Andrew Krentz, Lisa Fournier, Thomas Castiglione, Vasa Curcin, Camil Hamdane, Tianyi Liu, André Jaun
{"title":"Optimising the therapeutic response of statins using real-world evidence and machine learning: Personalised precision dosing recommends lower statin doses for some patients.","authors":"Andrew Krentz, Lisa Fournier, Thomas Castiglione, Vasa Curcin, Camil Hamdane, Tianyi Liu, André Jaun","doi":"10.1111/dom.16029","DOIUrl":"https://doi.org/10.1111/dom.16029","url":null,"abstract":"","PeriodicalId":158,"journal":{"name":"Diabetes, Obesity & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tamara Y Milder, Jialing Lin, Sallie-Anne Pearson, Juliana de Oliveira Costa, Brendon L Neuen, Carol Pollock, Min Jun, Jerry R Greenfield, Richard O Day, Sophie L Stocker, David Brieger, Michael O Falster
{"title":"Discontinuation of SGLT2i in people with type 2 diabetes following hospitalisation for heart failure: A cause for concern?","authors":"Tamara Y Milder, Jialing Lin, Sallie-Anne Pearson, Juliana de Oliveira Costa, Brendon L Neuen, Carol Pollock, Min Jun, Jerry R Greenfield, Richard O Day, Sophie L Stocker, David Brieger, Michael O Falster","doi":"10.1111/dom.16061","DOIUrl":"https://doi.org/10.1111/dom.16061","url":null,"abstract":"","PeriodicalId":158,"journal":{"name":"Diabetes, Obesity & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuxin Fan, Li Ding, Wei Li, Wei Li, Longhao Sun, Xin Li, Lina Chang, Qing He, Gang Hu, Bo Wang, Ming Liu
{"title":"The association between android-to-gynoid lean mass ratio and all-cause and specific-cause mortality in US adults: A prospective study.","authors":"Yuxin Fan, Li Ding, Wei Li, Wei Li, Longhao Sun, Xin Li, Lina Chang, Qing He, Gang Hu, Bo Wang, Ming Liu","doi":"10.1111/dom.16051","DOIUrl":"https://doi.org/10.1111/dom.16051","url":null,"abstract":"<p><strong>Objective: </strong>The associations of lean mass distribution with mortality risk are not fully elucidated. We aimed to evaluate the effects of a new lean mass distribution indicator-android/gynoid lean mass ratio (AGLR) evaluated by dual-energy x-ray absorptiometry (DXA) on the risk of all-cause and specific-cause mortality in a NHANES cohort.</p><p><strong>Methods: </strong>This was a population-based cohort study, which included 18 542 subjects aged 20 years and older from the US National Health and Nutrition Examination Survey (US NHANES, 2003-2006 and 2011-2018). The primary outcomes of our study were all-cause mortality, cardiovascular (CVD) mortality and cancer mortality, which were obtained from the linkage to registries. Cox proportional hazard regression models were used to investigate the association between lean mass distribution and mortality risk among the US NHANES general population. Restricted cubic spline nested in Cox regression was also used to test whether there was a non-linear association of AGLR as a continuous variable with the risk of mortality.</p><p><strong>Results: </strong>During a median follow-up of 6.9 years, 1412 participants died, of whom 435 were due to CVD and 340 were due to cancer. The multivariable-adjusted (Model 4) hazard ratios (HRs) for each SD increase in AGLR were 1.53 (95% confidence interval [CI] 1.40-1.67) for all-cause mortality, 1.56 (95% CI 1.30-1.87) for cancer mortality and 1.64 (95% CI 1.47-1.84) for CVD mortality. The associations were robust in sensitivity analyses and present in most subgroups.</p><p><strong>Conclusions: </strong>AGLR evaluated by DXA was associated with a higher risk of all-cause and specific-cause mortality among the general population from the US NHANES cohort.</p>","PeriodicalId":158,"journal":{"name":"Diabetes, Obesity & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nadan Gregorič, Jaka Šikonja, Andrej Janež, Mojca Jensterle
{"title":"Semaglutide improved sperm morphology in obese men with type 2 diabetes mellitus and functional hypogonadism.","authors":"Nadan Gregorič, Jaka Šikonja, Andrej Janež, Mojca Jensterle","doi":"10.1111/dom.16042","DOIUrl":"https://doi.org/10.1111/dom.16042","url":null,"abstract":"<p><strong>Aims: </strong>To compare the effects of semaglutide and testosterone replacement therapy (TRT) on semen quality and parameters of functional hypogonadism (FH) in men with type 2 diabetes mellitus and obesity.</p><p><strong>Materials and methods: </strong>We designed a randomised open-label trial in 25 men with type 2 diabetes (aged 50 [46-60] years, BMI 35.9 [32.8-38.7] kg/m<sup>2</sup>) and FH randomised to semaglutide (SEMA) 1 mg/week or intramuscular testosterone undecanoate (TRT) 1000 mg/10-12 weeks for 24 weeks. Semen analysis and parameters of FH were measured at baseline and after 24 weeks of treatment. Participants completed questionnaires of the International Index of Erectile Function-15 (IIEF-15) and the Aging Symptoms in Men (AMS).</p><p><strong>Results: </strong>The quality of baseline sperm parameters of our study cohort was poor, below the 5th percentile of reference values. In the SEMA group, there was a significant increase in morphologically normal sperm from baseline to the end of the study (2% [2; 3.5] vs. 4% [2; 5.5]; p = 0.012), whereas sperm concentration and total number decreased significantly in the TRT group. Compared to TRT, the SEMA group had a significantly higher number of morphologically normal sperm, sperm concentration and total number. Both groups experienced an increase in total testosterone and improvement in the AMS score, whereas the IIEF-15 score significantly improved only in the TRT group.</p><p><strong>Conclusion: </strong>Semaglutide markedly improved sperm morphology, total testosterone levels and symptoms of hypogonadism. These findings highlight semaglutide's potential as a therapeutic approach for men with obesity-related FH who desire fertility.</p><p><strong>Clinical trial registration number: </strong>NCT06489457, www.</p><p><strong>Clinicaltrials: </strong>gov.</p>","PeriodicalId":158,"journal":{"name":"Diabetes, Obesity & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Effect of smoking behaviour and related blood DNA methylation on visceral adipose tissues.","authors":"Zheng-Qi Song, Yi-Qi Chen, Chen-Hao Xuan, Tong-Tong Ni, Yu-Peng Xu, Xin-Yu Lu, Fang-Ran Chen, Yi-He Chen","doi":"10.1111/dom.16054","DOIUrl":"https://doi.org/10.1111/dom.16054","url":null,"abstract":"<p><strong>Background: </strong>Recent studies have found that tobacco smoking is associated with fat distribution, yet limited research has focused on its relationship with visceral adipose tissues (VATs). Furthermore, the cellular and molecular mechanisms underlying the interactions among smoking, epigenetic modifications, and VATs remain unknown.</p><p><strong>Method: </strong>We performed univariable Mendelian randomization (MR) analysis to elucidate the causal relationship between smoking behaviours and VATs, including epicardial and pericardial adipose tissue (EPAT), liver fat (LF), and pancreas fat (PF). This approach could minimize the impact of confounders and reverse causality through utilizing genetic variants to proxy the smoking behaviours. Mediation MR analysis were conducted to detect potential mediators. Additionally, summary-data-based MR (SMR) and colocalization analysis were performed to explore the association between smoking-related DNA methylation and VATs.</p><p><strong>Results: </strong>We identified a convincing association between smoking initiation and increased EPAT (beta: 0.15, 95% CI: 0.06, 0.23, p = 7.01 × 10<sup>-4</sup>) and LF area (beta: 0.15, 95% CI = 0.05, 0.24, p = 2.85 × 10<sup>-3</sup>), respectively. Further mediation analysis suggested type 2 diabetes mellitus (T2DM) as a potential mediator within these co-relationships. When further exploring the associations between the smoking related DNA methylation and VATs, we identified that WT1 methylation at cg05222924 was significantly linked to a lower EPAT area (beta: -0.12, 95% CI: -0.16, -0.06, P<sub>FDR</sub> = 2.24 × 10<sup>-3</sup>), while GPX1 methylation at cg18642234 facilitated the deposition of EPAT (beta: 0.15, 95% CI: 0.10, 0.20, P<sub>FDR</sub> = 1.66 × 10<sup>-4</sup>).</p><p><strong>Conclusion: </strong>Our study uncovered a significant causal effect between smoking and VATs, with T2DM identified as a potential mediator. Further investigation into DNA methylation yielded novel insights into the pathogenic role of smoking on EPAT.</p>","PeriodicalId":158,"journal":{"name":"Diabetes, Obesity & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The cellular and molecular mechanisms mediating the protective effects of sodium-glucose linked transporter 2 inhibitors against metabolic dysfunction-associated fatty liver disease.","authors":"Na Ao, Jian Du, Shi Jin, Linna Suo, Jing Yang","doi":"10.1111/dom.16043","DOIUrl":"https://doi.org/10.1111/dom.16043","url":null,"abstract":"<p><p>Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a common, highly heterogeneous condition that affects about a quarter of the world's population, with no approved drug therapy. Current evidence from preclinical research and a number of small clinical trials indicates that SGLT2 inhibitors could also be effective for MAFLD. MAFLD is associated with a higher risk of chronic liver disease and multiple extrahepatic events, especially cardiovascular disease (CVD) and chronic kidney disease (CKD). MAFLD is considered a more appropriate terminology than NAFLD because it captures the complex bidirectional interplay between fatty liver and metabolic dysfunctions associated with disease progression, such as obesity and type 2 diabetes mellitus (T2DM). SGLT2 inhibitors are antidiabetic drugs that block glucose reabsorption in the kidney proximal tubule. In this article, we reviewed current clinical evidence supporting the potential use of SGLT2 inhibitors as a drug therapy for MAFLD and discussed the possible cellular and molecular mechanisms involved. We also reviewed the clinical benefits of SGLT2 inhibitors against MAFLD-related comorbidities, especially CVD, CKD and cardiovascular-kidney-metabolic syndrome (CKM). The broad beneficial effects of SGLT2 inhibitors support their use, likely in combination with other drugs, as a therapy for MAFLD.</p>","PeriodicalId":158,"journal":{"name":"Diabetes, Obesity & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Johannes David Smeijer, Maria F Gomez, Peter Rossing, Hiddo J L Heerspink
{"title":"The effect of the endothelin receptor antagonist atrasentan on insulin resistance in phenotypic clusters of patients with type 2 diabetes and chronic kidney disease.","authors":"Johannes David Smeijer, Maria F Gomez, Peter Rossing, Hiddo J L Heerspink","doi":"10.1111/dom.16041","DOIUrl":"https://doi.org/10.1111/dom.16041","url":null,"abstract":"<p><strong>Aims: </strong>Type 2 diabetes (T2D) patients with a clinical phenotype characterized by a high degree of insulin resistance are at increased risk of chronic kidney disease (CKD). We previously demonstrated that the endothelin receptor antagonist (ERA) atrasentan reduced insulin resistance in T2D. In this study, we compared the effect of atrasentan on insulin resistance across different phenotypic clusters of patients with T2D.</p><p><strong>Materials and methods: </strong>We performed a post hoc analysis of the SONAR trial, a randomized, placebo-controlled trial of the ERA atrasentan in patients with T2D and CKD. Patients were stratified into four previously identified phenotypic clusters: severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD) and mild age-related diabetes (MARD). Changes in insulin resistance, assessed by HOMA-IR, were compared between the phenotypic clusters using a mixed effects model.</p><p><strong>Results: </strong>In total, 931 patients were included in the analysis. In the overall population, atrasentan compared to placebo reduced HOMA-IR by 12.9% [95%CI 3.5,21.4]. This effect of atrasentan was more pronounced in clusters characterized by insulin resistance or deficiency: (SIRD cluster 26.2% [95% CI 3.8,43.3] and SIDD cluster 18.5% [95%CI -3.8,35.9]), although the latter did not reach statistical significance. The effect of atrasentan compared to placebo was less pronounced in the other two clusters (MARD 12.2% [95% CI -1.7,24.12] and MOD -5.3% [95% CI -28.9,13.9]).</p><p><strong>Conclusions: </strong>Atrasentan significantly improved insulin sensitivity in patients with T2D and CKD, especially in those characterized by high insulin resistance (SIRD cluster). Further studies are warranted to investigate the long-term clinical outcomes of atrasentan treatment in these distinct phenotypic clusters.</p>","PeriodicalId":158,"journal":{"name":"Diabetes, Obesity & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Baoting He, Hugh Simon Lam, Xiu Qiu, Songying Shen, Shan Luo, Eric A W Slob, Shiu Lun Au Yeung
{"title":"Association and mediation pathways of maternal hyperglycaemia and liability to gestational diabetes with neonatal outcomes: A two-sample Mendelian randomization study.","authors":"Baoting He, Hugh Simon Lam, Xiu Qiu, Songying Shen, Shan Luo, Eric A W Slob, Shiu Lun Au Yeung","doi":"10.1111/dom.16045","DOIUrl":"https://doi.org/10.1111/dom.16045","url":null,"abstract":"<p><strong>Aims: </strong>Maternal hyperglycemia is linked to adverse neonatal outcomes. However, current evidence was insufficient for mechanistic pathways. We aim to use two-sample Mendelian randomization (MR) to obtain a comprehensive understanding of the causal association and mediation pathways.</p><p><strong>Materials and methods: </strong>Genetic variants of fasting glucose (FG), insulin sensitivity index (ISI), glycated haemoglobin (HbA1c), gestational diabetes mellitus (GDM) and type 2 diabetes (T2D) were used as instruments (N = 50 404-898 130). The associations with offspring birthweight, gestational duration, spontaneous preterm and post-term birth were assessed by the inverse-variance weighted method, using summary statistics of European genome-wide association studies (N = 131 279-210 248). Sensitivity analyses, including multivariable MR removing pleiotropic effect from maternal body mass index (BMI), assessed the robustness. Mediation via placental weight and maternal hypertension were assessed via a two-step MR design.</p><p><strong>Results: </strong>FG (0.46 SD per mmol/L, 95% confidence interval [95% CI]: 0.32, 0.61) and GDM liability (0.18 SD per log odds, 95% CI: 0.08, 0.18) were positively associated with birthweight, with consistent findings for HbA1c, T2D liability and ISI. These associations were mediated by placental weight (proportion mediated: 32.8% to 77.7%). Higher HbA1c, GDM and T2D liability were associated with preterm birth (odds ratios for GDM: 1.07, 95% CI: 1.01, 1.14) and shorter gestational duration, whilst the association for T2D attenuated after adjusted for maternal BMI and gestational hypertension.</p><p><strong>Conclusion: </strong>Maternal hyperglycemia is associated with higher birthweight (possibly indicating macrosomia), mediated via increased placental growth. GDM and T2D liability are related to preterm birth, whilst the association for T2D liability is driven by maternal adiposity.</p>","PeriodicalId":158,"journal":{"name":"Diabetes, Obesity & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chi-Ho Lee, David Tak-Wai Lui, Lung-Yi Mak, Carol Ho-Yi Fong, Kylie Sze-Wing Chan, Jimmy Ho-Cheung Mak, Chloe Yu-Yan Cheung, Wing-Sun Chow, Yu-Cho Woo, Man-Fung Yuen, Wai-Kay Seto, Karen Siu-Ling Lam
{"title":"Benefits of combining SGLT2 inhibitors and pioglitazone on risk of MASH in type 2 diabetes-A real-world study.","authors":"Chi-Ho Lee, David Tak-Wai Lui, Lung-Yi Mak, Carol Ho-Yi Fong, Kylie Sze-Wing Chan, Jimmy Ho-Cheung Mak, Chloe Yu-Yan Cheung, Wing-Sun Chow, Yu-Cho Woo, Man-Fung Yuen, Wai-Kay Seto, Karen Siu-Ling Lam","doi":"10.1111/dom.16049","DOIUrl":"https://doi.org/10.1111/dom.16049","url":null,"abstract":"<p><strong>Aims: </strong>Both pioglitazone and glucagon-like peptide 1 receptor agonists (GLP1RA) alone improve metabolic dysfunction-associated steatohepatitis (MASH) in randomized clinical trials, whereas preclinical studies suggested MASH benefits with sodium glucose co-transporter 2 inhibitors (SGLT2i). In the real world, patients with type 2 diabetes often require multiple agents for glycaemic control. Here, we investigated the benefits of combining these agents on risks of MASH.</p><p><strong>Materials and methods: </strong>Longitudinal changes in FibroScan-aspartate aminotransferase (FAST) score were measured in 888 patients with type 2 diabetes. Use of pioglitazone, GLP1RA and/or SGLT2i was defined as continuous prescriptions of ≥180 days prior to their last reassessment FibroScan. Multivariable logistic regression analysis was conducted to evaluate the associations between use of these agents and FAST score changes.</p><p><strong>Results: </strong>Over a median follow-up of 3.9 years, the increasing number of these agents used was significantly associated with more reductions in FAST score (p for trend <0.01). Dual combination was independently associated with a higher likelihood of achieving low FAST score at reassessment than single use of any of these agents (odds ratio [OR] 2.84, p = 0.01). Among the different drug combinations, using SGLT2i and pioglitazone (median dose 15 mg daily) together, as compared to not using any of these three agents, was associated with a higher likelihood of both low FAST score at reassessment (OR 6.51, p = 0.008) and FAST score regression (OR 12.52, p = 0.009), after adjusting for changes in glycaemic control and body weight during the study.</p><p><strong>Conclusions: </strong>Combining SGLT2i and pioglitazone is a potentially useful strategy to ameliorate 'at-risk' MASH in patients with type 2 diabetes.</p>","PeriodicalId":158,"journal":{"name":"Diabetes, Obesity & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amina Z Haggag, Jianfeng Xu, Laurie Butcher, Sandra Pagnussat, Graeme Davies, Sara Lundqvist, Wenyu Wang, Natalie Van Zuydam, Karin Nelander, Aruni Jha, Hongtao Yu, Alessandro Boianelli, Bosse Lindmark, Anna Ollerstam, Xuefeng Sun, Fan Wang, Xiaoliang Pan, Haihui Liu, Wengang Chen, Jianfeng Xu, Kristina Wallenius, Jingye Zhou
{"title":"Non-clinical and first-in-human characterization of ECC5004/AZD5004, a novel once-daily, oral small-molecule GLP-1 receptor agonist.","authors":"Amina Z Haggag, Jianfeng Xu, Laurie Butcher, Sandra Pagnussat, Graeme Davies, Sara Lundqvist, Wenyu Wang, Natalie Van Zuydam, Karin Nelander, Aruni Jha, Hongtao Yu, Alessandro Boianelli, Bosse Lindmark, Anna Ollerstam, Xuefeng Sun, Fan Wang, Xiaoliang Pan, Haihui Liu, Wengang Chen, Jianfeng Xu, Kristina Wallenius, Jingye Zhou","doi":"10.1111/dom.16047","DOIUrl":"https://doi.org/10.1111/dom.16047","url":null,"abstract":"<p><strong>Aims: </strong>GLP-1 receptor agonists (GLP-1 RAs) are proven therapies for type 2 diabetes mellitus (T2DM) and overweight or obesity. We performed non-clinical and first-in-human (FIH) evaluation of ECC5004/AZD5004, an oral small-molecule GLP-1 RA.</p><p><strong>Materials and methods: </strong>ECC5004 was profiled in cell lines overexpressing human GLP-1R, in glucose-stimulated insulin secretion (GSIS) assays in a human β-cell line and non-human primates (NHPs). To evaluate safety, ECC5004 was orally administered to NHPs for 9 months and a phase I, double-blind, placebo-controlled FIH study was conducted. This study evaluated single doses of ECC5004 (1-300 mg) in healthy volunteers, and multiple daily doses (5, 10, 30 and 50 mg) in patients with T2DM for 28 days.</p><p><strong>Results: </strong>ECC5004 bound to the hGLP-1R (IC<sub>50</sub> = 2.4 nM) augmented cAMP signalling without β-arrestin-2 recruitment or receptor internalization. ECC5004 potentiated GSIS in both EndoC-βH5 cells (EC<sub>50</sub> = 5.9 nM) and in vivo in NHPs (EC<sub>50</sub> = 0.022 nM). Dose-dependent body weight changes compared to control were seen in the 9-month NHP toxicity study. In the first-in-human study, ECC5004 was well tolerated with no serious adverse events. Dose-dependent reductions in glucose and body weight were observed with a dose-proportional exposure at doses ≥25 mg.</p><p><strong>Conclusion: </strong>ECC5004 engaged the GLP-1R across the therapeutic dose range tested and had a safety and tolerability profile consistent with other GLP-1 RAs, along with a pharmacokinetic profile compatible with once-daily oral dosing. These data support continued development of ECC5004 as a potential therapy for T2DM and overweight or obesity.</p><p><strong>Clinical trial registration: </strong>NCT05654831.</p>","PeriodicalId":158,"journal":{"name":"Diabetes, Obesity & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}