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BackgroundWeight gain and associated metabolic complications are increasingly prevalent among people with HIV (PWH). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin-based therapies for diabetes and weight management that have been shown to result in substantial weight loss; however, studies of their effects in PWH are limited.MethodsA retrospective single-center cohort study was conducted among PWH who were taking GLP-1RAs at UC San Diego Owen Clinic between 2/1/2021 to 2/1/2023. Baseline clinical data were collected and changes in weight, body mass index (BMI), and hemoglobin A1C (A1C) before starting GLP-1RAs compared to the most recent clinic visit were calculated (with a minimum of 3 months follow-up time required). Logistic regression was performed to identify variables associated with >5% of total body weight loss.ResultsA total of 225 patients received on average 13 months of GLP-1RA therapy, with 85 (37.8%) achieving the maximum GLP-1RA dose. GLP-1RA therapy resulted, on average, in a loss of 5.4 kg, decrease in BMI by 1.8 kg/m2, and decrease in A1C by 0.6%. In the multivariable analysis, higher baseline BMI [OR 1.10 (1.03-1.16)], treatment duration of GLP-1RA therapy greater than 6 months [OR 3.12 (1.49-6.49], and use of tirzepatide [OR 5.46 (1.44-20.76)] were significantly more likely to be associated with >5% weight loss.ConclusionsUse of GLP-1RAs led to declines in weight, BMI, and hemoglobin A1C among PWH and offers an additional strategy to address weight gain and diabetes.

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. [ABSTRACT FROM AUTHOR]

This article discusses a study on the real-life use of the weight loss medication liraglutide (Saxenda) in patients with obesity in France. The study found that patients who started treatment were generally less socially disadvantaged than those who did not start treatment, possibly due to the higher cost of the medication. The primary reasons for not initiating Saxenda were cost and concerns about side effects. Patients who continued treatment for more than 6 months achieved greater weight loss, and the cost of the medication varied widely. The study suggests that social factors and cost play a significant role in adherence to anti-obesity treatment. [Extracted from the article]

Introduction: Oral semaglutide provides an alternative to injectable glucagon-like peptide-1 receptor agonists (GLP-1RAs) for treatment of type 2 diabetes (T2D). The PIONEER REAL studies evaluate clinical outcomes of oral semaglutide treatment of T2D in a real-world setting. PIONEER REAL UK focused on adults living with T2D in the UK. Methods: The multi-centre, prospective and non-interventional single-arm study enrolled 333 participants and followed them for 34–44 weeks. Participants were treated as part of routine clinical practice and had not been previously treated with injectable glucose-lowering medication. The primary endpoint was change in glycated haemoglobin (HbA1C) from baseline to end of study (EOS). Secondary endpoints included change in body weight, proportion of participants with HbA1C < 7% (53 mmol/mol) at EOS and proportion of participants with ≥ 1%-point HbA1C reduction and body weight reduction of ≥ 3% or ≥ 5% at EOS. Treatment satisfaction was assessed by Diabetes Treatment Satisfaction Questionnaire (DTSQ) status and change. Results: Of 333 participants, 299 completed the study and 227 were on treatment at EOS. People treated with oral semaglutide experienced significantly reduced HbA1C by an estimated change of – 1.1%-points (95% CI – 1.27 to – 0.96; P < 0.0001) or – 12.2 mmol/mol (CI – 13.87 to – 10.47; P < 0.0001). Estimated change in body weight was – 4.8 kg (CI – 5.47 to – 4.12; P < 0.0001). At EOS, an HbA1C level < 7% (53 mmol/mol) was recorded in 46.3% of participants. A ≥ 1%-point reduction in HbA1C combined with a ≥ 3% reduction in body weight was observed in 36.4% of participants, and 27.1% had a ≥ 1%-point reduction in HbA1C and a ≥ 5% body weight reduction. Treatment satisfaction improved significantly during the study. No new safety concerns or cases of severe hypoglycaemia were reported. Conclusion: People living with T2D in the UK experienced a meaningful decrease in HbA1C and body weight after initiation of oral semaglutide treatment. No new safety issues were observed. Trial Registration: ClinicalTrials.gov: NCT04862923. Graphical plain language summary available for this article. Plain Language Summary: PIONEER REAL UK investigated the use of a tablet form of the medicine semaglutide in people living with type 2 diabetes in the UK. The purpose was to determine how well the tablet works for blood sugar control and weight loss in everyday clinical practice. The study followed 333 participants whose doctors had given them semaglutide tablets. Their blood sugar levels and body weight were measured before and after taking the semaglutide tablet for 34–44 weeks. The participants were also asked to fill out questionnaires about their treatment satisfaction and how it changed when taking the semaglutide tablet. The participants' blood sugar levels dropped a lot, and body weight was lowered by an average of 4.8 kg during the 34–44 weeks of the study. The participants were also more satisfied with their treatment at the end of the study than before taking the semaglutide tablet. Doctors treating the participants found the treatment to be a success in more than two-thirds of participants. The study also found that the semaglutide tablet was not associated with cases of too low blood sugar and was generally well tolerated. In summary, the semaglutide tablet is a good option for people living with type 2 diabetes who need better blood sugar control and would benefit from weight loss. The treatment is generally well tolerated, and people are very satisfied with it. Graphical Plain Language Summary: [ABSTRACT FROM AUTHOR]

Background Weight gain and associated metabolic complications are increasingly prevalent among people with human immunodeficiency virus (PWH). Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are incretin-based therapies for diabetes and weight management that have been shown to result in substantial weight loss; however, studies of their effects in PWH are limited. Methods A retrospective single-center cohort study was conducted among PWH who were taking GLP-1RAs at the University of California, San Diego Owen Clinic between 1 February 2021 and 1 February 2023. Baseline clinical data were collected and changes in weight, body mass index (BMI), and hemoglobin A1C (A1C) before starting GLP-1RAs compared to the most recent clinic visit were calculated (with a minimum of 3 months follow-up time required). Logistic regression was performed to identify variables associated with >5% of total body weight loss. Results A total of 225 patients received on average 13 months of GLP-1RA therapy, with 85 (37.8%) achieving the maximum GLP-1RA dose. GLP-1RA therapy resulted, on average, in a weight loss of 5.4 kg, decrease in BMI by 1.8 kg/m2, and decrease in A1C by 0.6%. In the multivariable analysis, higher baseline BMI (odds ratio [OR], 1.10 [95% confidence interval {CI}, 1.03–1.16]), treatment duration of GLP-1RA therapy >6 months (OR, 3.12 [95% CI, 1.49–6.49]), and use of tirzepatide (OR, 5.46 [95% CI, 1.44–20.76]) were significantly more likely to be associated with >5% weight loss. Conclusions Use of GLP-1RAs led to declines in weight, BMI, and A1C among PWH and offers an additional strategy to address weight gain and diabetes. [ABSTRACT FROM AUTHOR]

Background Results Conclusion Semaglutide, a glucagon‐like peptide‐1 (GLP‐1) receptor agonist, is a widely used drug for the treatment of type 2 diabetes that offers significant cardiovascular benefits.This review systematically examines the proteomic and metabolomic indicators associated with the cardiovascular effects of semaglutide. A comprehensive literature search was conducted to identify relevant studies. The review utilizes advanced analytical technologies such as mass spectrometry and nuclear magnetic resonance (NMR) to investigate the molecular mechanisms underlying the effects of semaglutide on insulin secretion, weight control, anti‐inflammatory activities and lipid metabolism. These “omics” approaches offer critical insights into metabolic changes associated with cardiovascular health. However, challenges remain such as individual variability in expression, the need for comprehensive validation and the integration of these data with clinical parameters. These issues need to be addressed through further research to refine these indicators and increase their clinical utility.Future integration of proteomic and metabolomic data with artificial intelligence (AI) promises to improve prediction and monitoring of cardiovascular outcomes and may enable more accurate and effective management of cardiovascular health in patients with type 2 diabetes. This review highlights the transformative potential of integrating proteomics, metabolomics and AI to advance cardiovascular medicine and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Summary The rapid and widespread clinical adoption of highly effective incretin‐mimetic drugs (IMDs), particularly semaglutide and tirzepatide, for the treatment of obesity has outpaced the updating of clinical practice guidelines. Consequently, many patients may be at risk for adverse effects and uncertain long‐term outcomes related to the use of these drugs. Of emerging concern is the loss of skeletal muscle mass and function that can accompany rapid substantial weight reduction; such losses can lead to reduced functional and metabolic health, weight cycling, compromised quality of life, and other adverse outcomes. Available evidence suggests that clinical trial participants receiving IMDs for the treatment of obesity lost 10% or more of their muscle mass during the 68‐ to 72‐week interventions, approximately equivalent to 20 years of age‐related muscle loss. The ability to maintain muscle mass during caloric restriction‐induced weight reduction is influenced by two key factors: nutrition and physical exercise. Nutrition therapy should ensure adequate intake and absorption of high‐quality protein and micronutrients, which may require the use of oral nutritional supplements. Additionally, concurrent physical activity, especially resistance training, has been shown to effectively minimize loss of muscle mass and function during weight reduction therapy. All patients receiving IMDs for obesity should participate in comprehensive treatment programs emphasizing adequate protein and micronutrient intakes, as well as resistance training, to preserve muscle mass and function, maximize the benefit of IMD therapy, and minimize potential risks. [ABSTRACT FROM AUTHOR]

Background: Off-label use of semaglutide for non-diabetic weight loss (which regulators have linked to social media promotion) created worldwide supply shortages. We evaluated worldwide semaglutide interest measured by online search behavior to gauge social media and conventional print media reporting's effect on search interest. Methods: Using Google Trends Extended for Health (GTEH) multiple sampling, we retrieved regional online interest (ROI) for all countries and extracted timelines and top search queries for January 2021–August 2023 for countries with median ROI ≥ 20 using the "semaglutide" topic. We obtained semaglutide media reporting from the ProQuest database. We estimated the effect of media and within-country semaglutide interest on between-country interest with Granger causality analysis. We determined changepoints for trends within each country with joinpoint regression. We determined prominent themes in search queries for each country with natural language processing thematic analysis. Results: Twenty-seven countries were included. Most countries showed an increase in semaglutide interest over time, with Canada and the USA showing the largest sustained interest. Most of the search interest arose from 2022 onwards. Granger's analysis showed that media coverage could only partially explain interest, and interest in some countries partially preceded interest in others, with the UK and Germany showing strong relationships between news reports and lagged search interest. Joinpoint analysis identified up to four significant within-country changepoints. Most countries showed significant positive weekly trends in 2021–2022, although uptrends in search interest varied considerably between countries. One episode of the Dr. Oz show (TV media event) coincided with strong peaks in numerous countries. Natural language processing of top search queries showed some agreement between countries and country-specific themes. Weight loss was a major theme in most countries, while a diabetes theme was generally absent or weak. Some countries (Australia, Chile, South Africa, UK) had themes for buying Ozempic from (named) local retailers, and Germany had a theme related to buying Ozempic without a script. Conclusions: GTEH data provided insights into global search interest in semaglutide and regional variation. Studies focusing on specific countries which include social media data can elucidate specific drivers behind the surge in off-label use of semaglutide. [ABSTRACT FROM AUTHOR]

Weight loss induced by glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and dual glucagon‐like peptide‐1 receptor (GLP‐1R)/glucose‐dependent insulinotropic polypeptide receptor agonists is coming closer to the magnitudes achieved with surgery. However, with greater weight loss there is concern about potential side effects on muscle quantity (mass), health and function. There is heterogeneity in the reported effects of GLP‐1‐based therapies on lean mass changes in clinical trials: in some studies, reductions in lean mass range between 40% and 60% as a proportion of total weight lost, while other studies show lean mass reductions of approximately 15% or less of total weight lost. There are several potential reasons underlying this heterogeneity, including population, drug‐specific/molecular, and comorbidity effects. Furthermore, changes in lean mass may not always reflect changes in muscle mass as the former measure includes not only muscle but also organs, bone, fluids, and water in fat tissue. Based on contemporary evidence with the addition of magnetic resonance imaging‐based studies, skeletal muscle changes with GLP‐1RA treatments appear to be adaptive: reductions in muscle volume seem to be commensurate with what is expected given ageing, disease status, and weight loss achieved, and the improvement in insulin sensitivity and muscle fat infiltration likely contributes to an adaptive process with improved muscle quality, lowering the probability for loss in strength and function. Nevertheless, factors such as older age and severity of disease may influence the selection of appropriate candidates for these therapies due to risk of sarcopenia. To further improve muscle health during weight loss, several pharmacological treatments to maintain or improve muscle mass designed in combination with GLP‐1‐based therapies are under development. Future research on GLP‐1‐based and other therapies designed for weight loss should focus on more accurate and meaningful assessments of muscle mass, composition, as well as function, mobility or strength, to better define their impact on muscle health for the substantial number of patients who will likely be taking these medications well into the future. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Dulaglutide is a relatively unpopular GLP‐1 receptor agonist used for weight loss. This case demonstrates that dulaglutide may be beneficial for weight loss in morbidly obese patients with multiple comorbidities after thoroughly evaluating its efficacy, benefits, and long‐term adverse effects through clinical trials. We present a case of a 27‐year‐old ex‐sumo wrestler with bipolar II disorder, morbid obesity, hypertension, Type 2 Diabetes Mellitus (DM), and a Body Mass Index (BMI) of 49.66 kg/m2. He was non‐compliant with lifestyle modifications and resistant to conventional treatments, including metformin, and was also using multiple antipsychotic drugs. After introducing dulaglutide, he achieved a 40 kg (−21%) weight loss and a BMI reduction of 10.3 kg/m2 over 6 months, with no side effects and improved glycemic control, demonstrating dulaglutide's efficacy for weight loss in such challenging presentations. [ABSTRACT FROM AUTHOR]

Introduction: The study was designed to assess outcomes with once-daily oral semaglutide in adults with type 2 diabetes (T2D) naïve to injectable glucose-lowering agents, in Swedish clinical practice. Methods: In this non-interventional, multicentre study, participants initiated oral semaglutide and were followed for 34–44 weeks. The primary endpoint was glycated haemoglobin (HbA1c) change from baseline to end of study (EOS). Secondary endpoints included body weight (BW) change from baseline to EOS, proportion of participants achieving HbA1c < 7%, and proportion achieving both a HbA1c reduction ≥ 1% and BW reduction of ≥ 3% or ≥ 5%, at EOS. Participants completed Diabetes Treatment Satisfaction Questionnaires (DTSQ status/change) and a dosing conditions questionnaire. Results: A total of 187 participants (mean age 62.5 years) initiated oral semaglutide. Baseline mean HbA1c and BW were 7.8% (n = 177) and 96.9 kg (n = 165), respectively. Estimated mean changes in HbA1c and BW were − 0.88%-points (95% confidence interval [CI] − 1.01 to − 0.75; P < 0.0001) and − 4.72% (95% CI − 5.58 to − 3.86; P < 0.0001), respectively. At EOS, 64.6% of participants had HbA1c < 7%, and 22.9% achieved HbA1c reduction of ≥ 1% and BW reduction of ≥ 5%. DTSQ status and change scores improved by 1.44 (P = 0.0260) and 12.3 points (P < 0.0001), respectively. Oral semaglutide was easy or very easy to consume for 86.4% of participants. Most common adverse events (AEs) were gastrointestinal disorders; nine participants (4.8%) had serious AEs; one (0.5%) experienced severe hypoglycaemia. Conclusion: In this real-world study population, we observed significant reductions in HbA1c and BW in people living with T2D when prescribed semaglutide tablets as part of routine clinical practice in Sweden, with improved treatment satisfaction among participants and no new safety concerns. Trial Registration: NCT04601753. [ABSTRACT FROM AUTHOR]

Introduction: Bile acid diarrhea is a common cause of bowel symptoms and often goes unrecognized or misdiagnosed. Many aspects of management remain contentious. Areas Covered: The primary, idiopathic condition should be suspected in people with functional diarrhea or diarrhea-predominant irritable bowel syndrome. Secondary causes include ileal resection, inflammation, and post-cholecystectomy. Diagnostic tests vary globally, being unavailable in many countries, and further refinement of testing strategy is needed. Management is usually long-term symptom control, rather than reversal of the causative factors, which are still being defined. Bile acid sequestrants remain the main drugs used. They are relatively inexpensive, and better-quality data is now available for colesevelam. However, optimal use, including timing and formulation, needs clarification. The GLP-1 receptor agonist, liraglutide, is also effective, although mechanisms of action and whether this effect is common to other class members is unclear. They are more expensive, and availability varies. FXR agonists can also be effective but require further validation. The role of dietary factors in symptom development is a major patient concern, needing more formal studies. Expert opinion: To build on recent findings, bile acid diarrhea needs further investment into causes, diagnosis and therapy to guide present and future patient care. Plain Language Summary: The condition known as bile acid diarrhea (BAD) causes frequent loose stools, which need to be passed urgently, sometimes causing incontinence. It can be a complication of surgery or other intestinal disorders, and gives similar symptoms to IBS. It is not widely known and clinicians often fail to diagnose it. In this article, we review recent publications about how to make the diagnosis of BAD. Some of these are contentious and there may be limited availability of the tests or poor accuracy. We then review current treatments and how to best manage BAD. There are some new treatments, which are not yet fully proven or accepted for general use. We review these and express opinions regarding the current best practices in diagnosis and treatment, and how these may change in the next 5 years. [ABSTRACT FROM AUTHOR]

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Mei Liu,1,&ast; Sili Guo,1,&ast; Xiaohan Li,1,&ast; Yang Tian,1 Yanjie Yu,2 Lili Tang,1 Qimei Sun,1 Ting Zhang,1 Mingwei Fan,3 Lili Zhang,1 Yingjiang Xu,4 Jiajia An,5 Xiangqian Gao,6 Lei Han,7 Lei Zhang1 1Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 2Department of Ultrasound Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 3Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 4Department of Interventional Vascular Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 5Department of Clinical Laboratory, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 6Department of Pathology, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 7Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lei Zhang, Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China, Email binzhouzhanglei@outlook.comBackground: 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-1β, 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-1β 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-1β levels decreased significantly, whereas estradiol and progestin levels increased significantly. Follicular cystic dilation significantly improved. The expression of TNF-α, IL-6, IL-1β, 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/NF‑κB signaling pathway in PCOS mice.Keywords: GLP-1 receptor agonist, polycystic ovary syndrome, semaglutide, inflammation

Cardiovascular (CV) diseases are the leading causes of death worldwide in both sexes alike. However, there have been significant developments in CV pharmacotherapy, percutaneous intervention, and systems of care over the past three decades in parallel. Several landmark studies were presented and discussed in American Heart Association (AHA) 2023 Scientific Sessions held in Philadelphia. The dapagliflozin-myocardial infarction (MI) and SELECT discussed the CV benefits of newer antidiabetic drugs. The AZALEA-TIMI and ARTESIA evaluated newer anticoagulants in atrial fibrillation. VERVE-101 and LEPODISIRAN studies were related to lipid-lowering in clinical practice. The ESPRIT trial demonstrated the benefits of intensive blood lowering, while KARDIA-1 tested a new RNA-based therapeutic agent for blood pressure lowering. The MINT trial evaluated strategies for blood transfusion in anemia concomitant with acute MI. ORBITA-2 study demonstrated the positive impact of percutaneous coronary intervention for angina control in stable coronary artery disease. Hence, these studies encompassed almost all aspects of cardiology, including heart failure, acute coronary syndrome, lipidology, anticoagulation, hypertension, obesity, and coronary intervention.

While many types of diabetes medications are currently available, orally administered formulations of glucagon-like peptide-1 (GLP-1) receptor agonists have recently been launched. Therefore, gastrointestinal epithelial cells will be increasingly exposed to GLP-1 receptor agonists; however, their effects on these cells remain unclear. The present study attempted to clarify the effects of GLP-1 receptor agonists on intestinal epithelial barrier functions. Semaglutide (5, 50, and 500 ng/mL) and dulaglutide (15, 150, and 1500 ng/mL) were selected as GLP-1 receptor agonists and applied to the Caco-2 cell line. Changes in mRNA and protein expression levels of epithelial cell barrier regulators due to exposure to GLP-1 receptor agonists were examined by real-time RT-PCR and Western blotting. Neither semaglutide nor dulaglutide changed the growth rate or ratio of Caco-2 cells. Furthermore, they did not significantly affect the mRNA expression levels of membrane proteins involved in epithelial cell barrier functions. However, dulaglutide increased the protein expression levels of these membrane proteins in a concentration-dependent manner, whereas semaglutide did not. Only dulaglutide enhanced epithelial cell barrier functions. Since various gastrointestinal symptoms develop in patients with diabetes and epithelial cell barrier functions may be compromised, medicines that promote barrier function, such as dulaglutide, may effectively attenuate these changes. However, their mechanisms of action remain unknown; therefore, further studies are warranted.

Aim: To investigate the most matchable price of tirzepatide (TIRZ) compared with semaglutide (SEMA) in the treatment of type 2 diabetes in China. Methods: The patient cohort and clinical efficacy data were derived from the SURPASS‐2 trial. Cost‐utility analysis and a binary search were performed to identify the most matchable price of TIRZ from a Chinese healthcare provider's perspective. Results: After lifetime simulation, the quality‐adjusted life years of TIRZ 5, 10, 15 mg and SEMA 1 mg were 11.17, 11.21, 11.27 and 11.12 years, respectively. Despite an initial assumption that the annual cost of TIRZ equals that of SEMA, our analysis revealed that TIRZ is probably more cost‐effective than SEMA. A thorough evaluation of pricing showed that the cost ranges for TIRZ at doses of 5, 10 and 15 mg were $1628.61‐$1846.23, $1738.40‐$2140.95 and $1800.30‐$2430.81, respectively. After adjustment in the univariate sensitivity analysis, the cost ranges for TIRZ 5, 10 and 15 mg were $1542.68‐$1757.57, $1573.00‐$1967.16 and $1576.54‐$2133.96, respectively. These cost intervals were validated through robust probabilistic sensitivity analysis and scenario analysis, except for the cost range for TIRZ 5 mg. Conclusions: This study shows that, using SEMA as a reference, the annual costs for TIRZ 10 and 15 mg are $1573.00‐$1967.16 and $1576.54‐$2133.96, respectively, for patients with type 2 diabetes in China. [ABSTRACT FROM AUTHOR]

Aim: To investigate growth/differentiation factor 15 (GDF‐15) levels in response to antiobesity medications, namely, liraglutide (Lira) and naltrexone/bupropion (N/B), in individuals with overweight or obesity. Materials and Methods: This was a prospective, non‐randomized clinical trial with a two‐arm, parallel design. A total of 42 individuals with overweight or obesity without type 1 or type 2 diabetes mellitus were enrolled. The participants received either Lira 3 mg or N/B 32/360 mg, along with diet and exercise, according to comorbidities, cost and method of administration. Participants underwent clinical and laboratory measurements at baseline, as well as at the 3‐ and 6‐month time points. Anthropometric measurements and body composition analysis via bioelectrical impendence analysis were performed. Total blood samples for GDF‐15 and H‐specific GDF‐15 were collected in the fasting state and every 30 min for 3 h after the consumption of a standardized mixed meal. Results: Overall, participants' weight was reduced by 9.29 ± 5.34 kg at Month 3 and 11.52 ± 7.52 kg at Month 6. Total and H‐specific GDF‐15 levels did not show significant changes during the mixed meal compared to values before the meal when all participants were examined at baseline, and at 3 and 6 month follow‐ups. No statistical significance was found when participants were examined by subgroup (Lira vs. N/B). No significant differences between treatment groups in postprandial area under the curve (AUC) or incremental AUC values were found at baseline or in the follow‐up months with regard to total and H‐specific GDF‐15 levels. Conclusion: Neither total nor H‐specific GDF‐15 levels are affected by Lira or N/B treatment in patients with overweight or obesity. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors are guideline-recommended therapies for the management of type 2 diabetes (T2D), atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease. We previously observed in people living with T2D and coronary artery disease that circulating vascular regenerative (VR) progenitor cell content increased following 6-mo use of the SGLT2 inhibitor empagliflozin. In this post hoc subanalysis of the ORIGINS-RCE CardioLink-13 study (ClinicalTrials.gov Identifier NCT05253521), we analyzed the circulating VR progenitor cell content of 92 individuals living with T2D, among whom 20 were on a GLP-1RA, 42 were on an SGLT2 inhibitor but not a GLP-1RA, and 30 were on neither of these vascular protective therapies. In the GLP-1RA group, the mean absolute count of circulating VR progenitor cells defined by high aldehyde dehydrogenase (ALDH) activity (ALDHhiSSClow) and VR progenitor cells further characterized by surface expression of the proangiogenic marker CD133 (ALDHhiSSClowCD133+) was higher than the group receiving neither a GLP-1RA nor an SGLT2 inhibitor (P = 0.02) and comparable with that in the SGLT2 inhibitor group (P = 0.25). The absolute count of proinflammatory, granulocyte-restricted precursor cells (ALDHhiSSChi) was significantly lower in the GLP-1RA group compared with the group on neither therapy (P = 0.031). Augmented vessel repair initiated by VR cells with previously documented proangiogenic activity, alongside a reduction in systemic, granulocyte precursor-driven inflammation, may represent novel mechanisms responsible for the cardiovascular-metabolic benefits of GLP-1RA therapy. Prospective, randomized clinical trials are now warranted to establish the value of recovering circulating VR progenitor cell content with blood vessel regenerative functions. NEW & NOTEWORTHY: In this post hoc subanalysis of 92 individuals living with T2D and at high cardiovascular risk, the authors summarize the differences in circulating vascular regenerative (VR) progenitor cell content between those on GLP-1RA therapy, on SGLT2 inhibitor without GLP-1RA therapy, and on neither therapy. Those on GLP-1RA therapy demonstrated greater circulating VR progenitor cell content and reduced proinflammatory granulocyte precursor content. These results offer novel mechanistic insights into the cardiometabolic benefits associated with GLP-1RA therapy. [ABSTRACT FROM AUTHOR]

Introduction: In this phase 4, multicentre, prospective, non-interventional PIONEER REAL Netherlands study, we assessed clinical outcomes associated with once-daily oral semaglutide use in real-world clinical practice in adults living with type 2 diabetes (T2D) naïve to injectable glucose-lowering medication. Methods: Participants initiated on oral semaglutide were followed for 34–44 weeks. Change in glycated haemoglobin (HbA1c) from baseline (BL) to end of study (EOS) was the primary endpoint; secondary endpoints included change in body weight (BW) from BL to EOS, the proportion of participants with HbA1c < 7.0% at EOS and the composite endpoints of HbA1c reduction ≥ 1.0%-points with BW reduction ≥ 3% or ≥ 5% at EOS. Treatment satisfaction was assessed using the Diabetes Treatment Satisfaction Questionnaire (DTSQ status/change). Safety was evaluated in all participants who initiated oral semaglutide treatment. Results: Oral semaglutide was initiated in 187 participants; 94.1% completed the study and 78.6% remained on treatment at EOS. At BL, 54.0% of participants were male, mean age was 58.8 years, mean duration of T2D was 8.7 years and mean body mass index was 35.1 kg/m2; mean HbA1c was 8.6% and mean BW was 103.1 kg. Significant improvements from BL to EOS were observed for HbA1c and BW (estimated change [95% confidence interval]: − 1.16%-points [− 1.48 to − 0.85]; p < 0.0001, and − 5.84 kg [− 6.88 to − 4.80]; p < 0.0001, respectively). At EOS, 47.5% of participants had an HbA1c level < 7.0%; 41.8% and 35.5% of participants achieved composite endpoints of HbA1c reduction ≥ 1.0%-points plus BW reduction ≥ 3% or ≥ 5%, respectively. DTSQ status and change scores improved by 2.1 (p = 0.0003) and 10.8 points (p < 0.0001), respectively. Oral semaglutide was easy or very easy to consume for 81.5% of participants. Adverse events were mostly mild/moderate, with gastrointestinal disorders being the most common. Conclusion: In this real-world population, we reported clinically significant reductions in HbA1c and BW, improved treatment satisfaction and no new safety concerns. A graphical abstract is available with this article. Clinical Trial Registration: NCT04601740. [ABSTRACT FROM AUTHOR]

Liraglutide, a glucagon-like peptide 1 analog used to treat type 2 diabetes and obesity, is a potential new treatment modality for bile acid (BA) diarrhea. Here, we show that administration of liraglutide significantly decreased total BAs, especially the primary BAs, including cholic acid, chenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, and β-muricholic acid, in the liver and feces. In addition, liraglutide significantly decreased tryptophan metabolites, including L-tryptophan, serotonin, 5-hydroxy indole-3-acetic acid, L-kynurenine, and xanthurenic acid, in the colon, whereas it significantly increased indole-3-propionic acid. Moreover, the administration of liraglutide remarkably decreased the expression of apical sodium-dependent bile acid transporter, which mediates BA uptake across the apical brush border member in the ileum, ileal BA binding protein, and fibroblast growth factor 15 in association with decreased expression of the BA-activated nuclear receptor farnesoid X receptor and the heteromeric organic solute transporter Ostα/β, which induces BA excretion, in the ileum. Liraglutide acutely decreased body weight and blood glucose levels in association with decreases in plasma insulin and serotonin levels in food-deprived mice. These findings suggest the potential of liraglutide as a novel inhibitor of primary BAs and serotonin in the colon. [ABSTRACT FROM AUTHOR]

Aim: To determine if the dispensing of glucagon‐like peptide (GLP)‐1 receptor agonists is associated with increased dispensing of antidepressants. Materials and Methods: We used cross‐sectional, case‐control and retrospective cohort study designs to examine the association between dispensed GLP‐1 receptor agonists and antidepressants between 2012 and 2022 in the 10% random sample of the Australian Pharmaceutical Benefits Scheme (PBS) data. PBS‐listed GLP‐1 receptor agonists, exenatide, dulaglutide and semaglutide were the exposures. Outcomes were the odds ratio [ORs; 99% confidence interval (CI)] and hazard ratio (99% CI) of being dispensed any antidepressant. Analyses were adjusted for demographic measures and the dispensing of medicines to manage cardiovascular diseases or anxiety/insomnia. Statistical tests were two‐sided at the 1% level of significance. Results: In total, 358 075 of 1 746 391 individuals were dispensed antidepressants, and 8495 of the 24 783 dispensed a GLP‐1 receptor agonist were also dispensed an antidepressant in 2022 (OR 1.44; 99% CI 1.38‐1.50); 24 103 of the 1 746 391 participants had been dispensed a GLP‐1 receptor agonist between 2012 and 2021, and of these 8083 were dispensed antidepressants in 2022 (OR 1.52; 99% CI 1.46‐1.59). The 2012 cohort included 1 213 316 individuals who had not been dispensed antidepressants that year. The hazard ratio of being dispensed an antidepressant between 2013 and 2022 following the dispensing of a GLP‐1 receptor agonist was 1.19 (99% CI 1.12‐1.27). Additional analyses restricting the time of exposure confirmed these associations for all PBS‐listed GLP‐1 receptor agonists. Conclusions: Individuals exposed to GLP‐1 receptor agonists are at greater risk of being dispensed antidepressants. The possible impact of GLP‐1 receptor agonists on the mood of consumers requires ongoing vigilance and further research. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We conducted a systematic review and network meta-analysis to compare the efficacy and safety of s.c. administered tirzepatide vs s.c. administered semaglutide for adults of both sexes with type 2 diabetes mellitus. Methods: We searched PubMed and Cochrane up to 11 November 2023 for RCTs with an intervention duration of at least 12 weeks assessing s.c. tirzepatide at maintenance doses of 5 mg, 10 mg or 15 mg once weekly, or s.c. semaglutide at maintenance doses of 0.5 mg, 1.0 mg or 2.0 mg once weekly, in adults with type 2 diabetes, regardless of background glucose-lowering treatment. Eligible trials compared any of the specified doses of tirzepatide and semaglutide against each other, placebo or other glucose-lowering drugs. Primary outcomes were changes in HbA1c and body weight from baseline. Secondary outcomes were achievement of HbA1c target of ≤48 mmol/mol (≤6.5%) or <53 mmol/mol (<7.0%), body weight loss of at least 10%, and safety outcomes including gastrointestinal adverse events and severe hypoglycaemia. We used version 2 of the Cochrane risk-of-bias tool (ROB 2) to assess the risk of bias, conducted frequentist random-effects network meta-analyses and evaluated confidence in effect estimates utilising the Confidence In Network Meta-Analysis (CINeMA) framework. Results: A total of 28 trials with 23,622 participants (44.2% female) were included. Compared with placebo, tirzepatide 15 mg was the most efficacious treatment in reducing HbA1c (mean difference −21.61 mmol/mol [−1.96%]) followed by tirzepatide 10 mg (−20.19 mmol/mol [−1.84%]), semaglutide 2.0 mg (−17.74 mmol/mol [−1.59%]), tirzepatide 5 mg (−17.60 mmol/mol [−1.60%]), semaglutide 1.0 mg (−15.25 mmol/mol [−1.39%]) and semaglutide 0.5 mg (−12.00 mmol/mol [−1.09%]). In between-drug comparisons, all tirzepatide doses were comparable with semaglutide 2.0 mg and superior to semaglutide 1.0 mg and 0.5 mg. Compared with placebo, tirzepatide was more efficacious than semaglutide for reducing body weight, with reductions ranging from 9.57 kg (tirzepatide 15 mg) to 5.27 kg (tirzepatide 5 mg). Semaglutide had a less pronounced effect, with reductions ranging from 4.97 kg (semaglutide 2.0 mg) to 2.52 kg (semaglutide 0.5 mg). In between-drug comparisons, tirzepatide 15 mg, 10 mg and 5 mg demonstrated greater efficacy than semaglutide 2.0 mg, 1.0 mg and 0.5 mg, respectively. Both drugs increased incidence of gastrointestinal adverse events compared with placebo, while neither tirzepatide nor semaglutide increased the risk of serious adverse events or severe hypoglycaemia. Conclusions/interpretation: Our data show that s.c. tirzepatide had a more pronounced effect on HbA1c and weight reduction compared with s.c. semaglutide in people with type 2 diabetes. Both drugs, particularly higher doses of tirzepatide, increased gastrointestinal adverse events. Registration: PROSPERO registration no. CRD42022382594 [ABSTRACT FROM AUTHOR]

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Purpose: Glucagon-like receptor agonists (GLP1-RAs) have raised peri-procedural concerns due to their potential to delay gastric emptying. The American Association of Anesthesiologists has advised pausing a single dose before elective endoscopy. However, a subsequent directive from multiple gastroenterology societies underscored the need for further assessment to substantiate this practice. We aimed to evaluate the frequency of serious adverse events and retained gastric products during endoscopic sleeve gastroplasty (ESG) with uninterrupted GLP1-RA use. Materials and Methods: We conducted a retrospective evaluation of all patients undergoing ESG while on GLP1-RAs at three centers from August 2022 to February 2024. Per standard protocol, all patients had refrained from solid foods for at least 24 h and maintained nil per os for 12 h preceding their ESG. Records were reviewed for patient characteristics and medication type and doses. Primary outcomes included serious adverse events and retained gastric products based on patient records, procedure reports, and procedural videos. Results: Fifty-seven consecutive adults (89.5% women, mean age of 44 ± 9 years, mean BMI of 40.1 ± 8.1 kg/m2, 35.1% with T2DM, and 26.3% with pre-T2DM) underwent ESG without stopping GLP1-RAs, which included semaglutide (45.6%), liraglutide (19.3%), dulaglutide (22.8%), and tirzepatide (12.3%). During intubation, endoscopy, and recovery, there were no instances of retained gastric solids, pulmonary aspiration, gastroesophageal regurgitation, or hypoxia. Conclusion: A ≥ 24-h pre-endoscopy liquid-only diet with ≥ 12-h pre-endoscopy fast may negate the need for GLP1-RA interruption for routine upper endoscopy in adults with native gastric anatomy. [ABSTRACT FROM AUTHOR]

Background To evaluate the efficacy and safety of once-weekly subcutaneous semaglutide treatment in overweight or obese patients without type 2 diabetes. Methods Randomized clinical trials that assessed the impact of once-weekly semaglutide on body weight and safety outcomes in overweight or obese patients were retrieved from PubMed, EMBASE, and Lilacs up to November 2023. Risk of bias was assessed with RoB 2.0, and certainty of evidence (CoE) with GRADE. A random-effects meta-analysis was conducted. Results Ten publications, with 22.155 patients, were included. Semaglutide decreased relative body weight (MD: −11.80; 95%CI: −13.53 to −10.07; CoE: High), absolute body weight (MD: −11.58; 95%CI: −13.25 to −9.90; CoE: High) and BMI (MD: −4.15; 95%CI: −4.85 to −3.45; CoE: High). Semaglutide also increased the proportion of patients who achieved 5%, 10%, and 15% of weight loss ([weight loss≥5%: RR 2.29, 95% CI: 1.88 to 2.80; CoE: High]; [weight loss≥10%: RR 4.54, 95% CI: 3.45 to 5.98; CoE: High]; [weight loss≥15%: RR 8.29, 95%CI: 5.54 to 12.39; CoE: High]). Semaglutide leads to small risk to adverse events (RR: 1.03; 95%CI: 1 to 1.06; CoE: High), no difference in the serious adverse events (RR: 1.07; 95%CI: 0.70 to 1.62; CoE: Low), but increases in the risk to discontinued treatment (RR: 2.03; 95%CI: 1.87 to 2.20; CoE: High) and gastrointestinal adverse events (RR: 3.26; 95%CI: 1.99 to 5.34; CoE: Moderate). Conclusion This up-to-date systematic review highlights that once-weekly semaglutide treatment resulted in clinically important weight loss, becoming a promising adjuvant therapy for obesity. [ABSTRACT FROM AUTHOR]

Aims: To assess the potential for precision medicine in type 2 diabetes by quantifying the variability of body weight as response to pharmacological treatment and to identify predictors which could explain this variability. Methods: We used randomized clinical trials (RCTs) comparing glucose‐lowering drugs (including but not limited to sodium‐glucose cotransporter‐2 inhibitors, glucagon‐like peptide‐1 receptor agonists and thiazolidinediones) to placebo from four recent systematic reviews. RCTs reporting on body weight after treatment to allow for calculation of its logarithmic standard deviation (log[SD], i.e., treatment response heterogeneity) in verum (i.e., treatment) and placebo groups were included. Meta‐regression analyses were performed with respect to variability of body weight after treatment and potential predictors. Results: A total of 120 RCTs with a total of 43 663 participants were analysed. A slightly larger treatment response heterogeneity was shown in the verum groups, with a median log(SD) of 2.83 compared to 2.79 from placebo. After full adjustment in the meta‐regression model, the difference in body weight log(SD) was −0.026 (95% confidence interval −0.044; 0.008), with greater variability in the placebo groups. Scatterplots did not show any slope divergence (i.e., interaction) between clinical predictors and the respective treatment (verum or placebo). Conclusions: We found no major treatment response heterogeneity in RCTs of glucose‐lowering drugs for body weight reduction in type 2 diabetes. The precision medicine approach may thus be of limited value in this setting. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) remains a prominent cause of global mortality, primarily driven by atherosclerosis. Diabetes mellitus, as a modifiable risk factor, significantly contributes to atherogenesis. Monocyte recruitment to the intima is a critical step in atherosclerotic plaque formation, involving chemokines and adhesion molecules such as selectins, ICAM-1, and MCP-1. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are a promising group of drugs for reducing cardiovascular risk in diabetic patients, prompting investigation into their mechanisms of action. This interventional study enrolled 50 diabetes patients with atherosclerotic plaque, administering GLP-1RA for 180 days. Serum concentrations of MCP-1, ICAM-1, and L-selectin were measured before and after treatment. Anthropometric and biochemical parameters were also assessed. GLP-1RA treatment resulted in significant improvements in anthropometric parameters, glycemic control, blood pressure, and biochemical markers of liver steatosis. Biomarker laboratory analysis revealed higher baseline levels of MCP-1, ICAM-1, and L-selectin in diabetic patients with atherosclerotic plaque compared to healthy controls. Following treatment, MCP-1 and L-selectin levels decreased significantly (p < 0.001), while ICAM-1 levels increased (p < 0.001). GLP-1RA treatment in diabetic patients with atherosclerotic plaque leads to favorable changes in serum molecule levels associated with monocyte recruitment to the endothelium. The observed reduction in MCP-1 and L-selectin suggests a potential mechanism underlying GLP-1RA-mediated cardiovascular risk reduction. Further research is warranted to elucidate the precise mechanisms and clinical implications of these findings in diabetic patients with atherosclerosis. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Divergent recommendations for periprocedural management of glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1 RA) medications rely on limited evidence. We performed a systematic review and meta-analysis to provide quantitative measures of gastric emptying relevant to mechanisms of weight loss and to periprocedural management of GLP-1 RA. We hypothesized that the magnitude of gastric emptying delay would be low and of limited clinical significance to procedural sedation risks. METHODS: A protocolized search identified studies on GLP-1 RA that quantified gastric emptying measures. Pooled estimates using random effects were presented as a weighted mean difference with 95% confidence intervals (CIs). Univariate meta-regression was performed to assess the influence of GLP-1 RA type, short-acting vs long-acting mechanism of action, and duration of treatment on gastric emptying. RESULTS: Fifteen studies met the inclusion criteria. Five studies (n = 247) utilized gastric emptying scintigraphy. Mean T1/2 was 138.4 minutes (95% CI 74.5-202.3) for GLP-1 RA vs 95.0 minutes (95% CI 54.9-135.0) for placebo, with a pooled mean difference of 36.0 minutes (95% CI 17.0-55.0, P < 0.01, I2 = 79.4%). Ten studies (n = 411) utilized the acetaminophen absorption test, with no significant delay in gastric emptying measured by Tmax, area under the curve (AUC) 4hr, and AUC 5hr with GLP-1 RA (P > 0.05). On meta-regression, the type of GLP-1 RA, mechanism of action, and treatment duration did not impact gastric emptying (P > 0.05). DISCUSSION: While a gastric emptying delay of ~36 minutes is quantifiable on GLP-1 RA medications, it is of limited magnitude relative to standard periprocedural fasting periods. There were no substantial differences in gastric emptying on modalities reflective of liquid emptying (acetaminophen absorption test), particularly at time points relevant to periprocedural care. [ABSTRACT FROM AUTHOR]

Guidelines for the management of obesity and type 2 diabetes (T2DM) emphasize the importance of lifestyle changes, including a reduced-calorie diet and increased physical activity. However, for many people, these changes can be difficult to maintain over the long term. Medication options are already available to treat obesity, which can help reduce appetite and/or reduce caloric intake. Incretin-based peptides exert their effect through G-protein-coupled receptors, the receptors for glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), and glucagon peptide hormones are important regulators of insulin secretion and energy metabolism. Understanding the role of intercellular signaling pathways and inflammatory processes is essential for the development of effective pharmacological agents in obesity. GLP-1 receptor agonists have been successfully used, but it is assumed that their effectiveness may be limited by desensitization and downregulation of the target receptor. A growing number of new agents acting on incretin hormones are becoming available for everyday clinical practice, including oral GLP-1 receptor agonists, the dual GLP-1/GIP receptor agonist tirzepatide, and other dual and triple GLP-1/GIP/glucagon receptor agonists, which may show further significant therapeutic potential. This narrative review summarizes the therapeutic effects of different incretin hormones and presents future prospects in the treatment of T2DM and obesity. [ABSTRACT FROM AUTHOR]

Background and Objectives: The rise in global diabetes cases, reaching a staggering 529 million in 2021 from 108 million in 1980, underscores the urgency of addressing its complications, notably macrovascular ones like coronary artery, cerebrovascular, and peripheral artery diseases, which contribute to over 50% of diabetes mortality. Atherosclerosis, linked to hyperglycemia-induced endothelial dysfunction, is pivotal in cardiovascular disease development. Cytokines, including pentraxin 3 (PTX3), copeptin, lipoprotein(a) [Lp(a)], and matrix metalloproteinase-9 (MMP-9), influence atherosclerosis progression and plaque vulnerability. Inhibiting atherosclerosis progression is crucial, especially in diabetic individuals. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs), increasingly used for type 2 diabetes, show promise in reducing the cardiovascular risk, sparking interest in their effects on atherogenesis. This study sought to examine the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on biomarkers that indicate the instability of atherosclerotic plaques. These biomarkers include pentraxin 3 (PTX3), copeptin (CPC), matrix metalloproteinase-9 (MMP-9), and lipoprotein(a) [Lp(a)]. Materials and Methods: A total of 34 participants, ranging in age from 41 to 81 years (with an average age of 61), who had been diagnosed with type 2 diabetes mellitus (with a median HbA1c level of 8.8%), dyslipidemia, and verified atherosclerosis using B-mode ultrasonography, were included in the study. All subjects were eligible to initiate treatment with a GLP-1 RA—dulaglutide. Results: Significant reductions in anthropometric parameters, blood pressure, fasting glucose levels, and HbA1c levels were observed posttreatment. Moreover, a notable decrease in biochemical markers associated with atherosclerotic plaque instability, particularly PTX3 and MMP-9 (p < 0.001), as well as Lp(a) (p < 0.05), was evident following the GLP-1 RA intervention. Conclusions: These findings underscore the potential of GLP-1 RAs in mitigating atherosclerosis progression and plaque vulnerability, thus enhancing cardiovascular outcomes in individuals with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Summary: Background: Visepegenatide, a once-weekly glucagon-like peptide-1 receptor agonist injection, demonstrated effective glycaemic control and good tolerability without the requirement of dose titration in the two completed phase 2 studies. We aimed to evaluate the efficacy and safety of visepegenatide in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin monotherapy in this phase 3 clinical study. Methods: This multicentre phase 3 clinical study included a 24-week, randomised, placebo-controlled, double-blind period followed by a 28-week open-label extended treatment period. Patients (N = 620) aged ≥18 and ≤75 years with glycated haemoglobin (HbA1c) ≥7.0% and ≤10.5% [≥53.0 and ≤91.27 mmol/mol], were randomized in a 1:1 ratio to receive visepegenatide 150-μg or placebo once-weekly subcutaneous injection during the double-blind period. Subsequently, the patients in the placebo group were switched to visepegenatide treatment (placebo→visepegenatide group), and the patients in the visepegenatide group continued the same treatment during the open-label extended treatment period. The primary endpoint was the change in HbA1c from baseline to week 24. Findings: At week 24, the placebo-adjusted least squares mean (LSM) change of HbA1c was −0.57% (95% CI −0.71 to −0.43) with visepegenatide (p

Background: Lipid-related risk and residual cardiovascular risk remain high in patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD). Significant treatment gaps exist in implementation of pluripotent and effective therapies that reduce these risks. Objective: This study evaluates the efficacy and impact of a dedicated, standalone cardiometabolic clinic designed to address treatment gaps through streamlined management and optimization of treatment strategies. Methods: We retrospectively collected data from the first 400 patients with T2D and ASCVD who underwent treatment at the clinic and presented for at least one follow-up visit. These patients were primarily managed for their cardiometabolic risks and received intensified lipid-lowering therapies, including adjunct non-statin therapies. Results: Significant findings included increased use of glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) to 84 % and 65 %, respectively, with 94 % of patients eventually on one therapy and 55 % on dual therapy. Increases in lipid-lowering therapies led to 89 % of patients achieving low-density lipoprotein cholesterol levels below patient-specific thresholds for intensification. Conclusion: This care model effectively manages high-risk patient needs, achieving significant intensification of lipid-lowering therapies and broad use of cardiometabolic drugs, and highlights the clinic's potential to serve as a model for similar high-risk populations.

Introduction and objective Obesity poses a significant public health challenge due to its association with an elevated risk of various chronic diseases, including cardiovascular conditions, type 2 diabetes, and overall mortality. While lifestyle modifications such as dietary changes and increased physical activity remain cornerstone interventions in obesity management, pharmacological treatments have emerged as an adjunctive approach to address this complex condition. The review aims to compare the effectiveness of current pharmacotherapy and show upcoming methods of treatment of obesity. Review methods The review was conducted by searching scientific publications in PubMed, Google Scholar, Clinicaltrials.gov, Summaries of Product Characteristics, URPL, FDA, and EMA databases. The articles on medications available in Poland for treating obesity and the latest clinical trials of upcoming drugs were analyzed, followed by a concise review of the collected data. Abbreviated description of the state of knowledge Currently, in the Polish market, medications available for obesity treatment include orlistat, the combination of naltrexone and bupropion, liraglutide, tirzepatide, and available as part of the target import - semaglutide. Promising clinical trials are being conducted on further medications for weight reduction, including retatrutide, orforglipron, cagrilintide, and amycretin. Regrettably, new and effective medications due to their high cost and insufficient funding. Summary New pharmacotherapy options for obesity, particularly anti-diabetic medications, are rapidly advancing. Glucagon-like peptide-1 (GLP-1) analogs have shown promising results in weight reduction, surpassing previous medications such as orlistat or naltrexone. Recent drugs offer weight loss ranging up to 25%. More studies are underway on novel and increasingly effective medications.

Key Clinical Message Dulaglutide is a relatively unpopular GLP‐1 receptor agonist used for weight loss. This case demonstrates that dulaglutide may be beneficial for weight loss in morbidly obese patients with multiple comorbidities after thoroughly evaluating its efficacy, benefits, and long‐term adverse effects through clinical trials. Abstract We present a case of a 27‐year‐old ex‐sumo wrestler with bipolar II disorder, morbid obesity, hypertension, Type 2 Diabetes Mellitus (DM), and a Body Mass Index (BMI) of 49.66 kg/m2. He was non‐compliant with lifestyle modifications and resistant to conventional treatments, including metformin, and was also using multiple antipsychotic drugs. After introducing dulaglutide, he achieved a 40 kg (−21%) weight loss and a BMI reduction of 10.3 kg/m2 over 6 months, with no side effects and improved glycemic control, demonstrating dulaglutide's efficacy for weight loss in such challenging presentations.

Background: Obesity and type 2 diabetes mellitus (T2DM) are increasingly common in the United States and worldwide. Because both conditions are associated with serious health consequences, weight reduction is recommended by professional medical and nutrition societies to improve outcomes. Due to the striking efficacy of glucagon-like peptide receptor agonists (GLP-1RAs) and dual mechanism glucose-dependent insulinotropic polypeptide/glucagon-like peptide receptor agonists (GIP/GLP-1RAs) for weight reduction and glycemic control, there is increased utilization for patients with obesity and/or T2DM. Yet, the impact of these medications on dietary intake is less understood. Methods: This narrative literature review summarizes clinical studies quantifying and characterizing dietary intake in people with obesity and/or T2DM using GLP-1 or GIP/GLP-1 RAs. Results: Though data from these studies reveal that total caloric intake was reduced by 16–39 %, few studies evaluated the actual composition of the diet. Conclusions: Further research is needed to understand the unique nutritional needs of adults on GLP-1 or dual GIP/GLP-1RAs and to support the development of nutritional guidelines for these individuals.

Diabetes, a metabolic disease caused by abnormally high levels of blood glucose, has a high prevalence rate worldwide and causes a series of complications, including coronary heart disease, stroke, peripheral vascular disease, end-stage renal disease, and retinopathy. Small-molecule compounds have been developed as drugs for the treatment of diabetes because of their oral advantages. Insulin secretagogues are a class of small-molecule drugs used to treat diabetes, and include sulfonylureas, non-sulfonylureas, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase 4 inhibitors, and other novel small-molecule insulin secretagogues. However, many small-molecule compounds cause different side effects, posing huge challenges to drug monotherapy and drug selection. Therefore, the use of different small-molecule drugs must be improved. This article reviews the mechanism, advantages, limitations, and potential risks of small-molecule insulin secretagogues to provide future research directions on small-molecule drugs for the treatment of diabetes.

Background: Efpeglenatide, a novel GLP-1 receptor agonist, has shown promise in improving glycemic control and inducing weight loss in individuals with type 2 diabetes (T2DM). This meta-analysis assessed its therapeutic potential and safety profile. Methods: A literature search was conducted on PubMed, SCOPUS, and Cochrane Central from inception until September 2023. We selected patients with T2DM and identified and compared those receiving efpeglenatide to placebo. Outcomes assessed included fasting plasma glucose (FPG), HbA1c, body weight, BMI, and cardiometabolic parameters. Data were analyzed using a random-effects model, with results presented as mean differences (MD) for continuous outcomes and risk ratios (RR) for safety analysis, along with their respective 95% confidence intervals. Quality assessment was conducted using the Cochrane risk of bias tool. Results: We included 11 studies in our analysis. Efpeglenatide demonstrated significant reductions in FPG (MD = -1.53 mmol/L, 95% CI = [-2.86, -0.66], p < 0.01), HbA1c (MD = -0.84, 95% CI= [-1.08, -0.60], p < 0.01), body weight (MD = -2.24 kg, 95% CI = [-4.20, -2.00], p < 0.01), and BMI (MD = -1.61 kg/m2, 95% CI= [-2.12, -1.09], p < 0.01). However, efpeglenatide was associated with a moderate increase in the risk of gastrointestinal adverse events, nausea, diarrhea, and vomiting. There was a non-significant elevated risk of hypoglycemia. Conclusions: Efpeglenatide significantly improves glycemic outcomes and promotes weight loss in individuals with diabetes. However, it is associated with moderate adverse effects related to the gastrointestinal system. Thus, further trials are warranted to comprehensively assess its safety and efficacy to derive a robust conclusion. [ABSTRACT FROM AUTHOR]

Introduction: Glucagon-like peptide 1 receptor (GLP-1R) agonists are widely used in therapy for type 2 diabetes mellitus (DM2) and obesity. There are also increasing amounts of data concerning the effectiveness of these drugs in the treatment of addictive disorders. This pilot study aimed to assess changes in alcohol-drinking and cigarette-smoking behaviours after the introduction of GLP-1R agonist therapy in patients with DM2. Methods: Forty-eight (48) patients with obesity and DM2 being treated with GLP-1R agonists completed a questionnaire designed by researchers, the Penn Alcohol Craving Scale (PACS), the Fagerstrom Test for Nicotine Dependence, and the Hunger-Satiety Scale. The severity of alcohol craving and nicotine dependence was compared between one month prior and the week before the evaluation. Results: Among the 48 patients enrolled on the study, 25 (52%) were treated with liraglutide, 11 (23%) with semaglutide and 12 (25%) with dulaglutide. It was found that changes in PACS total score were statistically significant only in patients treated with semaglutide and that these changes were affected by BMI, marital status, and whether the patient stated that they drank alcohol or smoked cigarettes. Smokers treated with semaglutide had lower Fagerstrom total scores than patients treated with liraglutide. Conclusion: Semaglutide exerts a reducing effect on alcohol and nicotine craving that was not seen for liraglutide or dulaglutide. [ABSTRACT FROM AUTHOR]

Objective Elevated rates of gluconeogenesis are an early pathogenic feature of youth-onset type 2 diabetes (Y-T2D), but targeted first-line therapies are suboptimal, especially in African American (AA) youth. We evaluated glucose-lowering mechanisms of metformin and liraglutide by measuring rates of gluconeogenesis and β-cell function after therapy in AA Y-T2D. Methods In this parallel randomized clinical trial, 22 youth with Y-T2D—age 15.3 ± 2.1 years (mean ± SD), 68% female, body mass index (BMI) 40.1 ± 7.9 kg/m2, duration of diagnosis 1.8 ± 1.3 years—were randomized to metformin alone (Met) or metformin + liraglutide (Lira) (Met + Lira) and evaluated before and after 12 weeks. Stable isotope tracers were used to measure gluconeogenesis [2H2O] and glucose production [6,6-2H2]glucose after an overnight fast and during a continuous meal. β-cell function (sigma) and whole-body insulin sensitivity (mSI) were assessed during a frequently sampled 2-hour oral glucose tolerance test. Results At baseline, gluconeogenesis, glucose production, and fasting and 2-hour glucose were comparable in both groups, though Met + Lira had higher hemoglobin A1C. Met + Lira had a greater decrease from baseline in fasting glucose (−2.0 ± 1.3 vs −0.6 ± 0.9 mmol/L, P =.008) and a greater increase in sigma (0.72 ± 0.68 vs −0.05 ± 0.71, P =.03). The change in fractional gluconeogenesis was similar between groups (Met + Lira: −0.36 ± 9.4 vs Met: 0.04 ± 12.3%, P =.9), and there were no changes in prandial gluconeogenesis or mSI. Increased glucose clearance in both groups was related to sigma (r = 0.63, P =.003) but not gluconeogenesis or mSI. Conclusion Among Y-T2D, metformin with or without liraglutide improved glycemia but did not suppress high rates of gluconeogenesis. Novel therapies that will enhance β-cell function and target the elevated rates of gluconeogenesis in Y-T2D are needed. [ABSTRACT FROM AUTHOR]

Once-weekly semaglutide is a widely used glucagon-like peptide-1 receptor agonist (GLP-1RA) used for the treatment of type 2 diabetes (T2D). In clinical trials, semaglutide improved glycemic control and obesity, and reduced major cardiovascular events. However, the reports are limited on its real-world efficacy relating to various metabolic factors such as dyslipidemia or metabolic dysfunction-associated steatotic liver disease (MASLD) in Asian patients with T2D. In our retrospective longitudinal study, we selected patients with T2D who were given once-weekly semaglutide and compared metabolic parameters before and after the start of semaglutide. Seventy-five patients were eligible. HbA1c decreased significantly, by 0.7–0.9%, and body weight by 1.4–1.7 kg during the semaglutide treatment. Non-HDL cholesterol decreased significantly at 3, 6 and 12 months after the initiation of semaglutide; LDL cholesterol decreased at 3 and 6 months; and HDL cholesterol increased at 12 months. The effects on body weight, HbA1c and lipid profile were pronounced in patients who were given semaglutide as a first GLP-1RA (GLP-1R naïve), whereas improvements in HbA1c were also observed in patients who were given semaglutide after being switched from other GLP-1RAs. During a 12-month semaglutide treatment, the hepatic steatosis index (HSI) tended to decrease. Moreover, a significant decrease in the AST-to-platelet ratio index (APRI) was observed in GLP-1RA naïve patients. Our real-world study confirmed the beneficial effects of once-weekly semaglutide, namely, improved body weight, glycemic control and atherogenic lipid profile. The beneficial effects on MASLD were also suggested. [ABSTRACT FROM AUTHOR]

Danuglipron (PF‐06882961) is an oral, small‐molecule glucagon‐like peptide‐1 receptor agonist in development for the treatment of type 2 diabetes (T2D) and obesity. Impaired renal function is prevalent in patients with T2D. This Phase 1, open‐label study evaluated the effect of renal impairment on the pharmacokinetics, safety, and tolerability of danuglipron (20 mg) in healthy participants with normal renal function (estimated glomerular filtration rate [eGFR] unnormalized for body surface area: ≥90 mL/min), in participants with T2D and normal renal function (eGFR ≥90 mL/min), and in participants with T2D and mild (eGFR 60‐89 mL/min), moderate (eGFR 30‐59 mL/min), or severe (eGFR <30 mL/min) renal impairment (N = 39). Log‐linear regression analyses and analyses of variance showed no evidence of a clinically significant effect of reduced renal function on danuglipron pharmacokinetics. Renal clearance of unchanged danuglipron was minimal (<1% across all renal function groups). Danuglipron pharmacokinetics were similar between healthy participants and participants with T2D and normal renal function. A single 20‐mg oral dose of danuglipron was generally safe and well tolerated in all participant groups. In participants with T2D, renal impairment had no clinically meaningful effect on the pharmacokinetic, safety, and tolerability profiles of danuglipron, indicating that dose adjustment of danuglipron will not be required when administered to patients with T2D and reduced renal function. [ABSTRACT FROM AUTHOR]

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are highly effective medications for the treatment of type 2 diabetes and obesity. Pharmacological studies in rodents support an association between the use of GLP-1 RAs and the development of medullary thyroid cancer (MTC) resulting in a black box warning for these agents in patients at risk for this condition. Yet, the association between GLP-1 RAs and non-MTC remains controversial. Excessive worry about unproven thyroid cancer risk might lead to underutilizing GLP-1 RAs in patients who could otherwise experience substantial benefits. Unwarranted concerns about thyroid cancer could lead to unnecessary thyroid cancer screening and harms from overdiagnosis. Summary: The body of evidence assessing the association between GLP-1 RA use and thyroid cancer spans a wide range of methodologies, including basic and translational research investigating biological plausibility; randomized trials assessing clinical efficacy and providing the strongest evidence for causality; observational studies providing real-life outcome evaluation in larger populations but with limited evaluation of covariates or dependable outcome definitions; and pharmacovigilance studies that provide postmarketing assessments of a safety signal but do not address causality. There is biological plausibility supporting an association between GLP-1 RA and MTC in rodents, which is less clear for non-MTC in humans. Clinical evidence from randomized trials and associated meta-analysis suggest thyroid cancer as a rare event making effect estimates imprecise but without conclusive and consistent evidence of increase risk in those receiving GLP-1 RA. Observational studies at higher risk of bias also show low event rates for thyroid cancer, with effect estimates that are inconsistent among different studies. Pharmacovigilance studies consistently show a signal of increased reporting of thyroid cancer in patients treated with GLP-1 RA. Conclusions: Evidence from randomized controlled trials indicates occurrence of thyroid cancer is infrequent in individuals exposed to GLP-1 RA. Observational studies at higher risk of bias yield inconsistent results. Overall there is no conclusive evidence of elevated thyroid cancer risk. These findings can help clinicians when addressing patient's concerns about a potential yet unproven link between GLP-1 RA therapy and thyroid cancer. [ABSTRACT FROM AUTHOR]

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of medications for management of diabetes and obesity. The objective of this study is to characterize the epidemiology of GLP-1RA cases reported to US poison centers. Methods: We analyzed cases involving a GLP-1RA reported to the National Poison Data System during 2017–2022. Results: There were 5,713 single-substance exposure cases reported to US poison centers involving a GLP-1RA. Most cases were among females (71.3%) and attributable to therapeutic errors (79.9%). More than one-fifth (22.4%) of cases were evaluated in a healthcare facility, including 0.9% admitted to a critical care unit and 4.1% admitted to a non-critical care unit. Serious medical outcomes were described in 6.2% of cases, including one fatality. The rate of cases per one million US population increased from 1.16 in 2017 to 3.49 in 2021, followed by a rapid increase of 80.9% to 6.32 in 2022. Trends for rates of serious medical outcomes and admissions to a healthcare facility showed similar patterns with 129.9% and 95.8% increases, respectively, from 2021 to 2022. Conclusions: Most GLP-1RA cases reported to US poison centers were associated with no or minimal effects and did not require referral for medical treatment; however, a notable minority of individuals experienced a serious medical outcome or healthcare facility admission. The rate of reported cases increased during the study period, including an 80.9% increase from 2021 to 2022. Opportunities exist to improve provider and patient awareness of the adverse effects of these medications. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus is an increasingly common long-term condition, and suboptimal perioperative glycaemic control can lead to postoperative harms. The advent of new antidiabetic drugs, in particular glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, has enabled perioperative continuation of these medicines, thus avoiding the harms of variable rate i.v. insulin infusions whilst providing glycaemic control. There are differences between medicines regulatory agencies and organisations on how these classes that are most often used to treat diabetes mellitus, (but also in the case of SGLT2 inhibitors chronic kidney disease and heart failure in those without diabetes) should be managed in the perioperative period. In this commentary, we argue that GLP-1 receptor agonists should continue during the perioperative period and that SGLT2 inhibitors should only be omitted the day prior to a planned procedure. The reasons for the differing advice advocated between regulatory agencies and what anaesthetic practitioners should do in the face of continuing uncertainty are discussed. [ABSTRACT FROM AUTHOR]

The article explores the efficacy of SGLT-2 inhibitors and GLP-1 receptor agonists in treating Type 2 diabetes, highlighting their benefits in reducing mortality, heart attacks, and end-stage kidney disease while also noting increased adverse events. Topics include the comparative benefits and risks of these medications, their impact on weight loss, and comparisons with metformin in terms of efficacy and side effects.

Introduction: Real-world data provide insight into how medications perform in clinical practice. The PIONEER REAL Switzerland study aimed to understand clinical outcomes with oral semaglutide in adults with type 2 diabetes (T2D). Methods: PIONEER REAL Switzerland was a 34–44-week, multicentre, prospective, non-interventional, single-arm study of adults with T2D naïve to injectable glucose-lowering medication who were initiated on oral semaglutide in routine clinical practice. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline (BL) to end of study (EOS); secondary endpoints included change in body weight (BW) from BL to EOS and the proportion of participants achieving HbA1c < 7.0% and the composite endpoints HbA1c reduction ≥ 1%-points with BW reduction ≥ 3% or ≥ 5% at EOS. Safety was assessed in participants who received ≥ 1 dose of oral semaglutide. Results: Of the 185 participants (female/male, n = 67/118) initiating oral semaglutide, 168 (90.8%) completed the study and 143 (77.3%) remained on treatment with oral semaglutide at EOS. At BL, participants had a mean age of 62 years, diabetes duration of 6.4 years, HbA1c of 7.7%, BW of 95.6 kg and body mass index of 33.2 kg/m2; 56.2% of participants were receiving glucose-lowering medications. Significant reductions were observed for HbA1c (estimated change − 0.91%; 95% confidence interval [CI] − 1.10, − 0.71; p < 0.0001) and BW (estimated change − 4.85%; 95% CI − 5.70, − 4.00; p < 0.0001). In total, 139 adverse events (AEs) were reported in 65 (35.1%) participants; most were mild or moderate. The most frequent AEs were gastrointestinal disorders (27.0%); 31 AEs in 20 (10.8%) participants led to discontinuation of oral semaglutide. Six serious AEs were reported; all were considered unlikely to be related to oral semaglutide. Conclusion: People living with T2D treated with oral semaglutide in Switzerland achieved clinically significant reductions in HbA1c and BW, with no new safety signals. Clinical Trial Registration: ClinicalTrials.gov: NCT04537624. A graphical abstract is available for this article. [ABSTRACT FROM AUTHOR]