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.

Risk of Anaphylaxis Among New Users of GLP-1 Receptor Agonists: A Cohort Study.

OBJECTIVE: To assess risk of anaphylaxis among patients with type 2 diabetes mellitus who are initiating therapy with a glucagon-like peptide 1 receptor agonist (GLP-1 RA), with a focus on those starting lixisenatide therapy. RESEARCH DESIGN AND METHODS: A cohort study was conducted in three large, U.S. claims databases (2017-2021). Adult (aged ≥18 years) new users of a GLP-1 RA who had type 2 diabetes mellitus and ≥6 months enrollment in the database before GLP-1 RA initiation (start of follow-up) were included. GLP-1 RAs evaluated were lixisenatide, an insulin glargine/lixisenatide fixed-ratio combination (FRC), exenatide, liraglutide or insulin degludec/liraglutide FRC, dulaglutide, and semaglutide (injectable and oral). The first anaphylaxis event during follow-up was identified using a validated algorithm. Incidence rates (IRs) and 95% CIs were calculated within each medication cohort. The unadjusted IR ratio (IRR) comparing anaphylaxis rates in the lixisenatide cohort with all other GLP-1 RAs combined was analyzed post hoc. RESULTS: There were 696,089 new users with 456,612 person-years of exposure to GLP-1 RAs. Baseline demographics, comorbidities, and use of other prescription medications in the 6 months before the index date were similar across medication cohorts. IRs (95% CIs) per 10,000 person-years were 1.0 (0.0-5.6) for lixisenatide, 6.0 (3.6-9.4) for exenatide, 5.1 (3.7-7.0) for liraglutide, 3.9 (3.1-4.8) for dulaglutide, and 3.6 (2.6-4.9) for semaglutide. The IRR (95% CI) for the anaphylaxis rate for the lixisenatide cohort compared with the pooled other GLP-1 RA cohort was 0.24 (0.01-1.35). CONCLUSIONS: Anaphylaxis is rare with GLP-1 RAs. Lixisenatide is unlikely to confer higher risk of anaphylaxis than other GLP-1 RAs.

Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin-4-IgG4-Fc in healthy subjects: A phase 1, single-centre, randomized, double-blind, dose escalation study.

AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.

The vascular function effects of adding exenatide or meal insulin to basal insulin therapy in early type 2 diabetes.

OBJECTIVE: Basal insulin glargine has a neutral effect on cardiovascular risk in type 2 diabetes (T2DM). In practice, basal insulin is often paired with a glucagon-like peptide-1 receptor agonist (GLP1-RA) or meal insulin; however, the cardiovascular implications of these combinations have not been fully elucidated. In this context, we sought to evaluate the vascular function effects of adding the GLP1-RA exenatide or meal insulin lispro to basal glargine therapy in early T2DM. METHODS: In this 20-week trial, adults with T2DM of < 7-years duration were randomized to 8-weeks treatment with (i) insulin glargine (Glar), (ii) glargine + thrice-daily lispro (Glar/Lispro), or (iii) glargine + twice-daily exenatide (Glar/Exenatide), followed by 12-weeks washout. At baseline, 8-weeks, and washout, fasting endothelial function was assessed with reactive hyperemia index (RHI) measurement by peripheral arterial tonometry. RESULTS: At baseline, there were no differences in blood pressure (BP), heart rate (HR) or RHI between participants randomized to Glar (n = 24), Glar/Lispro (n = 24), and Glar/Exenatide (n = 25). At 8-weeks, Glar/Exenatide decreased systolic BP (mean - 8.1 mmHg [95%CI - 13.9 to - 2.4], p = 0.008) and diastolic BP (mean - 5.1 mmHg [- 9.0 to - 1.3], p = 0.012) compared to baseline, with no significant changes in HR or RHI. Notably, baseline-adjusted RHI (mean ± SE) did not differ between the groups at 8-weeks (Glar 2.07 ± 0.10; Glar/Lispro 2.00 ± 0.10; Glar/Exenatide 1.81 ± 0.10; p = 0.19), nor did baseline-adjusted BP or HR. There were no differences between the groups in baseline-adjusted RHI, BP or HR after 12-weeks washout. CONCLUSION: Adding either exenatide or lispro to basal insulin therapy does not appear to affect fasting endothelial function in early T2DM. TRIAL REGISTRATION: ClinicalTrials.Gov NCT02194595.

The Effectiveness and Safety of Exenatide Versus Metformin in Patients with Polycystic Ovary Syndrome: A Meta-Analysis of Randomized Controlled Trials.

Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects women of childbearing age, resulting in reproductive dysfunction, hyperinsulinemia, and obesity. While several drugs are currently approved for use in these patients, their relative effectiveness remains controversial. The purpose of this meta-analysis was to evaluate the reproductive efficacy and safety of exenatide, a glucagon-like peptide-1 receptor agonist, versus metformin, an insulin sensitizer, in the treatment of patients with PCOS. Nine randomized controlled trials (RCTs) were included, comprising 785 PCOS patients, of whom 385 received exenatide and 400 received metformin. Compared with metformin, exenatide was significantly more effective in treating these patients, as demonstrated by increased pregnancy rate (relative risk (RR) = 1.93, 95% confidence interval (CI) 1.28 to 2.92, P = 0.002), greater ovulation rate (RR = 1.41, 95% CI 1.11 to 1.80, P = 0.004), decreased body mass index (mean difference = - 1.72 kg/m2, 95% CI - 2.27 to - 1.18, P = 0.00001), and improved insulin resistance (standard mean difference = - 0.62, 95% CI - 0.91 to - 0.33, P < 0.0001). There was no significant difference in the occurrence of adverse events (gastrointestinal reactions, hypoglycemia, etc.) between the two therapies. However, given the moderate to high quality and possible bias of the included studies, the available evidence is inconclusive. More high-quality studies are needed to assess the effects of exenatide in order to provide stronger evidence for its use in this patient population.

Glucagon-like peptide 1 receptor agonists and the potential risk of pancreatic carcinoma: a pharmacovigilance study using the FDA Adverse Event Reporting System and literature visualization analysis.

BACKGROUND: There are increasing data on the potential risk of pancreatic carcinoma associated with glucagon-like peptide 1 receptor agonists (GLP-1RAs). AIM: The study aimed to determine whether GLP-1RAs are associated with increased detection of pancreatic carcinoma based on the FDA Adverse Events Reporting System and clarify its potential mechanisms through keyword co-occurrence analysis from literature database. METHOD: Disproportionality and Bayesian analyses were used for signal detection using reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), and empirical Bayesian geometric mean (EBGM). Mortality, life-threatening events, and hospitalizations were also investigated. VOSviewer was adopted to generate visual analysis of keyword hotspots. RESULTS: A total of 3073 pancreatic carcinoma cases were related to GLP-1RAs. Five GLP-1RAs were detected with signals for pancreatic carcinoma. Liraglutide had the strongest signal detection (ROR 54.45, 95% CI 51.21-57.90; PRR 52.52, 95% CI 49.49-55.73; IC 5.59; EBGM 48.30). The signals of exenatide (ROR 37.32, 95% CI 35.47-39.28; PRR 36.45, 95% CI 34.67-38.32; IC 5.00; EBGM 32.10) and lixisenatide (ROR 37.07, 95% CI 9.09-151.09; PRR 36.09; 95% CI 9.20-141.64; IC 5.17, EBGM 36.09) were stronger than those of semaglutide (ROR 7.43, 95% CI 5.22-10.57; PRR 7.39; 95% CI 5.20-10.50; IC 2.88, EBGM 7.38) and dulaglutide (ROR 6.47, 95% CI 5.56-7.54; PRR 6.45; 95% CI 5.54-7.51; IC 2.67, EBGM 6.38). The highest mortality rate occurred in exenatide (63.6%). Based on the bibliometric investigation, cAMP/protein-kinase, Ca2+ channel, endoplasmic-reticulum stress, and oxidative stress are potential pathogenesis of pancreatic carcinoma resulting from GLP-1RAs. CONCLUSION: Based on this pharmacovigilance study, GLP-1RAs, except albiglutide, are associated with pancreatic carcinoma.

A case report of severe adverse reaction of exenatide: Anaphylactic shock.

BACKGROUND: Anaphylactic shock is the severe state of the allergic reaction, which is rapid in onset and fatal. This is the first study that discusses the anaphylactic shock of exenatide reexposure in the patient who has interrupted exenatide treatment. PATIENT CONCERNS: A 47-year-old man was treated with exenatide owing to high blood glucose and obesity. Then he developed localized urticarial on the face, white lip, hands tremble, nausea, vomit, chest stuffiness, dizziness, accompanying with confusion and dyspnea. His blood glucose was 4.6 millimole per liter (mmol/L) and blood pressure was 85/50 millimeters of mercury (mm Hg). DIAGNOSIS: Exenatide-induced anaphylactic shock was considered. INTERVENTIONS: The emergency electrocardiogram was performed. The patient was treated with dexamethasone sodium phosphate and calcium gluconate, combined with exenatide withdrawal. He also received oral antiallergic agents and intravenous nutrition treatment. OUTCOMES: After antishock treatment, the clinical response gradually alleviated. LESSONS: Although exenatide is not prone to anaphylaxis, it is the synthetic peptide that can induce antibody formation. Exenatide has immunogenicity with the potential to elicit an allergic reaction upon administration. Clinicians should always pay more attention to the anaphylactic shock of exenatide, when prescribing for diabetics.

Effect of race on cardiometabolic responses to once-weekly exenatide: insights from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).

BACKGROUND: To determine whether there were racial differences in short-term cardiometabolic responses to once-weekly exenatide (EQW) in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). METHODS: EXSCEL enrolled 14,752 patients with type 2 diabetes (hemoglobin A1c (HbA1c) 6.5-10.0% [48-86 mmol/mol]) with or without cardiovascular disease who were randomized double-blind to EQW or placebo. Background glucose-lowering/other cardiovascular therapies were unaltered for 6 months post-randomization unless clinically essential, facilitating comparison of EQW-associated effects in 14,665 evaluable participants self-identifying as White (n = 11,113), Asian (n = 1444), Black (n = 870), or Other Race (n = 1,238. Placebo-adjusted 6 month absolute changes in cardiometabolic variables were assessed using generalized linear models. RESULTS: Mean 6-month placebo-adjusted HbA1c reductions were similar in the four groups (range 0.54-0.67% [5.9 to 7.3 mmol/mol], P = 0.11 for race×treatment interaction), with no significant difference in Asians (reference) versus other groups after covariate adjustment (all P ≥ 0.10). Six-month placebo-adjusted mean changes in systolic (-1.8 to 0.0 mmHg) and diastolic (0.2 to 1.2 mmHg) blood pressure, serum LDL (- 0.06 to 0.02 mmol/L) and HDL (0.00 to 0.01 mmol/L) cholesterol, and serum triglycerides (-0.1 to 0.0 mmol/L) were similar in the racial groups (P ≥ 0.19 for race×treatment interaction and all P ≥ 0.13 for comparisons of Asians with other races). Resting pulse rate increased more in Asians (4 beats/min) than in other groups (≤ 3 beats/min, P = 0.016 for race×treatment interaction and all P ≤ 0.050 for comparisons of Asians with other races). CONCLUSIONS: Short-term cardiometabolic responses to EQW were similar in the main racial groups in EXSCEL, apart from a greater pulse rate increase in Asians. TRIAL REGISTRATION: https://clinicaltrials.gov NCT01144338.

The Antiobesity Effect and Safety of GLP-1 Receptor Agonist in Overweight/Obese Patients Without Diabetes: A Systematic Review and Meta-Analysis.

Aim To determine the antiobesity effect and safety of glucagon-like peptide-1 receptor agonist (GLP-1RA) including liraglutide, exenatide and semaglutide treatment in overweight/obese patients without diabetes. The random-effect model was used to pool data extracted from included literatures. The weighted mean difference (WMD), odds ratio and 95% confidence interval (CI) were used to present the meta-analysis results (PROSPERO registration number: CRD 42020173199). The sources of intertrial heterogeneity, bias and the robustness of results were evaluated by subgroup analysis, sensitivity analysis and regression analysis, respectively. A total of 24 RCTs were recruited in the present analysis which included 5867 patients. The results showed that the treatment of overweight/obese patients without diabetes with GLP-1RAs including liraglutide, exenatide and semaglutide significantly achieved greater weight loss than placebo [WMD=-5.39, 95% CI (-6.82, -3.96)] and metformin [WMD=-5.46, 95% CI (-5.87, -5.05)]. The subgroup analysis showed that semaglutide displayed the most obvious antiobesity effect in terms of weight loss, the reduction of body mass index (BMI) and waist circumference (WC). However, GLP-1RAs treatments had more gastrointestinal adverse events (such as nausea and vomiting) than placebo and Met. The subgroup analysis also represented that semaglutide displayed the lowest risk of gastrointestinal adverse events among three kinds of GLP-1RAs. Our meta-analysis demonstrated that GLP-1RA had a superior antiobesity effect than placebo/Met in overweight/obese patients without diabetes in terms of body weight, BMI, and WC, especially for semaglutide, which had more obvious antiobesity effect and lower GI adverse events than liraglutide and exenatide.

Mechanisms underlying the blood pressure lowering effects of dapagliflozin, exenatide, and their combination in people with type 2 diabetes: a secondary analysis of a randomized trial.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) lower blood pressure (BP). When SGLT2i and GLP-1RA are combined, synergistic effects on BP have been observed. The mechanisms underlying these BP reductions are incompletely understood. The aim of this study was to assess the mechanisms underlying the BP reduction with the SGLT2i dapagliflozin, GLP-1RA exenatide, and dapagliflozin-exenatide compared with placebo in people with obesity and type 2 diabetes. METHODS: Sixty-six people with type 2 diabetes were randomized to 16 weeks of dapagliflozin 10 mg/day, exenatide 10 µg twice daily, dapagliflozin-exenatide, or placebo treatment. The effect of treatments on estimates of: (1) plasma volume (calculated by Strauss formula, bioimpedance spectroscopy, hematocrit, (2) autonomic nervous system activity (heart rate variability), (3) arterial stiffness (pulse wave applanometry), (4) systemic hemodynamic parameters including peripheral vascular resistance, cardiac output and stroke volume (all derived from non-invasively systemic hemodynamic monitoring), and (5) natriuresis (24-hour urine collection) were assessed after 10 days and 16 weeks of treatment. RESULTS: After 10 days, dapagliflozin reduced systolic BP (SBP) by - 4.7 mmHg, and reduced plasma volume. After 16 weeks, dapagliflozin reduced SBP by - 4.4 mmHg, and reduced sympathetic nervous system (SNS) activity. Exenatide had no effect on SBP, but reduced parasympathetic nervous system activity after 10 days and 16 weeks. After 10 days, dapagliflozin-exenatide reduced SBP by - 4.2 mmHg, and reduced plasma volume. After 16 weeks, dapagliflozin-exenatide reduced SBP by - 6.8 mmHg, and the reduction in plasma volume was still observed, but SNS activity was unaffected. CONCLUSIONS: The dapagliflozin-induced plasma volume contraction may contribute to the initial SBP reduction, while a reduction in SNS activity may contribute to the persistent SBP reduction. Dapagliflozin-exenatide resulted in the largest decrease in SBP. The effect on plasma volume was comparable to dapagliflozin monotherapy, and SNS activity was not reduced, therefore other mechanisms are likely to contribute to the blood pressure lowering effect of this combination, which need further investigation. Trial registration Clinicaltrials.gov, NCT03361098.

The role of nursing care in the type 2 diabetes treatment associated with chronic liver diseases.

OBJECTIVE: Diabetes is the fifth leading cause of death in the People's Republic of China. The aim of the article is to compare the effects of nursing care on the laboratory findings and ultrasound results of diabetic patients with chronic liver diseases (CLD) who were treated with antiglycemic drugs. METHODS: Diabetic were patients treated with metformin hydrochloride in combination with gliclazide, pioglitazone hydrochloride, sitagliptin, exenatide or liraglutide. Non-alcoholic fatty liver disease (NAFLD) was evaluated by abdominal ultrasound, and fibrosis stages were evaluated at baseline and 8 months. All the patients were equally divided into two groups depending on the therapeutic approach. RESULTS: The first group of patients additionally received nursing care, and the second group adhered to the prescribed therapy on their own. In total 90 patients, or 55.6%, had NAFLD at baseline, and its course was dependent upon changes in the weight (P = 0.009) and waist circumference (P = 0.012). The proportions of patients who demonstrated an ultrasonographic improvement in the control group were: 24 (56.8%) with gliclazide, 15 (41.3%) with pioglitazone hydrochloride, 28 (66.1%) with sitagliptin, 16 (79%) with exenatide and 15 (66.7%) with liraglutide (P = 0.2). For the group that received nursing care an ultrasonographic improvement was in: 29 (68.16%) with gliclazide, 18 (49.56%) with pioglitazone hydrochloride, 33 (79.32%) with sitagliptin, 19 (94.8%) with exenatide and 21 80.04% with liraglutide (P = 0.2). CONCLUSIONS: Outcomes from the type 2 diabetes treatment paralleling of CLD were presented. Treatment of type 2 diabetes with pioglitazone hydrochloride, gliclazide, sitagliptin, liraglutide and exenatide was proven effective.

Exenatide-induced granulomatous panniculitis associated with poly(d,l-lactide-co-glycolide).

The extended-release formulation of exenatide for treatment of Type II diabetes mellitus is encapsulated in microspheres composed of poly(d,l-lactide-co-glycolide) (PLGA) and administered weekly. This medication has been reported to potentially cause injection-site reactions such as pruritus, transient nodules, and foreign body reaction. Here, we report a case of exenatide-induced granulomatous panniculitis. Our patient is a 63-year-old female with Type II diabetes presenting for concerns about painful nodules on her abdomen, developing approximately every week over the past year and migrating. Of note, the lesions appeared following exenatide injections in the same locations. Two deep-seated nodules of 1 cm were identified on examination. There were no overlying skin changes, and the lesions were tender to palpation. Punch biopsies of the two lesions were performed, which revealed a septal panniculitis containing amorphous material, along with a mixed inflammatory infiltrate. Gomori methenamine silver (GMS) and acid-fast bacilli (AFB) stains were negative for organisms. On infrared (IR) spectroscopy examination of the biopsy tissue, the spectral characteristics of (tissue) protein and PLGA were seen. Evaluation of the clinical and histopathologic findings, along with the IR spectroscopy match, determined that exenatide-induced panniculitis was the cause of the patient's nodules. This case highlights the importance of clinicians' awareness regarding injection-site reactions.

Efficacy of Exenatide Administered Twice Daily in Body Mass Index Reduction in Patients with Type 2 Diabetes Mellitus.

Background: Exenatide is a glucagon-like peptide-1 receptor agonist that can reduce body weight. This study aimed to determine the efficacy of exenatide on body mass index (BMI) reduction in patients with type 2 diabetes mellitus (T2DM) with differing baseline body weight, blood glucose, and atherosclerotic status and to determine if there is a correlation between BMI reduction and cardiometabolic indices in these patients. Methods: This retrospective cohort study used data from our randomized controlled trial. A total of 27 T2DM patients treated with combination therapy of exenatide twice daily and metformin for 52 weeks were included. The primary endpoint was a change in the BMI from the baseline to week 52. The secondary endpoint was a correlation between BMI reduction and cardiometabolic indices. Findings. The BMIs of overweight and obesity patients and those with glycated hemoglobin (HbA1c) ≥ 9% significantly decreased -1.42 ± 1.48 kg/m2(P=0.015) and -0.87 ± 0.93 kg/m2(P=0.003), respectively, at the baseline after 52 weeks of treatment. There was no reduction in BMI in patients with normal weight, HbA1c <9%, the nonatherosclerosis group, and the atherosclerosis group. The decrease in BMI was positively correlated with changes in blood glucose, high-sensitivity C-reactive protein (hsCRP), and systolic blood pressure (SBP). Conclusion: BMI scores improved after exenatide treatment for 52 weeks in T2DM patients. Weight loss was affected by baseline body weight and blood glucose level. In addition, BMI reduction from the baseline to 52 weeks was positively correlated with baseline HbA1c, hsCRP, and SBP. Trial Registration. Chinese Clinical Trial Registry (ChiCTR-1800015658).

Effect of Exenatide Use on Cognitive and Affective Functioning in Obese Patients With Type 2 Diabetes Mellitus: Exenatide Use Mediates Depressive Scores Through Increased Perceived Stress Levels.

PURPOSE/BACKGROUND: Glucagon-like peptide-1 (GLP-1) is a molecule used to treat type 2 diabetes mellitus (T2DM). Given their widespread expression in the nervous system, GLP-1 receptors also play a role in regulating mood and cognitive function. Here, we aimed to compare obese patients with T2DM, with or without exenatide (a GLP-1R agonist) use on cognitive and affective functioning. METHODS/PROCEDURES: A total of 43 patients with T2DM (23 on exenatide and 20 without exenatide) were evaluated with the Snaith-Hamilton Pleasure Scale, Cognitive Failures Questionnaire, Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7, Childhood Trauma Questionnaire, Perceived Stress Scale (PSS), and Chronic Stress Scale, in addition to laboratory-based measures of reward learning (the probabilistic reward task) and working memory (Letter-N-Back task). FINDINGS/RESULTS: Patients on exenatide had higher body mass index (BMI) (37.88 ± 5.44 vs 35.29 ± 6.30; P = 0.015), PHQ-9 (9.70 ± 4.92 vs 6.70 ± 4.66; P = 0.026), and PSS (29.39 ± 6.70 vs 23.35 ± 7.69; P = 0.015) scores. Other stress scales (Childhood Trauma Questionnaire and Chronic Stress Scale), Generalized Anxiety Disorder-7 scores, response bias, or discriminability as assessed by probabilistic reward task and self-report (Cognitive Failures Questionnaire) and laboratory-based (Letter-N-Back) cognitive measures were not significantly different between groups (both Ps > 0.05). Multivariate linear regression analyses adding BMI and PSS as covariates revealed that although BMI had no effect (P = 0.5), PSS significantly predicted PHQ-9 scores (P = 0.004). Mediation analysis showed that exenatide users reported higher PSS, with greater PSS associated with higher PHQ-9 levels (b = 0.236). There was no evidence on exenatide directly influencing PHQ-9 independent of PSS (c' = 1.573; P = 0.305; 95% bootstrap confidence interval, -1.487 to 4.634). IMPLICATIONS/CONCLUSIONS: Based on previous research and our findings, exenatide use might be mediating depression scores through disrupting stress responses.

Effect of once-weekly exenatide on hospitalization for acute coronary syndrome or coronary revascularization in patients with type 2 diabetes mellitus.

Cardiovascular (CV) outcome studies of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shifted the paradigm of type 2 diabetes management given their benefits regarding a reduction in major adverse CV events. However, the relationship between GLP-1 RAs and coronary revascularization remains poorly understood. In this EXSCEL post-hoc analysis, we used univariate Cox proportional models and Kaplan Meier survival analysis to evaluate the effect of once-weekly exenatide (EQW) on a composite outcome of hospitalization for acute coronary syndrome (ACS) or coronary revascularization. Similar models were utilized to evaluate the relationship between significant participant characteristics within the entire study population and the composite outcome. Of the 14,736 participants in EXSCEL with complete follow-up data, 1642 (11.1%) experienced an ACS or coronary revascularization event during a median follow-up of 3.3 years (interquartile range, 2.3-4.4). EQW had no effect on hospitalization for ACS or coronary revascularization (HR 1.00, 95% CI 0.91-1.10). Among EXSCEL participants, enrollment in Latin America (HR 0.51, 95% CI 0.43-0.60) and a history of peripheral artery disease (HR 0.79, 95% CI 0.70-0.90) were associated with a reduced risk for coronary revascularization, whereas enrollment in North America (HR 1.92, 95% CI 1.74-2.12), a history of CV disease (HR 3.24, 95% CI 2.78-3.78), and a previous myocardial infarction (HR 1.54, 95% CI 1.39-1.71) were associated with increased risk for study end points. EQW had no association with hospitalization for ACS or coronary revascularization. Participant enrollment location and CV disease burden may play a role in the variable CV efficacy of GLP-1 RAs that has been observed in trials thus far.

Safety, Pharmacokinetics and Pharmacodynamics of Multiple Escalating Doses of PEGylated Exenatide (PB-119) in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: At present, the deficiency of ß-cell function is progressive in patients with type 2 diabetes mellitus. Exenatide cannot only control blood glucose well, but also promotes the regeneration and proliferation of islet ß-cells and improves the function of ß cells. However, it needs to be given twice a day, and there are many adverse reactions such as nausea. PEGylated exenatide (study code: PB-119) needs to be administered only once a week. The purpose of this experiment was to evaluate the safety, pharmacokinetics and pharmacodynamics of an escalating dose regimen of subcutaneous PEGylated exenatide injections in healthy subjects. METHODS: Twelve healthy young adult subjects in each group received once-weekly subcutaneous injections of 165 µg, 330 µg, and 660 µg PEGylated exenatide for 6 weeks. Plasma drug concentration was determined in venous blood collected across selected time points. Safety and tolerability were evaluated by monitoring adverse events, laboratory parameters, and electrocardiogram. Blood glucose, insulin,  glucagon and C peptide were monitored at different time points to evaluate the pharmacodynamics of PEGylated exenatide. RESULTS: A total of 11, 10, and 12 subjects completed the study in 165 µg, 330 µg, and 660 µg dose groups, respectively. After 6 consecutive weeks of administration, the t1/2 in the 165 µg, 330 µg, and 660 µg dose groups was 55.67 ± 11.03 h, 56.99 ± 21.37 h, and 54.81 ± 13.87 h, respectively. The Cavg was 4.22 ± 0.78 ng/ml, 6.03 ± 1.43 ng/ml, and 10.50 ± 3.06 ng/ml, respectively. AUCss was 708.59 ± 131.87 h•ng/ml, 1012.63 ± 240.79 h•ng/ml, and 1763.81 ± 514.50 h•ng/ml, respectively. The accumulation index was 1.15 ± 0.07, 1.17 ± 0.11, and 1.14 ± 0.07. The CLss/F was 241.25 ± 51.13 ml/h, 341.53 ± 73.62 ml/h, and 450.06 ± 313.76 ml/h, respectively. A total of 10 of 36 (27.78%) subjects in the three dose groups developed specific antibodies after consecutive subcutaneous injections of PEGylated exenatide. The Cavg and Cmax were higher than those of antibody-negative subjects. Furthermore, in antibody-positive subjects, CLss/F, t1/2, AUCτ, accumulation index, MRT(0-inf) and other parameters were lower than those of antibody-negative subjects. In the 165 µg dose group, two subjects (16.67%) experienced 4 adverse events. In the 330 µg dose group, no subjects reported adverse events. In the 660 µg dose group, 8 subjects (66.67%) reported 16 adverse events, which were mostly gastrointestinal. There were no significant changes in the pharmacodynamic parameters except the glucagon level at day 36 in the 660 µg dose group, the 2h postprandial insulin and C peptide levels at day 36 and day 50 in the 165 µg dose group compared with baseline (- 1 day). CONCLUSION: A once-weekly subcutaneous injection of 165 µg and 330 µg PEGylated exenatide is safe. No significant effects on blood glucose or pancreatic hormone levels were observed in the subjects within these dose groups. The pharmacokinetic parameters of PEGylated exenatide may be affected by immunogenicity. CLINICAL TRIALS REGISTRATION: The study is registered at clinicaltrials.gov (No. NCT03062774).

Effect of COMBinAtion therapy with remote ischemic conditioning and exenatide on the Myocardial Infarct size: a two-by-two factorial randomized trial (COMBAT-MI).

Remote ischemic conditioning (RIC) and the GLP-1 analog exenatide activate different cardioprotective pathways and may have additive effects on infarct size (IS). Here, we aimed to assess the efficacy of RIC as compared with sham procedure, and of exenatide, as compared with placebo, and the interaction between both, to reduce IS in humans. We designed a two-by-two factorial, randomized controlled, blinded, multicenter, clinical trial. Patients with ST-segment elevation myocardial infarction receiving primary percutaneous coronary intervention (PPCI) within 6 h of symptoms were randomized to RIC or sham procedure and exenatide or matching placebo. The primary outcome was IS measured by late gadolinium enhancement in cardiac magnetic resonance performed 3-7 days after PPCI. The secondary outcomes were myocardial salvage index, transmurality index, left ventricular ejection fraction and relative microvascular obstruction volume. A total of 378 patients were randomly allocated, and after applying exclusion criteria, 222 patients were available for analysis. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. IS was similar between groups for the RIC (24 ± 11.8% in the RIC group vs 23.7 ± 10.9% in the sham group, P = 0.827) and the exenatide hypotheses (25.1 ± 11.5% in the exenatide group vs 22.5 ± 10.9% in the placebo group, P = 0.092). There were no effects with either RIC or exenatide on the secondary outcomes. Unexpected adverse events or side effects of RIC and exenatide were not observed. In conclusion, neither RIC nor exenatide, or its combination, were able to reduce IS in STEMI patients when administered as an adjunct to PPCI.

Extending our understanding of exenatide: a rare case of angio-oedema.

Exenatide is a subcutaneous injectable glucagon-like peptide 1 receptor agonist that has been approved by the Federal Drug Administration for the treatment of type 2 diabetes mellitus. While side effects such as nausea, vomiting and local hypersensitivity reactions are more commonly described, angio-oedema has never been previously reported in the literature. We present the case of a 67-year-old woman who presented to the emergency department with acute-onset tongue swelling, difficulty breathing, dizziness and diffuse itching which began shortly after receiving her first dose of intramuscular extended release (ER) exenatide. This case aims to raise awareness of the potential adverse effect of angio-oedema secondary to exenatide ER and serves as a reminder to clinicians to discuss possible adverse effects of medications and early recognition of symptoms which would prompt further medical attention.