Trends in Presentation and Management of Endogenous Hyperinsulinaemic Hypoglycaemia Over the Last Three Decades at a Tertiary Care Centre (1992-2022).

Introduction: Endogenous hyperinsulinaemic hypoglycaemia (EHH) is characterized by inappropriate insulin secretion from pancreatic beta cells despite low blood glucose concentrations. We aimed to evaluate the secular changes in presentation and management of EHH due to insulinoma/non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS) at our centre. Methods: This was a single-centre ambispective study (2014-2022). The clinical, biochemical, hormonal and radiological parameters (n = 63) collected as part of this study were compared with our earlier studies (1992-2005, n = 31; and 2006-2013, n = 35) and with other centres across the world. Results: A total of 63 patients (39 males) with a preoperative diagnosis of EHH (insulinoma, n = 58; and NIPHS, n = 5) and a mean age of 40.7 years were studied. The mean lag time from the onset of symptoms to diagnosis decreased from 4.6 years during the first study period to 1.9 years during this study period. However, the majority presented with fasting hypoglycaemia of 98.4%, and both fasting and postprandial hypoglycaemia of 32%. Exclusive postprandial hypoglycaemia was present in 1.7% of insulinoma. A histopathological diagnosis of insulinoma was made in 52 patients and nesidioblastosis in two patients. Intraoperative ultrasonography (IOUS) and intraoperative palpation (IOP) yielded 100% sensitivity, while endoscopic ultrasonography (EUS) and 68Ga-DOTA-Exendin-4 positron emission tomography/computed tomography (PET/CT) yielded sensitivity of 86% and 85%, respectively, for localizing insulinoma. Resolution of hypoglycaemia was noted in 53 of 57 (93%) patients who underwent surgery with a preoperative diagnosis of insulinoma. Conclusion: We observed a trend towards earlier diagnosis of EHH, increased patient numbers and availability of nuclear imaging techniques for preoperative localization in the last decade compared to earlier.

Glucagon-like peptide-1 receptor agonists in neoplastic diseases.

Glucagon-like peptide-1 receptor agonist (GLP-1RA), a novel hypoglycemic agent for the treatment of type 2 diabetes, has well-known effects such as lowering blood sugar, ameliorating inflammation, reducing weight, and lowering blood lipids. It has also been shown that it can influence the proliferation and survival of cells and has a certain effect on the prognosis of some neoplastic diseases. In this study, the potential effects of GLP-1RAs on the occurrence and development of tumors were reviewed to provide new ideas for the prevention and treatment of tumors in patients.

GLP-1 receptor agonists are a transformative prehabilitation tool for weight loss in obese patients undergoing elective hernia repair.

BACKGROUND: Obesity is an independent risk factor for complications after abdominal hernia repair. Glucagon-like-peptide-1 (GLP-1) receptor agonists are gaining popularity as pharmacologic weight loss adjuncts and may help patients reach weight loss goals for surgery. We examine our early experience utilizing GLP-1 agonists versus lifestyle modifications alone to achieve weight loss in patients before elective hernia repair. METHODS: This single-center, retrospective review identified obese patients who underwent elective hernia repair from 2014 to 2023. Patients were asked to achieve a BMI ≤ 33 kg/m2 before surgery. Patients who lost weight with GLP-1 therapy in addition to lifestyle changes were compared to a control cohort that achieved similar preoperative weight loss without GLP-1 therapy. Primary outcome was mean time from GLP-1 agonist initiation and initial surgery clinic visit to surgery. Secondary outcomes were 30-day morbidity, mortality, and reoperation rates, and hernia recurrence. RESULTS: Forty-six patients with ventral/incisional, flank, umbilical, parastomal, inguinal, and hiatal hernias were identified (GLP-1 N = 24, control N = 22). 81.8% (N = 18) of controls had a ventral/incisional hernia, compared to 45.8% (N = 11) of GLP-1 patients (p = 0.03). Mean BMI at GLP-1 agonist initiation was similar to mean BMI at initial clinic visit for controls (38.1 ± 4.9 vs 38.2 ± 2.7 kg/m2, p = 0.66). Preoperative mean percentage total weight loss (14.9 ± 7.5 vs 12.4 ± 6.9 kg, p = 0.39) and mean BMI reduction (6.0 ± 3.8 vs 4.9 ± 2.3 kg/m2, p = 0.43) were similar between groups. The mean time from GLP-1 agonist initiation to surgery was significantly shorter than initial clinic visit to surgery for controls (6.3 ± 4.0 vs 14.7 ± 17.6 months, p = 0.03). There was no statistically significant difference in time from initial clinic visit to surgery between groups (7.6 ± 4.4 vs 14.7 ± 17.6 months, p = 0.06). There was no significant difference in 30-day morbidity between groups (8.3 vs 27.3%, p = 0.13). CONCLUSION: GLP-1 agonists accelerate preoperative weight loss for obese hernia patients without negatively impacting postoperative outcomes.

Impact of Manufacturing Process and Compounding on Properties and Quality of Follow-On GLP-1 Polypeptide Drugs.

PURPOSE: The prevalence of follow-on and compounded products of glucagon-like peptide-1 analogs is increasing. We assessed glucagon-like peptide-1 analogs semaglutide and liraglutide for purity, potential immunogenicity, and expected stability, by comparing a representative selection of commercially available follow-on drug substances (DSs) and drug products (DPs) with their corresponding originators. METHODS: Tests included several chromatography methods coupled with ultraviolet and mass spectrometry detectors, inductively coupled plasma optical emission spectroscopy, inductively coupled plasma mass spectrometry, nuclear magnetic resonance, dissolution analyses, in silico peptide/major histocompatibility complex II-binding prediction, and fibrillation assays. RESULTS: Overall, 16 injectable semaglutide, 8 oral semaglutide, and 2 injectable liraglutide follow-on products were analyzed alongside originator products. Compared with originator, follow-on injectable semaglutide DSs and DPs had new impurities and impurity patterns, including high molecular weight proteins, trace metals, anions, counterions, and residual solvents. Analyses showed that several commercialized follow-on oral semaglutide DPs had a markedly lower quantity of semaglutide than the label claim, while dissolution tests indicated different semaglutide and sodium N-(8-[2-hydroxybenzoyl] amino)caprylate (SNAC) release profiles, which may reduce bioavailability. Neoepitopes were identified in DS and DP semaglutide follow-ons, indicating potential immunogenicity. Fibrillation assays showed increased fibrillation tendency and reduced physical stability in liraglutide follow-on DP samples compared with originator. CONCLUSION: This study highlights that differences in the manufacturing processes of follow-on semaglutide and liraglutide (vs those used for originators) can result in several changes to the DSs and DPs. The impact of these changes on efficacy and safety outcomes remains unknown and should be investigated by clinical studies.

Patients experience with preoperative use of anti-obesity medications and associations with bariatric surgery expectations.

BACKGROUND: Few studies have investigated the use of anti-obesity medications (AOMs) before bariatric surgery and how prior use impacts patients' goals and expectations for surgery. OBJECTIVES: This study investigated associations between patients' experiences with AOMs and weight loss expectations before bariatric surgery. SETTINGS: Single tertiary university hospital. METHODS: Patients were electronically surveyed with a 31-item questionnaire via email or the patient portal with a primary predictor variable of AOMs presurgery. Outcomes included degree of weight loss and weight regain and motivation for seeking surgery. RESULTS: A total of 346 persons were invited to complete the survey; 112 surveys (32.4%) were completed, with 7 excluded because of not answering the AOM question. 73% reported AOM use. Among those who took AOMs before seeking bariatric surgery, average weight loss was 13 kg (SD 10) corresponding to a 4.4-kg/m2 decrease in BMI. Of past AOM recipients, 87% reported weight regain on stopping AOMs. Average weight regain was 18 kg (SD 13; 126% increase). Patients reported improved longevity and quality of life as motivation for seeking surgery, with AOM use history having no effect. Subjects reported an average weight loss goal of 65.8 kg (39% of baseline weight) from bariatric surgery. CONCLUSIONS: AOMs were commonly used in those seeking bariatric surgery, but motivation for surgery did not differ by AOM use history. Motivations were most often related to goals for better overall health.

Brown Adipose Tissue Mimicking Head and Neck Cancer on PET Scan in a Patient on GLP-1 Drug.

To report a case of a patient undergoing GLP-1 receptor agonist therapy in which increased FDG uptake in brown adipose tissue (BAT) mimicked metastatic head and neck cancer on PET/CT imaging. A 61-year-old female with Class III obesity presented with a right-sided neck mass after significant weight loss following the use of the GLP-1 receptor agonist, Semaglutide. PET/CT revealed FDG uptake in the right level II lymph node and extensive BAT uptake throughout the neck and mediastinum, complicating the diagnosis. Increased FDG uptake in the cervical and supraclavicular BAT regions led to diagnostic confusion, mimicking diffuse regional metastasis. Careful interpretation of PET/CT imaging, with fusion of anatomical and functional data, was essential to differentiate hypermetabolic BAT from malignant disease. Increased BAT FDG uptake, particularly in patients using GLP-1 receptor agonists, can complicate the evaluation of head and neck cancer. Awareness of this interaction is critical to avoid misdiagnosis and overtreatment. Laryngoscope, 2024.

[New outcome studies with injectable semaglutide in different at risk populations]. / L'étude clinique du mois. Nouvelles études cliniques avec le sémaglutide injectable dans différentes populations à risque.

Injectable semaglutide at a dose of 1 mg once weekly has been shown to be the most efficacious glucagon-like peptide-1 receptor agonist when considering both the improvement in blood glucose control and the reduction in body weight in patients with type 2 diabetes (T2D). After the SUSTAIN-6 study, published in 2016, which demonstrated not only the good safety but also already the cardiovascular (CV) efficacy of semaglutide in patients with T2D and high CV risk, several large placebo-controlled randomised trials have confirmed improved prognosis with semaglutide in different at risk populations : patients with T2D and chronic kidney disease (FLOW trial), subjects with obesity and heart failure with preserved ejection fraction, with or without T2D (STEP-HFpEF trial) and people with overweight or obesity (but without T2D) and a confirmed atheromatous cardiovascular disease (SELECT trial). Studies performed in patients with obesity used a higher dose of 2.4 mg/week. These positive results, based upon major clinically relevant outcomes, extend the therapeutic possibilities with semaglutide among at high risk patients of cardiovascular and/or renal diseases.

Le sémaglutide injectable à la dose de 1 mg/semaine s'est révélé être l'agoniste des récepteurs de glucagon-like peptide-1 (ARGLP-1) le plus efficace en termes de contrôle glycémique et de perte de poids chez des patients avec un diabète de type 2 (DT2). Après l'étude SUSTAIN-6, publiée en 2016, ayant démontré la bonne sécurité et déjà l'efficacité cardiovasculaire (CV) du sémaglutide chez des patients avec DT2 à haut risque CV, plusieurs grands essais contrôlés ont prouvé une amélioration du pronostic dans différentes populations à risque : patients avec DT2 et maladie rénale chronique (étude FLOW), sujets avec obèsité et avec une insuffisance cardiaque à fraction d'éjection préservée (avec ou sans DT2) (étude STEP-HFpEF) et personnes avec un surpoids ou une obésité (mais sans DT2) et une maladie CV avérée (étude SELECT). Les études dans l'obésité ont été menées avec une posologie de 2,4 mg/semaine de sémaglutide. Ces résultats positifs, basés sur des critères de jugement cliniques majeurs, étendent donc les possibilités thérapeutiques offertes par le sémaglutide chez des patients à haut risque de maladies CV et/ou rénales.

N-acyl glycines produced by commensal bacteria potentiate GLP-1 secretion as GPCR ligands.

Commensal microbiota is crucial for nutrient digestion and production of biologically active molecules, many of which mimic endogenous ligands of human GPCRs. Bacteroides spp. are among the most abundant bacteria residing in the human gut and their absence has been positively correlated with metabolic disorders. In the present study, we focused on N-acylated glycines (NAGlys) as products of Bacteroides spp. and potential GPCR ligands modulating GLP-1 secretion. Representative strains of the most abundant commensal Bacteroides were cultured in either yeast- or animal-based nutrient broths. The broths post-culture were investigated in terms of the contents of NAGlys and stimulatory effects towards GLP-1 production in GLUTag and NCI-H716 cell lines. Pure preparations of the detected NAGlys were further studied to evaluate stimulation of GLP-1 production and related cellular signalling evoked. The most potent NAGlys were also tested as ligands of key lipid GPCRs involved in the regulation of carbohydrate metabolism: GPR40/FFAR1, GPR55, GPR119, and GPR120/FFAR4. We found that Bacteroides potentiate GLP-1 production, depending on the strain and provided nutrient mix. Long-chain unsaturated oleoyl and arachidonoyl glycines, produced by B. thetaiotaomicron and B. intestinalis in the animal-based broth, were particularly effective in stimulation of GLP-1 secretion. They served as agonists of all the receptors under study expressed in GLP-1-producing cells. The obtained results broaden the knowledge of microbial signalling molecules and their role in regulation of carbohydrate homeostasis. They also emphasise the importance of balanced diet as a source of building blocks for commensal bacteria to produce efficient agonists of lipid GPCRs.

A randomized, double-blind, placebo-controlled trial of weight loss using liraglutide 3.0 mg for weight recurrence after Roux-en-Y gastric bypass.

BACKGROUND: Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB) remains the gold standard for treating obesity. Most people regain weight from postsurgery nadir. OBJECTIVES: Liraglutide 3.0 mg is approved for weight management. This study will examine the effects on liraglutide 3.0 mg on weight regain post-RYGB. SETTING: University Hospital, United States. METHODS: A 56-week, double-blind, placebo-controlled study was conducted in 132 subjects, who achieved ≥25% total body weight loss (TBWL) status-post-RYGB and regained ≥10% TBWL after reaching nadir weight (NW). Subjects 18-120 months post-RYGB were randomized to receive liraglutide 3.0 mg/d (n = 89) or placebo (n = 43) with lifestyle counseling regularly for 56 weeks. The co-primary endpoints were the proportion of subjects losing at least 5%, 10%, and 15% TBWL and achieving weight lower than their NW. RESULTS: 53.4% of the placebo group and 65% of the liraglutide group completed the trial due to Severe acute respiratory syndrome coronavirus 2 pandemic. The change in %TBWL from baseline to 56-weeks was -8.8 (8.5, -29.2 to 9.7) and 1.1 (3.5, -7.9 to 5.99) in the liraglutide and placebo groups, respectively. 76% and 17% of subjects achieved ≥5% TBWL at 56 weeks in the liraglutide and placebo groups, respectively; 51% and 26.0% of the liraglutide group achieved ≥10% and ≥15% TBWL, respectively. None of the placebo group lost ≥10% TBWL. Twenty-one percent of subjects receiving liraglutide surpassed postoperative NW. No subjects on placebo met this goal. Nonserious adverse events occurred in 41.6% of subjects on liraglutide. Serious adverse events (SAE) occurred less often on liraglutide. CONCLUSIONS: Liraglutide was significantly more effective than placebo in treating weight regain that occurs post-RYGB without increased SAE.

Impact of GLP-1RA on the Risk of Adverse Liver Outcomes Among Patients With Alcohol-Associated Liver Disease and Type 2 Diabetes.

BACKGROUND AND AIMS: We sought to characterise the impact of GLP-1RA on adverse liver outcomes (ALO) among patients with alcohol-associated liver disease (ALD) and Type 2 diabetes mellitus (T2DM). METHODS: Patients with T2DM newly diagnosed with ALD between 2013 and 2020 were identified using IBM MarketScan database and were categorised by GLP-1RA exposure. Overlap propensity score weighting (OPSW) followed by Poisson regression models was used to analyse adjusted risk of ALO, a composite endpoint defined by first occurrence of hepatic decompensation (HD), portal hypertension (PH), hepatocellular carcinoma (HCC) or liver transplantation (LT) relative to GLP-1RA. RESULTS: Among 14 730 patients, most individuals were male (n = 9752, 66.2%) with median age of 57 (IQR 52-61) years; 2.2% (n = 317) of patients had GLP-1RA exposure. Overall, 32.0% (n = 4717) of patients experienced HD, 15.9% (n = 2345) had PH, 3.8% (n = 563) developed HCC, while 2.5% (n = 374) underwent transplantation. Non-GLP-1RA patients had higher incidence of HD (32.2% vs. 22.4%) and HCC (3.9% vs. 0.3%) versus patients taking GLP-1RA (both p < 0.001); in contrast, there was no difference in incidence of PH (14.5% vs. 16.0%) and LT (1.3% vs. 2.6%) (both p > 0.05). After OPSW, overall incidence of ALO was lower in GLP-1RA cohort (GLP-1RA: 12.0%, 95%CI 9.0-16.0 vs. non-GLP-1RA: 21.0%, 95%CI 20.0-22.0) with an absolute incidence risk reduction of 9.0% (95%CI 3.0%-15.0%) associated with GLP-1RA. GLP-1RA was most strongly associated with lower likelihood of HD with reduced adjusted incidence rate of 0.56 (95%CI 0.36-0.86) relative to non-GLP-1RA individuals. CONCLUSIONS: GLP-1RA may have a hepatoprotective impact among patients with ALD and T2DM.

Sex-specific Cardiovascular Risk Factors and Treatment in Females with T2DM and CVD: Developments and Knowledge Gaps.

PURPOSE: There are large disparities in the impact of diabetes on cardiovascular disease (CVD) risk and outcomes by sex and gender. Achieving health equity requires understanding risks and medication efficacy in female patients, especially now, as novel pharmacologic treatments are transforming the diabetes and CVD treatment landscape. This review examines two bodies of research that can inform sex differences in CVD in patients with diabetes: female-specific risk factors for CVD and sex-related limitations of clinical trial research in evaluating novel diabetes and CVD treatments. METHODS: Two literature searches were performed using Ovid Medline(R) All. The first retrieved manuscripts covering sex and gender differences related to CVD risk and therapies and diabetes. The second focused on randomized controlled trial data on sex/gender differences and GLP-1/SGLT-2/DPP-4 drugs. RESULTS: Female-specific risk factors for CVD include early menarche, premature or early menopause, irregular cycles and polycystic ovary syndrome (PCOS); pregnancy; adverse pregnancy outcomes; history of breast cancer; and autoimmune diseases. Clinical trials of novel pharmacological treatments for diabetes and CVD have undersampled female populations, and clinical characteristics of male and female participants have differed significantly. Thus, evidence to evaluate potential sex differences in treatment efficacy and side effects has been lacking. CONCLUSION: To improve health of female patients with diabetes, sex-specific cardiovascular risk factors should be taken into account in screening and treatment decisions. Further, studies of cardiovascular and diabetes medications must ensure adequate representation by sex and report participant characteristics and outcomes by sex.

Risk of major adverse cardiovascular events and all-cause mortality under treatment with GLP-1 RAs or the dual GIP/GLP-1 receptor agonist tirzepatide in overweight or obese adults without diabetes: a systematic review and meta-analysis.

Background: Among the currently approved antiobesity medications, the glucagon-like-peptide-1 receptor-agonists (GLP-1 RAs) liraglutide and semaglutide, and the dual glucose-dependent-insulinotropic-polypeptide (GIP)/GLP-1 RA tirzepatide have been suggested to reduce cardiovascular-risk in overweight or obesity without diabetes. Objectives: The objective of this study was to evaluate the cardio- and neuroprotective potential of these novel agents in the nondiabetic overweight/obese adult population. Data sources and methods: A systematic review and meta-analysis of randomized-controlled clinical trials (RCTs) was performed to estimate the risk of major adverse cardiovascular events (MACE), all-cause and cardiovascular mortality in overweight or obese adults without diabetes treated with GLP-1 or GIP/GLP-1 RAs (vs placebo). Secondary outcomes included the risk of myocardial infarction (MI) and stroke. Results: Sixteen RCTs (13 and 3 on GLP-1 RAs and tirzepatide, respectively) comprising 28,168 participants were included. GLP-1 or GIP/GLP-1 RAs reduced MACE (odds ratio (OR): 0.79; 95% confidence interval (CI): 0.71-0.89; p < 0.01; I 2 = 0) and all-cause mortality (OR: 0.80; 95% CI: 0.70-0.92; p < 0.01; I 2 = 0), while there was a trend toward lower cardiovascular-mortality (OR: 0.84; 95% CI: 0.71-1.01; p = 0.06; I 2 = 0%) compared to placebo. Additionally, GLP-1 or GIP/GLP-1 RAs reduced the odds of MI (OR: 0.72; 95% CI: 0.61-0.86; p < 0.01; I 2 = 0%) and nonfatal-MI (OR: 0.72; 95% CI: 0.61-0.85; p < 0.01; I 2 = 0%); while no associations between antiobesity treatment and fatal-MI, stroke, nonfatal, or fatal stroke were uncovered. Conclusion: GLP-1 and GIP/GLP-1 RAs reduce cardiovascular-risk and all-cause mortality in overweight or obese adults without diabetes. Additionally, GLP-1 RAs and GIP/GLP-1 RAs attenuate the risk of MI. Since data on stroke are still limited, future RCTs are warranted to evaluate the neuroprotective potential of these novel antiobesity agents. Trial registration: PROSPERO CRD42024515966.

Evaluation of gastric content in fasting patient during semaglutide use: an observational study.

BACKGROUND: The evident influence of GLP-1 agonists as semaglutide on gastric emptying even in adherence to recommended fasting protocols instigates debates. OBJECTIVE: To investigate the effect of semaglutide on gastric content by gastric ultrasonography in volunteers. SETTING: Private hospital. METHODS: The present study is an observational, cross-sectional, and single-center study. We included 30 consecutive volunteers aged ≥18 years who had undergone a minimum fasting period of 8 hours for solid foods and 2 hours for clear, residue-free liquids. The intervention group consisted of 15 volunteers who had used semaglutide within the last 7 days, whereas the control group consisted of 15 volunteers who had never used semaglutide. The main objective was to determine whether the stomach was full or not. RESULTS: Between June 2023 and August 2023, a total of 30 adult volunteers were included in the study, and no participant was excluded. The semaglutide group exhibited a higher prevalence of full stomach (11 of 15 [73%] versus 1 of 15 [7%], P < .001; adjusted to age P = .003). The semaglutide group also exhibited a higher prevalence of early satiety (10 of 15 [67%] versus 0 of 15 [0%], P < .001), loss of appetite (10 of 15 [67%] versus 0 of 15 [0%], P < .001), gastric fullness (8 of 15 [53%] versus 0 of 15 [0%], P = .002), and nausea (7 of 15 [47%] versus 1 of 15 [7%], P = .035). Additionally, there is no case in the semaglutide group with no gastric contents. CONCLUSIONS: The use of semaglutide is associated with full stomach even after appropriate overnight fasting. Semaglutide is also associated with increased gastrointestinal symptoms such as loss of appetite, early satiety, gastric fullness, and nausea.

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor agonist, exhibits favourable effects on pancreatic ß-cells and hepatic steatosis in obese type 2 diabetic db/db mice.

AIM: Tirzepatide, a dual agonist of glucagon-like peptide receptor and glucose-dependent insulinotropic polypeptide receptor, is expected to exhibit high clinical efficacy in obese type 2 diabetic patients. We evaluated the effects of tirzepatide on pancreatic ß-cells and the liver, an insulin-target organ, in a mouse model of obese type 2 diabetes mellitus. MATERIALS AND METHODS: Obese type 2 diabetic db/db mice (BKS.Cg-/+ Leprdb/+ Leprdb/Jcl*) were used in this study. Starting at 7 weeks of age, mice were treated with tirzepatide (30 nmol/kg, subcutaneous injection twice a week) or semaglutide (200 nmol/kg, subcutaneous injection twice a week). The control group received phosphate-buffered saline (40-50 µL/subcutaneous injection twice a week). After 4 weeks of drug administration, pancreatic ß-cells and the liver were removed and examined. RESULTS: Compared to the control group, blood glucose and body weight were significantly reduced in the group that received either tirzepatide or semaglutide (p < 0.001 and p < 0.05, respectively). Fasting insulin was significantly higher in the semaglutide and tirzepatide groups compared to the control group (p < 0.001). ß-Cell mass and quality of insulin granules in ß-cells similarly increased in the semaglutide and tirzepatide groups compared to the control group (p < 0.05 and p < 0.001, respectively). The fat staining area in the liver in oil red O staining and the liver-spleen ratio in computed tomography showed improvement only in the tirzepatide group (p < 0.001 and p < 0.005, respectively). Liver macrophage M1/M2 ratio similarly improved with semaglutide and tirzepatide (p < 0.05). CONCLUSION: Tirzepatide and semaglutide exhibited similar potent glucose-lowering effects. At concentrations used in the present experiments, tirzepatide exhibited more beneficial effects on ß-cell-related gene expression, insulin granule count and glucose-stimulated insulin secretion compared to semaglutide. In addition, tirzepatide exhibited a stronger favourable effect on hepatic fat deposition and improved inflammation in the liver. This is the first report showing that tirzepatide, a novel diabetes drug, exhibits a superior effect on pancreatic ß-cells and the liver of obese type 2 diabetic mice.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may reduce the risk of developing cancer-related lymphedema following axillary lymph node dissection (ALND).

Purpose: Patients undergoing axillary lymph node dissection (ALND) for breast cancer face a high risk of lymphedema, further increased by high body mass index (BMI) and insulin resistance. GLP-1 receptor agonists (GLP-1RAs) have the potential to reduce these risk factors, but their role in lymphedema has never been investigated. The purpose of this study was to determine if GLP-RAs can reduce the risk of lymphedema in patients undergoing ALND. Methods: All patients who underwent ALND at a tertiary cancer center between 2010 and 2023 were reviewed. Patients with less than 2 years of follow-up from the time of ALND were excluded. Race, BMI, radiation, chemotherapy history, pre-existing diagnosis of diabetes, lymphedema development after ALND, and the use of GLP-1RAs were analyzed. Multivariate logistic regression analysis was performed to assess if there was a significant reduction in the risk of developing lymphedema after ALND. A sub-group analysis of non-diabetic patients was also performed. Results: 3,830 patients who underwent ALND were included, 76 of which were treated with. GLP-1 RAs. The incidence of lymphedema in the GLP-1 RA cohort was 6.6% (5 patients). Compared to 28.5% (1,071 patients) in the non-GLP-1 RA cohort. On multivariate regression analysis, patients who were treated with GLP-1 RA were 86% less likely to develop lymphedema compared to the non-GLP-1 RA cohort (OR 0.14, 95% CI 0.04-0.32, p < 0.0001). A BMI of 25 kg/m 2 or greater was a statistically significant risk factor for developing lymphedema with an odds ratio of 1.34 (95% CI 1.16-1.56, p < 0.0001). Diabetes was associated with lymphedema development that closely approached statistical significance (OR 1.32, 95% CI 0.97-1.78, p = 0.06). A subgroup analysis solely on non-diabetic patients showed similar results. The odds of developing lymphedema were 84% lower for patients without diabetes treated with GLP1-RAs compared to those who did not receive GLP-1 RAs (OR 0.16, 95% CI 0.05-0.40, p < 0.0001). Conclusion: GLP1-RAs appear to significantly reduce the risk of lymphedema in patientsundergoing ALND. The mechanism of action may be multifactorial and not limited to weight reduction and insulin resistance. Future prospective analysis is warranted to clarify the role of GLP-1RAs in reducing lymphedema risk.

Semaglutide Alleviates Ovary Inflammation via the AMPK/SIRT1/NF­κB Signaling Pathway in Polycystic Ovary Syndrome Mice.

Background: GLP-1 receptor agonists (GLP-1 RA) have been proven to treat several metabolic diseases; however, the effects of GLP-1 RA on polycystic ovary syndrome (PCOS) remain unclear. Here, we aimed to investigate whether semaglutide, a novel GLP-1 RA, could alleviate ovarian inflammation in PCOS mice. Methods: Female C57BL/6J mice were subcutaneously injected with dehydroepiandrosterone for 21 days to establish the PCOS model. Then the mice were randomly divided into three groups: PCOS group (n = 6), S-0.42 group (semaglutide 0.42 mg/kg/w, n = 6), and S-0.84 group (semaglutide 0.84 mg/kg/w, n = 6). The remaining six mice were used as controls (NC). After 28 days of intervention, serum sex hormones and inflammatory cytokine levels were measured. Hematoxylin and eosin staining was used to observe the ovarian morphology. Immunohistochemical staining was used to detect the relative expression of CYP19A1, TNF-α, IL-6, IL-1ß, and NF-κB in ovaries. CYP17A1 and StAR were detected using immunofluorescence staining. Finally, the relative expressions of AMPK, pAMPK, SIRT1, NF-κB, IκBα, pIκBα, TNF-α, IL-6, and IL-1ß were measured using Western blotting. Results: First, after intervention with semaglutide, the weight of the mice decreased, insulin resistance improved, and the estrous cycle returned to normal. Serum testosterone and IL-1ß levels decreased significantly, whereas estradiol and progestin levels increased significantly. Follicular cystic dilation significantly improved. The expression of TNF-α, IL-6, IL-1ß, NF-κB, CYP17A1, and StAR in the ovary was significantly downregulated, whereas CYP19A1 expression was upregulated after the intervention. Finally, we confirmed that semaglutide alleviates ovarian tissue inflammation and improves PCOS through the AMPK/SIRT1/NF-κB signaling pathway. Conclusion: Semaglutide alleviates ovarian inflammation via the AMPK/SIRT1/NF­κB signaling pathway in PCOS mice.

A cost comparison of GLP-1 receptor agonists and bariatric surgery: what is the break even point?

BACKGROUND: With the prevalence of obesity rising in the US, medical management is of increasing importance. Two popular options for the treatment of obesity are bariatric surgery (e.g. sleeve gastrectomy and Roux-en-Y gastric bypass) and the increasingly popular GLP-1 Receptor Agonists (GLP-1 s). This study examines the initial and long-term costs of GLP-1 s compared to bariatric surgery. STUDY DESIGN: We compared average 2023 national retail prices for GLP-1 s to surgical cost estimates from 2015 adjusted for inflation. We then plotted the cumulative medication cost over time against the flat cost of each surgery, thus calculating "break-even points" (when medication costs equal surgery costs). The findings revealed a crucial insight, for some GLP-1 s like Saxenda and Wegovy, the high cost of ongoing use surpasses the cost of RYGB in less than a year and sleeve gastrectomy within nine months. Even the most affordable option, Byetta, becomes costlier than surgery after around 1.5 years. RESULTS: This highlights the importance of looking beyond the initial financial investment when considering cost-effectiveness. Additionally, while not directly assessed, this study acknowledges that GLP-1 s take time to reach full effectiveness, potentially delaying weight loss while accumulating costs. Concerns also exist about weight regain after discontinuing the medication. CONCLUSION: This study is limited by the real-world variation for individual treatment costs (e.g. insurance), a limited evaluation of long-term costs associated with either treatment modality and their co-morbidities, and the reality of patient preference providing subjective value to either modality. Overall, the study offers insights into the financial trade-offs between GLP-1 s and bariatric surgery.

Effects of the glucagon-like peptide-1 receptor agonist dulaglutide on sexuality in healthy men: a randomised, double-blind, placebo-controlled crossover study.

BACKGROUND: The reward-regulatory properties of GLP-1 are attracting increasing interest. Animal studies show that GLP-1 receptor agonists not only reduce consumption of addictive substances, but also influence sexual behaviour. We aimed to investigate the effect of dulaglutide versus placebo on sexual desire in humans. METHODS: In this randomised, double-blind, placebo-controlled crossover trial, healthy eugonadal men of normal weight, aged 18-50 years with active and satisfactory sex lifes were (1:1) randomly allocated to dulaglutide or placebo for four weeks. We assessed sexual desire (Massachusetts General Hospital-Sexual Functioning Questionnaire [MGH-SFQ]), hormones of the hypothalamic-pituitary-gonadal axis (total testosterone, follicle-stimulating hormone [FSH], luteinizing hormone [LH]) and sperm parameters. Changes in these parameters were compared under dulaglutide versus placebo using paired t-tests. FINDINGS: 24 out of 26 randomised participants completed the study (13 participants randomised to dulaglutide first and 13 to placebo first). No change in the MGH-SFQ was observed after four weeks of dulaglutide versus placebo (estimated difference 0.58 [95% CI -0.83 to 2.00], p-value = 0.402). Hormones of the hypothalamic-pituitary-gonadal axis (estimated differences: total testosterone (nmol/l) 0.9 [95% CI -1.5 to 3.3], FSH (IU/l) -0.2 [95% CI -0.3 to 0.0] and LH (IU/l) -0.8 [95% CI -1.5 to 0.0]) as well as sperm parameters all remained in the normal range without significant differences between the treatments. No severe adverse events occurred. INTERPRETATION: In this study of healthy men, we found no evidence of negative impacts of a four-week treatment with the widely used GLP-1 receptor agonist dulaglutide on sexual desire, hypothalamic-pituitary-gonadal axis hormones or sperm parameters. FUNDING: Swiss National Science Foundation (PZ00P3_193206), Gottfried and Julia Bangerter-Rhyner Foundation, Goldschmidt-Jacobson Foundation, Swiss Academy of Medical Sciences.

Impact of baseline characteristics on the efficacy of once-weekly subcutaneous semaglutide among participants with type 2 diabetes: A post hoc analysis of SUSTAIN China.

AIMS: To investigate the impact of baseline characteristics on the efficacy of once-weekly subcutaneous semaglutide 0.5 and 1.0 mg in participants with type 2 diabetes (T2D) from the SUSTAIN China trial. METHODS: In this post hoc analysis, data for semaglutide 0.5 and 1.0 mg versus sitagliptin 100 mg were analysed in the total (n = 868) and Chinese-only (n = 605) populations. Changes from baseline to end of treatment (EOT) in glycated haemoglobin (HbA1c) and body weight were analysed by baseline age, sex, body mass index, HbA1c, diabetes duration, and homeostatic model assessment of ß-cell function (HOMA-ß) tertile. Proportions of participants achieving HbA1c <7.0% (53 mmol/mol) by baseline HbA1c, change from baseline to EOT in standard deviation of seven-point self-monitored plasma glucose (SMPG), derived time-in-range (dTIR) of seven-point SMPG at Week 30, and HOMA-ß ratio to baseline at Week 30 were assessed for both populations. RESULTS: In both populations the efficacy of once-weekly subcutaneous semaglutide 0.5 and 1.0 mg versus sitagliptin was not significantly affected by most of the baseline characteristics studied. The proportion of participants achieving the target HbA1c <7% was not affected by baseline HbA1c (pinteraction > 0.05). SMPG fluctuation and dTIR indicated less glucose variability in participants treated with semaglutide 0.5 and 1.0 mg versus sitagliptin, and the HOMA-ß ratios to baseline at EOT were greater with semaglutide 0.5 and 1.0 mg versus sitagliptin (p < 0.05). CONCLUSIONS: These results support the effectiveness of once-weekly subcutaneous semaglutide 0.5 and 1.0 mg across a broad range of baseline characteristics, in participants with T2D from SUSTAIN China.