Glucagon-like peptide-1 receptor agonist exendin 4 ameliorates diabetes-associated vascular calcification by regulating mitophagy through the AMPK signaling pathway.

BACKGROUND: Vascular calcification (VC) is a complication in diabetes mellitus (DM) patients. Osteogenic phenotype switching of vascular smooth muscle cells (VSMCs) plays a critical role in diabetes-related VC. Mitophagy can inhibit phenotype switching in VSMCs. This study aimed to investigate the role of the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin 4 (EX4) in mitophagy-induced phenotype switching. MATERIALS AND METHODS: The status of VC in T2DM mice was monitored using Von Kossa and Alizarin Red S (ARS) staining in mouse aortic tissue. Human aortic smooth muscle cells were cultured in high glucose (HG) and ß-glycerophosphate (ß-GP) conditioned medium. Accumulation of LC3B and p62 was detected in the mitochondrial fraction. The effect of EX4 in vitro and in vivo was investigated by knocking down AMPKα1. RESULTS: In diabetic VC mice, EX4 decreased the percentage of von Kossa/ARS positive area. EX4 inhibited osteogenic differentiation of HG/ß-GP-induced VSMCs. In HG/ß-GP-induced VSMCs, the number of mitophagosomes was increased, whereas the addition of EX4 restored mitochondrial function, increased the number of mitophagosome-lysosome fusions, and reduced p62 in mitochondrial frictions. EX4 increased the phosphorylation of AMPKα (Thr172) and ULK1 (Ser555) in HG/ß-GP-induced VSMCs. After knockdown of AMPKα1, ULK1 could not be activated by EX4. The accumulation of LC3B and p62 could not be reduced after AMPKα1 knockdown. Knockdown of AMPKα1 negated the therapeutic effects of EX4 on VC of diabetic mice. CONCLUSION: EX4 could promote mitophagy by activating the AMPK signaling pathway, attenuate insufficient mitophagy, and thus inhibit the osteogenic phenotype switching of VSMCs.

Glucagon-like peptide 1 agonists for type 2 diabetes, weight loss, or both?

ABSTRACT: Glucagon-like peptide 1 agonists (GLP1s) and the novel glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 agonist are effective drugs for reducing A1C and weight in patients with type 2 diabetes. However, clinicians may find it difficult to discern which drug to prescribe in specific clinical scenarios. This article discusses evidence-based clinical use of these drugs.

Exploring the association between suicidal thoughts, self-injury, and GLP-1 receptor agonists in weight loss treatments: Insights from pharmacovigilance measures and unmasking analysis.

INTRODUCTION: The study addresses concerns about potential psychiatric side effects of Glucagon-like peptide-1 receptor agonists (GLP-1 RA). AIM: The aim of this work was to analyse adverse drug reports (ADRs) from the Food and Drug Administration Adverse Events Reporting System (FAERS) using metformin and orlistat as comparators. METHODS: Descriptive and pharmacovigilance disproportionality analyses was performed. RESULTS: A total of 209,354 ADRs were reported, including 59,300 serious cases. Of those, a total of 5378 psychiatric disorder cases, including 383 'serious' cases related to selected ADRs were registered during 2005-2023. After unmasking, 271 cases where individual GLP-1 RA were implicated showing liraglutide (n = 90; Reported Odds Ratio (ROR) = 1.64), exenatide (n = 67; ROR = 0.80), semaglutide (n = 61; ROR = 2.03), dulaglutide (n = 45; ROR = 0.84), tirzepatide (n = 5; ROR = 1.76) and albiglutide (n = 2; ROR = 0.04). A greater association between these ADRs with metformin was observed, but not orlistat. With regards to selected preferred terms (PTs), 42 deaths including 13 completed suicides were recorded. Suicidal ideation was recorded in n = 236 cases for 6/7 GLP-1 RA (excluding lixisenatide). DISCUSSION: Suicide/self-injury reports pertaining to semaglutide; tirzepatide; and liraglutide were characterised, although lower than metformin. It is postulated that rapid weight loss achieved with GLP-1 RA can trigger significant emotional, biological, and psychological responses, hence possibly impacting on suicidal and self-injurious ideations. CONCLUSIONS: With the current pharmacovigilance approach, no causality link between suicidal ideation and use of any GLP-1 RA can be inferred. There is a need for further research and vigilance in GLP-1 RA prescribing, particularly in patients with co-existing psychiatric disorders.

Impact of exenatide on weight loss and eating behavior in adults with craniopharyngioma-related obesity: the CRANIOEXE randomized placebo-controlled trial.

IMPORTANCE: A major issue in the management of craniopharyngioma-related obesity (CRO) is the ineffectiveness of the current therapeutic approaches. OBJECTIVE: To study the efficacy of glucagon-like peptide-1 analogs compared with placebo in adults with obesity CRO. DESIGN: A double-blind multicenter superiority randomized clinical in trial in two parallel arms. SETTING: Eleven French University Hospital Centers. PARTICIPANTS: Adults with CRO (body mass index > 30 kg/m²) without the sign of recurrence of craniopharyngioma in the past year. INTERVENTIONS: Exenatide or placebo injected subcutaneously twice a day during 26 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was the mean change in body weight at week 26 in the intention-to-treat population. Secondary outcomes were eating behavior, calories intake, energy expenditure, cardiovascular, metabolic risk factor, quality of life, and the tolerance profile. RESULTS: At week 26, weight decreased from baseline by a mean of -3.8 (SD 4.3) kg for exenatide and -1.6 (3.8) kg for placebo. The adjusted mean treatment difference was -3.1 kg (95% confidence interval [CI] -7.0 to 0.7, P = 0.11). Results were compatible with a higher reduction of hunger score with exenatide compared with placebo (estimated treatment difference in change from baseline to week 26: -2.3, 95% CI -4.5 to -0.2), while all other outcomes did not significantly differ between groups. Adverse events were more common with exenatide versus placebo, and occurred in, respectively, 19 (95%) participants (108 events) and 14 (70%) participants (54 events). CONCLUSIONS AND RELEVANCE: Combined with intensive lifestyle interventions, a 26-week treatment with exenatide was not demonstrated superior to placebo to treat craniopharyngioma-related obesity.

Glucagon-like peptide-1 receptor agonists modestly reduced blood pressure among patients with and without diabetes mellitus: A meta-analysis and meta-regression.

AIM: The cardiovascular benefits provided by glucagon-like peptide-1 receptor agonists (GLP-1RAs) extend beyond weight reduction and glycaemic control. One possible mechanism may relate to blood pressure (BP) reduction. We aim to quantify the BP-lowering effects of GLP1-RAs. METHODS: A comprehensive database search for placebo-controlled randomized controlled trials on GLP-1RA treatment was conducted until December 2023. Data extraction and quality assessment were carried out, employing a robust statistical analysis using a random effects model to determine outcomes with a mean difference (MD) in mmHg and 95% confidence intervals (CIs). The primary endpoint was the mean difference in systolic BP (SBP) and diastolic BP. Subgroup analyses and meta-regressions were done to account for covariates. RESULTS: Compared with placebo, GLP-1RAs modestly reduced SBP [semaglutide: MD -3.40 (95% CI -4.22 to -2.59, p < .001); liraglutide: MD -2.61 (95% CI -3.48 to -1.74, p < .001); dulaglutide: MD -1.46 (95% CI -2.20 to -0.72, p < .001); and exenatide: MD -3.36 (95% CI -3.63 to -3.10, p < .001)]. This benefit consistently increased with longer treatment durations. Diastolic BP reduction was only significant in the exenatide group [MD -0.94 (95% CI -1.78 to -0.1), p = .03]. Among semaglutide cohorts, mean changes in glycated haemoglobin and mean changes in body mass index were directly associated with SBP reduction. CONCLUSION: Patients on GLP-1RA experienced modest SBP lowering compared with placebo. This observed effect was associated with weight/body mass index reduction and better glycaemic control, which suggests that BP-lowering is an indirect effect of GLP-1RA and unlikely to be responsible for the benefits.

Evaluating appetite/satiety hormones and eating behaviours as predictors of weight loss maintenance with GLP-1RA therapy in adolescents with severe obesity.

INTRODUCTION: Whilst glucagon-like peptide-1 receptor agonists (GLP1-RAs) are effective for treating adolescent obesity, weight loss maintenance (WLM; preventing weight regain) remains a challenge. Our goal was to investigate appetite/satiety hormones and eating behaviours that may predict WLM with exenatide (a GLP1-RA) versus placebo in adolescents with severe obesity. METHODS: Adolescents who had ≥5% body mass index (BMI) reduction with meal replacement therapy were randomized to 52 weeks of once-weekly exenatide extended release or placebo. In this secondary analysis, eating behaviours and appetite/satiety regulation hormones post-meal replacement therapy (pre-randomization to exenatide or placebo) were evaluated as possible predictors of WLM. Percent change in BMI from randomization to 52 weeks served as the primary measure of WLM. RESULTS: The analysis included 66 adolescents (mean age 16.0 years; 47% female). Lower leptin response to meal testing was associated with greater WLM in terms of BMI percent change in those receiving exenatide compared to placebo (p = 0.007) after adjusting for sex, age and BMI. There were no other significant predictors of WLM. CONCLUSIONS: Prior to exenatide, lower leptin response to meals was associated with improved WLM with exenatide compared to placebo. The mostly null findings of this study suggest that GLP1-RA treatment may produce similar WLM for adolescents with obesity regardless of age, BMI, sex and eating behaviours.

Anti-obesity pharmacological agents for polycystic ovary syndrome: A systematic review and meta-analysis to inform the 2023 international evidence-based guideline.

This systematic review and meta-analysis evaluated the efficacy of anti-obesity agents for hormonal, reproductive, metabolic, and psychological outcomes in polycystic ovary syndrome (PCOS) to inform the 2023 update of the International Evidence-based Guideline on PCOS. We searched Medline, EMBASE, PsycInfo, and CINAHL until July 2022 with a 10-year limit to focus on newer agents. Eleven trials (545 and 451 participants in intervention and control arms respectively, 12 comparisons) were included. On descriptive analyses, most agents improved anthropometric outcomes; liraglutide, semaglutide and orlistat appeared superior to placebo for anthropometric outcomes. Meta-analyses were possible for two comparisons (exenatide vs. metformin and orlistat + combined oral contraceptive pill [COCP] vs. COCP alone). On meta-analysis, no differences were identified between exenatide versus metformin for anthropometric, biochemical hyperandrogenism, and metabolic outcomes, other than lower fasting blood glucose more with metformin than exenatide (MD: 0.10 mmol/L, CI 0.02-0.17, I2 = 18%, 2 trials). Orlistat + COCP did not improve metabolic outcomes compared with COCP alone (fasting insulin MD: -8.65 pmol/L, -33.55 to 16.26, I2 = 67%, 2 trials). Published data examining the effects of anti-obesity agents in women with PCOS are very limited. The role of these agents in PCOS should be a high priority for future research.

Effect of glucagon like peptide-1 receptor agonist exenatide, used as an intracranial pressure lowering agent, on cognition in Idiopathic Intracranial Hypertension.

BACKGROUND: Cognitive function can be affected in conditions with raised intracranial pressure (ICP) such as idiopathic intracranial hypertension (IIH). Drugs used off label to treat raised ICP also have cognitive side effects, underscoring the unmet need for effective therapeutics which reduce ICP without worsening cognition. The Glucagon Like Peptide-1 (GLP-1) receptor agonist, exenatide, has been shown to significantly reduce ICP in IIH, therefore this study aimed to determine the effects of exenatide on cognition in IIH. METHODS: This was an exploratory study of the IIH:Pressure trial (ISTCRN 12678718). Women with IIH and telemetric ICP monitors (n = 15) were treated with exenatide (n = 7) or placebo (n = 8) for 12 weeks. Cognitive function was tested using the National Institute of Health Toolbox Cognitive Battery at baseline and 12 weeks. RESULTS: Cognitive performance was impaired in fluid intelligence ((T-score of 50 = population mean), mean (SD) 37.20 (9.87)), attention (33.93 (7.15)) and executive function (38.07 (14.61)). After 12-weeks there was no evidence that exenatide compromised cognition (no differences between exenatide and placebo). Cognition improved in exenatide treated patients in fluid intelligence (baseline 38.4 (8.2), 12 weeks 52.9 (6.6), p = 0.0005), processing speed (baseline 43.7 (9.4), 12 weeks 58.4 (10.4), p = 0.0058) and episodic memory (baseline 49.4 (5.3), 12 weeks 62.1 (13.2), p = 0.0315). CONCLUSIONS: In patients with raised ICP due to IIH, exenatide, a drug emerging as an ICP lowering agent, does not adversely impact cognition. This is encouraging and has potential to be relevant when considering prescribing choices to lower ICP.

Exendin-4: A potential therapeutic strategy for Alzheimer's disease and Parkinson's disease.

Neurodegenerative disorders, which affect millions worldwide, are marked by a steady decline of neurons that are selectively susceptible. Due to the complex pathological processes underlying neurodegeneration, at present, there is no viable therapy available for neurodegenerative disorders. Consequently, the establishment of a novel therapeutic approach for such conditions is a clinical void that remains. The potential significance of various peptides as neuroprotective interventions for neurodegenerative disorders is gaining increasing attention. In the past few years, there has been growing scientific interest in glucagon-like peptide-1 receptor agonists due to their claimed neuroprotective effects. Exendin-4 is a glucagon-like peptide-1 receptor agonist that is known to possess anti-diabetic effects and does not degrade for hours, making it a superior candidate for such disorders. Moreover, exendin-4's neuroprotective effects have been reported in several preclinical studies. Exendin-4's diverse therapeutic targets suggest its potential therapeutic uses in neurodegenerative ailments like Alzheimer's disease and Parkinson's disease and have garnered an increasing amount of attention. Given the substantial body of evidence supporting the neuroprotective potential of exendin-4 in various research models, this article is dedicated to exploring the promising role of exendin-4 as a therapeutic agent for the treatment and management of Alzheimer's disease and Parkinson's disease. This review draws insights from the findings of numerous preclinical and clinical studies to highlight the collective neuroprotective advantages of exendin-4 and the potential mechanisms that underlie its neuroprotective effects.

The role of glucagon-like peptide 1 receptor agonists for weight control in individuals with acquired hypothalamic obesity-A systematic review.

Hypothalamic obesity does not respond well to conventional interventions for obesity. GLP-1 receptor agonists have mechanisms independent of the hypothalamus which may be potentially beneficial for managing hypothalamic obesity. This systematic review summarizes the efficacy and safety of GLP-1 receptor agonists use in hypothalamic obesity. A PRISMA-compliant systematic review was performed. Data was extracted from included studies and analysed based on change in weight, body mass index, glycaemic control, satiety, and safety profile with GLP-1 receptor agonist use. Ten studies comprising 5 case reports, 4 case series and 1 randomized-controlled trial included 54 patients (24 males, 30 females) with mean age of 25.2 (range 13-71) years with hypothalamic obesity who had received GLP-1 receptor agonists (exenatide = 48, liraglutide = 5 and dulaglutide = 1) over a mean duration of treatment of 12 (range 3-51) months. Mean weight reduction of 7.4 (SD 7.92) kg was observed in patients in whom weight was reported, with 85.7% of patients experiencing weight loss. All patients on liraglutide had weight reduction post-therapy. The sole trial had reported a non-significant reduction in BMI post-exenatide. Glycaemic control had either improved/maintained in all patients in whom this was measured. The main side effects of GLP-1 receptor agonist in individuals with hypothalamic obesity were nausea and vomiting; there were no major safety concerns. Based on limited published experience, GLP-1RA may be effective and safe for weight control in hypothalamic obesity, with the added benefit of improved glycaemic control in those with concurrent diabetes mellitus.

Exenatide and Metformin Improve Serum Indices and Intestinal Flora in patients with Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease.

The aim of the study was to investigate th e in flue nce of Exenatide comb ined with Met formin on fasti ng blood glucose, postpr andial glucose, triglycerides, total cholesterol, alanine aminotransferase, aspartate aminotransferase, and inte s tinal flora in typ e 2 diab etes mellitus cases with non-alcoholic fatty liver disease. A total of 128 type 2 diabetes mellitus patients with non-alcoholic fatty liver disease, diagnosed from Januar y 2019 to January 2022, were included and randomly assigned to either G roup A (n=64) or Gro up B (n =64). Group A received Metformin, while Group B received Exenatide injection and Metfor min. After 24 weeks of treat ment, blood glucose indices (fasting blood glucose and postprandial glucose), blood lipid indices (triglycerides and total cholesterol), liver func tion indices (alanine aminotransferase and aspar tate aminotransferase) were all lower in Group B than in Group A (p<0.001 for all). Counts o f Escherichia coli and Enterococcus faecalis were lower in Group B than in Group A (both p<0.05), counts of Bifidobacteria and Lactobacillus were highe r i n Group B than in Grou p A (both p<0.05). Combin ation of Exenati de and Metformi n may have synergistic effects in improving metabo lic an d hepatic pa rameters, a s well as re gulat ing intestinal flora, which cou ld provide a pro misin g therapeutic option for the management of these patients.

Institutional experience on the impact of glucagon-like peptide-1 agonists (GLP-1) on glycemic control and weight loss in patients with type 2 diabetes at the Dubai Diabetes Center, United Arab Emirates.

AIMS: To describe the effect of three classes of GLP1 analogues on HbA1c and weight over one year in a homogenous group of patients at the Dubai Diabetes Center in Dubai, United Arab Emirates. The specific objectives are to study the extent of change in HbA1c and weight loss on these medications as well as the sustainability of change over one year. METHODS: A retrospective audit of patients diagnosed Type 2 diabetes receiving one of the three following GLP-1 agonists (Exenatide LA 2 mg weekly, liraglutide 1.8 mg once daily, Dulaglutide 1.5 mg) over one year and documenting changes in HbA1c and weight at 3-, 6-, 9-, and 12-months intervals. RESULTS: The study shows that while there was significant reduction in HbA1c and weight in the first 3 months, this change was not clinically significant. Also, the change was not maintained at the end of the year. By the final quarter, the effect of the medication diminishes, accompanied by a partial regain of weight. CONCLUSION: GLP1 agonists favorable initial effect on HbA1c and weight may not be sustainable beyond a certain period. The exact reason and factors contributing to this need further exploration.

Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson's disease: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Converging lines of evidence suggest that microglia are relevant to Parkinson's disease pathogenesis, justifying exploration of therapeutic agents thought to attenuate pathogenic microglial function. We sought to test the safety and efficacy of NLY01-a brain-penetrant, pegylated, longer-lasting version of exenatide (a glucagon-like peptide-1 receptor agonist) that is believed to be anti-inflammatory via reduction of microglia activation-in Parkinson's disease. METHODS: We report a 36-week, randomised, double-blind, placebo-controlled study of NLY01 in participants with early untreated Parkinson's disease conducted at 58 movement disorder clinics in the USA. Participants meeting UK Brain Bank or Movement Disorder Society research criteria for Parkinson's disease were randomly allocated (1:1:1) to one of two active treatment groups (2·5 mg or 5·0 mg NLY01) or matching placebo, based on a central computer-generated randomisation scheme using permuted block randomisation with varying block sizes. All participants, investigators, coordinators, study staff, and sponsor personnel were masked to treatment assignments throughout the study. The primary efficacy endpoint for the primary analysis population (defined as all randomly assigned participants who received at least one dose of study drug) was change from baseline to week 36 in the sum of Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III. Safety was assessed in the safety population (all randomly allocated participants who received at least one dose of the study drug) with documentation of adverse events, vital signs, electrocardiograms, clinical laboratory assessments, physical examination, and scales for suicidality, sleepiness, impulsivity, and depression. This trial is complete and registered at ClinicalTrials.gov, NCT04154072. FINDINGS: The study took place between Jan 28, 2020, and Feb 16, 2023. 447 individuals were screened, of whom 255 eligible participants were randomly assigned (85 to each study group). One patient assigned to placebo did not receive study treatment and was not included in the primary analysis. At 36 weeks, 2·5 mg and 5·0 mg NLY01 did not differ from placebo with respect to change in sum scores on MDS-UPDRS parts II and III: difference versus placebo -0·39 (95% CI -2·96 to 2·18; p=0·77) for 2·5 mg and 0·36 (-2·28 to 3·00; p=0·79) for 5·0 mg. Treatment-emergent adverse events were similar across groups (reported in 71 [84%] of 85 patients on 2·5 mg NLY01, 79 [93%] of 85 on 5·0 mg, and 73 [87%] of 84 on placebo), with gastrointestinal disorders the most commonly observed class in active groups (52 [61%] for 2·5 mg, 64 [75%] for 5·0 mg, and 30 [36%] for placebo) and nausea the most common event overall (33 [39%] for 2·5 mg, 49 [58%] for 5·0 mg, and 16 [19%] for placebo). No deaths occurred during the study. INTERPRETATION: NLY01 at 2·5 and 5·0 mg was not associated with any improvement in Parkinson's disease motor or non-motor features compared with placebo. A subgroup analysis raised the possibility of motor benefit in younger participants. Further study is needed to determine whether these exploratory observations are replicable. FUNDING: D&D Pharmatech-Neuraly.

Effects of exenatide on coronary stent's endothelialization in subjects with type 2 diabetes: a randomized controlled trial. The Rebuild study.

BACKGROUND: Subjects with type 2 diabetes (T2D) have a higher risk of in-stent restenosis and stent thrombosis. The activation of the glucagon-like peptide-1 receptor (GLP-1R) has been suggested to induce several effects on the vasculature that may reduce the risk of stent failure following an angioplasty. The aim of this study is to evaluate the effect of the GLP-1R agonist exenatide on endothelialization of a modern drug-eluting stent (DES) in subjects with T2D. METHODS: 38 subjects with T2D who were eligible for revascularization with implantation of DES were randomized to treatment with exenatide (once weekly) plus standard treatment, or to standard treatment alone. After 12 weeks, a new coronary angiography was performed to evaluate the percentage of strut coverage (primary endpoint) and the presence of neo-atherosclerosis by optical coherence tomography. This study was approved by the Stockholm's Ethical Review Board. RESULTS: The two groups were well balanced regarding baseline clinical characteristics. Strut coverage was 95% (88.7-98.5%) in the exenatide group and 91.4% (88.8-98.5%) in the control group (p = 0.692). There were no significant differences between groups neither in the thickness of neo-intima (0.2 mm in both groups, p = 0.471), nor the maximal in-stent obstruction by neo-intima (15.5% in exenatide group vs 14.7% in control group, p = 0.801). No significant differences were detected in the rate of target lesion revascularization between groups (p = 0.224). CONCLUSION: Twelve weeks treatment with exenatide did not lead to a significantly better stent coverage in people with T2D. No significant differences in the occurrence of neo-atherosclerosis were detected between groups. TRIAL REGISTRATION: The study was registered at www. CLINICALTRIALS: gov (Rebuild Study, NCT02621489).

Comparison of exenatide alone or combined with metformin versus metformin in the treatment of polycystic ovaries: a systematic review and meta-analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility in women of childbearing age. Randomized controlled trials (RCTs) have reported that exenatide and metformin are effective in the treatment of PCOS. In this meta-analysis, we aimed to compare the effectiveness and safety of exenatide alone or in combination with metformin versus metformin in patients suffering from PCOS. METHODS: RCTs of exenatide therapy were identified through a search of electronic databases in November 2022 and updated in October 2023. Eligible studies were identified independently by the reviewers. Outcomes were analysed with Revman 5.4. RESULTS: Nine RCTs among 214 studies on 1059 women with PCOS were included in the analysis, and among the nine RCTs, eight studies compared exenatide with metformin. Our meta-analysis demonstrated that exenatide was more effective than metformin in terms of pregnancy rate (RR 1.85 [95% CI 1.19,2.86] P = 0.006), sex hormone-binding globulin (SHBG) (MD 5 [95% CI 3.82,6.18] P < 0.001), and follicle-stimulating hormone (FSH) (MD 0.82 [95% 0.41,1.24] P < 0.001). The reductions in total testosterone (TT) (SMD -0.43 [95% CI -0.84, -0.03] P = 0.04) was more significant after treatment with exenatide than after treatment with metformin. In terms of safety, exenatide had a lower diarrhea rate (RR 0.11 [95% CI 0.01, 0.84]) than metformin. In the other three studies, exenatide plus metformin was compared with metformin. Exenatide combined with metformin was more effective in improving SHBG (MD 10.38[95%CI 6.7,14.06] P < 0.001), Matsuda index (MD 0.21[95%CI 0.05,0.37]) and reducing free androgen index (FAI) (MD -3.34 [-4.84, -1.83] P < 0.001), Weight (MD -2.32 [95%CI -3.89, -0.66]) and WC (MD-5.61[95%CI -8.4, -2.82] P < 0.001). The incidence of side effects between exenatide plus metformin and metformin was not statistically significant. CONCLUSIONS: Exenatide alone or in combination with metformin is more effective than metformin for women with PCOS. Considering the evidence on effectiveness and safety, exenatide alone or in combination with metformin may be a better treatment approach than metformin for women with PCOS. TRIAL REGISTRATION: INPLASY https://inplasy.com/inplasy-protocols/ ID: 10.37766/inplasy2022.11.0055.

Management of Poststroke Hyperglycemia: Results of the TEXAIS Randomized Clinical Trial.

BACKGROUND: Hyperglycemia in acute ischemic stroke reduces the efficacy of stroke thrombolysis and thrombectomy, with worse clinical outcomes. Insulin-based therapies are difficult to implement and may cause hypoglycemia. We investigated whether exenatide, a GLP-1 (glucagon-like peptide-1) receptor agonist, would improve stroke outcomes, and control poststroke hyperglycemia with minimal hypoglycemia. METHODS: The TEXAIS trial (Treatment With Exenatide in Acute Ischemic Stroke) was an international, multicenter, phase 2 prospective randomized clinical trial (PROBE [Prospective Randomized Open Blinded End-Point] design) enrolling adult patients with acute ischemic stroke ≤9 hours of stroke onset to receive exenatide (5 µg BID subcutaneous injection) or standard care for 5 days, or until hospital discharge (whichever sooner). The primary outcome (intention to treat) was the proportion of patients with ≥8-point improvement in National Institutes of Health Stroke Scale score (or National Institutes of Health Stroke Scale scores 0-1) at 7 days poststroke. Safety outcomes included death, episodes of hyperglycemia, hypoglycemia, and adverse event. RESULTS: From April 2016 to June 2021, 350 patients were randomized (exenatide, n=177, standard care, n=173). Median age, 71 years (interquartile range, 62-79), median National Institutes of Health Stroke Scale score, 4 (interquartile range, 2-8). Planned recruitment (n=528) was stopped early due to COVID-19 disruptions and funding constraints. The primary outcome was achieved in 97 of 171 (56.7%) in the standard care group versus 104 of 170 (61.2%) in the exenatide group (adjusted odds ratio, 1.22 [95% CI, 0.79-1.88]; P=0.38). No differences in secondary outcomes were observed. The per-patient mean daily frequency of hyperglycemia was significantly less in the exenatide group across all quartiles. No episodes of hypoglycemia were recorded over the treatment period. Adverse events of mild nausea and vomiting occurred in 6 (3.5%) exenatide patients versus 0 (0%) standard care with no withdrawal. CONCLUSIONS: Treatment with exenatide did not reduce neurological impairment at 7 days in patients with acute ischemic stroke. Exenatide did significantly reduce the frequency of hyperglycemic events, without hypoglycemia, and was safe to use. Larger acute stroke trials using GLP-1 agonists such as exenatide should be considered. REGISTRATION: URL: www.australianclinicaltrials.gov.au; Unique identifier: ACTRN12617000409370. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03287076.

Comparative effectiveness of multiple different treatment regimens for nonalcoholic fatty liver disease with type 2 diabetes mellitus: a systematic review and Bayesian network meta-analysis of randomised controlled trials.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are closely related and mutually contribute to the disease's development. There are many treatment options available to patients. We provide a comprehensive overview of the evidence on the treatment effects of several potential interventions for NAFLD with T2DM. METHODS: This systematic review and network meta-analysis included searches of PubMed, Embase, Cochrane Library, and Web of Science from inception to June 30, 2023, for randomised controlled trials of treatment of NAFLD with T2DM. We performed Bayesian network meta-analyses to summarise effect estimates of comparisons between interventions. We applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) frameworks to rate all comparative outcomes' certainty in effect estimates, categorise interventions, and present the findings. This study was registered with PROSPERO, CRD42022342373. RESULTS: Four thousand three hundred and sixty-nine records were retrieved from the database and other methods, of which 24 records were eligible for studies enrolling 1589 participants. Eight clinical indicators and 14 interventions were finally in focus. Referring to the lower surface under the cumulative ranking curves (SUCRA) and the league matrix table, exenatide and liraglutide, which are also glucagon-like peptide-1 receptor agonists (GLP-1RAs), showed excellent potential to reduce liver fat content, control glycemia, reduce body weight, and improve liver function and insulin resistance. Exenatide was more effective in reducing glycated haemoglobin (HbA1c) (mean difference (MD) 0.32, 95%CI 0.12 to 0.52), lowering BMI (MD 0.81, 95%CI 0.18 to 1.45), and lowering alanine transaminase (ALT) (MD 10.96, 95%CI 5.27 to 16.66) compared to liraglutide. However, this evidence was assessed as low certainty. Omega-3 was the only intervention that did not have a tendency to lower HbA1c, with standard-treatment (STA-TRE) as reference (MD - 0.17, 95%CI - 0.42 to 0.07). Glimepiride is the only intervention that causes an increase in ALT levels, with standard-treatment (STA-TRE) as reference (MD - 11.72, 95%CI - 17.82 to - 5.57). Based on the available evidence, the treatment effects of pioglitazone, dapagliflozin, and liraglutide have a high degree of confidence. CONCLUSIONS: The high confidence mandates the confident application of these findings as guides for clinical practice. Dapagliflozin and pioglitazone are used for glycaemic control in patients with NAFLD combined with T2DM, and liraglutide is used for weight loss therapy in patients with abdominal obesity. The available evidence does not demonstrate the credibility of the effectiveness of other interventions in reducing liver fat content, visceral fat area, ALT, and insulin resistance. Future studies should focus on the clinical application of GLP-1Ras and the long-term prognosis of patients.

Screening for Inflammatory Markers Identifies IL-18Rα as a Potential Link between Exenatide and Its Anti-Inflammatory Effect: New Results from the Combat-JUDO Randomized Controlled Trial.

INTRODUCTION: Obesity is associated with chronic inflammation. Chronic inflammation has also been linked to insulin resistance and type 2 diabetes, metabolic associated fatty liver disease, and cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor analogs (GLP-1RA) are clinically used to treat obesity, with known anti-inflammatory properties. How the GLP-1RA exenatide effects inflammation in adolescents with obesity is not fully investigated. METHODS: Forty-four patients were randomized to receive weekly subcutaneous injections with either 2 mg exenatide or placebo for 6 months. Plasma samples were collected at baseline and at the end of the study, and 92 inflammatory proteins were measured. RESULTS: Following treatment with exenatide, 15 out of the 92 proteins were decreased, and one was increased. However, after adjustment for multiple testing, only IL-18Rα was significantly lowered following treatment. CONCLUSIONS: Weekly injections with 2 mg of exenatide lowers circulating IL-18Rα in adolescents with obesity, which may be a potential link between exenatide and its anti-inflammatory effect in vivo. This contributes to exenatide's pharmaceutical potential as a treatment for obesity beyond weight control and glucose tolerance, and should be further studied mechanistically.

Effects of GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation on offspring outcomes: a systematic review of the evidence.

Aims/hypothesis: Glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors are novel drugs which have recently seen rapid uptake in the treatment of type 2 diabetes and obesity. The paucity of data regarding their safety during pregnancy and lactation causes a dilemma for the physician. The aim of the present study was to systematically review all available data on the offspring effects of GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation. Methods: We systematically searched PubMed, clinicaltrials.gov, FDA and EMA product information on GLP-1 agonists and SGLT2 inhibitors in pregnancy and lactation from inception up to 19 April 2022 without language restrictions. We approached both the Netherlands Pharmacovigilance Centre Lareb on January 17th 2023 and the Teratology Information Service (TIS) of Switzerland on February 6th 2023. Eligible studies investigating the safety (including congenital anomalies, fetal growth, perinatal demise) in animals or humans, or reporting the degree of transfer of these drugs to the fetus, breast milk or breastfed neonate. Two reviewers independently assessed and selected studies for inclusion and subsequently resolved discrepancies by discussion. Results: We included 39 records (n=9 theoretical; based on drug properties, n=7 human; n=23 animal, including 76 human offspring, and an unknown number of animal offspring as these numbers could not be retrieved from the FDA and EMA product information). In animal studies, GLP1-agonists were associated with reduced fetal weight and/or growth, delayed ossification and skeletal variants, usually associated with a reduction in maternal weight gain and decreased food consumption. Exendin-4 (GLP1-agonist) was not transported across the maternal-fetal placental interface. In human studies, exenatide (GLP1-agonist) showed a fetal-to-maternal peptide concentration ratio of ≤ 0.017 in ex vivo human placental perfusion in a single placenta. Liraglutide (GLP1-agonist) showed no significant maternal to fetal transfer at least 3.5 hours after maternal exposure in a human study with one subject. In animal studies, GLP-1 agonists were excreted in breast milk; human data on excretion were not available. In animal studies, SGLT2 inhibitors were generally safe during the first trimester but exposure during postnatal day 21 to 90 in juvenile rats, a period coinciding with the late second and third trimester of human renal development, caused dilatation of the renal pelvis and tubules. Human data consisted of a pharmaceutical database of inadvertent pregnancies during SGLT2 inhibitor use, which found an increase in miscarriages and congenital malformations. In animal studies SGLT2 inhibitors were excreted in breast milk and affected neonatal growth, but human data are not available. Conclusion/interpretation: We found evidence for adverse offspring effects of GLP-1 agonists and SGLT2 inhibitors also in human studies. Our findings broadly support the advice to discontinue GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation, and also support the ongoing registration of pregnancy outcomes in pharmacological databases since the amount of available data is scarce and mostly limited to animal studies. Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=219877.

Cold Exposure and Oral Delivery of GLP-1R Agonists by an Engineered Probiotic Yeast Strain Have Antiobesity Effects in Mice.

Advanced microbiome therapeutics (AMTs) holds promise in utilizing engineered microbes such as bacteria or yeasts for innovative therapeutic applications, including the in situ delivery of therapeutic peptides. Glucagon-like peptide-1 receptor agonists, such as Exendin-4, have emerged as potential treatments for type 2 diabetes and obesity. However, current administration methods face challenges with patient adherence and low oral bioavailability. To address these limitations, researchers are exploring improved oral delivery methods for Exendin-4, including utilizing AMTs. This study engineered the probiotic yeast Saccharomyces boulardii to produce Exendin-4 (Sb-Exe4) in the gastrointestinal tract of male C57BL/6 mice to combat diet-induced obesity. The biological efficiency of Exendin-4 secreted by S. boulardii was analyzed ex vivo on isolated pancreatic islets, demonstrating induced insulin secretion. The in vivo characterization of Sb-Exe4 revealed that when combined with cold exposure (8 °C), the Sb-Exe4 yeast strain successfully suppressed appetite by 25% and promoted a 4-fold higher weight loss. This proof of concept highlights the potential of AMTs to genetically modify S. boulardii for delivering active therapeutic peptides in a precise and targeted manner. Although challenges in efficacy and regulatory approval persist, AMTs may provide a transformative platform for personalized medicine. Further research in AMTs, particularly focusing on probiotic yeasts such as S. boulardii, holds great potential for novel therapeutic possibilities and enhancing treatment outcomes in diverse metabolic disorders.