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Jiang WZ, Fan ZL, Xu ML, Qian EH, Lu KD. Association between insulin resistance and multiple chronic diseases: a cross-sectional study from CHARLS. JOURNAL OF HEALTH, POPULATION, AND NUTRITION 2025; 44:148. [PMID: 40346714 PMCID: PMC12065186 DOI: 10.1186/s41043-025-00878-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 04/11/2025] [Indexed: 05/11/2025]
Abstract
BACKGROUND Chronic disease is a global public health problem. This study aimed to explore the association between insulin resistance (IR)-related indices and various chronic diseases, and to evaluate the predictive capacity of IR-related indices for these diseases. METHODS The data used in this study came from CHARLS. Binary logistic regression analysis and RCS were used to analyze the relationship between IR-related indices, including TyG, TyG-BMI, TyG-WHtR, METS-IR and eGDR, with nine chronic diseases. Subgroup analysis was performed to test the stability of the results. Finally, the predictive power of IR-related indices for chronic diseases was tested by ROC curve. RESULTS A total of 8,177 participants were included in this study. The study found that elevated prevalence of multiple chronic diseases is positively associated with increases in TyG, TyG-BMI, TyG-WHtR, and METS-IR, and negatively associated with eGDR. ROC analysis revealed that IR-related indices had the best accuracy in predicting dyslipidemia compared to other diseases, with TyG being the best predictor. CONCLUSIONS IR-related indices were positively associated with the prevalence of multiple chronic diseases. The burden of chronic diseases can be reduced by improving IR in middle-aged and older people.
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Affiliation(s)
- Wen-Ze Jiang
- The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhen-Liang Fan
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Meng-Li Xu
- The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - En-Hui Qian
- The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Ke-Da Lu
- The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
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2
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Li W, Marx N, Yang Q, Fang D, Zhang Y. Obesity: Next game changer of allergic airway diseases? Clin Transl Med 2025; 15:e70316. [PMID: 40329860 PMCID: PMC12056501 DOI: 10.1002/ctm2.70316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 04/05/2025] [Accepted: 04/12/2025] [Indexed: 05/08/2025] Open
Abstract
Obesity and allergic diseases are global health concerns, both of which are seeing an increase in prevalence in recent years. Obesity has been recognised as an important comorbidity in subpopulations with allergic airway diseases, which represents a unique phenotype and endotype. Obesity-related allergic airway diseases are associated with exacerbated clinical symptom burden, altered immune response, increased disease severity and compromised predictive capability of conventional biomarkers for evaluating endotype and prognosis. Moreover, treatment of obesity-related allergic airway diseases is challenging because this unique endotype and phenotype is associated with poor response to standard therapeutic strategies. Therapeutic regimen that involves weight loss by non-surgical and surgical interventions, gut microbiome-targeted treatment, glucagon-like peptide-1 receptor agonist and other agents should be considered in this population. In this review, we outline the current knowledge of the impact of obesity on prevalence, endotypes, clinical symptom and management of allergic airway diseases. Increased understanding of the implications of obesity may contribute to better treatment options for the obesity-related refractory airway inflammation, particularly in precision medicine. KEY POINTS: Obesity can increase the prevalence of allergic airway diseases such as asthma, AR, and CRSwNP. Obesity alters the immune endotype and exacerbates clinical symptoms of respiratory allergic diseases. Obesity-related allergic airway diseases exhibit therapeutic resistance to standard treatment. Obesity-related allergic airway diseases constitute a distinct category of endotypes and phenotypes, requiring further in-depth research and novel therapeutic approaches.
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Affiliation(s)
- Wenlong Li
- Department of Otolaryngology‐Head and Neck SurgeryThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Department of AllergyThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Department of Otolaryngology‐Head and Neck SurgeryKey Laboratory of Airway Inflammatory Disease Research and Innovative Technology TranslationGuangzhouChina
- Naso‐Orbital‐Maxilla and Skull Base CenterThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Noah Marx
- Department of PathologyNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
| | - Qintai Yang
- Department of Otolaryngology‐Head and Neck SurgeryThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Department of AllergyThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Department of Otolaryngology‐Head and Neck SurgeryKey Laboratory of Airway Inflammatory Disease Research and Innovative Technology TranslationGuangzhouChina
- Naso‐Orbital‐Maxilla and Skull Base CenterThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Deyu Fang
- Department of PathologyNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
| | - Yana Zhang
- Department of Otolaryngology‐Head and Neck SurgeryThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Department of AllergyThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Department of Otolaryngology‐Head and Neck SurgeryKey Laboratory of Airway Inflammatory Disease Research and Innovative Technology TranslationGuangzhouChina
- Naso‐Orbital‐Maxilla and Skull Base CenterThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
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3
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Sun T, Yu H, Zhang D, Zhang D, Li D, Fu J. Glucagon-like peptide-1 receptor signaling activation in alveolar type II cells enhances lung development in neonatal rats exposed to hyperoxia. Redox Biol 2025; 82:103586. [PMID: 40080965 PMCID: PMC11954118 DOI: 10.1016/j.redox.2025.103586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 03/04/2025] [Accepted: 03/05/2025] [Indexed: 03/15/2025] Open
Abstract
BACKGROUND Many studies have reported the important role of glucagon-like peptide-1 receptor (GLP-1R) in regulating glucose homeostasis. However, in addition to the pancreas, GLP-1R is distributed in organs such as the lungs. A few researches have reported the mechanism of action of GLP-1R in acute and chronic lung diseases. Nevertheless, its effect on lung development remains unclear. In this research, we aimed to explore the role of GLP-1R in regulating lung development and its potential mechanisms in in vivo and in vitro bronchopulmonary dysplasia (BPD) models. METHODS Neonatal Sprague-Dawley rats were divided into hyperoxia (FIO2 = 0.85) and control (FIO2 = 0.21) groups. Lung tissues were extracted at 3, 7, 10, and 14 postnatal days and subjected to hematoxylin and eosin staining for histopathological and morphological observation. Single-cell RNA sequencing was performed to explore the role of GLP-1R in lung development. Western blotting was conducted to assess the expression of GLP-1R, dynamin-related protein 1 (DRP1), and glycolysis-associated enzymes, including phosphofructokinase (PFKM), hexokinase 2 (HK2), and lactate dehydrogenase A (LDHA), in the lung tissues, primary alveolar type II (ATII) cells, and RLE-6TN cells. Double immunofluorescence staining was performed to confirm the co-localization of GLP-1R, DRP1, and ATII cells. A Seahorse XF96 metabolic extracellular flux analyzer was used to perform real-time analyses of extracellular acidification rate and oxygen consumption rate in ATII cells isolated from lung tissues and RLE-6TN cells. The adenosine triphosphate (ATP) concentrations in ATII and RLE-6TN cells were measured using an ATP kit. Mitochondria were stained with MitoTracker and observed using HiS-SIM. GLP-1R gene levels in lung tissues, primary ATII cells, and RLE-6TN cells were tested using RT-qPCR. We used MeRIP-qPCR to determine the m6A modification level of GLP-1R mRNA in RLE-6TN cells. A reporter gene was used to verify the modification site and key methyltransferases. RESULTS We observed that GLP-1R signaling regulates lung development and plays a key role in ATII cells, particularly after birth. Hyperoxia inhibits GLP-1R protein and gene expression in ATII cells and accelerates BPD development. ATP production decreased and glycolysis levels increased in ATII cells under hyperoxia. Activation of GLP-1R signaling promotes ATP production and downregulates glycolysis by regulating DRP1 induced mitochondria fission. In RLE-6TN cells, we verified that the m6A modification level of GLP-1R mRNA decreased; the modification site was tested by MeRIP-qPCR and was primarily induced by the methyltransferase-like 14 (METTL14). CONCLUSION GLP-1R is primarily expressed in ATII cells of neonatal rats and can promote lung development during the early postnatal period. The GLP-1R signaling pathway modulates mitochondrial fission and glucose metabolism in ATII cells under hyperoxia. Hyperoxia can inhibit the activation of GLP-1R by inhibiting m6A methylation during BPD pathogenesis.
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Affiliation(s)
- Tong Sun
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Haiyang Yu
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Dingning Zhang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Dan Zhang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Danni Li
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
| | - Jianhua Fu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
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Duffus EK, Holguin F, Rastogi D. Non-T2 asthma. Curr Opin Pulm Med 2025; 31:287-293. [PMID: 40125574 PMCID: PMC11949703 DOI: 10.1097/mcp.0000000000001154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/25/2025]
Abstract
PURPOSE OF REVIEW This review provides a comprehensive overview of the non-T asthma phenotypes. Asthma is an umbrella term that defines a complex group of heterogenous airway disorders, which are broadly categorized into predominantly T2 or non-T2 phenotypes depending on the presence and levels of airway and systemic biomarkers associated with a T2 inflammatory response. Individuals with predominant T2 asthma have greater numbers of peripheral blood eosinophils, exhaled nitric oxide and IgE. These patients have more atopy and earlier onset asthma. In contrast, the absence or low levels of these biomarkers define non-T2 asthma. This is a heterogenous group with a later onset of asthma that is also more commonly associated with obesity and with females. RECENT FINDINGS This article summarizes new information regarding the plasticity that exists between T2 and non-T2 mechanisms, including their role in exacerbation-prone and nonexacerbating asthma, and many of the risk factors associated with the non-T2 phenotype, such as viral infections, ambient air pollution exposure, smoking, genetic and metabolic factors. It also provides new information on the immunological and metabolic mechanisms associated with non-T2 asthma. We also discuss how to manage this asthma phenotype and how treatment responses differ for these patients. SUMMARY Non-T2 asthma defines a heterogenous group of asthma phenotypes. However, acknowledging that the absence of T2 biomarkers is influenced by several factors is important and can longitudinally change in relation to exacerbations, particularly in children.
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Affiliation(s)
| | | | - Deepa Rastogi
- The Children's Hospital at Montefiore, Bronx, New York, USA
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5
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Pham H, Koehl R, Woo H, Wu TD, Qiu AY, Brigham EP, Hansel NN, McCormack MC. Association Between Hemoglobin A1c and Pediatric Asthma Control. J Asthma Allergy 2025; 18:649-654. [PMID: 40322736 PMCID: PMC12047264 DOI: 10.2147/jaa.s498269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 03/20/2025] [Indexed: 05/08/2025] Open
Abstract
Purpose To examine the relationship between Hemoglobin A1c (HbA1c) and asthma outcomes in an urban cohort of children with asthma. Methods The AIRWEIGHS Study was a randomized controlled clinical trial of an air cleaner intervention testing the hypothesis that overweight/obese children would experience greater improvement in asthma control compared to normal weight children. The study enrolled 164 children with asthma from Baltimore, MD and assessed HbA1c levels and asthma outcomes during clinic visits at baseline and three months. HbA1c levels were analyzed as a continuous measure and categorized as either normal (<5.7%) or consistent with pre-diabetes (≥5.7%). Asthma outcomes included standardized questionnaires, spirometry, and fractional exhaled nitric oxide (FeNO). Generalized Estimating Equation (GEE) regression models were used to analyze the association between the HbA1c and asthma outcomes. Results Participants included 164 children with an average age of 11 (± 2) years, predominately African American (85%), male (59%), moderate or severe asthma by NAEPP criteria (59%), households with an income below $34,999 (60%), publicly insured (83%), and overweight/obese (61%). 52 participants were excluded from the analysis due to unsuccessful blood draws or participant refusal. Twenty of 112 distinct participants (18%) had HbA1c measurements ≥5.7%, consistent with prediabetes. Increased HbA1c levels were associated with worse asthma control as indicated by an increase in the Asthma Therapy Assessment Questionnaire (β-0.74 p<0.05). In the interaction analysis, BMI percentile had a significant interaction with HbA1c such that HbA1c had a stronger association with maximum symptoms days and exacerbation risk among children with lower versus higher BMI percentile values. Conclusion Higher HbA1c levels were associated with worse asthma control among children with asthma, adding to evidence that metabolic dysfunction may influence asthma morbidity. Additionally, HbA1c could have a stronger influence among non-obese children with underlying metabolic dysfunction, suggesting the need for future studies to investigate metabolic pathways in asthma.
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Affiliation(s)
- Hewlett Pham
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Rachelle Koehl
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Han Woo
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Tianshi David Wu
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Anna Yue Qiu
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Emily P Brigham
- Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Nadia N Hansel
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Meredith C McCormack
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
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6
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Jin Z, Sun W, Huang J, Zhou M, Zhang C, Zhao B, Wang G. Association between triglyceride glucose index and asthma exacerbation: A population-based study. Heart Lung 2025; 70:1-7. [PMID: 39531988 DOI: 10.1016/j.hrtlng.2024.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/20/2024] [Accepted: 11/03/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Metabolic dysfunction is associated with respiratory diseases, and the triglyceride-glucose (TyG) index is an important indicator of metabolic dysfunction. OBJECTIVES The purpose of this study was to explore the possible relationship between TyG and asthma exacerbation, while also investigating potential subgroup differences in this relationship. METHODS Data from the 2009-2018 National Health and Nutrition Examination Survey (NHANES) were included. Multifactorial logistic regression, subgroup analysis, smoothed curve fitting, and threshold effect analysis models were used to explore the relationship between TyG and asthma exacerbations. RESULTS A total of 964 participants were included in the analysis (34.13 % male, 65.87 % female, 45.4 % Non-Hispanic White, 25.3 % Non-Hispanic Black), with a mean age of 50.57 ± 17.32 years. We found a nonlinear positive relationship between TyG and asthma exacerbation, which was maintained in all three models. In the fully adjusted model, the risk of asthma exacerbation increased by 25 % with each unit increase in the patient's TyG level (OR:1.25, 95 %CI: 1.21-1.30). Subgroup analysis showed significant associations between TyG and asthma exacerbations among females, as well as in individuals aged 20-59, body mass index (BMI) <25 or BMI≥30. Furthermore, a U-shaped relationship between TyG and asthma exacerbation was identified in males using smoothed curve fitting, with an inflection point at the TyG level of 9.15. CONCLUSIONS We found a nonlinear positive association between TyG and asthma exacerbation. Our study highlights the potential clinical value of TyG in managing asthma exacerbations, particularly emphasizing the need for gender-specific risk management strategies.
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Affiliation(s)
- Zhou Jin
- Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, China
| | - Wen Sun
- Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, China
| | - Junjun Huang
- Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, China
| | - Mengyun Zhou
- Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, China
| | - Chunbo Zhang
- Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, China
| | - Bangchao Zhao
- Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, China
| | - Guangfa Wang
- Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, China.
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Chami-Peña S, Caballero-Vázquez A, Mebrive-Jiménez MJ, Gómez-Urquiza JL, Romero-Bejar JL, Caballero-Mateos AM, Cañadas-De la Fuente GA. Therapeutic Management in Patients with Chronic Obstructive Pulmonary Disease Who Are Overweight or Obese: A Systematic Review and Meta-Analysis. J Clin Med 2025; 14:1230. [PMID: 40004760 PMCID: PMC11856468 DOI: 10.3390/jcm14041230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/05/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Introduction/Objective: The relationship between chronic obstructive pulmonary disease (COPD) and overweight is complex and multifaceted, as these conditions can interact in terms of symptoms, severity and clinical management. To analyse the clinical and therapeutic management of patients suffering from COPD and overweight. Methods: This systematic review was carried out, in accordance with the PRISMA statement, during November 2024, following a search of the Medline/PubMed databases. The search equation used, with MESH descriptors, was: "(Pulmonary Disease, Chronic Obstructive OR COPD) AND (obesity OR overweight)". Both inclusion and exclusion criteria were applied, focusing on the selection of clinical trials. The studies were classified into two main groups: by their focus on the relationship between overweight/obesity and COPD; and by the benefits provided by physical exercise to patients with these conditions. A random-effects meta-analysis was performed on the data obtained. The protocol was registered in the PROSPERO International Prospective Register of Systematic Reviews (CRD42024576389). Results: The search produced nine relevant clinical trials with a total of 1345 COPD patients. Four of the trials incorporated obesity (BMI ≥ 30) as an inclusion criterion, while the other five had mixed samples, with patients presenting either overweight or obesity (four patients with BMI ≥ 25 and one with BMI ≥ 27). The risk of bias tool for randomised trials showed that all nine studies had a low risk of bias. Overall, these studies highlight the importance of overweight management and reject the use of extreme measures. Furthermore, they confirm the association between overweight/obesity and COPD, for which this condition is a risk factor, to a degree depending on the BMI. Four studies reported significant improvements in the clinical management of COPD patients following appropriate physical exercise. Specifically, one study observed that supervised exercise improved cardio-vascular performance; another, that observed that aquatic exercise increased maximal capacity, endurance and quality of life; another, that found cycling improved ventilatory performance; and the fourth, that observed exercise complementary to standard therapy in hospitalised obese COPD patients improved strength, exercise capacity and other perceived variables such as anxiety, mobility and dyspnoea. Conclusions: The therapeutic management of overweight COPD patients should include weight control, physical exercise and appropriate pharmacological treatment. Physical exercise is associated with improvements in endurance, exercise capacity, cardio-vascular performance, ventilatory performance and strength. In addition, the participants in these studies self-perceived clinical improvement. These findings justify the performance of further RCTs examining the role of physical exercise in patients with COPD and overweight/obesity, in order to improve their clinical outcomes and quality of life.
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Affiliation(s)
- Sara Chami-Peña
- Centro de Salud Ronda Norte, AGS Serranía de Málaga, Andalusian Health Service, 29400 Ronda, Spain;
| | - Alberto Caballero-Vázquez
- Diagnostic Lung Cancer Unit, Broncopleural Techniques and Interventional Pulmonology Department, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain
| | | | - José L. Gómez-Urquiza
- Faculty of Health Sciences, University of Granada, Cortadura del Valle s/n, 51001 Ceuta, Spain
| | - José L. Romero-Bejar
- Department of Statistics and Operations Research, University of Granada, Av. de Fuente Nueva, s/n, 18071 Granada, Spain;
- Instituto de Investigación Biosanitaria (ibs. GRANADA), 18012 Granada, Spain
| | - Antonio M. Caballero-Mateos
- Department of Gastroenterology, San Cecilio University Hospital, Andalusian Health Service, Av. del Conocimiento s/n, 18016 Granada, Spain
- Department of Internal Medicine, Gastroenterology Section, Santa Ana Hospital, Andalusian Health Service, Av. Enrique Martín Cuevas, s/n, 18600 Motril, Spain
| | - Guillermo A. Cañadas-De la Fuente
- Faculty of Health Sciences, University of Granada, Av. Ilustración 60, 18016 Granada, Spain;
- Brain, Mind and Behaviour Research Centre (CIMCYC), University of Granada, Campus Universitario de Cartuja s/n, 18011 Granada, Spain
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Nassar M, Nassar O, Abosheaishaa H, Misra A. Comparative outcomes of systemic diseases in people with type 2 diabetes, or obesity alone treated with and without GLP-1 receptor agonists: a retrospective cohort study from the Global Collaborative Network : Author list. J Endocrinol Invest 2025; 48:483-497. [PMID: 39302577 DOI: 10.1007/s40618-024-02466-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 09/04/2024] [Indexed: 09/22/2024]
Abstract
BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used to manage type 2 diabetes (T2D) and obesity. Despite their recognized benefits in glycemic control and weight management, their impact on broader systemic has been less explored. OBJECTIVE This study aimed to evaluate the impact of GLP-1RAs on a variety of systemic diseases in people with T2D or obesity. METHODS We conducted a retrospective cohort study using data from the Global Collaborative Network, accessed through the TriNetX analytics platform. The study comprised two primary groups: individuals with T2D and those with obesity. Each group was further divided into subgroups based on whether they received GLP-1RA treatment or not. Data were analyzed over more than a 5-year follow-up period, comparing incidences of systemic diseases; systemic lupus erythematosus (SLE), systemic sclerosis (SS), rheumatoid arthritis (RA), ulcerative colitis (UC), crohn's disease (CD), alzheimer's disease (AD), parkinson's disease (PD), dementia, bronchial asthma (BA), osteoporosis, and several cancers. RESULTS In the T2D cohorts, GLP-1RA treatment was associated with significantly lower incidences of several systemic and metabolic conditions as compared to those without GLP-1RA, specifically, dementia (Risk Difference (RD): -0.010, p < 0.001), AD (RD: -0.003, p < 0.001), PD (RD: -0.002, p < 0.001), and pancreatic cancer (RD: -0.003, p < 0.001). SLE and SS also saw statistically significant reductions, though the differences were minor in magnitude (RD: -0.001 and - 0.000 respectively, p < 0.001 for both). Conversely, BA a showed a slight increase in risk (RD: 0.002, p < 0.001). CONCLUSIONS GLP-1RAs demonstrate potential benefits in reducing the risk of several systemic conditions in people with T2D or obesity. Further prospective studies are needed to confirm these effects fully and understand the mechanisms.
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Affiliation(s)
- Mahmoud Nassar
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
| | - Omar Nassar
- Williamsville East High School, Buffalo, NY, USA
| | - Hazem Abosheaishaa
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Anoop Misra
- Fortis-C-DOC Centre of Excellence for Diabetes, Metabolic Diseases and Endocrinology, New Delhi, India
- National Diabetes, Obesity and Cholesterol Foundation (N-DOC), New Delhi, India
- Diabetes Foundation (India) (DFI) India, New Delhi, India
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9
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Al-Beltagi M, Bediwy AS, Saeed NK, Bediwy HA, Elbeltagi R. Diabetes-inducing effects of bronchial asthma. World J Diabetes 2025; 16:97954. [PMID: 39817208 PMCID: PMC11718464 DOI: 10.4239/wjd.v16.i1.97954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 10/12/2024] [Accepted: 11/07/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND The relationship between diabetes mellitus (DM) and asthma is complex and can impact disease trajectories. AIM To explore the bidirectional influences between the two conditions on clinical outcomes and disease control. METHODS We systematically reviewed the literature on the relationship between DM and asthma, focusing on their impacts, mechanisms, and therapeutic implications. Various studies were assessed, which investigated the effect of glycemic control on asthma outcomes, lung function, and exacerbations. The study highlighted the role of specific diabetes medications in managing asthma. RESULTS The results showed that poor glycemic control in diabetes can exacerbate asthma, increase hospitalizations, and reduce lung function. Conversely, severe asthma, especially in obese individuals, can complicate diabetes management and make glycemic control more difficult. The diabetes-associated mechanisms, such as inflammation, microangiopathy, and oxidative stress, can exacerbate asthma and decrease lung function. Some diabetes medications exhibit anti-inflammatory effects that show promise in mitigating asthma exacerbations. CONCLUSION The complex interrelationship between diabetes and asthma suggests bidirectional influences that affect disease course and outcomes. Inflammation and microvascular complications associated with diabetes may worsen asthma outcomes, while asthma severity, especially in obese individuals, complicates diabetes control. However, the current research has limitations, and more diverse longitudinal studies are required to establish causal relationships and identify effective treatment strategies for individuals with both conditions.
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Affiliation(s)
- Mohammed Al-Beltagi
- Department of Pediatric, Faculty of Medicine, Tanta University, Tanta 31511, Alghrabia, Egypt
- Department of Pediatric, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Manama, Bahrain
| | - Adel Salah Bediwy
- Department of Pulmonology, Faculty of Medicine, Tanta University, Tanta 31527, Alghrabia, Egypt
- Department of Pulmonology, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Manama, Bahrain
| | - Nermin Kamal Saeed
- Medical Microbiology Section, Department of Pathology, Salmaniya Medical Complex, Ministry of Health, Kingdom of Bahrain, Manama 26671, Manama, Bahrain
- Medical Microbiology Section, Department of Pathology, Irish Royal College of Surgeon, Busaiteen 15503, Muharraq, Bahrain
| | | | - Reem Elbeltagi
- Department of Medicine, The Royal College of Surgeons in Ireland-Bahrain, Busiateen 15503, Muharraq, Bahrain
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10
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Lee B, Man KKC, Wong E, Tan T, Sheikh A, Bloom CI. Antidiabetic Medication and Asthma Attacks. JAMA Intern Med 2025; 185:16-25. [PMID: 39556360 PMCID: PMC11574725 DOI: 10.1001/jamainternmed.2024.5982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 09/09/2024] [Indexed: 11/19/2024]
Abstract
Importance Elevated body mass index (BMI) and type 2 diabetes are prevalent in asthma and are associated with an increase in the risk of asthma attacks. In experimental studies, the diabetes medications metformin and glucagon-like peptide-1 receptor agonists (GLP-1RA) have mitigated airway inflammation, hyperresponsiveness, and remodeling. However, epidemiological evidence is limited. Objective To estimate the association of metformin and add-on antidiabetic medications (GLP-1RA, dipeptidyl peptidase-4 inhibitors, sulphonylureas, sodium-glucose cotransporter-2 inhibitors, and insulin) with asthma attacks. Design, Setting, and Participants The study used data from the UK Clinical Practice Research Datalink (CPRD) Aurum linked hospital admissions and mortality data from 2004 to 2020. A triangulation approach was used that applied 2 distinct approaches to enhance robustness: a self-controlled case series (SCCS) and a metformin new user cohort with inverse probability of treatment weighting (IPTW). Eligible participants were new users of metformin with type 2 diabetes. To evaluate the association between metabolic phenotypes (BMI, glycemic control) and asthma phenotypes (type 2 inflammation, asthma severity), interaction analyses were conducted. Negative control analyses were conducted to assess for bias. Exposure The primary exposure was metformin; secondary exposures included add-on antidiabetic medications. Main Outcomes The primary outcome was first asthma exacerbation (short course of oral corticosteroids, unscheduled asthma-related hospital attendance, or death) during 12-month follow-up. Incidence rate ratios (IRRs) with 95% CIs were estimated using fixed-effect conditional Poisson models in the SCCS, and hazard ratios (HRs) were estimated using weighted Cox proportional hazards models in the cohort. Results Of more than 2 million adults with asthma, 4278 patients (2617 women [61.2%]; mean [SD] age, 52.9 [13.6] years) were identified for the SCCS and 8424 patients (4690 women [55.7%]; unexposed: mean [SD] age, 61.6 [13.2] years; exposed: mean [SD] age, 59.7 [13.7] years) for the IPTW cohort. Metformin was found to be associated with fewer asthma attacks of similar magnitude in both approaches (SCCS: IRR, 0.68; 95% CI, 0.62-0.75; IPTW: HR, 0.76; 95% CI, 0.67-0.85). Negative control analyses did not find evidence of significant bias. Hemoglobin A1c levels, BMI, blood eosinophil cell counts, and asthma severity did not modify the association. The only add-on antidiabetic medication to have an additive association was GLP-1RA (SCCS: IRR, 0.60; 95% CI, 0.49-0.73). Conclusions and Relevance The results of this cohort study suggest that metformin was associated with a lower rate of asthma attacks, with further reductions with the use of GLP-1RA. This appeared to be associated with mechanisms other than through glycemic control or weight loss and occurred across asthma phenotypes.
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Affiliation(s)
- Bohee Lee
- National Heart and Lung Institute, Imperial College London, London, England
| | - Kenneth K. C. Man
- Research Department of Practice and Policy, School of Pharmacy, University College London, London, England
| | - Ernie Wong
- National Heart and Lung Institute, Imperial College London, London, England
| | - Tricia Tan
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, England
| | - Aziz Sheikh
- Asthma UK Centre for Applied Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, England
| | - Chloe I. Bloom
- National Heart and Lung Institute, Imperial College London, London, England
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11
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Cahill KN, Foer D. Borrowing From the Type 2 Diabetes Armamentarium for Asthma. JAMA Intern Med 2025; 185:25-27. [PMID: 39556391 DOI: 10.1001/jamainternmed.2024.5983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Affiliation(s)
- Katherine N Cahill
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Dinah Foer
- Department of Medicine, Divisions of Allergy and Clinical Immunology and General Internal Medicine and Primary Care, Brigham and Women's Hospital, Boston, Massachusetts
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12
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Mailhot-Larouche S, Celis-Preciado C, Heaney LG, Couillard S. Identifying super-responders: A review of the road to asthma remission. Ann Allergy Asthma Immunol 2025; 134:31-45. [PMID: 39383944 DOI: 10.1016/j.anai.2024.09.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 09/25/2024] [Accepted: 09/27/2024] [Indexed: 10/11/2024]
Abstract
Asthma is a chronic respiratory disease marked by heterogeneity and variable clinical outcomes. Recent therapeutic advances have highlighted patients achieving optimal outcomes, termed "remission" or "super-response." This review evaluates the various definitions of these terms and explores how disease burden impedes the attainment of remission. We assessed multiple studies, including a recent systematic review and meta-analysis, on biologic treatments for asthma remission. Our review highlights that type 2 inflammation may be the strongest predictor of biologic response. Key comorbidities (eg, obesity and mood disorders) and behavioral factors (eg, poor adherence, improper inhalation technique, and smoking) were identified as dominant traits limiting remission. In addition, asthma burden and longer disease duration significantly restrict the potential for remission in patients with severe asthma under the current treatment paradigm. We review the potential for a "predict-and-prevent" approach, which focuses on early identification of high-risk patients with type 2 inflammation and aggressive treatment to improve long-term asthma outcomes. In conclusion, this scoping review highlights the following unmet needs in asthma remission: (1) a harmonized global definition, with better defined lung function parameters; (2) integration of nonbiologic therapies into remission strategies; and (3) a clinical trial of early biologic intervention in patients with remission-prone, very type 2-high, moderately severe asthma with clinical remission as a predefined primary end point.
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Affiliation(s)
- Samuel Mailhot-Larouche
- Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Carlos Celis-Preciado
- Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Liam G Heaney
- Centre for Experimental Medicine, Queen's University Belfast School of Medicine, Dentistry and Biomedical Sciences, Belfast, United Kingdom
| | - Simon Couillard
- Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.
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13
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Janić M, Škrgat S, Harlander M, Lunder M, Janež A, Pantea Stoian A, El-Tanani M, Maggio V, Rizzo M. Potential Use of GLP-1 and GIP/GLP-1 Receptor Agonists for Respiratory Disorders: Where Are We at? MEDICINA (KAUNAS, LITHUANIA) 2024; 60:2030. [PMID: 39768911 PMCID: PMC11728110 DOI: 10.3390/medicina60122030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/03/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025]
Abstract
Chronic respiratory disorders are the third leading cause of mortality globally. Consequently, there is a continuous pursuit of effective therapies beyond those currently available. The therapeutic potential of the glucagon-like peptide-1 (GLP-1) and the glucose-dependent insulinotropic polypeptide/GLP-1 (GIP/GLP-1) receptor agonists extends beyond the regulation of glycemia, including glucometabolic, cardiovascular, and renal effects, rendering them viable candidates, due to their mechanisms of action, for the possible treatment of respiratory disorders. This manuscript aims to provide a comprehensive evaluation of the evidence on potential direct (cellular) and indirect (metabolic) actions of GLP-1 and GIP/GLP-1 receptor agonists within the pulmonary systems. In addition, it examines their efficacy in addressing prevalent respiratory disorders, specifically chronic obstructive pulmonary disease (COPD), asthma, pneumonia, obstructive sleep apnea, pulmonary hypertension, lung cancer, and lung transplantation. Finally, the manuscript seeks to identify potential avenues for further focused research in this field.
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Affiliation(s)
- Miodrag Janić
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (M.L.); (A.J.)
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; (S.Š.); (M.H.)
- School of Medicine, PROMISE Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, 90133 Palermo, Italy (M.R.)
| | - Sabina Škrgat
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; (S.Š.); (M.H.)
- Department of Pulmonary Diseases and Allergy, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
| | - Matevž Harlander
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; (S.Š.); (M.H.)
- Department of Pulmonary Diseases and Allergy, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
| | - Mojca Lunder
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (M.L.); (A.J.)
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; (S.Š.); (M.H.)
| | - Andrej Janež
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (M.L.); (A.J.)
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; (S.Š.); (M.H.)
| | - Anca Pantea Stoian
- Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Mohamed El-Tanani
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates;
| | - Viviana Maggio
- School of Medicine, PROMISE Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, 90133 Palermo, Italy (M.R.)
| | - Manfredi Rizzo
- School of Medicine, PROMISE Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, 90133 Palermo, Italy (M.R.)
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates;
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14
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Cazzola M, Matera MG, Calzetta L, Lauro D, Rogliani P. Can glucagon-like peptide-1 receptor agonists induce asthma? An analysis of the FAERS database. J Asthma 2024; 61:1638-1645. [PMID: 38913778 DOI: 10.1080/02770903.2024.2372600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 06/17/2024] [Accepted: 06/21/2024] [Indexed: 06/26/2024]
Abstract
OBJECTIVE Glucagon-like peptide-1 receptor agonists (GLP1RAs), originally developed for the treatment of type 2 diabetes mellitus, have attracted attention for their potential therapeutic benefits in asthma due to their anti-inflammatory properties and effects on airway smooth muscle function. However, concerns have been raised about the possibility of GLP1RAs inducing or exacerbating asthma symptoms. METHODS We reviewed data from the US Food and Drug Administration's (FDA) adverse event (AE) reporting system (FAERS) to examine reports of cases of asthma observed in the real-world during treatment with GLP1RAs. RESULTS Analysis of the FAERS reporting system database has shown that certain GLP1RAs, particularly exenatide, semaglutide and liraglutide, were associated with a higher proportion of respiratory AEs, particularly asthma or asthma-like events. This association was statistically significant at least for semaglutide and liraglutide. Serious asthma-related events and deaths were also reported, with exenatide having the highest proportion of deaths. CONCLUSIONS The reasons for the observed differences in the AE profiles of the GLP1RAs remain unclear and may involve various factors such as pharmacological properties, patient characteristics and reporting biases. The complex interplay between the therapeutic benefits of GLP1RAs and the potential respiratory risks requires careful monitoring by clinicians, underpinned by ongoing research efforts to improve patient care and safety.
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Affiliation(s)
- Mario Cazzola
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome 'Tor Vergata', Rome, Italy
| | - Maria Gabriella Matera
- Unit of Pharmacology, Department of Experimental Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy
| | - Luigino Calzetta
- Unit of Respiratory Disease and Lung Function, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Davide Lauro
- Unit of Endocrinology and Metabolic Diseases, Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy
| | - Paola Rogliani
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome 'Tor Vergata', Rome, Italy
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15
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Weare-Regales N, Carr T, Holguin F, Tibbitt CA, Lockey RF. Obesity and hormonal influences on asthma: Mechanisms, management challenges, and emerging therapeutic strategies. J Allergy Clin Immunol 2024; 154:1355-1368. [PMID: 39362350 DOI: 10.1016/j.jaci.2024.09.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/13/2024] [Accepted: 09/13/2024] [Indexed: 10/05/2024]
Abstract
Obesity and hormone dysregulation, common comorbidities of asthma, not only influence asthma risk and onset but can also complicate its management. The pathobiologic characteristics of obesity, such as insulin resistance and metabolism alterations, can impact lung function and airway inflammation while highlighting potential opportunities for therapeutic intervention. Likewise, obesity alters immune cell phenotypes and corticosteroid pharmacokinetics. Hormones such as sex hormones, incretins, and thyroid hormones can also affect asthma. This review highlights the mechanisms underlying obesity-related asthma and hormonal pathologies while exploring potential therapeutic strategies and the need for more research and innovative approaches in managing these comorbid conditions.
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Affiliation(s)
- Natalia Weare-Regales
- Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, University of South Florida, Morsani College of Medicine, and the Division of Endocrinology, Department of Internal Medicine, James A. Haley Veterans Administration, Tampa.
| | - Tara Carr
- Asthma and Airway Disease Research Center, University of Arizona, and the Section of Allergy and Immunology, Department of Medicine, University of Arizona College of Medicine, Tucson
| | - Fernando Holguin
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Medical School, Aurora
| | - Christopher Andrew Tibbitt
- Department of Medicine Huddinge, Centre for Infectious Medicine, Karolinska Institutet, and the Clinical Lung and Allergy Research Medical Unit for Lung and Allergy Diseases, Karolinska University Hospital, Stockholm
| | - Richard F Lockey
- Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida, Morsani College of Medicine, Tampa
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16
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Toki S, Abney M, Zhang J, Rusznak M, Warren CM, Newcomb DC, Cahill KN, Drucker DJ, Niswender KD, Peebles RS. Endogenous Glucagon-Like Peptide-1 Receptor and Glucose-Dependent Insulinotropic Polypeptide Receptor Signaling Inhibits Aeroallergen-Induced Innate Airway Inflammation. Allergy 2024; 79:3373-3384. [PMID: 39559998 PMCID: PMC11842020 DOI: 10.1111/all.16402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 10/04/2024] [Accepted: 10/23/2024] [Indexed: 11/20/2024]
Abstract
BACKGROUND Anti-inflammatory effects of incretin signaling through the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) in mice have been reported. Therefore, we hypothesized that signaling through the endogenous GLP-1R and the GIPR individually decreases allergic airway inflammation and that the combination of GLP-1R and GIPR signaling together additively inhibits allergen-induced lung and airway inflammation. METHODS WT (C57BL/6J), GLP-1R knockout (KO), GIPR KO, and GLP-1R/GIPR double KO (DKO) mice were challenged intranasally with Alternaria alternata extract (Alt-Ext) or vehicle to evaluate the impact of signaling through these receptors on the innate allergen-induced inflammatory response that is primarily driven by group 2 innate lymphoid cells (ILC2). RESULTS Alt-Ext-induced IL-33 release in the bronchoalveolar lavage fluid (BALF) was not different between the mouse strains, but thymic stromal lymphopoietin (TSLP) was significantly increased in GLP-1R/GIPR DKO mice challenged with Alt-Ext compared to the other strains. Furthermore, Alt-Ext-induced protein expression of IL-5, IL-13, CCL11, and CCL24 in the lung homogenates, the number of eosinophils, lymphocytes, and neutrophils in the BALF, and the number of lung GATA3+ ILC2 were significantly increased in GLP-1R/GIPR DKO mice compared to the other 3 strains. Furthermore, ICAM-1 expression on lung epithelial cells was increased in GLP-1R/GIPR DKO mice challenged with Alt-Ext compared to the other 3 strains. CONCLUSIONS Deficiency of both GLP-1R and GIPR signaling together increased TSLP release, ILC2 activation, and early type 2 innate immune responses to aeroallergen exposure. Combined GLP-1R and GIPR signaling should be explored for the treatment of asthma.
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Affiliation(s)
- Shinji Toki
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Masako Abney
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Jian Zhang
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Mark Rusznak
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Christian M. Warren
- United States Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
| | - Dawn C. Newcomb
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Katherine N. Cahill
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Daniel J. Drucker
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Kevin D. Niswender
- United States Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
- Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - R. Stokes Peebles
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- United States Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
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17
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Tomasello A, Benfante A, Lisotta A, Macaluso D, Viswanathan S, Cahill KN, Scichilone N. Polypharmacy in older patients with asthma: hidden risks and opportunities for improvement. Expert Rev Respir Med 2024; 18:1047-1059. [PMID: 39708058 DOI: 10.1080/17476348.2024.2444331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/23/2024] [Accepted: 12/16/2024] [Indexed: 12/23/2024]
Abstract
INTRODUCTION Polypharmacy can be considered the norm in elderly patients, because older individuals experience an increasing number of concomitant respiratory and non-respiratory diseases other than asthma, carrying the risk of drug-to-drug-interactions and drug-to-comorbidities interactions. In this context, asthma in older adults, conventionally aging >65 years of age, cannot be adequately managed without considering their individual characteristics, as these challenge the traditional therapeutic algorithms/management strategies commonly applied to younger populations. AREAS COVERED The current article aims at addressing pitfalls and advantages of current pharmacological strategies in older individuals with asthma. Comorbidities become more common with increasing age and are also more frequent in adults with asthma than in those without it. Multiple medications are often needed to control asthma symptoms and prevent asthma exacerbations, and older patients with asthma may also take multiple medications for common comorbidities and complex health conditions, such as chronic cardiometabolic diseases. Polypharmacy is an emerging concern in the elderly population. EXPERT OPINION A patient-centered approach is crucial and polypharmacy in asthma requires careful management. A multidisciplinary approach will allow for a more holistic care and will ensure that all aspects of a patient's health are considered, optimizing medication management.
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Affiliation(s)
- Alessandra Tomasello
- Division of Respiratory Medicine, PROMISE Department, "Paolo Giaccone" University Hospital, University of Palermo, Palermo, Italy
- Division of Allergy, Pulmonary and Critical care Medicine, Vanderbilt University Medical Center, Nashville, USA
| | - Alida Benfante
- Division of Respiratory Medicine, PROMISE Department, "Paolo Giaccone" University Hospital, University of Palermo, Palermo, Italy
| | - Alessia Lisotta
- Division of Respiratory Medicine, PROMISE Department, "Paolo Giaccone" University Hospital, University of Palermo, Palermo, Italy
| | - Dario Macaluso
- Division of Respiratory Medicine, PROMISE Department, "Paolo Giaccone" University Hospital, University of Palermo, Palermo, Italy
| | | | - Katherine N Cahill
- Division of Allergy, Pulmonary and Critical care Medicine, Vanderbilt University Medical Center, Nashville, USA
| | - Nicola Scichilone
- Division of Respiratory Medicine, PROMISE Department, "Paolo Giaccone" University Hospital, University of Palermo, Palermo, Italy
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Althoff MD, Gaietto K, Holguin F, Forno E. Obesity-related Asthma: A Pathobiology-based Overview of Existing and Emerging Treatment Approaches. Am J Respir Crit Care Med 2024; 210:1186-1200. [PMID: 39311907 PMCID: PMC11568442 DOI: 10.1164/rccm.202406-1166so] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 09/20/2024] [Indexed: 10/04/2024] Open
Abstract
Although obesity-related asthma is associated with worse asthma outcomes, optimal treatment approaches for this complex phenotype are still largely unavailable. This state-of-the-art review article synthesizes evidence for existing and emerging treatment approaches for obesity-related asthma and highlights pathways that offer potential targets for novel therapeutics. Existing treatments targeting insulin resistance and obesity, including metformin and GLP-1 (glucagon-like-peptide 1) receptor agonists, have been associated with improved asthma outcomes, although GLP-1R agonist data in asthma are limited to individuals with comorbid obesity. Monoclonal antibodies approved for treatment of moderate to severe asthma generally appear to be effective in individuals with obesity, although this is based on retrospective or secondary analysis of clinical trials; moreover, although most of these asthma biologics are approved for use in the pediatric population, the impact of obesity on their efficacy has not been well studied in youth. Potential therapeutic targets being investigated include IL-6, arginine metabolites, nitro-fatty acids, and mitochondrial antioxidants, with clinical trials for each currently underway. Potential therapeutic targets include adipose tissue eosinophils and the GLP-1-arginine-advanced glycation end products axis, although data in humans are still needed. Finally, transcriptomic and epigenetic studies of "obese asthma" demonstrate enrichment of IFN-related signaling pathways, Rho-GTPase pathways, and integrins, suggesting that these too could represent future treatment targets. We advocate for further study of these potential therapeutic mechanisms and continued investigation of the distinct inflammatory pathways characteristic of obesity-related asthma, to facilitate effective treatment development for this unique asthma phenotype.
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Affiliation(s)
- Meghan D. Althoff
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado
| | - Kristina Gaietto
- Division of Pulmonary Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania; and
| | - Fernando Holguin
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado
| | - Erick Forno
- Division of Pediatric Pulmonology, Allergy, and Sleep Medicine, Department of Pediatrics, Indiana University, Indianapolis, Indiana
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Mendes FC, Garcia-Larsen V, Moreira A. Obesity and Asthma: Implementing a Treatable Trait Care Model. Clin Exp Allergy 2024; 54:881-894. [PMID: 38938020 DOI: 10.1111/cea.14520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/23/2024] [Accepted: 05/28/2024] [Indexed: 06/29/2024]
Abstract
Recognition of obesity as a treatable trait of asthma, impacting its development, clinical presentation and management, is gaining widespread acceptance. Obesity is a significant risk factor and disease modifier for asthma, complicating treatment. Epidemiological evidence highlights that obese asthma correlates with poorer disease control, increased severity and persistence, compromised lung function and reduced quality of life. Various mechanisms contribute to the physiological and clinical complexities observed in individuals with obesity and asthma. These encompass different immune responses, including Type IVb, where T helper 2 cells are pivotal and driven by cytokines like interleukins 4, 5, 9 and 13, and Type IVc, characterised by T helper 17 cells and Type 3 innate lymphoid cells producing interleukin 17, which recruits neutrophils. Additionally, Type V involves immune response dysregulation with significant activation of T helper 1, 2 and 17 responses. Finally, Type VI is recognised as metabolic-induced immune dysregulation associated with obesity. Body mass index (BMI) stands out as a biomarker of a treatable trait in asthma, readily identifiable and targetable, with significant implications for disease management. There exists a notable gap in treatment options for individuals with obese asthma, where asthma management guidelines lack specificity. For example, there is currently no evidence supporting the use of incretin mimetics to improve asthma outcomes in asthmatic individuals without Type 2 diabetes mellitus (T2DM). In this review, we advocate for integrating BMI into asthma care models by establishing clear target BMI goals, promoting sustainable weight loss via healthy dietary choices and physical activity and implementing regular reassessment and referral as necessary.
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Affiliation(s)
- Francisca Castro Mendes
- EPIUnit-Instituto de Saúde Pública, Universidade do Porto, Porto, Portugal
- Laboratório Para a Investigação Integrativa e Translacional Em Saúde Populacional (ITR), Universidade do Porto, Porto, Portugal
- Basic and Clinical Immunology Unit, Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Vanessa Garcia-Larsen
- Program in Human Nutrition, Department of International Health, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland, USA
| | - André Moreira
- EPIUnit-Instituto de Saúde Pública, Universidade do Porto, Porto, Portugal
- Laboratório Para a Investigação Integrativa e Translacional Em Saúde Populacional (ITR), Universidade do Porto, Porto, Portugal
- Basic and Clinical Immunology Unit, Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
- Serviço de Imunoalergologia, Centro Hospitalar Universitário São João, Porto, Portugal
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20
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Wang T, Keil AP, Buse JB, Keet C, Kim S, Wyss R, Pate V, Jonsson-Funk M, Pratley RE, Kvist K, Kosorok MR, Stürmer T. Glucagon-like Peptide 1 Receptor Agonists and Asthma Exacerbations: Which Patients Benefit Most? Ann Am Thorac Soc 2024; 21:1496-1506. [PMID: 39012183 PMCID: PMC11568508 DOI: 10.1513/annalsats.202309-836oc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 07/11/2024] [Indexed: 07/17/2024] Open
Abstract
Rationale: Although recent evidence suggested that glucagon-like peptide 1 receptor agonists (GLP1RAs) might reduce the risk of asthma exacerbations, it remains unclear which subpopulations might derive the most benefit from GLP1RA treatment. Objectives: To identify characteristics of patients with asthma that predict who might benefit the most from GLP1RA treatment using real-world data. Methods: We implemented an active-comparator, new-user design analysis using commercially ensured patients 18-65 years of age from MarketScan data for 2007-2019 and identified two cohorts: GLP1RAs versus thiazolidinediones and GLP1RAs versus sulfonylureas. The outcome was acute exacerbation of asthma (hospital admission or emergency department visit for asthma) within 180 days after initiation. We applied iterative causal forest, a novel causal machine learning subgrouping algorithm, to assess heterogeneous treatment effects. In identified subgroups, we predicted propensity score, conducted propensity score trimming, and then estimated adjusted risk differences for the effect of GLP1RAs relative to comparators on asthma exacerbation using inverse probability treatment weighting in the propensity score-trimmed subpopulation. Results: Among 10,989 patients initiating GLP1RAs or thiazolidinediones and 17,088 patients initiating GLP1RAs versus sulfonylurea, GLP1RA initiators had fewer exacerbations, with adjusted risk differences of -0.5% (95% confidence interval [CI], -1.1% to 0.1%) and -1.6% (95% CI, -2.2% to -1.1%), respectively. In the GLP1RA versus sulfonylurea cohort, in which we observed a beneficial effect, our iterative causal forest analysis identified five subgroups with different treatment effects, defined by the number of emergency department visits, the number of prescriptions for short-acting β2-agonists, the number of prescriptions for inhaled steroids and long-acting β-agonists (either combination therapy or concurrent use), and age ≥ 50 years. Among these, patients with two or more emergency department visits during the 12-month baseline period had the largest absolute exacerbation risk reduction, with a decrease of 2.8% for GLP1RAs (95% CI, -4.8% to -0.9%). Conclusions: GLP1RAs demonstrated a beneficial effect on reducing asthma exacerbation relative to sulfonylureas. Patients with asthma with two or more emergency department visits (a proxy for disease severity) benefit most from GLP1RAs. Emergency department visit frequency, the number of maintenance and reliever inhalers, and age might help individualize prediction of the short-term benefit of GLP1RAs on asthma exacerbation.
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Affiliation(s)
| | | | | | - Corinne Keet
- Department of Pediatrics, School of Medicine, University of North Carolina, Chapel Hill, North Carolina
| | - Siyeon Kim
- Department of Biostatistics, Gillings School of Global Public Health, and
| | - Richard Wyss
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Boston, Massachusetts
| | | | | | | | | | - Michael R. Kosorok
- Department of Biostatistics, Gillings School of Global Public Health, and
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21
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Drucker DJ. Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity. Diabetes Care 2024; 47:1873-1888. [PMID: 38843460 DOI: 10.2337/dci24-0003] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 04/14/2024] [Indexed: 10/23/2024]
Abstract
The development of glucagon-like peptide 1 receptor agonists (GLP-1RA) for type 2 diabetes and obesity was followed by data establishing the cardiorenal benefits of GLP-1RA in select patient populations. In ongoing trials investigators are interrogating the efficacy of these agents for new indications, including metabolic liver disease, peripheral artery disease, Parkinson disease, and Alzheimer disease. The success of GLP-1-based medicines has spurred the development of new molecular entities and combinations with unique pharmacokinetic and pharmacodynamic profiles, exemplified by tirzepatide, a GIP-GLP-1 receptor coagonist. Simultaneously, investigational molecules such as maritide block the GIP and activate the GLP-1 receptor, whereas retatrutide and survodutide enable simultaneous activation of the glucagon and GLP-1 receptors. Here I highlight evidence establishing the efficacy of GLP-1-based medicines, while discussing data that inform safety, focusing on muscle strength, bone density and fractures, exercise capacity, gastrointestinal motility, retained gastric contents and anesthesia, pancreatic and biliary tract disorders, and the risk of cancer. Rapid progress in development of highly efficacious GLP-1 medicines, and anticipated differentiation of newer agents in subsets of metabolic disorders, will provide greater opportunities for use of personalized medicine approaches to improve the health of people living with cardiometabolic disorders.
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Affiliation(s)
- Daniel J Drucker
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada
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22
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Zahra MA, Pessin J, Rastogi D. A clinician's guide to effects of obesity on childhood asthma and into adulthood. Expert Rev Respir Med 2024; 18:759-775. [PMID: 39257361 PMCID: PMC11473229 DOI: 10.1080/17476348.2024.2403500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 08/20/2024] [Accepted: 09/09/2024] [Indexed: 09/12/2024]
Abstract
INTRODUCTION Obesity, one of the most common chronic conditions affecting the human race globally, affects several organ systems, including the respiratory system, where it contributes to onset and high burden of asthma. Childhood onset of obesity-related asthma is associated with high persistent morbidity into adulthood. AREAS COVERED In this review, we discuss the disease burden in children and adults to highlight the overlap between symptoms and pulmonary function deficits associated with obesity-related asthma in both age ranges, and then discuss the potential role of three distinct mechanisms, that of mechanical fat load, immune perturbations, and of metabolic perturbations on the disease burden. We also discuss interventions, including medical interventions for weight loss such as diet modification, that of antibiotics and anti-inflammatory therapies, as well as that of surgical intervention on amelioration of burden of obesity-related asthma. EXPERT OPINION With increase in obesity-related asthma due to increasing burden of obesity, it is evident that it is a disease entity distinct from asthma among lean individuals. The time is ripe to investigate the underlying mechanisms, focusing on identifying novel therapeutic targets as well as consideration to repurpose medications effective for other obesity-mediated complications, such as insulin resistance, dyslipidemia and systemic inflammation.
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Affiliation(s)
- Mahmoud Abu Zahra
- Division of Respiratory and Sleep Medicine, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Jeffrey Pessin
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Deepa Rastogi
- Division of Respiratory and Sleep Medicine, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, United States
- Norman Fleischer Institute of Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, NY, United States
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23
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McCoy RG, Swarna KS, Neumiller JJ, Polley EC, Deng Y, Mickelson MM, Herrin J. Risk of Severe Hypoglycemia After Initiation of Noninsulin Glucose-Lowering Therapies in Adults With Type 2 Diabetes at Moderate Cardiovascular Disease Risk. Clin Diabetes 2024; 43:59-70. [PMID: 39829688 PMCID: PMC11739335 DOI: 10.2337/cd24-0007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
In this emulated comparative effectiveness target trial of glucagon-like peptide 1 (GLP-1) receptor agonist, sodium-glucose cotransporter 2 (SGLT2) inhibitor, dipeptidyl peptidase 4 (DPP-4) inhibitor, and sulfonylurea therapy among adults with type 2 diabetes at moderate cardiovascular disease risk, sulfonylurea use was associated with a significantly higher risk of hypoglycemia requiring emergency department or hospital care than treatment with DPP-4 inhibitors, GLP-1 receptor agonists, or SGLT2 inhibitors. This consideration can guide the choice of glucose-lowering therapy in this highly prevalent patient population, in whom avoidance of hypoglycemia is important, yet among whom the risk of severe hypoglycemia has not been examined previously.
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Affiliation(s)
- Rozalina G. McCoy
- Division of Endocrinology, Diabetes, & Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
- University of Maryland Institute for Health Computing, Bethesda, MD
- OptumLabs, Eden Prairie, MN
| | - Kavya Sindhu Swarna
- OptumLabs, Eden Prairie, MN
- Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Rochester, MN
| | - Joshua J. Neumiller
- Department of Pharmacotherapy, Washington State University, Spokane, WA
- Providence Medical Research Center, Spokane, WA
| | - Eric C. Polley
- Department of Public Health Sciences, University of Chicago, Chicago, IL
| | - Yihong Deng
- OptumLabs, Eden Prairie, MN
- Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Rochester, MN
| | - Mindy M. Mickelson
- Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Rochester, MN
| | - Jeph Herrin
- Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT
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24
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Badulescu S, Tabassum A, Le GH, Wong S, Phan L, Gill H, Llach CD, McIntyre RS, Rosenblat J, Mansur R. Glucagon-like peptide 1 agonist and effects on reward behaviour: A systematic review. Physiol Behav 2024; 283:114622. [PMID: 38945189 DOI: 10.1016/j.physbeh.2024.114622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 06/17/2024] [Accepted: 06/25/2024] [Indexed: 07/02/2024]
Abstract
INTRODUCTION The roles of metabolic signals, including Glucagon-like peptide 1 (GLP-1), have been implicated in multiple domains outside metabolic regulation. There is a growing interest in repurposing Glucagon-like peptide 1 receptor agonists (GLP-1RAs) as therapeutics for motivation and reward-related behavioural disturbances. Herein, we aim to systematically review the extant evidence on the potential effects of GLP-1RAs on the reward system. METHODS The study followed PRISMA guidelines using databases such as OVID, PubMed, Scopus, and Google Scholar. The search focused on "Reward Behavior" and "Glucagon Like Peptide 1 Receptor Agonists" and was restricted to human studies. Quality assessment achieved by the NIH's Quality Assessment of Controlled Intervention Studies RESULTS: GLP-1RAs consistently reduced energy intake and influenced reward-related behaviour. These agents have been associated with decreased neurocortical activation in response to higher rewards and food cues, particularly high-calorie foods, and lowered caloric intake and hunger levels. DISCUSSION GLP-1RAs show promise in addressing reward dysfunction linked to food stimuli, obesity, and T2DM. They normalize insulin resistance, and might also modulate dopaminergic signalling and reduce anhedonia. Their effects on glycemic variability and cravings suggest potential applications in addiction disorders.
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Affiliation(s)
- Sebastian Badulescu
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada.
| | - Aniqa Tabassum
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
| | - Gia Han Le
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
| | - Sabrina Wong
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada
| | - Lee Phan
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
| | - Hartej Gill
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
| | - Cristian-Daniel Llach
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
| | - Roger S McIntyre
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada
| | - Joshua Rosenblat
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada
| | - Rodrigo Mansur
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
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25
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Hayashi Y, Tanabe N, Shimizu K, Maetani T, Shiraishi Y, Oguma T, Sunadome H, Sakamoto R, Sato A, Sato S, Date H, Matsumoto H, Hirai T. Lower skeletal muscle density and airway structure on computed tomography in asthma. Ann Allergy Asthma Immunol 2024:S1081-1206(24)00527-1. [PMID: 39179101 DOI: 10.1016/j.anai.2024.08.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 08/09/2024] [Accepted: 08/12/2024] [Indexed: 08/26/2024]
Abstract
BACKGROUND Lower skeletal muscle density may reflect muscle adiposity and metabolic dysregulation that potentially impair disease control and lung function independent of high body mass index (BMI) in patients with asthma. OBJECTIVE To investigate whether the lower density of pectoralis muscles (PMs) and erector spinae muscles (ESMs) on chest computed tomography was associated with airway structural changes in patients with asthma. METHODS Consecutive patients with asthma and healthy controls undergoing chest computed tomography were retrospectively analyzed. The ESM and PM density, areas of subcutaneous adipose tissue near the PM and epicardial adipose tissue, wall area percent of the airways, and airway fractal dimension (AFD) were quantified on computed tomography. RESULTS The study included 179 patients with asthma (52% women) and 88 controls (47% women). All the controls were 60 years old or younger. The PM and ESM density in female patients with asthma who were 60 years old or younger were significantly lower than those in controls after adjustment for BMI. In female patients with asthma at all ages, lower PM and ESM density (but not subcutaneous or epicardial adipose tissue area) was associated with greater wall area percent of the airways and lower AFD after adjusting for age, height, BMI, smoking status, blood eosinophil count, and oral corticosteroid use. The only association between ESM density and AFD was found in male patients with asthma. CONCLUSION Lower skeletal muscle density may be associated with airway wall thickening and less complexity of the airway luminal tree in female patients with asthma.
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Affiliation(s)
- Yusuke Hayashi
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Naoya Tanabe
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| | - Kaoruko Shimizu
- Department of Respiratory Medicine, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Tomoki Maetani
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yusuke Shiraishi
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tsuyoshi Oguma
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Respiratory Medicine, Kyoto City Hospital, Kyoto, Japan
| | - Hironobu Sunadome
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Respiratory Care and Sleep Control Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ryo Sakamoto
- Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsuyasu Sato
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Susumu Sato
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Respiratory Care and Sleep Control Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Date
- Department of Thoracic Surgery, Kyoto University, Kyoto, Japan
| | - Hisako Matsumoto
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Respiratory Medicine and Allergology, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Toyohiro Hirai
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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26
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Wu TD, Cahill KN. Impact of Antihyperglycemic Drugs on Asthma Outcomes: Diversifying the Research Portfolio. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2024; 12:2045-2046. [PMID: 39122331 DOI: 10.1016/j.jaip.2024.05.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Accepted: 05/21/2024] [Indexed: 08/12/2024]
Affiliation(s)
- Tianshi David Wu
- Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, Texas; Center for Innovations in Quality, Effectiveness, and Safety, Michael E. Debakey VA Medical Center, Houston, Texas
| | - Katherine N Cahill
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tenn.
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27
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Kimura Y, Jo T, Inoue N, Suzukawa M, Hashimoto Y, Kumazawa R, Ishimaru M, Matsui H, Yokoyama A, Tanaka G, Sasabuchi Y, Yasunaga H. Association of Novel Antihyperglycemic Drugs Versus Metformin With a Decrease in Asthma Exacerbations. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2024; 12:2035-2044. [PMID: 38734374 DOI: 10.1016/j.jaip.2024.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 04/10/2024] [Accepted: 05/01/2024] [Indexed: 05/13/2024]
Abstract
BACKGROUND Similar to metformin, dipeptidyl peptidase-4 inhibitors (DPP-4 Is), glucagon-like peptidase 1 receptor agonists (GLP-1 RAs), and sodium glucose co-transporter-2 inhibitors (SGLT-2 Is) may improve control of asthma owing to their multiple potential mechanisms, including differential improvements in glycemic control, direct anti-inflammatory effects, and systemic changes in metabolism. OBJECTIVE To investigate whether these novel antihyperglycemic drugs were associated with fewer asthma exacerbations compared with metformin in patients with asthma comorbid with type 2 diabetes. METHODS Using a Japanese national administrative database, we constructed 3 active comparators-new user cohorts of 137,173 patients with a history of asthma starting the novel antihyperglycemic drugs and metformin between 2014 and 2022. Patient characteristics were balanced using overlap propensity score weighting. The primary outcome was the first exacerbation requiring systemic corticosteroids, and the secondary outcomes included the number of exacerbations requiring systemic corticosteroids. RESULTS DPP-4 Is and GLP-1 RAs were associated with a higher incidence of exacerbations requiring systemic corticosteroids compared with metformin (DPP-4 Is: 18.2 vs 17.4 per 100 person-years, hazard ratio: 1.09, 95% confidence interval [CI]: 1.05-1.14; GLP-1 RAs: 24.9 vs 19.0 per 100 person-years, hazard ratio: 1.14, 95% CI: 1.01-1.28). In contrast, the incidence of exacerbations requiring systemic corticosteroids was similar between the SGLT-2 Is and metformin groups (17.3 vs 18.1 per 100 person-years, hazard ratio: 1.00, 95% CI: 0.97-1.03). While DPP-4 Is and GLP-1 RAs were associated with more exacerbations requiring systemic corticosteroids, SGLT-2 Is were associated with slightly fewer exacerbations requiring systemic corticosteroids (53.7 vs 56.6 per 100 person-years, rate ratio: 0.95, 95% CI: 0.91-0.99). CONCLUSIONS While DPP-4 Is and GLP-1 RAs were associated with poorer control of asthma compared with metformin, SGLT-2 Is offered asthma control comparable to that of metformin.
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Affiliation(s)
- Yuya Kimura
- Department of Clinical Epidemiology and Health Economics, School of Public Health, the University of Tokyo, Tokyo, Japan; Clinical Research Center, National Hospital Organization Tokyo Hospital, Tokyo, Japan.
| | - Taisuke Jo
- Department of Health Services Research, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan; Department of Respiratory Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Norihiko Inoue
- Department of Health Policy and Informatics, Tokyo Medical and Dental University Graduate School, Tokyo, Japan; Department of Clinical Data Management and Research, Clinical Research Center, National Hospital Organization Headquarters, Tokyo, Japan
| | - Maho Suzukawa
- Clinical Research Center, National Hospital Organization Tokyo Hospital, Tokyo, Japan
| | - Yohei Hashimoto
- Save Sight Institute, the University of Sydney, Sydney, NSW, Australia
| | - Ryosuke Kumazawa
- Department of Clinical Epidemiology and Health Economics, School of Public Health, the University of Tokyo, Tokyo, Japan
| | - Miho Ishimaru
- Department of Clinical Epidemiology and Health Economics, School of Public Health, the University of Tokyo, Tokyo, Japan; Department of Health Services Research, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Hiroki Matsui
- Department of Clinical Epidemiology and Health Economics, School of Public Health, the University of Tokyo, Tokyo, Japan
| | - Akira Yokoyama
- Department of Respiratory Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Goh Tanaka
- Department of Respiratory Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Yusuke Sasabuchi
- Department of Real-world Evidence, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Hideo Yasunaga
- Department of Clinical Epidemiology and Health Economics, School of Public Health, the University of Tokyo, Tokyo, Japan
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28
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Burak MF, Tuncman G, Ayci AN, Chetal K, Seropian GYL, Inouye K, Lai ZW, Dagtekin N, Sadreyev RI, Israel E, Hotamışlıgil GS. An Adipo-Pulmonary Axis Mediated by FABP4 Hormone Defines a Therapeutic Target Against Obesity-Induced Airway Disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.15.603433. [PMID: 39071372 PMCID: PMC11275790 DOI: 10.1101/2024.07.15.603433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Obesity-related airway disease is a clinical condition without a clear description and effective treatment. Here, we define this pathology and its unique properties, which differ from classic asthma phenotypes, and identify a novel adipo-pulmonary axis mediated by FABP4 hormone as a critical mediator of obesity-induced airway disease. Through detailed analysis of murine models and human samples, we elucidate the dysregulated lipid metabolism and immunometabolic responses within obese lungs, particularly highlighting the stress response activation and downregulation of surfactant-related genes, notably SftpC. We demonstrate that FABP4 deficiency mitigates these alterations, demonstrating a key role in obesity-induced airway disease pathogenesis. Importantly, we identify adipose tissue as the source of FABP4 hormone in the bronchoalveolar space and describe strong regulation in the context of human obesity, particularly among women. Finally, our exploration of antibody-mediated targeting of circulating FABP4 unveils a novel therapeutic avenue, addressing a pressing unmet need in managing obesity-related airway disease. These findings not only define the presence of a critical adipo-pulmonary endocrine link but also present FABP4 as a therapeutic target for managing this unique airway disease that we refer to as fatty lung disease associated with obesity. One Sentence Summary Investigating FABP4's pivotal role in obesity-driven airway disease, this study unveils an adipo-pulmonary axis with potential therapeutic implications.
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29
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Pilkington AW, Buragamadagu B, Johnston RA. Weighted Breaths: Exploring Biologic and Non-Biologic Therapies for Co-Existing Asthma and Obesity. Curr Allergy Asthma Rep 2024; 24:381-393. [PMID: 38878250 PMCID: PMC11233394 DOI: 10.1007/s11882-024-01153-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/21/2024] [Indexed: 07/10/2024]
Abstract
PURPOSE OF REVIEW To discuss the effectiveness of biologics, some of which comprise the newest class of asthma controller medications, and non-biologics in the treatment of asthma co-existing with obesity. RECENT FINDINGS Our review of recent preliminary and published data from clinical trials revealed that obese asthmatics respond favorably to dupilumab, mepolizumab, omalizumab, and tezepelumab, which are biologics currently indicated as add-on maintenance therapy for severe asthma. Furthermore, clinical trials are ongoing to assess the efficacy of non-biologics in the treatment of obese asthma, including a glucagon-like peptide-1 receptor agonist, a Janus kinase inhibitor, and probiotics. Although many biologics presently indicated as add-on maintenance therapy for severe asthma exhibit efficacy in obese asthmatics, other phenotypes of asthma co-existing with obesity may be refractory to these medications. Thus, to improve quality of life and asthma control, it is imperative to identify therapeutic options for all existing phenotypes of obese asthma.
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Affiliation(s)
- Albert W Pilkington
- Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, United States Department of Health and Human Services, 1000 Frederick Lane, Morgantown, WV, 26508-5402, USA
| | - Bhanusowmya Buragamadagu
- Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, School of Medicine, West Virginia University, Morgantown, WV, USA
| | - Richard A Johnston
- Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, United States Department of Health and Human Services, 1000 Frederick Lane, Morgantown, WV, 26508-5402, USA.
- Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, School of Medicine, West Virginia University, Morgantown, WV, USA.
- Department of Physiology, Pharmacology, and Toxicology, School of Medicine, West Virginia University, Morgantown, WV, USA.
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30
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Olejnik AE, Kuźnar-Kamińska B. Association of Obesity and Severe Asthma in Adults. J Clin Med 2024; 13:3474. [PMID: 38930006 PMCID: PMC11204497 DOI: 10.3390/jcm13123474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 06/06/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024] Open
Abstract
The incidence of obesity and asthma continues to enhance, significantly impacting global public health. Adipose tissue is an organ that secretes hormones and cytokines, causes meta-inflammation, and contributes to the intensification of bronchial hyperreactivity, oxidative stress, and consequently affects the different phenotypes of asthma in obese people. As body weight increases, the risk of severe asthma increases, as well as more frequent exacerbations requiring the use of glucocorticoids and hospitalization, which consequently leads to a deterioration of the quality of life. This review discusses the relationship between obesity and severe asthma, the underlying molecular mechanisms, changes in respiratory function tests in obese people, its impact on the occurrence of comorbidities, and consequently, a different response to conventional asthma treatment. The article also reviews research on possible future therapies for severe asthma. The manuscript is a narrative review of clinical trials in severe asthma and comorbid obesity. The articles were found in the PubMed database using the keywords asthma and obesity. Studies on severe asthma were then selected for inclusion in the article. The sections: 'The classification connected with asthma and obesity', 'Obesity-related changes in pulmonary functional tests', and 'Obesity and inflammation', include studies on subjects without asthma or non-severe asthma, which, according to the authors, familiarize the reader with the pathophysiology of obesity-related asthma.
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Affiliation(s)
- Aneta Elżbieta Olejnik
- Department of Pulmonology, Allergology and Pulmonary Oncology, Poznan University of Medical Sciences, Szamarzewskiego 84 Street, 60-569 Poznan, Poland;
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31
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Chan R, Duraikannu C, Thouseef MJ, Lipworth B. Lower paraspinal muscle density is associated with small airway dysfunction in women with persistent asthma. Ann Allergy Asthma Immunol 2024; 132:767-768. [PMID: 38401757 DOI: 10.1016/j.anai.2024.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 02/09/2024] [Accepted: 02/12/2024] [Indexed: 02/26/2024]
Affiliation(s)
- Rory Chan
- Scottish Centre for Respiratory Research, School of Medicine, University of Dundee, Dundee, United Kingdom.
| | - Chary Duraikannu
- Department of Radiology, Ninewells Hospital, Dundee, United Kingdom
| | | | - Brian Lipworth
- Scottish Centre for Respiratory Research, School of Medicine, University of Dundee, Dundee, United Kingdom
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Akenroye A, Nopsopon T, Hacker JJ, Laidlaw TM. Ratio of plasma IL-13/TNF- ∝ and CXCL10/CCL17 predicts mepolizumab and omalizumab response in asthma better than eosinophil count or immunoglobulin E level. Sci Rep 2024; 14:10404. [PMID: 38710930 PMCID: PMC11074109 DOI: 10.1038/s41598-024-60864-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Accepted: 04/29/2024] [Indexed: 05/08/2024] Open
Abstract
To date, most studies to identify biomarkers associated with response to the anti-interleukin 5 agent, mepolizumab, and to the anti-immunoglobulin E agent, omalizumab have focused on clinically available biomarkers, such as the peripheral blood eosinophil counts (BEC) and total immunoglobulin E (IgE). However, these biomarkers often have low predictive accuracy, with many patients with eosinophilic or allergic asthma failing to demonstrate clinical response to mepolizumab or omalizumab respectively. In this study, we evaluated the association of baseline pre-biologic plasma levels of 26 cytokines and chemokines, including T-helper 1 (Th1)-, Th2-, Th17-related cytokines, and their ratios with subsequent clinical response to mepolizumab or omalizumab. We defined clinical response as a reduction in the baseline annual exacerbation rate by half or more over the one-year period following initiation of the biologic. Baseline levels of plasma IL-13 were differentially elevated in responders versus non-responders to mepolizumab and plasma CXCL10 levels were differentially elevated in responders to omalizumab. The ratio of IL-13/TNF-α had the best sensitivity and specificity in predicting response to mepolizumab and CXCL10/CCL17 to omalizumab, and these performed better as predictive biomarkers of response than BEC and IgE. Cytokines and chemokines associated with airway eosinophilia, allergic inflammation, or Th2 inflammation, such as IL-13 and CXCL10, may be better predictors of clinical response to mepolizumab and omalizumab, than IL-5 or IgE, the targets of mepolizumab and omalizumab.
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Affiliation(s)
- Ayobami Akenroye
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Road, Boston, MA, 02115, USA.
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
| | - Tanawin Nopsopon
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Road, Boston, MA, 02115, USA
| | - Jonathan J Hacker
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Road, Boston, MA, 02115, USA
| | - Tanya M Laidlaw
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Road, Boston, MA, 02115, USA
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Witte A, Türk Y, Braunstahl GJ. Obesity-related asthma: new insights leading to a different approach. Curr Opin Pulm Med 2024; 30:294-302. [PMID: 38441436 DOI: 10.1097/mcp.0000000000001073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2024]
Abstract
PURPOSE OF REVIEW Obesity is a growing global health threat that significantly contributes to the burden of asthma by increasing the risk of developing asthma and exerting a distinct effect on lung function and inflammation. The treatment of obesity-related asthma is hindered by a poor response to standard asthma treatments, leading to worse asthma control. Weight loss strategies have a significant effect on asthma symptoms but are not feasible for a large proportion of patients, underscoring the need for a better understanding of the pathophysiology and the development of additional treatment options. RECENT FINDINGS Recent literature focusing on pathophysiology particularly delved into nontype 2 inflammatory mechanisms, associations with the metabolic syndrome and small airway impairment. Additionally, several new treatment options are currently investigated, including biologics, weight reduction interventions, and novel antiobesity drugs. SUMMARY Obesity-related asthma is a highly prevalent asthma phenotype for which weight loss strategies currently stand as the most specific treatment. Furthermore, novel pharmacological interventions aiming at metabolic processes are on the way.
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Affiliation(s)
- Adjan Witte
- Department of Pulmonology, Franciscus Gasthuis & Vlietland, The Netherlands
| | - Yasemin Türk
- Department of Pulmonology, Franciscus Gasthuis & Vlietland, The Netherlands
- Dutch Asthma Center Davos, Davos, Switzerland
| | - Gert-Jan Braunstahl
- Department of Pulmonology, Franciscus Gasthuis & Vlietland, The Netherlands
- Department of Pulmonary Disease, Erasmus MC, Rotterdam, The Netherlands
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Foer D, Forno E, Holguin F, Cahill KN. Weight Loss Interventions for Adults With Obesity-Related Asthma. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2024; 12:840-847. [PMID: 38159807 PMCID: PMC10999349 DOI: 10.1016/j.jaip.2023.12.041] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 11/27/2023] [Accepted: 12/21/2023] [Indexed: 01/03/2024]
Abstract
Obesity is a common asthma comorbidity in adults, contributing to higher patient morbidity and mortality. Conversely, weight loss can reduce the impact of obesity on asthma and improve patient outcomes by diverse mechanisms including modulating airway inflammation, reducing oxidative stress, and improving lung function. Multiple lifestyle, nonpharmacological, pharmacological, and surgical interventions are effective at reducing weight in the general population. Fewer have been studied specifically in the context of patients with asthma. However, increasingly effective pharmacologic options for weight loss highlight the need for allergists and pulmonologists to understand the range of approaches that may directly or indirectly yield clinical benefits in asthma management. Weight loss interventions often require multidisciplinary support to create strategies that can realistically achieve a patient's personalized asthma and weight goals. This includes minimizing the adverse weight effects of glucocorticoids, which remain a mainstay of asthma management. Disparities in access, cost, and insurance coverage of weight loss interventions remain acute challenges for providers and patients. Future studies are needed to elucidate mechanisms of action of specific weight loss interventions on short-term and long-term asthma outcomes.
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Affiliation(s)
- Dinah Foer
- Division of General Internal Medicine and Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass
| | - Erick Forno
- Division of Pulmonology, Allergy/Immunology, and Sleep Medicine, Department of Pediatrics, Indiana University School of Medicine and Riley Hospital for Children, Indianapolis, Ind
| | - Fernando Holguin
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, Colo
| | - Katherine N Cahill
- Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tenn.
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Bartziokas K, Papaioannou AI, Drakopanagiotakis F, Gouveri E, Papanas N, Steiropoulos P. Unraveling the Link between Ιnsulin Resistance and Bronchial Asthma. Biomedicines 2024; 12:437. [PMID: 38398039 PMCID: PMC10887139 DOI: 10.3390/biomedicines12020437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 02/10/2024] [Accepted: 02/12/2024] [Indexed: 02/25/2024] Open
Abstract
Evidence from large epidemiological studies has shown that obesity may predispose to increased Th2 inflammation and increase the odds of developing asthma. On the other hand, there is growing evidence suggesting that metabolic dysregulation that occurs with obesity, and more specifically hyperglycemia and insulin resistance, may modify immune cell function and in some degree systemic inflammation. Insulin resistance seldom occurs on its own, and in most cases constitutes a clinical component of metabolic syndrome, along with central obesity and dyslipidemia. Despite that, in some cases, hyperinsulinemia associated with insulin resistance has proven to be a stronger risk factor than body mass in developing asthma. This finding has been supported by recent experimental studies showing that insulin resistance may contribute to airway remodeling, promotion of airway smooth muscle (ASM) contractility and proliferation, increase of airway hyper-responsiveness and release of pro-inflammatory mediators from adipose tissue. All these effects indicate the potential impact of hyperinsulinemia on airway structure and function, suggesting the presence of a specific asthma phenotype with insulin resistance. Epidemiologic studies have found that individuals with severe and uncontrolled asthma have a higher prevalence of glycemic dysfunction, whereas longitudinal studies have linked glycemic dysfunction to an increased risk of asthma exacerbations. Since the components of metabolic syndrome interact with one another so much, it is challenging to identify each one's specific role in asthma. This is why, over the last decade, additional studies have been conducted to determine whether treatment of type 2 diabetes mellitus affects comorbid asthma as shown by the incidence of asthma, asthma control and asthma-related exacerbations. The purpose of this review is to present the mechanism of action, and existing preclinical and clinical data, regarding the effect of insulin resistance in asthma.
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Affiliation(s)
| | - Andriana I. Papaioannou
- 1st University Department of Respiratory Medicine, “Sotiria” Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece;
| | - Fotios Drakopanagiotakis
- Department of Pneumonology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | - Evanthia Gouveri
- Diabetes Centre, 2nd Department of Internal Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.G.); (N.P.)
| | - Nikolaos Papanas
- Diabetes Centre, 2nd Department of Internal Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.G.); (N.P.)
| | - Paschalis Steiropoulos
- Department of Pneumonology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
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Tashiro H, Kurihara Y, Kuwahara Y, Takahashi K. Impact of obesity in asthma: Possible future therapies. Allergol Int 2024; 73:48-57. [PMID: 37659887 DOI: 10.1016/j.alit.2023.08.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 07/10/2023] [Accepted: 07/31/2023] [Indexed: 09/04/2023] Open
Abstract
Obesity is one of the factors associated with the severity of asthma. Obesity is associated with aggravation of the pathophysiology of asthma, including exacerbations, airway inflammation, decreased pulmonary function, and airway hyperresponsiveness. The present review addresses the characteristics of asthma with obesity, focusing especially on the heterogeneity caused by the degree of type 2 inflammation, sex differences, the onset of asthma, and race differences. To understand the severity mechanisms in asthma and obesity, such as corticosteroid resistance, fatty acids, gut microbiome, and cytokines, several basic research studies are evaluated. Finally, possible future therapies, including weight reduction, microbiome-targeted therapies, and other molecular targeted therapies are addressed. We believe that the present review will contribute to better understanding of the severity mechanisms and the establishment of novel treatments for severe asthma patients with obesity.
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Affiliation(s)
- Hiroki Tashiro
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.
| | - Yuki Kurihara
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Yuki Kuwahara
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Koichiro Takahashi
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
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37
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Foer D, Amin T, Nagai J, Tani Y, Feng C, Liu T, Newcomb DC, Lai J, Hayashi H, Snyder WE, McGill A, Lin A, Laidlaw T, Niswender KD, Boyce JA, Cahill KN. Glucagon-like Peptide-1 Receptor Pathway Attenuates Platelet Activation in Aspirin-Exacerbated Respiratory Disease. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:1806-1813. [PMID: 37870292 PMCID: PMC10842986 DOI: 10.4049/jimmunol.2300102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 10/03/2023] [Indexed: 10/24/2023]
Abstract
Platelets are key contributors to allergic asthma and aspirin-exacerbated respiratory disease (AERD), an asthma phenotype involving platelet activation and IL-33-dependent mast cell activation. Human platelets express the glucagon-like peptide-1 receptor (GLP-1R). GLP-1R agonists decrease lung IL-33 release and airway hyperresponsiveness in mouse asthma models. We hypothesized that GLP-1R agonists reduce platelet activation and downstream platelet-mediated airway inflammation in AERD. GLP-1R expression on murine platelets was assessed using flow cytometry. We tested the effect of the GLP-1R agonist liraglutide on lysine-aspirin (Lys-ASA)-induced changes in airway resistance, and platelet-derived mediator release in a murine AERD model. We conducted a prospective cohort study comparing the effect of pretreatment with liraglutide or vehicle on thromboxane receptor agonist-induced in vitro activation of platelets from patients with AERD and nonasthmatic controls. GLP-1R expression was higher on murine platelets than on leukocytes. A single dose of liraglutide inhibited Lys-ASA-induced increases in airway resistance and decreased markers of platelet activation and recruitment to the lung in AERD-like mice. Liraglutide attenuated thromboxane receptor agonist-induced activation as measured by CXCL7 release in plasma from patients with AERD and CD62P expression in platelets from both patients with AERD (n = 31) and nonasthmatic, healthy controls (n = 11). Liraglutide, a Food and Drug Administration-approved GLP-1R agonist for treatment of type 2 diabetes and obesity, attenuates in vivo platelet activation in an AERD murine model and in vitro activation in human platelets in patients with and without AERD. These data advance the GLP-1R axis as a new target for platelet-mediated inflammation warranting further study in asthma.
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Affiliation(s)
- Dinah Foer
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA
| | - Taneem Amin
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jun Nagai
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA
| | - Yumi Tani
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
| | - Chunli Feng
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA
| | - Tao Liu
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA
| | - Dawn C. Newcomb
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN
| | - Juying Lai
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
| | - Hiroaki Hayashi
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
| | - William E. Snyder
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Alanna McGill
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
| | - Anabel Lin
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Tanya Laidlaw
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA
| | - Kevin D. Niswender
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
- United States Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
| | - Joshua A. Boyce
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA
| | - Katherine N. Cahill
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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Staggers KA, Minard C, Byers M, Helmer DA, Wu TD. Metabolic Dysfunction, Triglyceride-Glucose Index, and Risk of Severe Asthma Exacerbation. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:3700-3705.e2. [PMID: 37716524 PMCID: PMC10840907 DOI: 10.1016/j.jaip.2023.09.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/25/2023] [Accepted: 09/04/2023] [Indexed: 09/18/2023]
Abstract
BACKGROUND Metabolic conditions may worsen asthma. There is a need to define a composite biomarker of metabolic dysfunction that has relevance to asthma outcomes. OBJECTIVE To determine the association of the triglyceride-glucose index (TyG), a biomarker of metabolic syndrome and insulin resistance, with risk of severe asthma exacerbation. METHODS A 5-year retrospective cohort of patients with asthma receiving health care from the US Veterans Health Administration from January 1, 2015, to December 31, 2019, was constructed. Fasting TyG values were extracted. Patients were followed for a severe asthma exacerbation, defined as an asthma-related corticosteroid prescription fill or an emergency encounter or hospitalization for asthma. Adjusted models estimated the relative hazard of exacerbation associated with elevated TyG, accounting for known exacerbation risk factors. RESULTS A total of 108,219 patients fulfilled study criteria. Over 286,343 person-years of follow-up, 21,467 exacerbations were identified, corresponding to a crude rate of 7.5 exacerbations/100 person-years. In exploratory analysis, we found a threshold effect at a TyG of 8.3, which was defined as elevated. In a fully adjusted model, patients with an elevated TyG had a 6% (95% CI, 3%-10%) higher hazard for severe asthma exacerbation, independent of eosinophil count, smoking, obesity, and asthma treatment intensity. CONCLUSIONS Elevated TyG is a risk factor for severe asthma exacerbation independent of conventional predictors. Elevated TyG may identify patients who warrant more intensive asthma treatment and who are candidates for future clinical trials of metabolic intervention for purposes of improving asthma morbidity.
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Affiliation(s)
- Kristen A Staggers
- Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey VA Medical Center, Houston, Texas; Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas
| | - Charles Minard
- Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey VA Medical Center, Houston, Texas; Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas
| | - Michelle Byers
- Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, Texas
| | - Drew A Helmer
- Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey VA Medical Center, Houston, Texas; Section of Health Services Research, Baylor College of Medicine, Houston, Texas
| | - Tianshi David Wu
- Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey VA Medical Center, Houston, Texas; Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, Texas.
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39
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Foer D, Strasser ZH, Cui J, Cahill KN, Boyce JA, Murphy SN, Karlson EW. Association of GLP-1 Receptor Agonists with Chronic Obstructive Pulmonary Disease Exacerbations among Patients with Type 2 Diabetes. Am J Respir Crit Care Med 2023; 208:1088-1100. [PMID: 37647574 PMCID: PMC10867930 DOI: 10.1164/rccm.202303-0491oc] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 08/30/2023] [Indexed: 09/01/2023] Open
Abstract
Rationale: Patients with chronic obstructive pulmonary disease (COPD) and type 2 diabetes (T2D) have worse clinical outcomes compared with patients without metabolic dysregulation. GLP-1 (glucagon-like peptide 1) receptor agonists (GLP-1RAs) reduce asthma exacerbation risk and improve FVC in patients with COPD. Objectives: To determine whether GLP-1RA use is associated with reduced COPD exacerbation rates, and severe and moderate exacerbation risk, compared with other T2D therapies. Methods: A retrospective, observational, electronic health records-based study was conducted using an active comparator, new-user design of 1,642 patients with COPD in a U.S. health system from 2012 to 2022. The COPD cohort was identified using a previously validated machine learning algorithm that includes a natural language processing tool. Exposures were defined as prescriptions for GLP-1RAs (reference group), DPP-4 (dipeptidyl peptidase 4) inhibitors (DPP-4is), SGLT2 (sodium-glucose cotransporter 2) inhibitors, or sulfonylureas. Measurements and Main Results: Unadjusted COPD exacerbation counts were lower in GLP-1RA users. Adjusted exacerbation rates were significantly higher in DPP-4i (incidence rate ratio, 1.48 [95% confidence interval, 1.08-2.04]; P = 0.02) and sulfonylurea (incidence rate ratio, 2.09 [95% confidence interval, 1.62-2.69]; P < 0.0001) users compared with GLP-1RA users. GLP-1RA use was also associated with significantly reduced risk of severe exacerbations compared with DPP-4i and sulfonylurea use, and of moderate exacerbations compared with sulfonylurea use. After adjustment for clinical covariates, moderate exacerbation risk was also lower in GLP-1RA users compared with DPP-4i users. No statistically significant difference in exacerbation outcomes was seen between GLP-1RA and SGLT2 inhibitor users. Conclusions: Prospective studies of COPD exacerbations in patients with comorbid T2D are warranted. Additional research may elucidate the mechanisms underlying these observed associations with T2D medications.
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Affiliation(s)
- Dinah Foer
- Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Zachary H. Strasser
- Harvard Medical School, Boston, Massachusetts
- MGH Laboratory of Computer Science and
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Jing Cui
- Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Katherine N. Cahill
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; and
| | - Joshua A. Boyce
- Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Shawn N. Murphy
- Harvard Medical School, Boston, Massachusetts
- MGH Laboratory of Computer Science and
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Elizabeth W. Karlson
- Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
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40
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Miravitlles M. Improving Outcomes of Chronic Obstructive Pulmonary Disease through the Treatment of Comorbidities: One Step Beyond. Am J Respir Crit Care Med 2023; 208:1017-1019. [PMID: 37672750 PMCID: PMC10867943 DOI: 10.1164/rccm.202309-1546ed] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 09/06/2023] [Indexed: 09/08/2023] Open
Affiliation(s)
- Marc Miravitlles
- Pneumology Department Hospital Universitari Vall d'Hebron / Vall d'Hebron Institut de Recerca (VHIR) Barcelona, Spain
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41
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Chiarella SE, Barnes PJ. Endogenous inhibitory mechanisms in asthma. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. GLOBAL 2023; 2:100135. [PMID: 37781649 PMCID: PMC10509980 DOI: 10.1016/j.jacig.2023.100135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 05/16/2023] [Accepted: 05/21/2023] [Indexed: 10/03/2023]
Abstract
Endogenous inhibitory mechanisms promote resolution of inflammation, enhance tissue repair and integrity, and promote homeostasis in the lung. These mechanisms include steroid hormones, regulatory T cells, IL-10, prostaglandin E2, prostaglandin I2, lipoxins, resolvins, protectins, maresins, glucagon-like peptide-1 receptor, adrenomedullin, nitric oxide, and carbon monoxide. Here we review the most recent literature regarding these endogenous inhibitory mechanisms in asthma, which remain a promising target for the prevention and treatment of asthma.
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Shailesh H, Bhat AA, Janahi IA. Obesity-Associated Non-T2 Mechanisms in Obese Asthmatic Individuals. Biomedicines 2023; 11:2797. [PMID: 37893170 PMCID: PMC10603840 DOI: 10.3390/biomedicines11102797] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 09/30/2023] [Accepted: 10/06/2023] [Indexed: 10/29/2023] Open
Abstract
Obesity and asthma are two common health issues that have shown increased prevalence in recent years and have become a significant socioeconomic burden worldwide. Obesity increases asthma incidence and severity. Obese asthmatic individuals often experience increased exacerbation rates, enhanced airway remodeling, and reduced response to standard corticosteroid therapy. Recent studies indicate that obesity-associated non-T2 factors such as mechanical stress, hyperinsulinemia, systemic inflammation, adipose tissue mediators, metabolic dysregulation, microbiome dysbiosis, and high-fat-diet are responsible for increased asthma symptoms and reduced therapeutic response in obese asthmatic individuals. This manuscript reviews the recent findings highlighting the role of obesity-associated factors that contribute to airway hyper-reactivity, airway inflammation and remodeling, and immune cell dysfunction, consequently contributing to worsening asthma symptoms. Furthermore, the review also discusses the possible future therapies that might play a role in reducing asthma symptoms by diminishing the impact of obesity-associated non-T2 factors.
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Affiliation(s)
| | - Ajaz A. Bhat
- Precision Medicine in Diabetes, Obesity and Cancer Research Program, Department of Human Genetics, Sidra Medicine, Doha 26999, Qatar;
| | - Ibrahim A. Janahi
- Department of Medical Education, Sidra Medicine, Doha 26999, Qatar;
- Department of Pediatric Medicine, Sidra Medicine, Doha 26999, Qatar
- Department of Pediatrics, Weill Cornell Medicine, Doha 24144, Qatar
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43
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Baer B, Putz ND, Riedmann K, Gonski S, Lin J, Ware LB, Toki S, Peebles RS, Cahill KN, Bastarache JA. Liraglutide pretreatment attenuates sepsis-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 2023; 325:L368-L384. [PMID: 37489855 PMCID: PMC10639010 DOI: 10.1152/ajplung.00041.2023] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 06/28/2023] [Accepted: 07/23/2023] [Indexed: 07/26/2023] Open
Abstract
There are no effective targeted therapies to treat acute respiratory distress syndrome (ARDS). Recently, the commonly used diabetes and obesity medications, glucagon-like peptide-1 (GLP-1) receptor agonists, have been found to have anti-inflammatory properties. We, therefore, hypothesized that liraglutide pretreatment would attenuate murine sepsis-induced acute lung injury (ALI). We used a two-hit model of ALI (sepsis+hyperoxia). Sepsis was induced by intraperitoneal injection of cecal slurry (CS; 2.4 mg/g) or 5% dextrose (control) followed by hyperoxia [HO; fraction of inspired oxygen ([Formula: see text]) = 0.95] or room air (control; [Formula: see text] = 0.21). Mice were pretreated twice daily with subcutaneous injections of liraglutide (0.1 mg/kg) or saline for 3 days before initiation of CS+HO. At 24-h post CS+HO, physiological dysfunction was measured by weight loss, severity of illness score, and survival. Animals were euthanized, and bronchoalveolar lavage (BAL) fluid, lung, and spleen tissues were collected. Bacterial burden was assessed in the lung and spleen. Lung inflammation was assessed by BAL inflammatory cell numbers, cytokine concentrations, lung tissue myeloperoxidase activity, and cytokine expression. Disruption of the alveolar-capillary barrier was measured by lung wet-to-dry weight ratios, BAL protein, and epithelial injury markers (receptor for advanced glycation end products and sulfated glycosaminoglycans). Histological evidence of lung injury was quantified using a five-point score with four parameters: inflammation, edema, septal thickening, and red blood cells (RBCs) in the alveolar space. Compared with saline treatment, liraglutide improved sepsis-induced physiological dysfunction and reduced lung inflammation, alveolar-capillary barrier disruption, and lung injury. GLP-1 receptor activation may hold promise as a novel treatment strategy for sepsis-induced ARDS. Additional studies are needed to better elucidate its mechanism of action.NEW & NOTEWORTHY In this study, pretreatment with liraglutide, a commonly used diabetes medication and glucagon-like peptide-1 (GLP-1) receptor agonist, attenuated sepsis-induced acute lung injury in a two-hit mouse model (sepsis + hyperoxia). Septic mice who received the drug were less sick, lived longer, and displayed reduced lung inflammation, edema, and injury. These therapeutic effects were not dependent on weight loss. GLP-1 receptor activation may hold promise as a new treatment strategy for sepsis-induced acute respiratory distress syndrome.
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Affiliation(s)
- Brandon Baer
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Nathan D Putz
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Kyle Riedmann
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Samantha Gonski
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Jason Lin
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Lorraine B Ware
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Shinji Toki
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - R Stokes Peebles
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- United States Department of Veterans Affairs, Nashville, Tennessee, United States
| | - Katherine N Cahill
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Julie A Bastarache
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
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Khan J, Moran B, McCarthy C, Butler MW, Franciosi AN. Management of comorbidities in difficult and severe asthma. Breathe (Sheff) 2023; 19:230133. [PMID: 38020342 PMCID: PMC10644109 DOI: 10.1183/20734735.0133-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 10/03/2023] [Indexed: 12/01/2023] Open
Abstract
Difficult-to-treat and severe asthma are challenging clinical entities. In the face of suboptimal asthma control, the temptation for clinicians is to reflexively escalate asthma-directed therapy, including increasing exposure to corticosteroids and commencement of costly but potent biologic therapies. However, asthma control is objectively and subjectively assessed based on measurable parameters (such as exacerbations or variability in pulmonary physiology), symptoms and patient histories. Crucially, these features can be confounded by common untreated comorbidities, affecting clinicians' assessment of asthma treatment efficacy.
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Affiliation(s)
- Jehangir Khan
- University College Dublin, Dublin, Ireland
- St Vincent's University Hospital, Dublin, Ireland
- Shared first authorship
| | - Barry Moran
- St Vincent's University Hospital, Dublin, Ireland
- Shared first authorship
| | - Cormac McCarthy
- University College Dublin, Dublin, Ireland
- St Vincent's University Hospital, Dublin, Ireland
| | - Marcus W. Butler
- University College Dublin, Dublin, Ireland
- St Vincent's University Hospital, Dublin, Ireland
- Shared senior authorship
| | - Alessandro N. Franciosi
- University College Dublin, Dublin, Ireland
- St Vincent's University Hospital, Dublin, Ireland
- Shared senior authorship
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45
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Hudler AC, Díaz IRR, Sharma S, Holguin F. Gaps and Future Directions in Clinical Research on Obesity-Related Asthma. Pulm Ther 2023; 9:309-327. [PMID: 37330948 PMCID: PMC10447703 DOI: 10.1007/s41030-023-00230-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 06/05/2023] [Indexed: 06/20/2023] Open
Abstract
Obesity is a major comorbidity for the development and worsening of asthma. It is associated with increased disease incidence, reduced response to inhaled and systemic steroids, increased asthma exacerbations, and poor disease control. Over the past two decades, we have learned that there are clinical asthma phenotypes associated with obesity, which have unique immune, inflammatory, and metabolic disease mechanisms. The objectives of this review are to provide a brief overview of the associations and gaps between these chronic inflammatory diseases and the role that traditional therapies have on treating patients with obesity-related asthma, and to describe new clinical research of therapeutic developments targeting mechanisms that are more specific to this patient population.
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Affiliation(s)
- Andi C Hudler
- Division of Pulmonary Sciences and Critical Care, University of Colorado, Aurora Colorado, USA
| | | | - Sunita Sharma
- Division of Pulmonary Sciences and Critical Care, University of Colorado, Aurora Colorado, USA
| | - Fernando Holguin
- Division of Pulmonary Sciences and Critical Care, University of Colorado, Aurora Colorado, USA.
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46
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Reyes Noriega N, Del-Río-Navarro BE, Berber A, de Jesús Romero Tapia S, Molina Díaz DJM. Effect of Obesity on Lung Function in the Pediatric and Adult Populations with Asthma: A Review. J Clin Med 2023; 12:5385. [PMID: 37629427 PMCID: PMC10456025 DOI: 10.3390/jcm12165385] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 08/16/2023] [Accepted: 08/17/2023] [Indexed: 08/27/2023] Open
Abstract
Obesity and asthma are major global health concerns, particularly in industrialized nations. Obesity has been shown to have detrimental effects on the respiratory system and lung function owing to metabolic issues and immunological consequences. Research has indicated that obese patients with asthma (atopic or T2-high and non-atopic or T2-low) have diminished lung function in terms of functional residual capacity (FRC), residual volume (RV), expiratory reserve volume (ERV), the FEV1/FVC ratio, and FEF 25-75% due to mechanical fat loading on the diaphragm and central adiposity when compared to non-obese asthmatic patients. Therefore, it is plausible that changes in lung function are the result of a combination of mechanical (fat loading on the diaphragm, central adiposity, bronchial hyper-reactivity, and an increase in cholinergic tone), environmental (diet and exercise), and inflammatory factors (local and systemic), which can lead to the obesity-related asthma phenotype characterized by severe asthma symptoms, poor response to corticosteroid treatment, loss of lung function, and poor quality of life from an early age.
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Affiliation(s)
- Nayely Reyes Noriega
- Allergy and Immunology Pediatric Department, Hospital Infantil de México Federico Gómez, Ciudad de México 06720, Mexico; (N.R.N.); (A.B.)
| | - Blanca E. Del-Río-Navarro
- Allergy and Immunology Pediatric Department, Hospital Infantil de México Federico Gómez, Ciudad de México 06720, Mexico; (N.R.N.); (A.B.)
| | - Arturo Berber
- Allergy and Immunology Pediatric Department, Hospital Infantil de México Federico Gómez, Ciudad de México 06720, Mexico; (N.R.N.); (A.B.)
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47
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Yu M, Wang R, Pei L, Zhang X, Wei J, Wen Y, Liu H, Ye H, Wang J, Wang L. The relationship between the use of GLP-1 receptor agonists and the incidence of respiratory illness: a meta-analysis of randomized controlled trials. Diabetol Metab Syndr 2023; 15:164. [PMID: 37491292 PMCID: PMC10369734 DOI: 10.1186/s13098-023-01118-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 06/19/2023] [Indexed: 07/27/2023] Open
Abstract
AIM We aimed to assess the association between the use of Glucagon-like peptide-1 receptor agonists and the risk of 12 respiratory diseases in patients with type 2 diabetes, obesity, or overweight. METHOD The PubMed (MEDLINE), EMBASE, Cochrane Library, and ClinicalTrials.gov databases were searched from the establishment of the database to December 24, 2022. Dichotomous outcomes were analyzed using RR and 95% CI calculated from fixed-effects models. RESULTS Twenty-eight RCTs were ultimately included for analysis, involving a total of 77,485 participants. Compared to controls, patients with GLP-1RAs have a 14% lower risk of respiratory disease (RR 0.86, 95% CI 0.81-0.93 p < 0.0001), with Semaglutid (RR 0.82, 95% CI 0.68-0.97, p = 0.02), Liraglutide (RR 0.86. 95% CI 0.75-0.98, p = 0.03), Dulaglutide (RR 0.82, 95% CI 0.70-0.96, p = 0.02), Albiglutide (RR 0.93,95% CI 0.79-1.10, p = 0.40), Exenatide (RR 0.93, 95% CI 0.74-1.18, p = 0.55), Lixisenatide (RR 0.83, 95% CI 0.62-1.12, p = 0.22), and Efpeglenatide (RR 0.76, 95% CI 0.46-1.24, p = 0.27). Semaglutide, Liraglutide and Dulaglutide reduce the risk of respiratory diseases by 18%, 14% and 18%, respectively.Trial duration, control type, and indication were not associated with the impact of GLP-1 receptor agonists on overall respiratory disease. Among secondary outcomes, the risk of Pulmonary edema (RR 0.66, 95% CI 0.44-0.98, p = 0.04), and Bronchitis (RR 0.86, 95% CI 0.74-1.00, p = 0.04) was reduced. CONCLUSION In conclusion, GLP-1RAs were linked to a lower risk of overall respiratory diseases, especially Pulmonary edema and Bronchitis. In the future, physicians should pay attention to the relationship between GLP-1 RA and the risk of respiratory diseases and evaluate the efficacy of GLP-1RAs in the primary and secondary prevention of respiratory diseases. Trial registration CRD42023396138.
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Affiliation(s)
- Meixin Yu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Jinan University, No. 613, Huang pu Avenue West, Guangzhou, Guangdong, China
| | - Ruxin Wang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Jinan University, No. 613, Huang pu Avenue West, Guangzhou, Guangdong, China
| | - Ling Pei
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Jinan University, No. 613, Huang pu Avenue West, Guangzhou, Guangdong, China
| | - Xiaofang Zhang
- Clinical Experimental Center, The First Affiliated Hospital of Jinan University, No. 613, Huang pu Avenue West, Guangzhou, Guangdong, China
| | - Jinjing Wei
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Jinan University, No. 613, Huang pu Avenue West, Guangzhou, Guangdong, China
| | - Yun Wen
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Jinan University, No. 613, Huang pu Avenue West, Guangzhou, Guangdong, China
| | - Han Liu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Jinan University, No. 613, Huang pu Avenue West, Guangzhou, Guangdong, China
| | - Haowen Ye
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Jinan University, No. 613, Huang pu Avenue West, Guangzhou, Guangdong, China
| | - Jinghao Wang
- Department of Pharmacy, The First Affiliated Hospital of Jinan University, No. 613, Huang pu Avenue West, Guangzhou, Guangdong, China.
| | - Lihong Wang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Jinan University, No. 613, Huang pu Avenue West, Guangzhou, Guangdong, China.
- The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, The First Affiliated Hospital, Jinan University, Guangzhou, China.
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48
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Cazzola M, Rogliani P, Ora J, Calzetta L, Matera MG. Cardiovascular diseases or type 2 diabetes mellitus and chronic airway diseases: mutual pharmacological interferences. Ther Adv Chronic Dis 2023; 14:20406223231171556. [PMID: 37284143 PMCID: PMC10240559 DOI: 10.1177/20406223231171556] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 04/06/2023] [Indexed: 06/08/2023] Open
Abstract
Chronic airway diseases (CAD), mainly asthma and chronic obstructive pulmonary disease (COPD), are frequently associated with different comorbidities. Among them, cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) pose problems for the simultaneous treatment of CAD and comorbidity. Indeed, there is evidence that some drugs used to treat CAD negatively affect comorbidity, and, conversely, some drugs used to treat comorbidity may aggravate CAD. However, there is also growing evidence of some beneficial effects of CAD drugs on comorbidities and, conversely, of the ability of some of those used to treat comorbidity to reduce the severity of lung disease. In this narrative review, we first describe the potential cardiovascular risks and benefits for patients using drugs to treat CAD and the potential lung risks and benefits for patients using drugs to treat CVD. Then, we illustrate the possible negative and positive effects on T2DM of drugs used to treat CAD and the potential negative and positive impact on CAD of drugs used to treat T2DM. The frequency with which CAD and CVD or T2DM are associated requires not only considering the effect that drugs used for one disease condition may have on the other but also providing an opportunity to develop therapies that simultaneously favorably impact both diseases.
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Affiliation(s)
- Mario Cazzola
- Chair of Respiratory Medicine, Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Paola Rogliani
- Chair of Respiratory Medicine, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
- Division of Respiratory Medicine, University Hospital Tor Vergata, Rome, Italy
| | - Josuel Ora
- Division of Respiratory Medicine, University Hospital Tor Vergata, Rome, Italy
| | - Luigino Calzetta
- Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Maria Gabriella Matera
- Chair of Pharmacology, Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
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49
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Matsuyama T, Machida K, Mizuno K, Matsuyama H, Dotake Y, Shinmura M, Takagi K, Inoue H. The Functional Role of Group 2 Innate Lymphoid Cells in Asthma. Biomolecules 2023; 13:893. [PMID: 37371472 DOI: 10.3390/biom13060893] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 05/24/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
Asthma is a heterogeneous disease characterized by chronic airway inflammation. Group 2 innate lymphoid cells (ILC2) play an important role in the pathogenesis of asthma. ILC2s lack antigen-specific receptors and respond to epithelial-derived cytokines, leading to the induction of airway eosinophilic inflammation in an antigen-independent manner. Additionally, ILC2s might be involved in the mechanism of steroid resistance. Numerous studies in both mice and humans have shown that ILC2s induce airway inflammation through inflammatory signals, including cytokines and other mediators derived from immune or non-immune cells. ILC2s and T helper type 2 (Th2) cells collaborate through direct and indirect interactions to organize type 2 immune responses. Interestingly, the frequencies or numbers of ILC2 are increased in the blood and bronchoalveolar lavage fluid of asthma patients, and the numbers of ILC2s in the blood and sputum of severe asthmatics are significantly larger than those of mild asthmatics. These findings may contribute to the regulation of the immune response in asthma. This review article highlights our current understanding of the functional role of ILC2s in asthma.
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Affiliation(s)
- Takahiro Matsuyama
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Kentaro Machida
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Keiko Mizuno
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Hiromi Matsuyama
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Yoichi Dotake
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Masahiro Shinmura
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Koichi Takagi
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Hiromasa Inoue
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
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50
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Kim HR, Ingram JL, Que LG. Effects of Oxidative Stress on Airway Epithelium Permeability in Asthma and Potential Implications for Patients with Comorbid Obesity. J Asthma Allergy 2023; 16:481-499. [PMID: 37181453 PMCID: PMC10171222 DOI: 10.2147/jaa.s402340] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 03/15/2023] [Indexed: 05/16/2023] Open
Abstract
20 million adults and 4.2 million children in the United States have asthma, a disease resulting in inflammation and airway obstruction in response to various factors, including allergens and pollutants and nonallergic triggers. Obesity, another highly prevalent disease in the US, is a major risk factor for asthma and a significant cause of oxidative stress throughout the body. People with asthma and comorbid obesity are susceptible to developing severe asthma that cannot be sufficiently controlled with current treatments. More research is needed to understand how asthma pathobiology is affected when the patient has comorbid obesity. Because the airway epithelium directly interacts with the outside environment and interacts closely with the immune system, understanding how the airway epithelium of patients with asthma and comorbid obesity is altered compared to that of lean asthma patients will be crucial for developing more effective treatments. In this review, we discuss how oxidative stress plays a role in two chronic inflammatory diseases, obesity and asthma, and propose a mechanism for how these conditions may compromise the airway epithelium.
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Affiliation(s)
- Haein R Kim
- Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Durham, NC, USA
| | - Jennifer L Ingram
- Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Durham, NC, USA
| | - Loretta G Que
- Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Durham, NC, USA
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