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Aims: Patients with type 2diabetesmellitus (T2DM) have high fracture risk. This study explored the associations between pancreatic computed tomography (CT) attenuation, a marker of pancreatic fat, and risk of vertebral fracture in T2DM patients., Methods: A total of 1486 T2DM patients who aged 50 years and older and without preexisting vertebral fractures during 2019-2023 at our institutions were followed up untilJanuary 2024. CT attenuation of the pancreas, bone and spleen were measured. Pancreatic attenuation/spleen attenuation ratio (P/S) was calculated. Vertebral fractures were evaluated on spine CT images according to Genant's semiquantitative scoring system., Results: A total of 135 cases of vertebral fracture were identified during 26 months of follow-up and 270 patients without vertebral fracture were matched. Pancreatic CT attenuation and the P/S ratio were negatively associated with the risk of vertebral fracture (adjusted hazard ratio (aHR) = 0.97, 95 %confidence interval (CI): 0.96-0.99; aHR = 0.26, 95 %CI: 0.12-0.58). Addition of pancreatic attenuation or P/S ratio improved the performance of bone attenuation-based model (area under the curve = 0.72-0.763 vs 0.63-0.728)., Conclusion: Pancreatic fat infiltration is an associated factor for vertebral fracture in T2DM patients. Addition of pancreatic fat infiltration improved the predictive performance of the bone-based model., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: To develop a machine learning model for predicting rapid kidney function decline in people with type 2 diabetes (T2D) and chronic kidney disease (CKD) and to pinpoint key modifiable risk factors for targeted interventions., Methods: We conducted a retrospective cohort study on 6,924 individuals with T2D and CKD at Seoul National University Hospital. Kidney function decline was assessed using estimated glomerular filtration rate slopes. The performance of the eXtreme Gradient Boosting (XGBoost) model was evaluated through model diagnosis and time-to-event analyses. Copula simulation was conducted to stratify risk subgroups using modifiable risk factors., Results: A total of 906 (13.1 %) individuals experienced rapid kidney function decline. The XGBoost model demonstrated optimal performance (area under the receiver operating characteristic curve: 0.826). The hazard of end-stage kidney disease within eight years increased across risk quartiles, with statistically significant hazard ratios in Q3 (2.06; 95 % confidence interval [CI]: 1.29-3.29) and Q4 (10.9; 95 % CI: 7.36-16.2). Simulation analysis identified high-risk subgroups by stage A3 albuminuria and at least two of the following: haematocrit < 39.0 %, systolic blood pressure > 120 mmHg, and glycated hemoglobin A1c > 6.5 %., Conclusions: The XGBoost model, augmented by copula simulation, successfully stratified kidney prognosis in individuals with T2D and CKD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: In Europe, 27 % of patients with a podiatric complication of diabetes are referred to a specialized structure for surgery after more than 3 months' disease progression. Our study aimed to analyze access to healthcare and future self-projection in patients with severe diabetic foot conditions., Methods: We performed a qualitative study with semi-structured interviews in patients hospitalized with diabetic foot conditions requiring surgical treatment. We collected quantitative data on the diabetes characteristics, levels of social precariousness, anxiety and depression., Results: We conducted 13 interviews with 2 females and 11 males; mean age 62.7 years. Five had undergone surgical debridement, six toe amputation, and two mid-tarsal amputation. Most were socioeconomically deprived and/or isolated. Three discourse themes emerged: 1) heterogeneity in the care pathway, with systemic barriers, negligence or overtrust 2) relationship between social support and the ability to project oneself into the future, 3) poverty of speech., Conclusions: Education should emphasize the importance of prompt referral to a specialized structure after the onset of a wound. The lack of support from loved ones and social support appeared to be associated with patients' failure to plan for their future. We advocate for a psychological evaluation and support for all these patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [BIHAN reports financial support was provided by Public Assistance Hospitals Paris]., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: To explore the 5-year incidence and relative rates of sleep disorders in younger (16-≤40 years) and middle-older (=>40 years) age adults with and without newly diagnosed type 2 diabetes., Methods: This retrospective, observational cohort study utilised data from the US Collaborative Network within the TriNetX database. We compared 5-year cumulative incidence of sleep disorders in younger (n = 110,088) and middle-older populations (n = 1,185,961)., Results: The absolute risk of developing any type of sleep disorder was greater in individuals with type 2 diabetes vs. those without. Over the 5-year follow-up period, 14.2 % of younger adults and 18.5 % of middle-older age adults with newly diagnosed type 2 diabetes developed any form of sleep disorder, compared to 4.5 % and 7.9 % propensity matched individuals without diabetes. We observed a more pronounced relative rate across the observed sleep disorders in younger adults., Conclusions: The 5-year risk of sleep disorders is higher in those with newly diagnosed type 2 diabetes vs. those without. A higher absolute risk was seen in middle-older adults, but relative rates were consistently higher in younger adults with type 2 diabetes. Sleep should be regularly discussed as part of a holistic approach to diabetes care, particularly in those aged ≤40., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [TY has received research funding from AstraZeneca and Abbott. KK has served as a consultant, speaker or received research grants/support from AstraZeneca, Boehringer Ingelheim, Lilly, and Novo Nordisk. MJD has acted as consultant, advisory board member and speaker for Boehringer Ingelheim, Lilly, Novo Nordisk and Sanofi, an advisory board member and speaker for AstraZeneca, an advisory board member for Janssen, Lexicon, Pfizer, Medtronic and ShouTi Pharma Inc and as a speaker for Napp Pharmaceuticals, Novartis and Takeda Pharmaceuticals International Inc. She has received grants in support of investigator and investigator-initiated trials from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, AstraZeneca and Janssen. The other authors have no conflicts of interest to declare]., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Metabolic dysfunction-associated steatotic liver disease (MASLD), represents a growing health concern due to its strong association with metabolic syndrome, obesity, and type 2 diabetes mellitus (T2DM). This condition, characterized by excessive fat accumulation in the liver not attributed to alcohol consumption, has emerged as a leading cause of chronic liver disease globally. MASLD significantly elevates the risk of major adverse cardiovascular events (MACE) through mechanisms like increased oxidative stress, insulin resistance, and chronic inflammation, all of which contribute to the development of atherosclerosis and endothelial dysfunction. Effective management of MASLD is crucial not only for liver health but also for cardiovascular disease (CVD) prevention. Lifestyle modifications, particularly weight loss achieved through dietary changes and increased physical activity, are the cornerstone of MASLD treatment. Additionally, pharmacological interventions, especially antihyperglycemic agents, play a pivotal role in treating MASLD in patients with T2DM. Novel therapeutic agents targeting various pathways of metabolic and liver dysfunction are under investigation, offering hope for more effective management strategies. This review explores the interconnectedness of MASLD and CVD, highlighting current and emerging therapeutic approaches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Functional complete revascularization (CR) after percutaneous coronary intervention (PCI), as assessed by the residual functional SYNTAX score (rFSS), has been correlated with enhanced prognostic outcomes., Methods: A total of 1,555 patients with available post-PCI quantitative flow ratio (QFR) were included, whose data were collected from PANDA III trial. Functional CR was defined as rFSS=0, while anatomic CR was defined as residual SYNTAX score (rSS) = 0. Structural equation modeling was used to analysis whether functional CR explained the relationship between T2DM (Type 2 diabetes mellitus) and the risk of 2-year rates of major adverse cardiac events (including all-cause death, all myocardial infarction, or any ischemia-driven revascularization)., Results: Multiple cox regression revealed that T2DM was associated with MACE (P=0.007), but not after adding functional CR to the model (P=0.05), suggesting a mediation effect. Structural equation modeling analysis revealed a significant indirect effect of T2DM on MACE through functional CR (P=0.006, Mediated [%] = 27.3), suggesting a partial mediation effect., Conclusion: The degree of functional revascularization may emerge as a central mechanism pivotal in elucidating the association between T2DM and the risk of MACE. Cardiologists should prioritize functional complete revascularization during the initial PCI procedure for patients with diabetes mellitus., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: To investigate the impact of diagnosis age of type 2 diabetes mellitus (T2DM) on subsequent adverse outcomes within the Chinese population., Methods: 549,959 eligible T2DM patients were included from Ningbo and Jinhua city in Zhejiang province, China. Standardized ratio was used to evaluate the risks of coronary heart disease (CHD), stroke, cancer and all-cause death in different T2DM diagnosis age groups., Results: For all adverse outcomes, higher excess risks were observed in the youngest age group (30-39) than in the oldest age group (≥80) with T2DM. The standardized incidence ratios (SIR) were 5.93 (95% CI: 3.46, 10.14) for CHD, 5.45 (95% CI: 3.72, 7.99) for stroke and 1.85 (95% CI: 1.38, 2.49) for cancer in the youngest age group, and were 1.32 (95% CI: 1.08, 1.60) for CHD, 1.25 (95% CI: 1.08, 1.44) for stroke, and 0.78 (95% CI: 0.56, 1.09) for cancer, respectively, in the oldest age group. The standardized mortality ratios (SMR) for all-cause death were 3.15 (1.69, 5.84) vs. 1.12 (0.88, 1.43). These excess risks decreased with increasing diagnosis age (all P value < 0.001). Consistent results were observed when individuals were stratified by sex or further excluded with the time from T2DM diagnosis to endpoints less than 1 or 2 years., Conclusions: Th earlier the diagnosis of T2DM, the higher the risk for subsequent adverse outcomes. It is imperative to enhance the management and monitoring of early-onset patients during follow-up., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: To replicate the European subtypes of type 2 diabetes mellitus (T2DM) in the Chinese diabetes population and investigate the risk of complications in different subtypes., Methods: A diabetes cohort using real-world patient data was constructed, and clustering was employed to subgroup the T2DM patients. Kaplan-Meier analysis and the Cox models were used to analyze the association between diabetes subtypes and the risk of complications., Results: A total of 2,652 T2DM patients with complete clustering data were extracted. Among them, 466 (17.57 %) were classified as severe insulin-deficient diabetes (SIDD), 502 (18.93 %) as severe insulin-resistant diabetes (SIRD), 672 (25.34 %) as mild obesity-related diabetes (MOD), and 1,012 (38.16 %) as mild age-related diabetes (MARD). The risk of chronic kidney disease (CKD) and diabetic retinopathy (DR) were different in the four subtypes. Compared with MARD, SIRD had a higher risk of CKD (HR 2.40 [1.16, 4.96]), and SIDD had a higher risk of DR (HR 2.16 [1.11, 4.20]). The risk of stroke and coronary events had no difference., Conclusions: The European T2DM subtypes can be replicated in the Chinese diabetes population. The risk of CKD and DR varied among different subtypes, indicating that proper interventions can be taken to prevent specific complications in different subtypes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Diabetes mellitus (DM) and heart failure (HF) share vascular, skeletal and metabolic abnormalities that can reduce exercise capacity. We investigated whether exercise capacity differ in patients with type 2 DM compared to those without DM with HF of similar severity., Methods and Results: The Studies Investigating Co-morbidities Aggravating HF (SICA-HF) prospectively enrolled 615 patients with chronic HF, 259 (42.1 %) of whom had DM. We assembled a propensity score-matched cohort of 231 pairs of patients with HF with or without DM who were balanced on age, sex and variables reflecting HF severity. Patients with DM had lower median peak VO 2 (15.7 [13.0-19.1] vs. 17.3 [14.1-21.0] ml/min/kg; p = 0.005). Forearm blood flow reserve (per 1 ml/min/100 ml increase) was associated with lower exercise capacity (peak VO2 ≤ 16.6 ml/min/kg) in patients with DM (OR, 0.92; 95 % CI, (0.85-0.98; p = 0.014), but not in those without DM (OR, 0.98; 95 % CI, 0.93-1.02). A similar heterogeneity was also observed for HDL cholesterol., Conclusions: Diabetes is associated with a reduced exercise capacity in patients with HF. Most predictors of lower exercise capacity in HF are similar regardless of DM except impaired vascular function and lower HDL cholesterol which predict lower exercise capacity only in those with DM., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Stefan Anker reports a relationship with CSL Vifor that includes: consulting or advisory and funding grants. Stefan Anker reports a relationship with Bayer AG that includes: consulting or advisory. Stefan Anker reports a relationship with Boehringer Ingelheim GmbH that includes: consulting or advisory. Stefan Anker reports a relationship with Servier that includes: consulting or advisory. Stefan Anker reports a relationship with Abbott Vascular Inc that includes: consulting or advisory and funding grants. Stefan Anker reports a relationship with Cardiac Dimensions Inc that includes: consulting or advisory. Stefan Anker reports a relationship with Actimed Therapeutics that includes: consulting or advisory. Stefan Anker reports a relationship with AstraZeneca that includes: consulting or advisory. Stefan Anker reports a relationship with Amgen Inc that includes: consulting or advisory. Stefan Anker reports a relationship with BioVentrix Inc that includes: consulting or advisory. Stefan Anker reports a relationship with V-Wave Ltd that includes: consulting or advisory. Stefan Anker reports a relationship with Brahms that includes: consulting or advisory. Stefan Anker reports a relationship with Cordio that includes: consulting or advisory. Stefan Anker reports a relationship with Occlutech GmbH that includes: consulting or advisory. Stefan Anker reports a relationship with Cardior that includes: consulting or advisory. Stefan Anker reports a relationship with CVRx Inc that includes: consulting or advisory. Stefan Anker reports a relationship with Cytokinetics Inc that includes: consulting or advisory. Stefan Anker reports a relationship with Edwards that includes: consulting or advisory. Stefan Anker reports a relationship with Farraday Pharmaceuticals that includes: consulting or advisory. Stefan Anker reports a relationship with GSK that includes: consulting or advisory. Stefan Anker reports a relationship with HeartKinetics that includes: consulting or advisory. Stefan Anker reports a relationship with Impulse Dynamics that includes: consulting or advisory. Stefan Anker reports a relationship with Pfizer Inc that includes: consulting or advisory. Stefan Anker reports a relationship with Repairon that includes: consulting or advisory. Stefan Anker reports a relationship with Medical Sensible that includes: consulting or advisory. Stefan Anker reports a relationship with Vectorious that includes: consulting or advisory. John GF Cleland reports a relationship with British Heart Foundation that includes: board membership and funding grants. John GF Cleland reports a relationship with Pharmacosmos, Inc. that includes: consulting or advisory, funding grants, and travel reimbursement. John GF Cleland reports a relationship with CSL-Vifor that includes: funding grants. John GF Cleland reports a relationship with Abbott Vascular Inc that includes: consulting or advisory. John GF Cleland reports a relationship with Biopeutics that includes: consulting or advisory and travel reimbursement. John GF Cleland reports a relationship with Medtronic Inc that includes: board membership. John GF Cleland reports a relationship with Deputy Editor of European Heart Journal that includes: board membership. Stephan von Haehling reports a relationship with Amgen Inc that includes: funding grants. Stephan von Haehling reports a relationship with AstraZeneca that includes: consulting or advisory, funding grants, and speaking and lecture fees. Stephan von Haehling reports a relationship with Boehringer Ingelheim GmbH that includes: consulting or advisory, funding grants, and speaking and lecture fees. Stephan von Haehling reports a relationship with Pharmacosmos, Inc. that includes: consulting or advisory, funding grants, and speaking and lecture fees. Stephan von Haehling reports a relationship with IMI that includes: funding grants. Stephan von Haehling reports a relationship with German Center for Cardiovascular Research (DZHK) that includes: funding grants. Stephan von Haehling reports a relationship with BRAHMS that includes: consulting or advisory. Stephan von Haehling reports a relationship with MSD that includes: consulting or advisory. Stephan von Haehling reports a relationship with Novo Nordisk Inc that includes: consulting or advisory and speaking and lecture fees. Stephan von Haehling reports a relationship with Novartis that includes: consulting or advisory and speaking and lecture fees. Stephan von Haehling reports a relationship with Pfizer that includes: consulting or advisory. Stephan von Haehling reports a relationship with Respicardia that includes: consulting or advisory. Stephan von Haehling reports a relationship with Roche that includes: consulting or advisory. Stephan von Haehling reports a relationship with Servier that includes: consulting or advisory. Stephan von Haehling reports a relationship with Vifor that includes: consulting or advisory and speaking and lecture fees. Stephan von Haehling reports a relationship with Bayer AG that includes: speaking and lecture fees. Stephan von Haehling reports a relationship with Edwards Lifesciences Corporation that includes: speaking and lecture fees. Stephan von Haehling reports a relationship with Amomed Pharma GmbH that includes: consulting or advisory. Stephan von Haehling reports a relationship with Actimed that includes: equity or stocks. Wolfram Doehner reports a relationship with Vifor that includes: consulting or advisory and funding grants. Wolfram Doehner reports a relationship with Boehringer Ingelheim GmbH that includes: board membership, consulting or advisory, and funding grants. Wolfram Doehner reports a relationship with Aimediq that includes: consulting or advisory. Wolfram Doehner reports a relationship with AstraZeneca that includes: consulting or advisory. Wolfram Doehner reports a relationship with Bayer AG that includes: consulting or advisory. Wolfram Doehner reports a relationship with Boston Scientific Corp that includes: consulting or advisory. Wolfram Doehner reports a relationship with Medtronic that includes: consulting or advisory. Wolfram Doehner reports a relationship with Cardiomatics that includes: consulting or advisory. Wolfram Doehner reports a relationship with ICON Clinical Research LLC that includes: consulting or advisory. Wolfram Doehner reports a relationship with Pharmacosmos, Inc. that includes: travel reimbursement. Wolfram Doehner reports a relationship with IQVIA that includes: board membership. Wolfram Doehner reports a relationship with European Society of cardiology (ESC) that includes: board membership. Wolfram Doehner reports a relationship with ESC Council on Stroke that includes: board membership. Wolfram Doehner reports a relationship with Society of cachexia and wasting disorders that includes: board membership. Ewa A. Jankowska reports a relationship with Vifor Pharma that includes: board membership, consulting or advisory, and speaking and lecture fees. Ewa A. Jankowska reports a relationship with Pharmacosmos, Inc. that includes: board membership, consulting or advisory, and speaking and lecture fees. Ewa A. Jankowska reports a relationship with Novartis that includes: board membership, consulting or advisory, and speaking and lecture fees. Ewa A. Jankowska reports a relationship with Novo Nordisk that includes: board membership, consulting or advisory, and speaking and lecture fees. Ewa A. Jankowska reports a relationship with AstraZeneca that includes: board membership, consulting or advisory, and speaking and lecture fees. Ewa A. Jankowska reports a relationship with Boehringer Ingelheim that includes: board membership, consulting or advisory, and speaking and lecture fees. Ewa A. Jankowska reports a relationship with Pfizer that includes: board membership, consulting or advisory, and speaking and lecture fees. Ewa A. Jankowska reports a relationship with Zoll that includes: board membership and consulting or advisory. Ewa A. Jankowska reports a relationship with Respicardia that includes: board membership and consulting or advisory. Ewa A. Jankowska reports a relationship with Bayer that includes: board membership, consulting or advisory, and speaking and lecture fees. Ewa A. Jankowska reports a relationship with Abbott that includes: board membership, consulting or advisory, and speaking and lecture fees. Ewa A. Jankowska reports a relationship with Cardiac Dimensions Inc that includes: board membership and consulting or advisory. Ewa A. Jankowska reports a relationship with Amicus that includes: consulting or advisory. Ewa A. Jankowska reports a relationship with Swixx Biopharma that includes: speaking and lecture fees. Ewa A. Jankowska reports a relationship with Ewopharma that includes: speaking and lecture fees. Ewa A. Jankowska reports a relationship with Servier that includes: board membership and speaking and lecture fees. Ewa A. Jankowska reports a relationship with Takeda that includes: speaking and lecture fees. Ewa A. Jankowska reports a relationship with Sanofi that includes: speaking and lecture fees. Ewa A. Jankowska reports a relationship with Executive Committee of the HFA Board 2016–2022 that includes: board membership. Miroslava Valentova reports a relationship with Bayer that includes: speaking and lecture fees. Stefan Anker has patent #MR-proANP (DE 102,007,010,834 & DE 102007022367) issued to BRAHMS. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Non-alcoholic (now: metabolic) steatohepatitis (MASH) is the progressive inflammatory form of metabolic dysfunction-associated steatotic liver disease (MASLD), which often coexists and mutually interacts with type 2 diabetes (T2D), resulting in worse hepatic and cardiovascular outcomes. Understanding the intricate mechanisms of diabetes-related MASH progression is crucial for effective therapeutic strategies. This review delineates the multifaceted pathways involved in this interplay and explores potential therapeutic implications. The synergy between adipose tissue, gut microbiota, and hepatic alterations plays a pivotal role in disease progression. Adipose tissue dysfunction, particularly in the visceral depot, coupled with dysbiosis in the gut microbiota, exacerbates hepatic injury and insulin resistance. Hepatic lipid accumulation, oxidative stress, and endoplasmic reticulum stress further potentiate inflammation and fibrosis, contributing to disease severity. Dietary modification with weight reduction and exercise prove crucial in managing T2D-related MASH. Additionally, various well-known but also novel anti-hyperglycemic medications exhibit potential in reducing liver lipid content and, in some cases, improving MASH histology. Therapies targeting incretin receptors show promise in managing T2D-related MASH, while thyroid hormone receptor-β agonism has proven effective as a treatment of MASH and fibrosis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SG declares no competing interests. MR reports consulting fees and/or speaker’s fees from Astra Zeneca, Echosens, Eli Lilly, Madrigal, MSD, Novo Nordisk and Boehringer Ingelheim and is supported for investigator-initiated trials by Boehringer Ingelheim and Novo Nordisk. LC reports consulting fees from Boston pharmaceutical, Echosens, Gilead, GSK, Madrigal, MSD, Novo Nordisk, Pfizer, Sagimet and Siemens Healthineers and speaker fees from Echosens, Gilead, Inventiva, Madrigal and Novo Nordisk., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: This systematic review was aimed to assess the association between magnitude of body weight loss (BWL) in type 2 diabetes (T2D) patients and cardiovascular (CV) risk in CV outcome trials (CVOTs)., Methods: We searched electronic databases (PubMed, Cochrane and Scopus) for available CVOTs, observational cohort studies or post hoc analyses of clinical trials of adult T2D patients investigated the association of BWL with CV outcomes and/or all-cause mortality., Results: 19 RCTs of novel glucose-lowering drugs (GLP-1RA, DPP-4i and SGLT2i) and 6 RCT or observational trial of different strategies (intensive treatment or standard care) were included (379.904 T2D patients). Higher BWL during GLP-1RA treatment, in comaprison to lower BWL, was associated with higher decrease in risk of MACE, while DPP-4i had not that effect. With SGLT2i the higher decrease in risk of MACE was associated with lower BWL. In contrast, in other different strategies, higher BWL lead to increase in risk for MACE and all-cause mortality., Conclusions: In CVOTs, treatment of T2D patients resulted in BWL, which correlated with reduction in risk for CV outcomes, particularly with GLP-1 RAs. However, interventional non-CVOTs are warning that in the absence of structured behavioral intervention and relevant medication, the large BWL might be harmful for CV outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: We aim to determine the association of seven major candidate protein biomarkers and diabetic kidney disease (DKD) progression among Asians with young-onset type 2 diabetes mellitus (T2DM)., Methods: 824 T2DM patients (onset ≤ 40 years old) were classified as DKD progressors based on yearly estimated glomerular filtration rate (eGFR) decline of >3 ml/min/1.73 m 2 or >40 % from baseline. Plasma leucine-rich α-2-glycoprotein 1 (pLRG1), tumor necrosis factor-receptor 1 (pTNF-R1), pigment epithelium-derived factor (pPEDF), urinary α-1-microglobulin (uA1M), kidney injury molecular 1 (uKIM-1), haptoglobin (uHP) and uromodulin (uUMOD) were measured using enzyme-linked immunoassays., Results: Over 5.7 years of follow-up, 25.2 % of patients were DKD progressors. Elevated levels of pLRG1, pTNF-R1, pPEDF, uA1M, uKIM-1 and uHP were associated with DKD progression. The association between pTNF-R1 levels and DKD progression persisted after adjusting for clinical covariates (OR 1.84, 95 %CI 1.44-2.34, p < 0.001). The effects of pTNF-R1 were partially mediated through hyperglycemia (8 %) and albuminuria (10 %). Inclusion of pTNF-R1 in a clinical variable-based model improved the area under the receiver operating characteristics curve for predicting DKD progression by 0.02, from 0.72 (95 %CI 0.68-0.76) to 0.74 (95 %CI 0.70-0.78), p = 0.099., Conclusions: Among seven major candidate proteins, pTNF-R1, partially mediated through hyperglycemia and albuminuria, robustly predicted DKD progression among Asians with young-onset T2DM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Type 2 diabetes (T2D) is associated with increased risk for chronic kidney disease (CKD). It is estimated that 40 % of people with diabetes have CKD, which consequently leads to increase in morbidity and mortality from cardiovascular diseases (CVDs). Diabetic kidney disease (DKD) is leading cause of CKD and end-stage renal disease (ESRD) globally. On the other hand, DKD is independent risk factor for CVDs, stroke and overall mortality. According to the guidelines, using spot urine sample and assessing urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) are both mandatory methods for screening of CKD in T2D at diagnosis and at least annually thereafter. Diagnosis of CKD is confirmed by persistent albuminuria followed by a progressive decline in eGFR in two urine samples at an interval of 3 to 6 months. However, many patients with T2D remain underdiagnosed and undertreated, so there is an urgent need to improve the screening by detection of albuminuria at all levels of health care. This review discusses the importance of albuminuria as a marker of CKD and cardiorenal risk and provides insights into the practical aspects of methods for determination of albuminuria in routine clinical care of patients with T2D., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: To assess the rate of diabetic retinopathy (DR) progression in an Australian cohort and to identify the determinants of DR progression in pregnancy., Methods: A total of 367 pregnancies of women with Type 1 or 2 diabetes mellitus attending King Edward Memorial Hospital, Western Australia, between June 2020 and July 2023 were included. These women were screened for the presence and severity of DR in the first trimester and/or at 28-32 weeks gestation via retinal imaging with a DRS camera., Results: DR was seen in 121 (33 %) pregnancies at baseline and DR progression was seen in 62 (17 %) pregnancies. Only 11 (4 %) women with no baseline DR developed DR and none of these progressed to more than moderate non-proliferative DR. A total of 51 (42 %) women with baseline DR had DR progression. The presence of baseline DR was the only significant predictor for DR progression on multivariate analysis (OR 9.88 (4.43-22.07), p < 0.001)., Conclusions: Women without DR at baseline are unlikely to progress to more severe forms of DR and usually do not require treatment. The presence of DR at baseline screening during pregnancy is a strong predictor of DR progression during pregnancy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Aim: Among multi-ethnic Asians, type 2 diabetes (T2D) clustered in three subtypes; mild obesity-related diabetes (MOD), mild age-related diabetes with insulin insufficiency (MARD-II) and severe insulin-resistant diabetes with relative insulin insufficiency (SIRD-RII) had differential cardio-renal complication risk. We assessed the proteomic profiles to identify subtype specific biomarkers and its association with diabetes complications., Methods: 1448 plasma proteins at baseline were measured and compared across the T2D subtypes. Multivariable cox regression was used to assess associations between significant proteomics features and cardio-renal complications., Results: Among 645 T2D participants (SIRD-RII [19%], MOD [45%], MARD-II [36%]), 295 proteins expression differed significantly across the groups. These proteins were enriched in cell adhesion, neurogenesis and inflammatory response processes. In SIRD-RII group, ADH4, ACY1, THOP1, IGFBP2, NEFL, ENTPD2, CALB1, HAO1, CTSV, ITGAV, SCLY, EDA2R, ERBB2 proteins significantly associated with progressive CKD and LILRA5 protein with incident heart failure (HF). In MOD group, TAFA5, RSPO3, EDA2R proteins significantly associated with incident HF. In MARD-II group, FABP4 protein significantly associated with progressive CKD and PTPRN2 protein with major adverse cardiovascular events. Genetically determined NEFL and CALB1 were associated with kidney function decline., Conclusions: Each T2D subtype has unique proteomics signature and association with clinical outcomes and underlying mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: To investigate alterations in cerebrum and cerebellum in prediabetes. Cerebellar injury in diabetes is traceable, but it has not been systematically studied, and whether cerebellar injury occurs and the degree of damage in prediabetes are not known., Methods: The current study investigated cerebral and cerebellar gray matter volume, white matter volume, white matter microstructure and white matter hyperintensity on T1-weighted, T2-weighted fluid-attenuated inversion recovery and diffusion tensor imaging scans in 78 individuals with normal glucose metabolism, 92 with prediabetes, and 108 with type 2 diabetes., Results: Participants with prediabetes showed significant gray matter and white matter atrophy, microstructural damage in the cerebellar and cerebral regions. Additionally, widespread structural alterations were observed in the diabetic stage. The function of the damaged brain area was further decoded in Neurosynth, and the damaged cerebellar area with prediabetic lesions was closely related to motor function, while the area affected by diabetes was related to complex cognitive function in addition to motor function., Conclusions: Cerebellar injury had already appeared in the prediabetic stage, and cerebellar injury was aggravated in the diabetic stage; therefore, the cerebellum is a key area that is damaged early in the development of diabetes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Continuous glucose monitoring (CGM)-derived metrics have been used to accurately assess glycemic variability (GV) to facilitate management of diabetes mellitus, yet their relationship with diabetic peripheral neuropathy (DPN) is not fully understood. We performed a systematic review and meta-analysis to evaluate the association between GV metrics and the risk of developing DPN. Nine studies totaling 3,649 patients with type 1 and type 2 diabetes mellitus were included. A significant association was found between increased GV, as indicated by metrics including standard deviation (SD) with OR and 95% CI of 2.58 (1.45-4.57), mean amplitude of glycemic excursions (MAGE) with OR and 95% CI of 1.90 (1.01-3.58), mean of daily difference (MODD) with OR and 95% CI of 2.88 (2.17-3.81) and the incidence of DPN. Our findings support a link between higher GV and an increased risk of DPN in patients with diabetes. These findings highlight the potential of GV metrics as indicators for the development of DPN, advocating for their inclusion in diabetes management strategies to potentially mitigate neuropathy risk. Longitudinal studies with longer observation periods and larger sample sizes are necessary to validate these associations across diverse populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: To quantify the relationship of neutrophil-to-lymphocyte ratio (NLR) with cardiovascular events and all-cause mortality in patients with type 2 diabetes (T2D), independent of C-reactive protein (CRP)., Methods: Patients with T2D from the UCC-SMART-cohort were studied using multivariable-adjusted Cox regression. The relationship of NLR and CRP with vascular events (cerebrovascular events, myocardial infarction and vascular death) and all-cause mortality was quantified., Results: During 10,833 person-years, 232 vascular events and 302 deaths occurred in 1,239 patients with T2D. Risk of vascular events and all-cause mortality increased per standard deviation (SD) in NLR (hazard ratio (HR) 1.27; 95 % confidence interval (CI):1.11-1.46) and 1.15; 95 % CI:1.02-1.30) after adjustment for CRP. CRP was not associated with vascular events after adjustment for NLR, (HR per SD 1.03; 95 % CI: 0.90-1.19), but was associated with all-cause mortality (HR per SD 1.18; 95 % CI: 1.04-1.33). Notably, NLR was related to vascular events in patients with CRP < 2 mg/L (HR per unit 1.45; 95 % CI: 1.19-1.77)., Conclusion: In patients with T2D, NLR is related to higher risk of CVD and all-cause mortality, independently from CRP. NLR is related to CVD even when CRP is low, indicating that NLR is a marker of CVD-risk in addition to CRP. Both NLR and CRP are independently related to all-cause mortality in T2D patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: Our study aimed to investigate the correlation between glycated hemoglobin (HbA1c) and adverse prognostic events in patients with diabetes and triple-vessel coronary disease (TVD)., Methods: This study ultimately included 2051 patients with TVD and diabetes. Patients were categorized into five groups based on their HbA1c levels: < 6.0 %, 6.0-6.4 %, 6.5-6.9 %, 7.0-7.9 %, and ≥ 8.0 %. The primary endpoint was all-cause death, and the secondary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE)., Results: The median follow-up time was 5.88 years. During this period, a total of 323 (15.7 %) all-cause deaths and 537 (26.2 %) MACCEs were recorded. The relationship between HbA1c and the risk of endpoint events showed a J-shaped pattern, with the lowest risk observed between 6.0 % and 6.4 %. Further analysis revealed a significant interaction between HbA1c and age. In the subgroup with age < 70 years, as HbA1c increased, the risk of endpoint events gradually rose. While in the subgroup with age ≥70 years, there was an L-shaped relationship between HbA1c and endpoint events, with the highest risk observed in patients with HbA1c < 6.0 %., Conclusion: Our study revealed variations in the relationship between HbA1c levels and endpoint events among patients with TVD and diabetes of different ages. In younger patients, elevated HbA1c levels were associated with a higher risk of death and MACCE, while in older patients, excessively low HbA1c levels (HbA1c < 6 %) were linked to a higher risk of death and MACCE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: Autoantibodies against hexokinase 1 (HK1) were recently proposed to be associated with diabetic macular edema (DME). We hypothesized that anti-HK1 autoantibodies can be used as DME markers and to predict DME onset., Materials and Methods: Serum from patients with 1) DME, 2) diabetes mellitus (DM), 3) allergies or autoimmunities, and 4) control subjects was tested for anti-HK1 and anti-hexokinase 2 (HK2) autoantibodies by immunoblotting. Patients with DM were prospectively followed for up to nine years, and the association of anti-HK1 antibodies with new-onset DME was evaluated. The vitreous humor was also tested for autoantibodies., Results: Among patients with DME, 32 % were positive for anti-HK1 autoantibodies (42 % of those with underlying type 1 DM and 31 % of those with underlying type 2 DM), and 12 % were positive for anti-HK2 autoantibodies, with only partial overlap of these two groups of patients. Anti-HK1 positive were also 7 % of patients with DM, 6 % of patients with allergies and autoimmunities, and 3 % of control subjects. The latter three groups were anti-HK2 negative. Only one of seven patients with DM who were initially anti-HK1 positive developed DME., Conclusions: Anti-HK1 autoantibodies can be used as DME markers but fail to predict DME onset., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: To evaluate the relationship of 25-hydroxyvitamin D (25(OH)D), lipoprotein-associated phospholipase A2 (Lp-PLA2), and coronary artery disease (CAD) in type 2 diabetes mellitus (T2DM) patients with no history or symptoms of cardiovascular disease., Methods: The study identified 66 pairs of T2DM patients with and without CAD using propensity score matching. All subjects performed coronary computed tomography angiography (CCTA). Data on 25(OH)D, Lp-PLA2, and metabolic indexes were collected and analyzed., Results: Compared to the patients without CAD, the patients with CAD had lower 25(OH)D levels and the rate of vitamin D sufficiency, but higher Lp-PLA2 levels. Meanwhile, subjects in the vitamin D sufficiency group had a lower prevalence of CAD and Lp-PLA2 levels. Furthermore, 25(OH)D was inversely correlated with Lp-PLA2, Gensini score, Leiden score, segment involvement score, and segment stenosis score (P < 0.05). After adjusting for age, gender, blood lipids and blood pressure, 25(OH)D was associated with a decreased risk of CAD (aOR 0.933, 95 %CI 0.887-0.983, P = 0.009), while Lp-PLA2 was associated with an increased risk of CAD (aOR 1.014, 95 %CI 1.005-1.022, P = 0.002)., Conclusions: Decreased 25(OH)D and increased Lp-PLA2 could identify patients with a high risk of CAD and are associated with the severity of coronary artery stenosis in T2DM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: Long-term HbA1c (glycated haemoglobin) variability is associated with micro- and macrovascular complications in Type 2 diabetes (T2D). We explored prospective associations between HbA1c variability and serious infections, and how these vary by HbA1c level, age, sex and ethnicity., Methods: 411,963 T2D patients in England, aged 18-90, alive on 01/01/2015 in the Clinical Practice Research Datalink with ≥ 4 HbA1c measurements during 2011-14. Poisson regression estimated incidence rate ratios (IRRs) for infections requiring hospitalisation during 2015-19 by HbA1c variability score (HVS) and average level, adjusting for confounders, and stratified by age, sex, ethnicity and average level. Attributable risk fractions (AF) were calculated using reference categories for variability (HVS < 20) and average level (42-48 mmol/mol)., Results: An increased infection risk (IRR > 1.2) was seen with even modest variability (HVS ≥ 20, 73 % of T2D patients), but only at higher average levels (≥64 mmol/mol, 27 % patients). Estimated AFs were markedly greater for variability than average level (17.1 % vs. 4.1 %). Associations with variability were greater among older patients, and those with lower HbA1c levels, but not observed among Black ethnicities., Conclusions: HbA1c variability between T2D patients' primary care visits appears to be associated with more serious infections than average level overall. Well-designed trials could test whether these associations are causal., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The metabolic syndrome, characterized by type 2 diabetes mellitus (T2DM), hypertension, hyperlipidemia, and obesity, collectively increases the risk of cardiovascular diseases. Nonalcoholic fatty liver disease (NAFLD) is a prominent manifestation, affecting over a third of the global population with a concerning annual increase in prevalence. Nearly 70 % of overweight individuals have NAFLD, and NAFLD-related deaths are predicted to rise, especially among young adults. The association of T2DM and NAFLD has led to the proposal of "metabolic dysfunction-associated steatotic liver disease" (MASLD) terminology, encompassing individuals with T2DM, overweight/obesity, hypertension, hypertriglyceridemia, or low HDL-cholesterol. Patients with MASLD will likely have double the risk of developing T2DM, and the combination of insulin resistance, overweight/obesity, and MASLD significantly elevates the risk of T2DM. Cardiovascular diseases remain the leading cause of mortality in the MASLD and T2DM population, with MASLD directly associated with coronary artery disease, compounded by coexisting insulin resistance and T2DM. Urgency lies in early detection of subclinical cardiovascular diseases among patients with T2DM and MASLD. Novel strategies targeting multiple pathways offer hope for effectively improving cardiometabolic health. Understanding and addressing the intertwined factors contributing to these disorders can pave the way towards better management and prevention of cardiometabolic complications., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [C.S.P.L. is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Abbott, Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as cofounder and nonexecutive director of Us2.ai. N.W.S.C. has received research grant support from NUHS Seed Fund and National Medical Research Council Research Training Fellowship.]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The incidence and prevalence of metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are rising globally. MetS and T2DM are associated with significant morbidity and mortality, which is partly related to liver and cardiovascular disease. Insulin resistance is central to MetS and T2DM pathophysiology, and drives ectopic fat deposition in the liver, also known as metabolic dysfunction-associated steatotic liver disease (MASLD). MetS and T2DM are not only risk factors for developing MASLD but are also independently associated with disease progression to steatohepatitis, cirrhosis, and hepatocellular carcinoma. In addition to the risk of liver disease, MetS and T2DM are independent risk factors for cardiovascular disease (CVD), including coronary artery disease (CAD) and heart failure (HF). Importantly, there is a bidirectional relationship between liver and CVD due to shared disease pathophysiology in patients with MetS and T2DM. In this review, we have described studies exploring the relationship of MetS and T2DM with MASLD and CVD, independently. Following this we discuss studies evaluating the interplay between liver and cardiovascular risk as well as pragmatic risk mitigation strategies in this patient population., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [MSS: Consulting (Novo Nordisk, Sagimet, AMRA). AM: Research grant (Novartis). No other disclosures]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: To investigate the causal relationship between metabolic syndrome (MetS) and its components and 14 cardiovascular diseases using Mendelian randomization (MR)., Methods: We used summary statistics from large-scale genome-wide association studies of MetS, its components, and cardiovascular diseases. We performed a two-sample MR analysis using the inverse-variance weighted method and other sensitivity methods. We also performed multivariate MR to adjust for potential risk factors., Results: Our study found that MetS was causally associated with an increased risk of ischemic stroke, abdominal aortic aneurysm, pulmonary embolism, coronary heart disease, heart failure, and peripheral artery disease. Waist circumference was causally associated with an increased risk of 6 cardiovascular diseases. Type 2 diabetes mellitus, diastolic blood pressure, systolic blood pressure, triglycerides, and high-density lipoprotein cholesterol were all causally associated with coronary heart disease, with varying causal relationships with the remaining 5 cardiovascular diseases. Multivariate MR showed that, except for ischaemic stroke, waist circumference remained causally associated with the remaining five cardiovascular diseases after adjusting for potential confounders., Conclusion: Our study provides evidence that metabolic syndrome is causally associated with 6 cardiovascular diseases. Waist circumference is the most important component of these relationships. These findings have implications for the prevention and management of metabolic syndrome and cardiovascular diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Metabolic targets are controversial in older people with type 2 diabetes due to functional heterogeneity and morbidity burden. Tight blood pressure and metabolic control appears beneficial in fit individuals who are newly diagnosed with type 2 diabetes and have fewer comorbidities. The benefits of low blood pressure and tight metabolic control is attenuated with the development of comorbidities, especially frailty. Guidelines consider frail older people as one category and recommend relaxed targets. However, sarcopenic obese frail individuals may benefit from tight targets and intensification of therapy due to their unfavourable metabolic profile, accelerated diabetes trajectory and high cardiovascular risk. In addition, the early use of sodium glucose transporter-2 inhibitors and glucagon like peptide-1 receptor agonists may be beneficial in this frailty phenotype due to their cardio-renal protection, which is independent of glycaemic control, provided they are able to engage in resistance exercise training to avoid loss of muscle mass. In the anorexic malnourished frail individual, early use of insulin, due to its weight gain and anabolic properties, is appropriate. In this phenotype, targets should be relaxed with deintensification of therapy due to significant weight loss, decelerated diabetes trajectory and increased risk of medication side effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: To evaluate the impact of remnant cholesterol (remnant-C) on chronic kidney disease (CKD) incidence in newly-diagnosed type 2 diabetes., Methods: This retrospective cohort study used Korean National Health Insurance Service data on 212,836 patients with newly-diagnosed type 2 diabetes between 2009 and 2014. We conducted cox regression analysis to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for developing CKD according to remnant-C tertile., Results: During a median follow-up duration of 5.23 years, 6,850 CKD cases developed. In the fully adjusted model, HRs and 95 % CIs for incident CKD increased in the highest tertile of baseline remnant-C compared to the lowest (HR [95 % CI]; 1.234 [1.159-1.314]). This association was more prominent in patients with hypertension or low-income status (P for interaction < 0.05). Increased HRs in the highest tertile of remnant-C was sustained in type 2 diabetes patients within target range of conventional lipid profile such as low-density lipoprotein cholesterol (LDL-C) < 100 mg/dL and < 70 mg/dL (1.165 [1.041-1.304] and 1.308 [1.063-1.609]), high-density lipoprotein cholesterol (HDL-C) (1.243 [1.155-1.338]) and triglyceride (1.168 [1.076-1.268]), respectively., Conclusions: In newly-diagnosed type 2 diabetes patients, higher remnant-C is independently associated with CKD incidence, even when conventional lipid values are well-controlled., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To evaluate and summarize the association between interleukin (IL) concentrations and diabetes mellitus (DM) and its complications., Methods: Meta-analyses and eligible individual studies of observational studies investigating the associations between IL and DM and its complications were included. The random-effects model was used to estimate the summary effect, and the heterogeneity among studies was assessed using the Q-statistic and the I 2 metric; The Egger's regression and the χ 2 test were used to test for small study effects and excess significance bias., Results: This overview identified 34 meta-analyses that investigated the association between IL concentrations and DM and its complications. Meta-analyses of prospective studies indicated that elevated circulating IL-6 and IL-1β had predictive value for the incident of type 2 diabetes mellitus (T2DM), type 1 diabetes mellitus (T1DM) as well as gestational diabetes mellitus (GDM), and the overall Hazard Ratio (HR) of T2DM was 1.28 (95 % CI: 1.17, 1.40; P＜0.001) per 1 log pg/ml increment in IL-6 levels, however, there was no correlation between circulating IL-10 levels and DM. Meanwhile, the increased level of IL-6 was significantly associated several diabetic complications (Diabetic kidney disease[DKD], diabetic peripheral neuropathy[DPN], and cognitive impairment[CI]), and for the diabetic retinopathy (DR), the levels of IL-1β, IL-8 and IL-10 in the aqueous humor and vitreous humor, but not the blood were significantly correlated with it., Conclusion: Multiple ILs, such as the IL-6 and IL-1β, are definitively linked to DM and its complications, and they may be new targets for the diagnosis and treatment, but stronger evidence needs to be confirmed by prospective studies with larger sample sizes and longer observation periods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The impacts of subcutaneous Lixisenatide on body weight in patients with type 2 DM, remain inadequately understood; consequently, this systematic review and meta-regression analysis of randomized controlled trials (RCTs) was conducted to evaluate the influence of subcutaneous Lixisenatide administration on BW and BMI values in individuals with Type 2 diabetes., Methods: A comprehensive literature search was conducted across four databases, spanning from their inception to February 2023. We computed effect sizes employing the random-effects model and reported results in terms of weighted mean differences (WMD) along with their corresponding 95% confidence intervals (CI)., Results: 23 articles with 26 RCT arms were included in the meta-analysis. The combined findings from a random-effects model demonstrated a significant reduction in body weight (WMD: -0.97 kg, 95 % CI: -1.10, -0.83, p < 0.001) and BMI (WMD: -0.48 kg/m 2 , 95 % CI: -0.67, -0.29, P < 0.001) after subcutaneous administration of Lixisenatide. Furthermore, a more pronounced reduction in body weight was discovered in RCTs lasting less than 24 weeks (WMD: -1.56 kg, 95 % CI: -2.91, -0.20, p < 0.001), employing a daily dosage of subcutaneous Lixisenatide lower than 19 Âµg per day (WMD: -1.94 kg, 95 % CI: -2.54, -1.34, p < 0.001) and with a mean participant age of 60 years or more (WMD: -1.86 kg, 95 % CI: -3.16, -0.57, p = 0.005)., Conclusions: Lixisenatide was found to significantly decrease BW and BMI in patients with type 2 DM and could be considered as a therapeutic option for those suffering from weight gain caused by other anti-diabetic agents. However, while prescribing Lixisenatide, careful consideration of patient-specific factors is recommended., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: To determine contemporary incidence rates and risk factors for major adverse events in youth-onset T1D and T2D., Methods: Participant interviews were conducted once during in-person visits from 2018 to 2019 in SEARCH (T1D: N = 564; T2D: N = 149) and semi-annually from 2014 to 2020 in TODAY (T2D: N = 495). Outcomes were adjudicated using harmonized, predetermined, standardized criteria., Results: Incidence rates (events per 10,000 person-years) among T1D participants were: 10.9 ophthalmologic; 0 kidney; 11.1 nerve, 3.1 cardiac; 3.1 peripheral vascular; 1.6 cerebrovascular; and 15.6 gastrointestinal events. Among T2D participants, rates were: 40.0 ophthalmologic; 6.2 kidney; 21.2 nerve; 21.2 cardiac; 10.0 peripheral vascular; 5.0 cerebrovascular and 42.8 gastrointestinal events. Despite similar mean diabetes duration, complications were higher in youth with T2D than T1D: 2.5-fold higher for microvascular, 4.0-fold higher for macrovascular, and 2.7-fold higher for gastrointestinal disease. Univariate logistic regression analyses in T1D associated age at diagnosis, female sex, HbA1c and mean arterial pressure (MAP) with microvascular events. In youth-onset T2D, composite microvascular events associated positively with MAP and negatively with BMI, however composite macrovascular events associated solely with MAP., Conclusions: In youth-onset diabetes, end-organ events were infrequent but did occur before 15 years diabetes duration. Rates were higher and had different risk factors in T2D versus T1D., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

There is increasing appreciation of the complex interaction between nonalcoholic fatty liver disease (NAFLD) with type 2 diabetes (T2D) and insulin resistance. Not only is the prevalence of NAFLD disease high among patients with T2D, the liver disease is also more progressive. Currently, the global prevalence of NAFLD in the general population (2016-2019) is 38 %. The prevalence of T2D among those with NAFLD is approximately 23 % while the prevalence of NAFLD among those with T2D can be as high as 70 %. The prevalence of nonalcoholic steatohepatitis (NASH) is approximately 7 % in the general population and 37 % among patients with T2D. Globally, the MENA and Latin America regions of the world appear to have the highest burden of both NAFLD and T2D. Compared to those with NAFLD but without T2D, those with NAFLD and T2D are at a much higher risk for disease progression to cirrhosis and for decompensated cirrhosis, hepatocellular carcinoma, and all-cause mortality. Given that highly effective new treatments are available for T2D, high risk NAFLD with T2D should be considered for these regimens. This requires implementation of risk stratification algorithms in the primary care and endocrinology practices to identify those patients at highest risk for adverse outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Zobair M. Younossi, MD, MPH reports financial support was provided by Intercept, Cymabay, Gilead Sciences, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, NovoNordisk, AstraZeneca, Siemens, Madrigal, Merck, 89Bio, Abbott. Linda Henry, PhD has nothing to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: To evaluate the prevalence of heart failure (HF) in patients with diabetes in tertiary care, and the implementation of sodium-glucose co-transporter 2 inhibitor (SGLT2i)., Methods: Between 28.09.2020 and 31.03.2022, patients enrolled in the Swiss Diabetes Registry at one study centre were screened for HF based on the recommendations by the European Society of Cardiology. Indicated patients were referred for echocardiography and a clinical evaluation of HF, further stratified by preserved (HFpEF), mildly reduced (HFmrEF), and reduced (HFrEF) left ventricular ejection fraction., Results: In total, 534 patients were screened (31.5%, type 1 diabetes (T1D); 59.7%, type 2 diabetes (T2D); 8.8%, other forms). Overall, HF was present in 11.2% (HFpEF, 56.7%; HFmrEF, 11.7%; HFrEF, 31.7%). Prevalence by diabetes type was 2.4%, T1D; 16.0%, T2D; and 10.6%, other forms. Of the identified cases, 40.0% were previously diagnosed and 60.0% were diagnosed as a result of the screening. Of the 24 patients with previously known HF, 50.0% were prescribed SGLT2i (including 2 out of 3 patients with HFrEF)., Conclusions: The fact that most cases of HF were previously undiagnosed and treatment with SGLT2i could be improved highlights the need to increase awareness of HF among healthcare professionals treating patients with diabetes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: To investigate the association between antidepressant prescribing and the rate of insulin initiation in type 2 diabetes., Methods: Using UK primary care records we completed a nested-case control study in a individuals with comorbid depression and type 2 diabetes. Cases were defined as individuals initiating insulin, controls were individuals remaining on oral antidiabetic medication. We used conditional logistic regression to estimate incident rate ratios (IRR) and the 95% confidence intervals (CI) for the association between antidepressant prescribing and initiating insulin. We adjusted for demographic characteristics, comorbidities, health service and previous medication use., Results: We included 11,862 cases who initiated insulin, and 43,452 controls. Increased rates of insulin initiation were associated with any antidepressant prescription (IRR 3.78, 95% CI 3.53-4.04), longer (24+ months) durations of antidepressant treatment (IRR 5.61, 95% CI 5.23-6.03), and higher numbers (3+) of different antidepressant agents prescribed (IRR 5.72, 95% CI 5.25-6.24). There was no difference between recent and non-recent antidepressant prescriptions, or between different antidepressant agents., Conclusions: Antidepressant prescribing was highly associated with the initiation of insulin therapy. However, this may not indicate a direct causal effect of the antidepressant medication itself, and may be a marker of more severe depression influencing diabetic control., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: This study aimed to conduct a prospective, randomized, controlled clinical trial using, Qidan Tangshen Granule, a traditional Chinese medicine (TCM), as an antioxidant, to treat diabetic kidney disease (DKD) patients., Methods: A total of 355 patients were enrolled, and after exclusions, 219 patients were divided into an intervention group (n = 109) receiving Qidan Tangshen Granule treatment and a control group (n = 110) receiving conventional treatment. Demographic and physiological parameters were evaluated at baseline and 3 months and 12 months of follow-up. The levels of serum oxidants including 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 3-nitrotyrosine (3-NT), and the enzymic anti-oxidant, superoxide dismutase (SOD), were evaluated using enzyme-linked immunosorbent assays., Results: Qidan Tangshen Granule treatment significantly reduced hemoglobin A1c (HbA1c) and albumin-to-creatinine ratio (UACR) levels, improved renal function, and exerted antioxidative effects in DKD patients. Compared to the control group, the intervention group showed increased levels of SOD and decreased levels of 8-OHdG and 3-NT, indicating reduced oxidative stress. Furthermore, the intervention group demonstrated a significant decrease in HbA1c and UACR levels and an improvement in glomerular filtration rate compared to the control group., Conclusions: Qidan Tangshen Granule may be a potential therapeutic option for the treatment of DKD, offering improved clinical outcomes for patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: To evaluate sustainability of peer support (PS) benefits in diabetes management., Methods: Supporting a Peer Leader program through Community Health Centers (CHCs) included trainings and consultations from baseline to 12 months. Evaluation at baseline, 12-month, and 18-month follow-up included primary outcome, HbA 1c , and other outcomes of SBP, DBP, LDLc, PHQ-8, diabetes distress, and EQ-5D., Results: 1284 participants with type 2 diabetes mellitus were recruited from 9 CHCs. Mean (SD) for age = 68.00 (7.55) years, 43.07 % male, mean (SD) for diabetes duration = 11.79 (7.34) years. Across 18-months, linear mixed model analyses controlling for confounders found the least square mean (SE) of HbA 1c improved significantly from 7.62 % (0.06 %) to 7.53 % (0.06 %) for all, and from 9.25 % (0.09 %) to 8.52 % (0.11 %) among those ≥8 % at baseline. Parallel improvements were found among all for SBP, DBP, PHQ-8, diabetes distress, and, among those elevated at baseline for all outcomes. EQ-5D showed significant but modest increase from baseline to 18 months. No significant reversals between 12 and 18 months were found except for LDLc. Supporting robustness of findings, patterns were similar across age, diabetes duration, and gender., Conclusions: Relative to the fundamentally progressive nature of diabetes, it is striking that improvements associated with PS were generally sustained after program support ended., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Edwin B. Fisher reports a relationship with Eli Lilly Company that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: To investigate the risk of major depression and dementia in patients with type 2 diabetes, including dementia resulting from depression, and their impact on diabetes-related complications and mortality., Methods: We conducted a population-based retrospective cohort study including 11,441 incident cases of diabetes in 2015-2017, with follow-up until 2022. A multi-state survival analysis was performed on a seven-state model with 15 transitions to capture disease progression and onset of mental disorders., Results: Eight-year probabilities of depression, dementia, diabetes-related complications, and death were 9.7% (95% CI 8.7-10.7), 0.9% (95% CI 0.5-1.3), 10.4% (95% CI 9.5-11.4), and 14.8% (95% CI 13.9-15.7), respectively. Depression increased the risk of dementia up to 3.7% (95% CI 2.0-5.4), and up to 10.3% (95% CI 0.3-20.4) if coupled with diabetes complications. Eight-year mortality was 37.5% (95% CI 33.1-42.0) after depression, 74.1% (95% CI 63.7-84.5) after depression plus complications, 76.4% (95% CI 68.8-83.9) after dementia, and 98.6% (95% CI 96.1-100.0) after dementia plus complications., Conclusions: The interconnections observed across depression, dementia, complications, and mortality underscore the necessity for comprehensive and integrated approaches in managing diabetes. Early screening for depression, followed by timely and targeted interventions, may mitigate the risk of dementia and improve diabetes prognosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: Antidepressants are widely used by individuals with type 2 diabetes mellitus (T2DM). This study aimed to explore the correlation between antidepressant use, considering specific antidepressant subclasses or cumulative doses, and diabetic foot ulcer (DFU) risk., Methods: This nested case-control study was conducted using a representative population-based Korean cohort database from 2002 to 2019. Participants with DFUs were matched with participants without DFUs based on age, sex, date of T2DM diagnosis, and follow-up duration. In total, 791 DFUs and 3900 controls were included. The association between antidepressant use or cumulative dose of each antidepressant subclass, DFU risk and amputation risk was examined using a conditional logistic regression model., Results: Antidepressant ever-use was associated with an increased incidence of DFUs compared with non-use. Furthermore, an increase in DFU risk was evident with increasing cumulative antidepressant dosage, particularly among tricyclic antidepressant (TCA) ever-users and selective serotonin reuptake inhibitors (SSRIs) ever-users. Additionally, antidepressant ever-users displayed a higher risk of DFUs requiring amputation, which was consistently observed when the cumulative dosages of overall antidepressants and TCAs were considered., Conclusion: Caution is advised when administering TCAs and SSRIs in antidepressant-naïve T2DM patients to reduce DFU and the consequent amputation risk., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Sodium glucose co-transporter 2 inhibitors (SGLT2is) and/or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with proven cardio- and reno-protective benefits are recommended in people with type 2 diabetes (T2D) at high risk of cardiovascular disease, chronic kidney disease, and/or heart failure. This pooled analysis compared efficacy and safety outcomes of iGlarLixi with or without SGLT2is in people with T2D., Methods: This post hoc analysis evaluated outcomes in participants who were receiving an SGLT2i when initiating iGlarLixi (SGLT2i users) and those who were not (SGLT2i non-users) in a pooled dataset from three trials: LixiLan-G (advancing from a GLP-1 RA), SoliMix and LixiLan ONE CAN (advancing from basal insulin)., Results: Baseline characteristics were generally similar between 219 users and 746 non-users. Least squares mean changes in HbA 1c from baseline to Week 26 were similar for users (-1.2 % [95 % confidence intervals: -1.4 %, -1.1 %]) and non-users (-1.2 % [-1.2 %, -1.1 %]). Changes in body weight, fasting glucose and post-prandial glucose were similar between groups, as were hypoglycaemic events., Conclusions: Pooled results from three studies of adults with T2D demonstrated that iGlarLixi provided similar clinically meaningful improvements in glycaemic control without increased hypoglycaemia risk, regardless of concomitant use of SGLT2is., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: FG: has served as an advisor for Eli Lilly, Medtronic, Novo Nordisk, Roche Diabetes Care and Sanofi; has received payment of honoraria for lectures, presentations, manuscript writing or education events from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Medtronic, Novo Nordisk, Roche Diabetes Care and Sanofi; has patents planned, issued or pending for Roche Diabetes Care; has served as a research investigator for Eli Lilly, Novo Nordisk and Roche Diabetes Care, and has received grants from Eli Lilly and Roche Diabetes Care. CG: has participated in scientific advisory boards for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk and Sanofi and has received consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Krka, Merck KGaA, MSD, Novo Nordisk, Sanofi and Servier. HA: Nothing to disclose. FL is an employee of Sanofi; may hold shares and/or stock options. LMM: Employee of Ividata Life Sciences, Levallois-Perret, France, contracted by Sanofi. JR has served on advisory panels for Applied Therapeutics, Boehringer Ingelheim, Eli Lilly, Hanmi, Intarcia, Novo Nordisk, Oramed, Sanofi, Structure Therapeutics, Terns Pharma and Zealand, and has received research support from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Intarcia, Merck, Novo Nordisk, Oramed, Pfizer and Sanofi., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cardiovascular disease (CVD) risk in those with diabetic foot disease is very high. Non-pharmacological interventions may improve this risk, though no previous evidence synthesis has been completed. This systematic review aimed to investigate the impact of non-pharmacological interventions on CVD risk factors in diabetic ulcer disease. Multiple databases and trials registers were searched from inception to December 6th 2023. We included reports of randomised controlled trials investigating the impact of non-pharmacological interventions on cardiovascular risk in those with type 1 or type 2 diabetes and current or previous diabetic foot disease. Twenty studies were included. Extracted data included: study design and setting; participant sociodemographic factors; and change in cardiovascular risk factors. Data were synthesised using random effects meta-analyses and narrative syntheses. Interventions included nutritional supplementation, collaborative care, hyperbaric oxygen therapy, patient education, nurse-led intervention, self-management, family support, relaxation and exercise, over a median duration of 12 weeks. Significant post-intervention changes were observed in fasting plasma glucose, serum insulin levels, insulin sensitivity and resistance, glycated haemoglobin, triglycerides, total cholesterol, low-density lipoprotein-cholesterol and C-reactive protein. No effects were detected in very low- or high-density lipoprotein-cholesterol or body mass index. Non-pharmacological interventions show promise in improving CVD risk in diabetic foot disease., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JV is National Clinical Director for Diabetes and Obesity at NHS England. JV is supported by the NW London NIHR Applied Research Collaboration and the Imperial NIHR Biomedical Research Centre. MD has acted as consultant, advisory board member and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk and Sanofi, an advisory board member Lexicon, Pfizer, ShouTi Pharma Inc, AstraZeneca and Medtronic and as a speaker for AstraZeneca, Napp Pharmaceuticals, Novartis and Amgen, and has received grants from AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Janssen and Sanofi-Aventis and Eli Lilly. KK has acted as a consultant, speaker or received grants for investigator-initiated studies for Astra Zeneca, Bayer, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly and Merck Sharp & Dohme, Boehringer Ingelheim, Oramed Pharmaceuticals, Roche and Applied Therapeutics., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: In this study, we aimed to evaluate the impact of overall cardiovascular disease (CVD) risk on the development of incident T2DM in patients with prediabetes., Methods: We retrospectively enrolled 5,908 subjects with prediabetes who underwent health check-ups at the Asan Medical Center. CVD risk was estimated using the Framingham Risk Score (FRS). We compared moderate- to high-risk groups with low-risk controls based on the FRS. Cox proportional hazards regressions were conducted to estimate the time-to-develop incident T2DM., Results: Among the 5908 subjects with prediabetes, 3031 (51.8 %) were identified to have either moderate or high CVD risk scores. During a median follow-up of 5.2 years, 278 (9.2 %) patients from the moderate- to high-risk group and 171 (5.9 %) from the low-risk group were diagnosed with T2DM. The covariate-adjusted hazard ratio for the incident T2DM was 1.30 (95 % CI, 1.06-1.60, p = 0.011) in the moderate- to high-risk group compared to the low-risk controls., Conclusion: Among patients with prediabetes, those with high CVD risk were more likely to develop incident T2DM, as determined by the FRS. CVD risk factors should be properly evaluated and managed in individuals with prediabetes to reduce the risk of both incident T2DM and associated cardiovascular complications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: This Mendelian randomization (MR) study aimed to investigate the relationships between type 1 diabetes (T1D), type 2 diabetes (T2D), and glycemic traits, including fasting insulin, fasting glucose, and HbA1c, with cardiovascular diseases (CVDs)., Methods: We selected genetic instruments for predisposition to T1D, T2D, fasting insulin, fasting glucose, and HbA1c based on published genome-wide association studies. Using a 2-Sample MR approach, we assessed associations with 12 common CVDs sourced from the FinnGen and UK Biobank studies, along with stroke subtypes obtained from the GIGASTROKE and MEGASTROKE Consortium., Results: T1D was associated with SVS. T2D showed associations with AIS, LAA, CES, SVS, coronary heart disease, myocardial infarction, pulmonary embolism, DVT of lower extremities, peripheral vascular diseases. Genetically predicted higher HbA1c levels were associated with eight CVDs. The results of MVMR aligned with the primary findings for T1D and T2D., Conclusions: T1D and T2D exhibit different genetic predisposition to CVDs. BMI, LDL, and HDL play intermediary roles in connecting TID and T2D to specific types of CVDs, providing insights into the potential underlying pathways and mechanisms involved in these relationships. Strategies aimed at achieving sustained reductions in HbA1c levels may offer potential for reducing the risk of various CVDs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: To assess the impact of age on the prognostic value of NT-proBNP concentration in patients with type-2 diabetes mellitus (T2DM) stabilised after an Acute Coronary Syndrome (ACS)., Methods: The AleCardio study compared aleglitazar with placebo in 7226 patients with T2DM and recent ACS. Patients with heart failure were excluded. Median follow-up was 104 weeks. Baseline NT-proBNP plasma concentration was measured centrally. Multivariable Cox regression was used to determine the mortality predictive information provided by NT-proBNP across age groups., Results: Median age was 61y (IQR 54, 67). NT-proBNP concentration increased by quartile (Q) of age (median 264, 318, 391, and 588 pg/ml). Compared to Q1, patients in Q4 of NT-proBNP had higher (p < 0.001) adjusted HR for all-cause (aHR 6.9; 95 % CI 4.0-12) and cardiovascular (11; 5.4-23) death. Within each age Q, baseline NT-proBNP in patients who died was 3 times higher than in survivors (all p < 0.001). When age and NT-proBNP levels were modeled as continuous variables, their interaction term was nonsignificant. The relative prognostic information provided by NT-proBNP (percent of total X 2 ) increased from 38 % in age Q1 to 75 % in age Q4 for mortality, and from 50 % to 88 % for CV death., Conclusions: Among patients with T2DM stabilised after an ACS, NT-proBNP level predicts death irrespective of age., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: To assess the impact of long-term visit-to-visit variability in HbA 1c on microvascular outcomes in type 2 diabetes mellitus (T2DM), and its influence on the effects of intensive glycemic control., Methods: Included were participants with T2DM enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) who had at least three measurements of HbA 1c prior to new-onset microvascular outcomes, namely nephropathy, retinopathy and neuropathy. Variability in HbA 1c was defined as the coefficient of variation (CV) across HbA 1c measurements obtained from enrollment to the transition from intensive to standard glycemic therapy., Results: During a median of 22,005, 23,121, and 13,080 person-years of follow-up, 2,905 nephropathy, 2,655 retinopathy, and 1,974 neuropathy cases were recorded, respectively. Median CV (IQR) was 7.91 % (5.66 %-10.76 %) in the standard treatment group and 9.79 % (7.32 %-13.35 %) in the intensive treatment group. In the standard treatment group, lower HbA 1c -CV (the first versus the second quartile) was associated with a higher risk of all microvascular outcomes, while higher HbA 1c -CV (the fourth quartile) was associated with a higher risk of nephropathy only. In the intensive treatment group, only higher HbA 1c -CV was associated with a higher risk of developing the microvascular outcomes. Intensive therapy reduced all microvascular outcomes among individuals with lower HbA 1c -CV, but increased the risk among those with the highest HbA 1c -CV (all P values for interaction < 0.0001). For example, hazard ratios (95 % CI) of retinopathy comparing intensive with standard treatments were 0.65 (0.56-0.75), 0.84 (0.71-0.98), 0.97 (0.82-1.14) and 1.28 (1.08-1.53) across the lowest to the highest quartiles of HbA 1c variability., Conclusions: The effects of intensive glycemic control on microvascular outcomes in T2DM appear to be modified by the variability of HbA 1c during the treatment process, suggesting the significance of dynamic monitoring of HbA 1c levels and timely adjustments to the therapeutic strategy among individuals with a high HbA 1c variability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: Type 2 diabetes (T2D) and coronary artery disease (CAD) often coexist and share genetic factors.This study aimed to investigate the common genetic factors underlying T2D and CAD in patients with CAD., Methods: A three-step association approach was conducted: a) a discovery step involving 943 CAD patients with T2D and 1,149 CAD patients without T2D; b) an eliminating step to exclude CAD or T2D specific variants; and c) a replication step using the UK Biobank data., Results: Ten genetic loci were associated with T2D in CAD patients. Three variants were specific to either CAD or T2D. Five variants lost significance after adjusting for covariates, while two SNPs remained associated with T2D in CAD patients (rs7904519*G: TCF7L2 and rs17608766*C: GOSR2). The T2D susceptibility rs7904519*G was associated with increased T2D risk, while the CAD susceptibility rs17608766*C was negatively associated with T2D in CAD patients. These associations were replicated in a UK Biobank data, confirming the results., Conclusions: No significant common T2D and CAD susceptibility genetic association was demonstrated indicating distinct disease pathways. However, CAD patients carrying the T2D susceptibility gene TCF7L2 remain at higher risk for developing T2D emphasizing the need for frequent monitoring in this subgroup., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Aims: The prevalence of Type 2 Diabetes Mellitus (T2DM) is projected to be 7 % in 2030. Despite its need for long-term diabetes care, the adherence rate of injectable medications such as insulin is around 60 %, lower than the acceptable threshold of 80 %. This study aims to create classification models to predict insulin adherence among adult T2DM naïve insulin users., Methods: Clinical data were extracted from Taipei Medical University Clinical Research Database (TMUCRD) from January 1st, 2004 to December 30th, 2020. A patient was regarded as adherent if his/her medication possession ratio (MPR) was at least 80 %. Seven domains of predictors were created, including demographics, baseline medications, baseline comorbidities, baseline laboratory data, healthcare resource utilization, index insulins, and the concomitant non-insulin T2DM medications. We built two Xgboost models for internal and external testing respectively., Results: Using a cohort of 4134 patients from Taiwan, our model achieved the Area Under the curve of the Receiver Operating Characteristic (AUROC) of the internal test was 0.782 and the AUROC of the external test was 0.771. the SHAP (SHapley Additive exPlanations) value showed that the number of prescribed medications, the number of outpatient visits, and laboratory data were predictive of future insulin adherence., Conclusions: This is the first study to predict adherence among adult naïve insulin users. The developed model is a potential clinical decision support tool to identify possible non-adherent patients for healthcare providers to design individualized education plans., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Glucagon-like peptide-1 receptor (GLP-1R) agonists are approved treatments for Type 2 diabetes mellitus, with liraglutide and semaglutide also approved for the treatment of obesity. The natural gut hormone oxyntomodulin is a weak dual agonist of the glucagon receptor (GCGR) and GLP-1R. Development of poly-agonists mimicking oxyntomodulin, such as the novel dual GCGR/GLP-1R agonist survodutide, represents an important step towards a more effective treatment for people with Type 2 diabetes mellitus and obesity. Survodutide is a 29-amino acid peptide derived from glucagon, with the incorporation of potent GLP-1 activities. It contains a C18 diacid which mediates binding to albumin, thereby prolonging the half-life to enable once-weekly subcutaneous dosing. The utilisation of GCGR agonism aims to enhance body weight-lowering effects by increasing energy expenditure in addition to the anorectic action of GLP-1R agonists. Glucose-lowering efficacy of survodutide has been demonstrated in a Phase II trial in patients with Type 2 diabetes mellitus and obesity and was associated with clinically meaningful body weight loss. These data highlight the potential of dual GCGR/GLP-1R agonism for reducing glycated haemoglobin and body weight in patients with Type 2 diabetes mellitus, and for greater therapeutic efficacy compared with GLP-1R agonism alone., Competing Interests: Declaration of Competing Interest The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE) and did not receive payment related to the development of this manuscript. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy, as well as intellectual property considerations. Thomas Klein, Robert Augustin and Anita M. Hennige are employees of Boehringer Ingelheim., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: This study examined the association between hypoglycemia and mild cognitive impairment (MCI) among patients with type 2 diabetes mellitus (T2DM) and identified risk factors for MCI in patients with hypoglycemia., Methods: In this retrospective study, 328 patients with T2DM were screened in 2019 and followed up in 2022. Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA). The diagnosis of MCI was based on established criteria. Risk ratio (RR) with 95 % confidence intervals (CI) was calculated to estimate the risk of MCI. Univariate and multivariate logistic regression analyses were conducted to identify risk factors for MCI in those with hypoglycemia., Results: Patients with hypoglycemia had lower cognitive performance 3 years later. The RR of MCI was 2.221 (95 % CI 1.269-3.885). Multivariate logistic analysis showed that low grip strength, existing diabetic retinopathy (DR), and multiple hypoglycemia episodes were associated with higher odds of MCI in patients with hypoglycemia (adjusted odds ratio [OR] 0.909 [95 % CI 0.859-0.963]), 3.078 [95 % CI 1.158-12.358], and 4.642 [95 % CI 1.284-16.776], respectively, all P < 0.05)., Conclusions: Hypoglycemia increased MCI risk among patients with T2DM. Low grip strength, DR, and multiple hypoglycemia episodes may be potential risk factors for hypoglycemia-associated MCI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Aim: To assess the relationship of the presence of sarcopenia and malnutrition with unfavorable clinical outcomes: prolonged length of hospital stay (LOS), readmission, and one-year mortality in older patients with type 2 diabetes (T2D)., Methods: Were included 319 patients with ≥ 60 years of age with T2D hospitalized at a university hospital in Southern Brazil. Sarcopenia was diagnosed according to handgrip strength (HGS), calf circumference (CC), and the timed up and go (TUG) walking test, and malnutrition according to the subjective global assessment (SGA) and the mini nutritional assessment long form (MNA-LF). Multivariate analyses, adjusted for confounders, were performed to assess the association of sarcopenia and malnutrition with clinical outcomes. One-year survival was compared using Kaplan-Meier analysis., Results: The association between sarcopenia and malnutrition increased by 2.42 times (95 %CI 1.35-4.36) the probability of LOS ≥ 14 days and by 2.01 times (95 %CI 1.09-3.72) the risk of one-year mortality. Older patients with malnutrition and sarcopenia have a higher risk of one-year mortality (log-rank p < 0.05) compared with well-nourished patients without sarcopenia., Conclusion: In older patients with type 2 diabetes, those with sarcopenia, and malnutrition have higher odds of prolonged hospitalization and risk of mortality within one year after hospital discharge., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: To investigate the prevalence of peripheral artery disease (PAD) and diabetic peripheral neuropathy (DPN) and the associated risk factors among Chinese patients with type 2 diabetes mellitus., Methods: A cross-sectional study was conducted using data between November 1, 2018, and December 31, 2022. PAD was defined as ABI ≤ 0.9. DPN diagnosis involved specialized physician assessments using questionnaires and vibration perception threshold tests. Logistic regression analysis was used to identify related factors. We also evaluated the association between the clustering of risk factors and disease incidence., Results: The study population comprised 13,315 patients (mean age: 63.3 years). 4.9 % of the patients had PAD and 43.9 % had DPN. Multivariate regression analysis revealed advanced age, smoking, hypertension, coronary heart disease, dyslipidemia, elevated HbA1c, and uric acid levels as independent risk factors for PAD. For DPN, independent risk factors included advanced age, female gender, hypertension, coronary heart disease, elevated total cholesterol, triglycerides, lipoprotein(a), fasting plasma glucose, HbA1c, alkaline phosphatase, cystatin C, albumin-to-creatinine ratio, and elevated homocysteine levels, whereas apolipoprotein A was a protective factor. The clustering of risk factors was prevalent and associated with higher disease risk., Conclusions: Our study contributed to identifying high-risk individuals and improving lower limb health among diabetic individuals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: To develop a metric termed the diabetic retinopathy-related homeostatic dysregulation (DRHD) value, and estimate its association with future risk of mortality in individuals with type 2 diabetes., Methods: With the data of the NHANES, the biomarkers associated with DR were identified from 40 clinical parameters using LASSO regression. Subsequently, the DRHD value was constructed utilizing the Mahalanobis distance approach. In the retrospective cohortof 6420 type 2 diabetes patients, we estimated the associations between DRHD values and mortality related to all-cause, cardiovascular disease (CVD) and diabetes-specific causes using Cox proportional hazards regression models., Results: A set of 14 biomarkers associated with DR was identified for the construction of DRHD value. During an average of 8 years of follow-up, the multivariable-adjusted HRs and corresponding 95 % CIs for the highest quartiles of DRHD values were 2.04 (1.76, 2.37), 2.32 (1.78, 3.01), and 2.29 (1.72, 3.04) for all-cause, CVD and diabetes-specific mortality, respectively. Furthermore, we developed a web-based calculator for the DRHD value to enhance its accessibility and usability (https://dzwxl-drhd.streamlit.app/)., Conclusions: Our study constructed the DRHD value as a measure to assess homeostatic dysregulation among individuals with type 2 diabetes. The DRHD values exhibited potential as a prognostic indicator for retinopathy and for mortality in patients affected by type 2 diabetes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)