obe-sity in patients with or without T2DM (liraglutide – LIR, semaglutide - SEM, and tir-zepatide - TIR). Social media had an important influence on the off-label use of GLP-1 RAs for obesity, especially for SEM. We analysed the Google queries related to SEM to assess people's interest in this drug. We also investigated the occurrence of adverse drug reactions (ADRs) by searching the EudraVigilance database (EV) for Individual Case Safety Reports (ICSRs) that reported SEM as the suspected drug and performed a descriptive and a disproportionality analysis. Data obtained for SEM were compared to other GLP-1 RAs. SEM had the highest proportions of searches on Google associated with the term “weight loss” and presented the lowest number of severe ADRs, but it also had the highest number of ICSRs reported in EV. Even though no unexpected safety issues have been reported for it until now, SEM has a high tendency for overdose reports. The most frequent off-label use was reported for SEM and TIR. In order to lower the ADRs’ risks, the off-label use should be reduced and carefully monitored.

Recent media reports commented about a possible antidiabetics’ misuse issue related to molecules promoted as a weight-loss treatment in non-obese people. We evaluated here available pharmacovigilance misuse/abuse signals related to semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, in comparison to other GLP-1 receptor agonists (albiglutide; dulaglutide; exenatide; liraglutide; lixisenatide; tirzepatide) and the phentermine-topiramate combination. To that aim, we analysed the Food and Drug Administration-FDA Adverse Events Reporting System (FAERS) dataset, performing a descriptive analysis of adverse event reports (AER) and calculating related pharmacovigilance measures, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR). During January 2018-December 2022, a total of 31,542 AER involving the selected molecules were submitted to FAERS; most involved dulaglutide (n=11,858; 37.6%) and semaglutide (n=8,249; 26.1%). In comparing semaglutide vs the remaining nolecules, the AER ‘drug abuse’, ‘drug withdrawal syndrome’, ‘prescription drug used without a prescription’ and ‘intentional product use issue’ respective PRR values were 4.05, 4.05, 3.60 and 1.80 (all<0.01). The same comparisons of semaglutide vs the phentermine-topiramate combination were not associated with any significant differences. To the best of our knowledge, this is the first study documenting the misusing/abusing potential of semaglutide in comparison with other GLP1 analogues and the phentermine-topiramate combination. Current findings will need to be confirmed by further empirical investigations to fully understand the safety profile of those molecules.

Recent media reports commented about a possible antidiabetics’ misuse issue related to molecules promoted as a weight-loss treatment in non-obese people. We here evaluated available pharmacovigilance misuse/abuse signals related to semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, in comparison to other GLP-1 receptor agonists (albiglutide; dulaglutide; exenatide; liraglutide; lixisenatide; tirzepatide) and the phentermine-topiramate combination. To that aim, we analysed the Food and Drug Administration-FDA Adverse Events Reporting System (FAERS) dataset, performing a descriptive analysis of adverse event reports (AER) and calculating related pharmacovigilance measures, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR). During January 2018-December 2022, a total of 31,542 AER involving the selected molecules were submitted to FAERS; most involved dulaglutide (n=11,858; 37.6%) and semaglutide (n=8,249; 26.1%). In comparing semaglutide vs the remaining antidiabetics, the AER ‘drug abuse’, ‘drug withdrawal syndrome’, ‘prescription drug used without a prescription’ and ‘intentional product use issue’ respective PRR values were 4.05, 4.05, 3.60 and 1.80 (all<0.01). The same comparisons of semaglutide vs the phentermine-topiramate combination were not associated with any significant differences. To our best, this is the first study documenting the misusing/abusing potential of semaglutide in comparison with other novel antidiabetics and the phentermine-topiramate combination. Current findings will need to be confirmed by further empirical investigations to fully understand the safety profile of those molecules.

Background Obesity is a major healthcare challenge worldwide. Recently, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a promising pharmacological option for managing type 2 diabetes mellitus (T2DM) and obesity in diabetic patients. Objective This systematic review aims to evaluate the efficacy and safety of GLP-1RAs in nondiabetic patients. Methods We systematically reviewed 2356 published articles from the past ten years (2013 to November 22, 2023). After rigorous screening, 11 articles were selected for an in-depth review. The analysis focused on the efficacy and safety of GLP-1RAs in nondiabetic patients, considering various baseline characteristics and subgroups. Results The review found that GLP-1RAs, including exenatide, liraglutide, semaglutide, and the dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist (GIP/GLP-1RA) tirzepatide, significantly promoted weight loss in obese/overweight nondiabetic patients. Additionally, these agents positively affected cardiovascular risk factors such as blood pressure, glycemic control, nephropathy, lipid levels, serum insulin levels, and C-reactive protein (CRP) profiles. However, GLP-1RAs, including tirzepatide, were associated with gastrointestinal adverse drug reactions such as nausea, diarrhea, vomiting, and constipation. These adverse events were typically transient, mild-to-moderate in severity, and subsided over time. Conclusion GLP-1RAs are effective and relatively safe for weight management and improving cardiovascular risk factors in nondiabetic patients, despite the occurrence of some gastrointestinal side effects. Further research is warranted to optimize the use of these agents in nondiabetic populations.

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. Recent data highlight similarities between neurodegenerative diseases including PD and type 2 diabetes mellitus (T2DM) suggesting a crucial interplay between the gut–brain axis. GLP-1R agonists, known for their use in T2DM treatment, are currently extensively studied as novel PD modifying agents. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles and clinical trials regarding GLP-1R agonists and PD, published in the English language with no time restrictions. We also screened the references of the selected articles for possible additional articles in order to include most of the key recent evidence. Our research was conducted between February 2023 and February 2024. We used the terms “GLP-1”, “GLP-1 receptor”, “GLP-1R agonists”, “PD”, “T2DM”, “insulin”, “neurodegenerative disease”, “glucose”, “animal models”, “clinical trials” in different combinations. Many data on animal models and preclinical studies show that GLP1-R agonists can restore dopamine levels, inhibit dopaminergic loss, attenuate neuronal degeneration and alleviate motor and non-motor features of PD. Evidence from clinical studies are also very promising enhancing the possibility of adding GLP1-R agonists in the current armamentarium of drugs available for PD treatment.