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Abstract Context Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are established therapeutics for type 2 diabetes and obesity. Among other mechanisms, they slow gastric emptying and motility of the small intestine. This helps to limit postprandial glycemic excursions and reduce chylomicron formation and triglyceride absorption. Conversely, motility effects may have detrimental consequences, eg, retained gastric contents at endoscopy or general anesthesia, potentially complicated by pulmonary aspiration or bowel obstruction. Data Acquisition We searched the PubMed database for studies involving GLP-1RA therapy and adverse gastrointestinal/biliary events. Data Synthesis Retained gastric contents at the time of upper gastrointestinal endoscopy are found more frequently with GLP-1 RAs but rarely are associated with pulmonary aspiration. Well-justified recommendations for the periprocedural management of GLP-1RAs (eg, whether to withhold these medications and for how long) are compromised by limited evidence. Important aspects to be considered are (1) their long half-lives, (2) the capacity of GLP-1 receptor agonism to slow gastric emptying even at physiological GLP-1 concentrations, (c) tachyphylaxis observed with prolonged treatment, and (d) the limited effect on gastric emptying in individuals with slow gastric emptying before initiating treatment. Little information is available on the influence of diabetes mellitus itself (ie, in the absence of GLP-1 RA treatment) on retained gastric contents and pulmonary aspiration. Conclusion Prolonged fasting periods regarding solid meal components, point-of-care ultrasound examination for retained gastric content, and the use of prokinetic medications like erythromycin may prove helpful and represent an important area needing further study to increase patient safety for those treated with GLP-1 RAs.

Traumatic brain injury (TBI) represents a significant health concern, with an estimated 70 million annual cases worldwide. Mild brain trauma (concussions) is the most common TBI (81%), followed by moderate (11%) and severe (8%). Cytokine release and neuroinflammation after TBI may cause blood–brain barrier and tissue damage, triggering unfavorable outcomes, including disabilities and mortality. Current TBI treatments, focused on preventing secondary injury, are limited and insufficient. Therefore, new therapeutic approaches are necessary. A growing body of recent literature supports the potential use of incretins: glucagon-like peptide-1, glucose-dependent insulinotropic peptide, and glucagon receptor agonists, as potent neurotrophic/neuroprotective agents. Experiments performed in cellular and animal models, and a limited number of clinical studies, provide evidence that incretins might be a novel and effective treatment for TBI. Incretin-based compounds have already been shown to be safe and efficacious for the treatment of type 2 diabetes mellitus in humans. Therefore, incretins are ideal candidates for rapid evaluation in clinical trials of TBI and might become a novel therapeutic tool for a condition that has very few disease modifying treatments available. Well-designed human clinical trials are urgently needed to determine optimal dosing, timing, and patient selection for effective incretin use in concussion and TBI.

Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A(1c) (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of > or = 3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety. Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5 mug exenatide, or 10 mug exenatide for 30 weeks, followed by 5 mug exenatide BID for 4 weeks, then 10 mug exenatide BID for > or = 3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas. 217 patients (64% male, age 58 +/- 10 years, weight 99 +/- 18 kg, BMI 34 +/- 5 kg/m(2), A1C 8.2 +/- 1.0% [mean +/- SD]) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (-1.1 +/- 0.1% [mean +/- SEM]) were sustained to 3 years (-1.0 +/- 0.1%; p < 0.0001), with 46% achieving A1C < or = 7%. Exenatide progressively reduced body weight from baseline (-5.3 +/- 0.4 kg at 3 years; p < 0.0001). Patients with elevated serum alanine aminotransferase (ALT) at baseline (n = 116) had reduced ALT (-10.4 +/- 1.5 IU/L; p < 0.0001) and 41% achieved normal ALT. Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline (-6.1 +/- 0.6 kg vs. -4.4 +/- 0.5 kg; p = 0.03), however weight change was minimally correlated with baseline ALT (r = -0.01) or ALT change (r = 0.31). Homeostasis Model Assessment B (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n = 151). Triglycerides decreased 12% (p = 0.0003), total cholesterol decreased 5% (p = 0.0007), LDL-C decreased 6% (p < 0.0001), and HDL-C increased 24% (p < 0.0001). Exenatide was generally well tolerated. The most frequent adverse event was mild-to-moderate nausea. The main limitation of this study is the open-label, uncontrolled nature of the study design which does not provide a placebo group for comparison. Adjunctive exenatide treatment for > or = 3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.

Ozempic (semaglutide) has received widespread attention for its appetite-suppressing effects, leading to extensive off-label use for weight loss. Although gastrointestinal side effects are well documented, less is known about how users assess the trade-off between perceived benefits and adverse effects, or how these assessments influence treatment discontinuation. Importantly, existing insights are often limited to clinical trial populations and may not fully reflect real-world experiences. This study applies a novel infoveillance approach to examine patient-reported experiences with off-label Ozempic use for weight loss and to identify the factors most strongly associated with user satisfaction and treatment discontinuation. We analyzed 60 publicly available, self-selected, anonymous user reviews of Ozempic from Drugs.com. Reviews were initially examined using thematic analysis to identify key themes describing patients' lived experiences with treatment. These qualitative themes were then linked to user-provided ratings of perceived drug efficacy (1-10 scale) and statements regarding intent to continue or discontinue treatment. This mixed methods approach enabled the integration of qualitative depth with quantitative patterns within naturally occurring, deidentified online data. Three major themes emerged from the thematic analysis: (1) change in body weight and appetite, (2) nonweight-related symptoms and side effects, and (3) plans for ongoing use versus discontinuation. Two-thirds of respondents reported reduced appetite, food cravings, or body weight. Gastrointestinal complaints were common (reported by 37 of 60, 62%, reviewers) but did not significantly (P=.39) influence satisfaction ratings or decisions to continue treatment. Instead, minimal/no weight loss and the emergence of nongastrointestinal side effects were more frequently associated with low overall satisfaction and discontinuation. Effective weight loss, even when accompanied by gastrointestinal side effects, was associated with a greater willingness to continue Ozempic treatment. This study presents a novel application of infoveillance methods to characterize real-world patient attitudes toward off-label Ozempic use. Satisfaction was driven primarily by perceived effectiveness rather than tolerability. Key limitations are the self-selected nature of the sample, reliance on anonymous, self-reported data, and the lack of demographic, dosing, or treatment-duration information. Nonetheless, these findings underscore the value of online health forums as a rich and underutilized source of patient-centered insights to inform obesity treatment strategies, adherence interventions, and public health communication.

ABSTRACT Background: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A1c (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of ≥ 3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety. Methods: Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5 µg exenatide, or 10 µg exenatide for 30 weeks, followed by 5 µg exenatide BID for 4 weeks, then 10 µg exenatide BID for ≥3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas. Results: 217 patients (64% male, age 58 ± 10 years, weight 99 ± 18 kg, BMI 34 ± 5 kg/m2, A1C 8.2 ± 1.0% [mean ± SD]) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (−1.1 ± 0.1% [mean ± SEM]) were sustained to 3 years (−1.0 ± 0.1%; p < 0.0001), with 46% achieving A1C ≤ 7%. Exenatide progressively reduced body weight from baseline (−5.3 ± 0.4 kg at 3 years; p < 0.0001). Patients with elevated serum alanine aminotransferase (ALT) at baseline (n = 116) had reduced ALT (−10.4 ± 1.5 IU/L; p < 0.0001) and 41% achieved normal ALT. Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline (−6.1 ± 0.6 kg vs. −4.4 ± 0.5 kg; p = 0.03), however weight change was minimally correlated with baseline ALT (r = −0.01) or ALT change (r = 0.31). Homeostasis Model Assessment B (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n = 151). Triglycerides decreased 12% (p = 0.0003), total cholesterol decreased 5% (p = 0.0007), LDL-C decreased 6% (p < 0.0001), and HDL-C increased 24% (p < 0.0001). Exenatide was generally well tolerated. The most frequent adverse event was mild-to-moderate nausea. The main limitation of this study is the open-label, uncontrolled nature of the study design which does not provide a placebo group for comparison. Conclusion: Adjunctive exenatide treatment for ≥3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.

Considerable clinical data on the treatment of type 2 diabetes with incretin-based therapies (glucagon-like peptide 1 receptor agonists [GLP-1RAs] and dipeptidyl-peptidase IV [DPP-4] inhibitors) are available. This meta-analysis was performed to support the understanding of the overall evidence by summarizing the findings from studies of the incretin-based therapies. The MEDLINE, EMBASE, BIOSIS, and BIOSIS trial databases were searched for relevant literature published between January 1, 1990, and June 30, 2011. Search terms included GLP-1, DPP-4, the names of drugs that have been approved by the US Food and Drug Administration for the treatment of diabetes, and the names of drugs that have not been approved but are in late-stage research. Studies were included if they were randomized controlled trials of 12 to 52 weeks' duration and having change from baseline in hemoglobin (Hb) A1c as the primary end point. The random effects meta-analyses models examined HbA1c, fasting plasma glucose (FPG), and body weight for individual therapies, but did not compare effects between therapies. The reviewers identified 362 unique clinical studies, of which 80 were eligible for inclusion in the present meta-analysis. Mean baseline HbA1c values ranged from 7.4% to 10.3% (GLP-1RA studies) and 7.2% to 9.3% (DPP-4 inhibitor studies). The highest maintenance doses of the GLP-1RAs and the DPP-4 inhibitors were associated with changes from baseline in mean HbA1c of −1.1% to −1.6% and −0.6% to −1.1%, respectively. Mean reductions in FPG with exenatide once weekly (QW) or liraglutide once daily were apparently greater than those with exenatide twice daily (BID) and the DPP-4 inhibitors, with the exception of vildagliptin. Mean weight losses with the GLP-1RAs and the DPP-4 inhibitors were >–2.0 and −0.2 to −0.6 kg, respectively. The limitations of the present analysis included a lack of adjustment for placebo use and interstudy heterogeneity associated with differences in methodology (eg, management of concurrent medications, blinding, criteria for treatment discontinuation). All of the incretin-based therapies in the present meta-analysis were associated with significant reductions from baseline in HbA1c and FPG. Further direct comparative studies between the GLP-1RAs and the DPP-4 inhibitors and within the GLP-1RA class are justified.

Glucagon-like peptide-1 (GLP-1)-based drugs have been approved by the United States Food and Drug Administration (FDA) and are widely used to treat type 2 diabetes mellitus (T2DM) and obesity. More recent developments of unimolecular peptides targeting multiple incretin-related receptors (“multi-agonists”), including the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and the glucagon (Gcg) receptor (GcgR), have emerged with the aim of enhancing drug benefits. In this study, we utilized human and mouse microglial cell lines, HMC3 and IMG, respectively, together with the human neuroblastoma SH-SY5Y cell line as cellular models of neurodegeneration. Using these cell lines, we studied the neuroprotective and anti-inflammatory capacity of several multi-agonists in comparison with a single GLP-1 receptor (GLP-1R) agonist, exendin-4. Our data demonstrate that the two selected GLP-1R/GIPR dual agonists and a GLP-1R/GIPR/GcgR triple agonist not only have neurotrophic and neuroprotective effects but also have anti-neuroinflammatory properties, as indicated by the decreased microglial cyclooxygenase 2 (COX2) expression, nitrite production, and pro-inflammatory cytokine release. In addition, our results indicate that these multi-agonists have the potential to outperform commercially available single GLP-1R agonists in neurodegenerative disease treatment.

Purpose Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for managing metabolic disorders such as type 2 diabetes mellitus (T2DM) and obesity. Beyond their metabolic benefits, GLP-1 RAs exhibit neuroprotective and psychotropic effects, potentially benefiting mental health conditions like depression and anxiety. This systematic review aims to synthesize existing evidence on the effects of GLP-1 RAs on mental health outcomes, including both potential therapeutic benefits across various psychiatric disorders and the risk of associated adverse mental health effects. Methods This systematic review was conducted across PubMed/MEDLINE and Web of Science. Inclusion criteria encompassed human and animal studies examining the impact of GLP-1 RAs on mental health. Data from 81 selected studies were extracted and analyzed, focusing on mental health outcomes and reported adverse effects. Findings GLP-1 RAs exhibit potential beneficial effects on depressive symptoms, cognitive function, and reduced risk of suicidal ideation in animal and human models through antioxidative, anti-inflammatory mechanisms, and modulation of neurotransmitter pathways. Additionally, GLP-1 RAs were effective in reducing alcohol and substance use and binge eating behaviors. Adverse psychiatric effects associated with GLP-1 RAs, including depression, anxiety, and suicidal ideation, are noted in pharmacovigilance analyses, with variations among different GLP-1 RAs. Summary GLP-1 RAs hold promise for addressing psychiatric conditions such as depression, anxiety, alcohol and substance use disorders. Despite their potential benefits, the risk of psychiatric adverse effects requires cautious administration. Graphical Abstract

Aims/hypothesis The aim of this 52-week, open-label, non-inferiority trial was to compare the safety and efficacy of exenatide (an incretin mimetic) with that of biphasic insulin aspart. Materials and methods Patients on metformin and a sulfonylurea were randomised to exenatide (n = 253; 5 μg twice daily for 4 weeks, 10 μg thereafter) or biphasic insulin aspart (n = 248; twice-daily doses titrated for optimal glucose control), while continuing with metformin and sulfonylurea treatment. Results Glycaemic control achieved with exenatide was non-inferior to that achieved with biphasic insulin aspart (mean±SEM, HbA₁c change: exenatide -1.04 ± 0.07%, biphasic insulin aspart -0.89 ± 0.06%; difference -0.15 [95% CI -0.32 to 0.01]%). Exenatide-treated patients lost weight, while patients treated with biphasic insulin aspart gained weight [between-group difference -5.4 (95% CI -5.9 to -5.0) kg]. Both treatments reduced fasting serum glucose (exenatide -1.8 ± 0.2 mmol/l, p < 0.001; biphasic insulin aspart -1.7 ± 0.2 mmol/l, p < 0.001). Greater reductions in postprandial glucose excursions following morning (p < 0.001), midday (p = 0.002) and evening meals (p < 0.001) were observed with exenatide. The withdrawal rate was 21.3% (54/253) for exenatide and 10.1% (25/248) for biphasic insulin aspart. Nausea (33% incidence, 3.5% discontinuation) was the most common adverse event observed with exenatide. Conclusions/interpretation Exenatide treatment resulted in HbA₁c reduction similar to biphasic insulin aspart and provided better postprandial glycaemic control, making it a potential alternative for the treatment of type 2 diabetes. Treatment with biphasic insulin aspart was associated with weight gain and lower risk of adverse gastrointestinal events. Although the availability of glucose-lowering agents associated with weight reduction may be considered a therapeutic advance, the long-term implications of progressive weight reduction observed with exenatide have yet to be defined.

This study investigated the neuroprotective effects of exendin-4 (EXE-4), an analog of the glucagon-like peptide 1 receptor (GLP-1R) on memory and on the neuronal populations that constitute the hippocampus of rats submitted to a sporadic dementia of Alzheimer’s type (SDAT). Male Wistar rats received streptozotocin (STZ icv, 3 mg/kg diluted in aCFS, 5 µl/ventricle) and were treated for 21 days with EXE-4 (10 µg/kg, ip; saline as the vehicle). Four groups were formed: vehicle, EXE-4, STZ, and STZ + EXE-4. The groups were submitted to Y-Maze (YM), object recognition (ORT), and object displacement tasks (ODT) to assess learning and memory. The brains were used for immunohistochemical and immunofluorescent techniques with antibodies to NeuN, cleaved caspase-3 (CC3), PCNA, doublecortin (DCX), synaptophysin (SYP), and insulin receptor (IR). STZ worsened spatial memory in the YMT, as well as short-term (STM) and long-term (LTM) memories in the ORT and ODT, respectively. EXE-4 protected against memory impairment in STZ animals. STZ reduced mature neuron density (NeuN) and increased cell apoptosis (CC3) in the DG, CA1, and CA3. EXE-4 protected against neuronal death in all regions. EXE-4 increased PCNA + cells in all regions of the hippocampus, and STZ attenuated this effect. STZ reduced neurogenesis in DG per se as well as synaptogenesis induced by EXE-4. EXE-4 increased immunoreactivity to IR in the CA1. From these findings, EXE-4 showed a beneficial effect on hippocampal pyramidal and granular neurons in the SDAT showing anti-apoptotic properties and promoting cell proliferation. In parallel, EXE-4 preserved the memory of SDAT rats. EXE-4 appears to enhance synapses at CA3 and DG. In conclusion, these data indicate that agonists to GLP-1R have a beneficial effect on hippocampal neurons in AD.