Type 2 Diabetes Mellitus Research Articles

Telomere shortening and cardiac alterations in asymptomatic type 2 diabetes patients: impact of sex

Abstract Background Telomere shortening is associated with the occurrence of deleterious events in the context of cardiometabolic disorders, including type 2 diabetes mellitus (T2DM). However, no evidence is available on the link between leukocyte telomere length (LTL) and subclinical cardiac alterations in T2DM patients. Purpose Our aim is to evaluate the relation between LTL and cardiovascular function in asymptomatic T2DM patients, taking into consideration the impact of the sex. Methods We analyzed a cohort of asymptomatic T2DM patients free from any overt cardiovascular disease (including coronary artery disease) and other T2DM comorbidities. A detailed metabolic and echocardiographic evaluation was performed together with LTL measurements at inclusion and after 2 years of follow-up. Univariate analyses in regard of the comparison of three graded LTL tertiles and different gender were used to test individual relationships betweenbioclinical and echocardiographic parameters and LTL measures. Subsequently, an unsupervised clustering method (self-organizing maps [SOM]) was used to identify cluster at risk of cardiomyopathy. Results We studied 89 T2DM patients aged 50±4 years (43% female) with a mean T2DM duration of 10±5.8 years and an average follow-up of 2.1±0.2 years. Leukocyte TL analysis demonstrated a slight but significant attrition after 2 years. The analysis of echocardiographic variables (transmitral flow velocities, velocity of mitral annular motion, left ventricular ejection fraction) did not show any evidence for ouvert cardiomyopathy. However, in the lower LTL tertile a higher proportion of patients with global longitudinal strain [GLS]<18% was found [41.6% vs. 22.8% vs. 21.6%]. Interestingly, leukocyte TL was associated with T2DM duration, FIB-4, a noninvasive indice used to assess fibrosis associated with non-alcoholic fatty liver disease (NAFLD), and usage of GLP-1 agonists. Comparison of men and women by univariate analysis did not show any differences in both LTL and echocardiographic parameters. However, unsupervised cluster method (SOM) unmasked a subgroup of female T2DM patients with diastolic alterations (e’ mean) and systolic alteration (GLS) both linked with lower LTL, whereas no specific subgroup in male T2DM patients could be distinguished. Conclusion Our study identifies subclinical diastolic and systolic dysfunction together with shorter LTL in a subgroup of female T2DM patients. These findings raise the importance of considering sex effect in the understanding of diabetic cardiomyopathy.

Empagliflozin's role in reducing ventricular repolarization heterogeneity: insights into cardiovascular mortality decline from the EMPATHY-HEART trial

Abstract Introduction The incidence of myocardial infarction (MI) and sudden cardiac death (SCD) is significantly higher in individuals with Type 2 Diabetes Mellitus (T2DM). Predictive measures for fatal arrhythmias are often inadequate, highlighting the need for novel non-invasive diagnostic tools. The T-wave heterogeneity (TWH) index, which measures variations in ventricular repolarization, has emerged as a promising predictor for severe ventricular arrhythmias. Although the EMPA-REG trial reported reduced cardiovascular mortality with empagliflozin, the underlying mechanisms remain unclear. This study investigates the potential of empagliflozin in mitigating electrical instability in patients with T2DM and coronary heart disease (CHD) by examining changes in TWH. Methods Participants were adult outpatients with T2DM and CHD, exhibiting a baseline TWH of at least 80 µV. They received a 25mg daily dose of empagliflozin and were evaluated clinically, including ECG measurements at baseline and after 4 weeks. TWH was computed from leads V4, V5, and V6 using a validated technique. The primary study outcome was the alteration in TWH following empagliflozin administration, assessed via the Wilcoxon test, with a significance threshold of p<0.05. Results An initial review of 6,000 medical records pinpointed 800 patients for TWH evaluation. Of these, 412 exhibited TWH above 80 µV, with 144 completing clinical assessments and 90 meeting the criteria for high cardiovascular risk enrollment. Empagliflozin adherence exceeded 80%, resulting in notable reductions in blood pressure without affecting heart rate. Side effects were generally mild, with 13.3% experiencing mostly Level 1 hypoglycemia, alongside infrequent urinary and genital infections. The treatment consistently reduced median TWH from 116 to 103 µV (p=0.01), as detailed in Figure 1. Conclusion The EMPATHY-HEART trial preliminarily suggests that empagliflozin decreases heterogeneity in ventricular repolarization among patients with T2DM and CHD. This reduction in TWH may provide insight into the mechanism behind the decreased cardiovascular mortality observed in previous trials, potentially offering a therapeutic pathway to mitigate the risk of severe arrhythmias in this population.Table 1 Figure 1

Investigating socioeconomic disparities in prescribing new diabetes medication

Abstract Background There is a concern regarding socioeconomic disparities in prescription of new medications such as SGLT-2is or GLP-1RAs in type 2 diabetes mellitus (T2DM). This study aims to analyze prescription patterns of these medications and assess socioeconomic disparities in their initiation among individuals with T2DM with very high cardiovascular risk. Methods Individuals diagnosed with T2DM and very high cardiovascular risk were identified (N = 10,768) based on general practitioner’ electronic health record data. Socioeconomic status (SES) was based on standardized disposable household income in quintiles. The association between SES and the prescription of SGLT-2is and GLP-1RAs in 2022 was investigated by logistic regression analyses, adjusting for potential confounding factors. SGLT-2is and GLP-1RAs prescription patterns were examined over 2019-2022, stratified for age-groups and sex. Results We found a positive association between SES quintile 1 (referent) and quintile 4 in SGLT-2is prescription in all models (OR 1.29 95%CI:1.08-1.54 in the fully adjusted model). For prescriptions of GLP-1RAs, we found no significant differences in SES. Proportionally, men are more frequently prescribed SGLT-2is, while there are no sex disparities in GLP-1RAs prescription. Older individuals consistently receive fewer SGLT-2is and GLP-1RAs prescriptions compared to other age categories. Conclusions We observed sex and age disparities but no profound socioeconomic differences in initiation of SGLT-2is and GLP-1RAs in the Netherlands. The latter may be due to guidelines’ clear indication of the eligible population (T2DM and very high cardiovascular risk) and GP education. Future development and potential disparities in initiation and maintenance should be monitored. Key messages • We found no disparities in prescribing new Type 2 diabetes medication based on socioeconomic status. • The adoption of prescribing new medication for Type 2 diabetes patients takes time.

Association of insulin resistance with cardiovascular disease and all-cause mortality in type 1 diabetes mellitus: systematic review and meta-analysis

Abstract Background Insulin resistance (IR) is a key factor in the pathogenesis of type 2 diabetes mellitus (T2DM) and is associated with a higher risk of cardiovascular disease (CVD) and mortality. However, the association between IR and these outcomes in type 1 diabetes mellitus (T1DM) is less clear. This systematic review and meta-analysis aimed to investigate the associations between CVD outcomes and IR in T1DM. Methods PubMed, EMBASE, and the Cochrane Library databases were searched from inception to 15 March 2023 and updated on 31 October 2023. Observational studies (cohort studies or post hoc analysis of clinical trials) reporting the associations between IR measured by estimated glucose disposal rate (eGDR) level and the risk of CVD and all-cause mortality in individuals with T1DM were eligible. Data, pooled by random effects models, were presented as hazard ratios (95% confidence intervals, CI). The primary outcomes were the composite CVD outcome and all-cause mortality. Results Eight studies involving 21,930 individuals were included, of which five studies involving 19,960 T1DM individuals reported the risk of CVD. During a median follow-up of 10 years, there were 2,149 cases of incident CVD. The pooled hazard ratio for composite CVD outcome per 1-unit increase in the eGDR index was 0.83 (95% CI 0.78–0.90, I2 = 58.9%). Five studies involving 19,403 T1DM individuals reported the risk of all-cause mortality. During a median follow-up of 10 years, a total of 1,279 deaths were observed. The pooled hazard ratio for all-cause mortality per 1-unit increase in the eGDR index was 0.84 (95% CI 0.81–0.87, I2 = 0%). Conclusions IR as measured by eGDR may be an additional risk factor for cardiovascular disease and all-cause mortality in individuals with T1DM. Modification of IR by lifestyle interventions or pharmacological treatments could be a viable therapeutic target to lower the risk of CVD in T1DM.Figure 1 Literature flowchartFigure2 Forest plot

The condition of myocardium reserves score from a cloud-based analytics platform of Holter ECG data indicates better cardiometabolic function in heart failure

Abstract Introduction Cardiometabolic dysregulation, particularly type 2 diabetes mellitus (T2DM), is associated with subtle myocardial pathologies, even in individuals without known cardiovascular disease. These subclinical changes, often undetectable by standard electrocardiogram (ECG) analytics, can offer valuable insights into the relationship between metabolic health and cardiac function. Novel ECG markers, developed through machine learning and artificial intelligence (AI), may provide the sensitivity needed to detect such changes. Aim This study aims to evaluate novel composite cardiac parameters from an analytics platform in the context of heart failure (HF), seeking to understand their relationship to cardiometabolic dysregulation. Methods Data from the MyoVasc study, a prospective cohort on HF, were analysed. Participants underwent extensive clinical phenotyping, including a Holter ECG assessment. Holter ECG data was processed based on machine learning and AI models on a cloud-based analytics platform (Cardiolyse, Helsinki, Finland), generating both traditional and proprietary ECG, and heart rate variability cardiac health markers. LASSO-penalized logistic regression adjusted for sex and age was performed to select the marker most strongly associated with T2DM. The identified marker was then evaluated in relation to cardiac function and structure as well as HF-related outcome. Results A total of 953 subjects (mean±SD age 64.6±10.5 years; 35.7% women) were included in the analyses. Symptomatic HF stage C/D was present in 54.8% (n=522) of subjects and diabetes mellitus in 22.4% (n=213). The Condition of Myocardium Reserves Score (CMRS) was the novel composite cardiac parameter selected based on its relationship with T2DM. In a Poisson regression model with robust variance adjusted for sex and age, a lower score was associated with T2DM (Prevalence ratio per SD 1.24, 95% confidence interval [1.14;1.36], P=0.0002). In multivariable linear regressions adjusted for traditional cardiovascular risk factors, comorbidities, and medication, a higher CMRS was associated with better global longitudinal strain (β per SD –0.82 [–1.11;–0.53], P<0.0001), diastolic function (left ventricular E/e’; β per SD –0.04 [–0.06;–0.01], P=0.0059) and systolic function (LV ejection fraction; β per SD 2.06 [1.46;2.67], P<0.0001). A lower CMRS independently predicted all-cause death (Hazard ratio per SD 1.25 [1.09;1.45], P=0.0020) and worsening of HF (HR per SD 1.44 [1.21;1.72], P<0.0001) in Cox regression analysis adjusted for the same confounders. Conclusion The Condition of Myocardium Reserves Score exhibited a strong association with cardiometabolic dysregulation. A higher CMRS indicated preserved cardiac function, while a lower score independently predicted increased risk of all-cause death and worsening HF. This novel score offers potential as a non-invasive tool for assessing cardiometabolic health and stratifying risk in patients with HF.

Predicting mortality of type-2 diabetes mellitus by applying machine learning to electronic medical records in the west of scotland and hong kong

Abstract Introduction Type 2 diabetes mellitus (T2DM) is associated with accelerated development of atherosclerosis and a reduced life expectancy. Using machine learning (ML) to identify novel characteristics from electronic medical records (EMRs) associated with prognosis may increase prognostic precision and find new targets for investigation and treatment. Aim We used a novel ML approach to investigate the use of EMRs to predict all-cause mortality in two ethnically and geographically different populations; one from the West of Scotland (WoS) and the other from Hong Kong. Methods We obtained EMRs including demographics, prior comorbidities, laboratory measurements, medications, and mortality. Multivariable Cox regression and time-dependent random forest model were used to identify predictors of all-cause mortality in patients with T2DM. Subsequently, we applied a state-of-the-art ML interpretability method, to gain further insight into the key predictors. Results In WoS, 46,031 individuals received a new diagnosis of T2DM between 2009 and 2019. Their median age was 66 (IQR: 56 to 75) years. Within 10 years, 11,727 (25%) deaths were recorded. In Hong Kong, 273,876 patients with a first-attendance with T2DM at public hospitals or clinics were included, with follow-up until December 2019. The median age of the patients was 64 (IQR: 57 to 72) years. Within 10 years, 91,155 (33%) deaths were recorded. For both cohorts, the strongest predictor for all-cause mortality was prescription of loop diuretics (Figure 1). For the WoS, other important predictors were greater age, lower serum albumin, elevated alanine transaminase (ALT), increased alkaline phosphatase (ALP), and lower estimated glomerular function rate (eGFR) (c-index: 0.83; Brier score: 0.07). For Hong Kong, predictive variables were remarkably similar and included greater age, lower eGFR, lower haemoglobin and lymphocytes, lower serum albumin, and elevated ALP (c-index: 0.85; Brier score: 0.06). Multivariable Cox regression adjusting for age and sex showed a higher mortality amongst those prescribed loop diuretics compared to those who were not (WoS: hazard ratio: 1.549, 95% CI: 1.521 to 1.575; Hong Kong: hazard ratio: 1.745 (95% CI: 1.721 to 1.769). Only a minority of patients prescribed loop diuretics had a diagnosis of heart failure, end-stage renal disease or resistant hypertension. Conclusion Amongst patients with recent-onset T2DM, prescription of loop diuretics was the most important predictor of all-cause mortality in both WoS and Hong Kong. Prescription of loop diuretics might be a pharmacological marker of congestion and undiagnosed heart failure or loop diuretics might have deleterious effects on the outcome of patients with T2DM.Fig 1:Predictors of all-cause Mortality

Acupuncture-assisted lifestyle intervention improve the metabolic status and spontaneous brain activity of type 2 diabetes Mellitus patients: a randomized, clinical trial

BackgroundAggressive weight management in patients with type 2 diabetes mellitus has demonstrated numerous metabolic advantages, however, existing therapies for weight control have not reached satisfactory results. This study aimed to evaluate the efficacy and safety of acupuncture in the weight management of type 2 diabetes mellitus (T2DM) patients by using a randomized, sham-controlled clinical trial design.MethodsIn this single-blind randomized clinical trial, 102 overweight adult T2DM patients were randomized into two groups. The control group receives diet, exercise, and sham acupuncture intervention, whereas the acupuncture group receives diet and exercise and acupuncture intervention, both for 1 month. Body weight and other anthropometric and laboratory indices were assessed at baseline and endpoint, meanwhile, the body fat content and spontaneous brain activity were measured by functional magnetic resonance imaging(fMRI)as the exploratory outcomes.ResultsNo significant difference was observed between the studied parameters at the baseline. The body weight and BMI were significantly reduced both in the control and acupuncture groups after intervention, without statistical difference between the two groups. What’s interesting is that compared to the control, the acupuncture group displayed a greater improvement in central fat tissue. It notes that the acupuncture group achieved significant liver fat content reduction than the sham acupuncture group. At the same time, the spontaneous brain activity in the occipital lobe and parietal lobe significantly increased in the acupuncture group.ConclusionOne month of acupuncture treatment preferentially improved ectopic fat deposition and was accompanied by changes in brain activity compared with the control group, even before significant changes in total body weight had occurred. further studies of longer duration are necessary for validation.Trial registration: The protocol of this clinical trial is registered at the Acupuncture-Moxibustion Clinical Trial Registry (AMCTR, http://www.acmctr.org/, No. AMCTR-IOR-20000341).

Comparative Study on the Genetic Architecture of Type 2 Diabetes in Indian and Other Ethnic Groups: A Review

Type 2 diabetes mellitus (T2DM) is a condition of metabolism that impacts people worldwide regardless of country, age group, and gender. In addition to a sedentary lifestyle, genetic susceptibility, specifically single nucleotide polymorphisms, is implicated in the emergence and progression of T2DM. This study compares the genetic variants of the Indian population with three other ethnic cohorts: African, European, and Chinese. Based on the literature survey, common and unique Single Nucleotide Polymorphisms (SNPs) and genes were explored in different Populations, including PPARG, TCF7L2, THADA, CDKN2A, IGF2BP2, SLC30A8, HHEX and CDKAL1. Identifying common and specific markers may help in risk prediction and early detection of T2DM. In conclusion, this comparative study of T2DM-susceptible SNPs in Indian and other ethnic groups highlights the complexity and diversity of genetic factors contributing to T2DM. By shedding light on the similarities and disparities in genetic predisposition across populations, this review contributes to the ongoing efforts to develop more effective and tailored approaches for managing and avoiding T2DM in diverse global populations.

The Presence of Heavy Metals in Drinking Water and Its Possible Impact on the Development of Type 1 Diabetes in Children

This study aimed to determine the relationship between the concentration of heavy metals in drinking water and the number of type 1 diabetes mellitus (T1DM) cases in two regions of Poland. The number of births in 2015-16 in Pomeranian Voivodeship was 50,461, while the number of new T1DM cases was 219. In Lublin Voivodeship, the number of births in the same period reached 39,381, and the number of new T1DM cases was 221. The incidence of T1DM, calculated per 100 live births, amounted to 0.43 and 0.56 in Pomeranian and Lublin. The statistical analysis of collected data proved that the number of new T1DM cases in Pomeranian Voivodeship is correlated to the concentrations of selenium (Se; p < 0.0001), lead (Pb; p < 0.00001), cadmium (Cd; p < 0.00001), zinc (Zn; p < 0.00001) and arsenic (As; p = 0.00001). In the case of Lublin Voivodeship, the number of new T1DM cases was correlated to the concentrations of Se (p = 0.0000001), Pb (p < 0.000001), Cd (p = 0.0000001) and Zn (p < 0.00001) in drinking water. No correlation was found between the number of new T1DM cases and arsenic concentration in the drinking water samples from Lublin Voivodeship. The results indicated that environmental exposure to specific heavy metals may contribute to the risk of T1DM, underscoring the need for stringent environmental controls and public health policies to mitigate these risks.

Factors associated with type 2 diabetes control in hard-to-reach communities in Esmeraldas, Ecuador

Abstract Background The rising prevalence of type 2 diabetes mellitus (T2DM) and its detrimental effects on population health make it an urgent public health concern. Maintaining blood glucose control is crucial for avoiding complications; however, there are notable socioeconomic disparities in disease management, especially in low- and middle-income settings. We aimed to examine the factors associated with controlled fasting capillary glucose in a difficult-to-access rural setting of Esmeraldas, Ecuador, and to examine the role of social support in this context. Methods Between October 2020 and May 2022, we conducted a cross-sectional study of T2DM adult patients in Esmeraldas’ Eloy Alfaro health district. We collected data on socio-demographic and clinical patient characteristics using a questionnaire and measured Fasting Capillary Blood Glucose levels. We estimated the prevalence of controlled glycaemia and used logistic regression to calculate odds ratios (OR) with 95% confidence intervals. Results Only 18.1% (95%CI: 14.9-21.8) of the 476 study participants had controlled glucose levels, with a significantly higher percentage in men (28.2%) compared to women (13.8%). Participants reported moderate perceived social support (median=2.33, on a scale of 1 to 4), without significant impact on glycaemic control. Women in urbanised areas were more likely to have controlled glucose levels compared to those in rural areas (aOR=2.34, 95%CI: 1.23-4.44) after adjusting for family support. In contrast, unemployed and older men had non-significant trends towards better odds of achieving controlled fasting glycaemia. Conclusions The complex interplay of factors affecting diabetes management and glycaemic control highlights the need for targeted, context and gender-specific public health strategies to address diabetes disparities in vulnerable populations. Key messages • The majority of individuals with T2DM residing in the remote communities of Eloy Alfaro district in Esmeraldas (Ecuador) have uncontrolled glycaemia, showing notable gender-specific disparities. • Participants reported a moderate level of social support, with family as the most important source. Yet, this perceived support may not effectively overcome contextual barriers in T2DM management.

Identification of new phenotypes in type 2 diabetes with acute myocardial infarction: toward a precision medicine?

Abstract Background Type 2 diabetes mellitus (T2DM) is a highly heterogeneous entity, with multiple subgroups differing by clinic presentation, disease progression and risk of complications such as myocardial infarction (MI). A new T2DM phenotyping classification has been recently proposed to help to improve treatment tailoring and target early treatments, and we aimed to identify the prevalence and characteristics of the new phenotypes. Methods All consecutive adults with a history T2DM hospitalized in a french Coronary Intensive Care Unit for an acute MI between February 1st, 2021 and January 31st, 2023 were included. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA1c, and homoeostatic model assessment 2 estimates of β-cell function and insulin resistance). We stratified patients into five subgroups : 1/ SAID=severe autoimmune diabetes; 2/ SIDD=severe insulin-deficient diabetes; 3/ SIRD=severe insulin-resistant diabetes; 4/ MOD=mild obesity-related diabetes; and 5/ MARD=mild age-related diabetes. Results Among the 266 patients included, characteristics according to diabetes phenotypes are summarized in the Table. Conclusions Our prospective study showed that in real-world T2DM patients with acute MI, unclassical phenotypes, i.e. hyperinsulinaemic and insulinopaenic were common. Given the large discrepancies in characteristics, our findings suggest the relevance of the new substratification. However, its clinical utlity and translation in tailored treatment strategies and prognosis remains to be determined.Table.

Persistence and Adherence to GLP-1 RA treatment in Type 2 Diabetes Mellitus: a Nationwide registry study

Abstract Background The use of glucagon-like peptide-1 receptor agonsists (GLP-1 RA) continues to rise and is increasingly important in the treatment of type-2 diabetes mellitus (T2DM). Though the use of GLP-1 RA continues to increase, persistence and adherence to therapy remains suboptimal. Purpose We aimed to assess the level of adherence and persistence to GLP-1 RA using real-world data and to investigate sociodemographic and clinical factors associated with discontinuation of GLP-1 RA therapy. Methods In this retrospective cohort study, all first-time users of GLP-1 RA with T2DM ≥18 years from 2007-2020 were identified using the Danish registries (Figure 1A-1B). All participants had 18 months of follow-up. Medication possession ratio (MPR) was calculated by summing days of medication supply from all dispensed prescription made during the study period divided by number of days in study period. MPR ≥0.80 was used to define adherence. Discontinuation was defined as >90 days between the last day of prescription coverage and the first day of a new dispensed prescription. Adherence to GLP-1 RA therapy and the risk of discontinuing therapy was estimated at 6- and 12-months of follow-up. Multivariable logistic regression was used to identify sociodemographic and clinical factors associated with discontinuing GLP-1 RA therapy. Results In total, 44,343 first-time users of GLP-1 RA with T2DM were identified (mean age: 58.6 years, 42.7% female, 21.3% had cardiovascular disease, median duration of T2DM was 6.8 years, median HbA1c was 65 mmol/mol). The absolute risk of discontinuing GLP-1 RA at 6 and 12 months was 14.2% (95%CI: 13.9-14.6) and 21.4% (95%CI: 21.1-21.8), respectively (Figure 2A). Of the 9,520 (21.5%) who discontinued therapy during the 12-month follow-up, 1,947 (20.5%) occurred within the first 31 days of treatment. At 6 months, 58.5% were adherent to GLP-1 RA therapy with a median MPR of 0.84 [IQR: 0.70-0.95]. At 12 months, 61.1% were adherent to therapy with a median MPR of 0.85 [IQR: 0.71, 0.94]. In the multivariable model, low (<40 years) and high age (>75 years), lower household income, educational level, longer diabetes duration, and higher comorbidity burden were associated with a higher risk of discontinuing GLP-1 RA whereas baseline HbA1c was not (Figure 2B-2E). Conclusion Approximately one in five patients discontinued therapy within 12 months and a little over 60% were adherent. Sociodemographic factors, including household income, age, and comorbidity burden were associated with risk of discontinuing GLP-1 RA therapy. Given the changing landscape of who should be treated with GLP-1 RA, the cardio-renal benefits reported in recent trials, and the ongoing trials in the field, future research into adherence and persistence to GLP-1 RA and possible interventions to improve these, are needed.

The effect of Glucagon-like peptide-1 receptor agonists on cardiovascular outcomes in type 2 diabetes mellitus patients with coronary artery disease

Abstract Background Cardiovascular disease is the primary cause of mortality in patients with type 2 diabetes mellitus (T2DM). Randomized controlled trials (RCT) have shown that Glucagon-like peptide-1 receptor agonists (GLP-1RA) improve cardiovascular outcomes in T2DM patients, with greater therapeutic benefits observed in patients with established atherosclerotic cardiovascular disease. However, the effect of GLP1-RA therapy on cardiovascular outcomes has been inconsistent and the RCT have not been sufficiently powered to examine the effect of GLP1-RA on mortality or their therapeutic effect in different subgroups of T2DM patients. Purpose This study aimed to examine the effect of GLP1-RA therapy on cardiovascular outcomes and mortality in a real-world cohort of T2DM patients with coronary artery disease (CAD). Methods This study included T2DM patients with CAD who were treated with metformin at a daily dose of ≥ 1g for a period of ≥ 180 days. CAD was defined as ≥ 50% luminal stenosis in any coronary artery segment according to a nationwide angiography and angioplasty registry. We performed sequential emulated target trials at monthly intervals between January 1, 2013 and December 31, 2020 to examine the effect of GLP1-RA therapy on major adverse cardiovascular outcomes (MACE), a composite of myocardial infarction, ischemic stroke and all-cause mortality. Secondary outcomes included the individual components of MACE. Marginal structural models were used to compute pooled effect estimates. This was an intention-to-treat analysis with 5 years of follow-up for each emulated target trial. Inverse probability of treatment weighting was used to adjust for confounding due to differences in patient demographics at baseline. Results This study consisted of 26,746 individuals who were treated with GLP1-RA and 74,638 controls. The 5-year cumulative risk of MACE was 27.7 % in the GLP1-RA group and 32.7 % in the control group (risk ratio 0.85 [95% confidence interval 0.82 – 0.88]). GLP1-RA therapy was associated with a lower risk of all-cause mortality (risk ratio 0.76 [95% confidence interval 0.72 – 0.79]) and myocardial infarction (risk ratio 0.95 [95% confidence interval 0.89 – 1.00]). We found little or no effect of GLP1-RA therapy on the risk of ischemic stroke (risk ratio 1.13 [95% confidence interval 0.97 – 1.27]). Conclusions In this large real-world cohort of T2DM patients with established CAD, we observed that GLP1-RA therapy was associated with a lower risk of MACE, myocardial infarction and all-cause mortality.

Effectiveness of specialist involvement in case discussion conferences with primary healthcare providers on the management of type 2 diabetes patients: a study protocol for a cluster randomized controlled trial

BackgroundIn supporting primary healthcare in delivering high-quality care for individuals with type 2 diabetes mellitus (T2DM), previous research emphasized strategies to facilitate communication and collaboration between primary healthcare providers and hospitals. This study aims to evaluate the effectiveness of case discussion conferences between specialists from hospitals and primary healthcare providers in China on the optimization of diabetes management and the improvement of patient health outcomes.MethodsThis study will be a parallel cluster randomized controlled trial in which primary healthcare institutions in Shouguang city and Shangsi County will be randomly allocated to the intervention and control groups. The intervention will involve regular case discussion conferences where attendants will meet to discuss complex cases with patients diagnosed with type 2 diabetes mellitus, exchange experiences, and seek and provide expert advice. Family doctor teams from primary healthcare institutions and specialists from secondary or tertiary hospitals will engage in these conferences. Data will be collected at baseline and at the 6- and 12-month follow-ups. The primary clinical outcome measures will focus on the changes in the HbA1c and FBG levels of patients under management. The secondary outcomes will include other physiological indicators, such as blood pressure, BMI, and cholesterol. The evaluation will extend to changes in the capabilities and behaviors of primary healthcare providers. Furthermore, the feasibility and adherence of this intervention will be thoroughly assessed.DiscussionThis study is designed to generate robust evidence on the effectiveness of case discussion conferences, an interprofessional collaboration strategy, in enhancing diabetes care delivery in primary healthcare, with the ultimate goal of improving patient health outcomes.Trial registrationChinese Clinical Trial Registry ChiCTR2300078829. Registered on December 19, 2023. https://www.chictr.org.cn/showproj.html?proj=210293

Body composition trajectories before the diagnosis of type 2 diabetes mellitus in Whitehall II study

Abstract Background The trajectories of anthropometric and body composition measures (important predictors of diabetes) are rarely explored before diabetes diagnosis. Our study aimed to compare trajectories of fat mass (FM), fat-free mass (FFM), body mass index (BMI), and waist circumference (WC) preceding type 2 diabetes mellitus (T2DM) to aging trajectories of individuals without diabetes during follow-up. Methods We used data from the Whitehall II study, a prospective cohort of British civil servants. 5-yearly BMI and WC were available for up to 20 years, while 5-yearly FM and FFM measures were available for up to 10 years. Linear mixed models with a backward timescale (from diabetes diagnosis or end of follow-up) were performed stratified by sex and adjusted for age, occupational grade, ethnicity, and lifestyle factors. Results A total of 1674/990 (anthropometric/body composition analysis) women (233/81 incident diabetes) and 3917/2710 men (479/217 incident diabetes) 49.81 [0.08]/60.91 [0.9] (mean [SE]) years of age at baseline were included. All outcomes were higher in cases compared to controls. Women’s FM, BMI, and WC followed a quadratic increase in both groups with a faster increase among incident diabetes cases (dBMI 0.04 [0.01] kg/m2/year, dFM 0.19 [0.09] kg/year, dWC 0.2 cm/year [0.05]). FFM decreased linearly with similar slopes in cases and controls. Men’s FM, BMI, and WC also showed a quadratic increase with faster increase in incident cases compared to controls (dBMI 0.03 [0.01] kg/m2/year, dFM 0.23 [0.04] kg/year, dWC 0.08 [0.02] cm/year). FFM followed a quadratic decrease in both groups with a slower rate (0.06 [0.03] kg/year) in incident cases. Conclusions Incident diabetes cases have higher anthropometric and body composition measures 10-20 years before diabetes diagnosis compared to controls. Furthermore, incident cases showed faster increases in these measures except for FFM that decreased during follow-up with similar or lower speeds in cases than controls. Key messages • Traditional anthropometric measures do not capture the underlying changes in body composition. • The inclusion of body composition in risk calculators may result in more precise diabetes prediction.

Diabetes among people with intellectual disabilities vs the general population: a register study

Abstract People with intellectual disabilities have an increased risk of diabetes mellitus (DM). They tend to develop it at earlier ages than the general population, resulting in even higher risks in younger people. However, few studies have separated Type 1 and Type 2 DM. The aim of this study was to assess prevalence of different types of DM in different age groups in relation to the general population. We categorized all people in Skåne, Sweden, as ID (service and support for people with ID and/or autism, or a diagnosis of ID or Down syndrome; n = 14 716) or general population (gPop; excluding family members of people in ID; n = 1 226 955). Data regarding diagnoses of Type 1 (E10 in ICD-10) and Type 2 (E11) DM were collected for 2014-2021. Age at inclusion (i.e., 2014) was considered as children (0-12 years), adolescents (13-18), young adults (19-24), adults (25-44), lower middle-age (45-54), upper middle-age (55-64), older people (65+). The overall prevalence of Type 1 DM was 2.3% in ID and 1.6% in gPop (relative risk [RR] 2.14, 95% confidence interval 1.93-2.38). In ID, the prevalence was below 2% in the youngest age groups, and then increased with age until upper middle-age, where it reached 6.0%. The risk of Type 1 DM among people with ID compared to gPop was relatively stable, with the RR ranging between 1.16 (older people) to 2.83 (adults). For Type 2 DM, the overall prevalence was 7.2% in ID and 7.8% in gPop (RR 2.00, 1.89-2.13). There was a consistent age-related increase in prevalence in ID, from 0.3% among children to 27.4% among older people. The opposite pattern was found for the risk compared to gPop, with the higher risks (RR 3.63-6.98) in the younger age groups and lower risks (RR 1.27-4.41) in the older age groups. Both types of DM were more prevalent among people with intellectual disabilities than in the general population. However, the patterns of prevalence and risk compared to the general population differed for the two types. Key messages • People with intellectual disabilities have increased risk of both Type 1 and Type 2 diabetes mellitus. • Type 1 and Type 2 diabetes mellitus displays different age patterns among people with intellectual disabilities.

Neurodegeneration is highly associated with comorbidity burden in HFrEF patients

Abstract Background Heart failure (HF) is associated with cognitive decline and risk for dementia. Blood levels of amyloid beta 40 and 42 (Aβ40, Aβ42), tau protein (tau), and neurofilament light chain (NfL) have been found to be altered in neurodegenerative disease. Previous research has established a clear association between these neuromarkers and the risk of developing cognitive dysfunction and mortality in the general population. Objective The aim of this study was to investigate the association between the respective neuromarkers and comorbidity burden, as well as to explore whether comorbidity burden impacts the relationship between neuromarkers and outcome in HF patients. Methods Plasma levels of Aβ40, Aβ42, tau, and NfL were quantified using a single-molecule array assay. The primary outcome parameter was all-cause mortality. Results A total of 470 HFrEF patients were enrolled in the study, with a median age of 62 years (IQR: 52–72); 77% were male. Median NT-proBNP concentration was 1812 pg/ml (IQR: 718–3881). Elevated levels of all biomarkers were closely associated with comorbidity burden (Figure 1). All neuromarkers showed increased levels in individuals with chronic kidney disease (CKD) and known carotid artery stenosis (CAS), except for Aβ40, which did not show significant elevation in CAS (NfL: p<0.001 for both; t-tau: p<0.001 and p=0.041; Aβ40: p<0.001 and p=0.050; Aβ42: p<0.001 and p=0.033, respectively). In patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD), only NfL levels were significantly elevated (p<0.001 for both), whereas atrial fibrillation (AF) was associated with higher levels of NfL and t-tau (p<0.001 for both). In individuals with iron deficiency, only Aβ42 levels were significantly higher (p=0.025). All biomarkers showed significant associations with all-cause mortality [crude HR for an increase in 1-log unit (95%CI): NfL 4.44 (3.02-6.53), t-tau 5.04 (2.97-8.58), Aβ40 3.90 (2.27-6.72), Aβ42 5.14 (2.84-9.32); p<0.001 for all] (Figure 2). These associations remained statistically significant after adjusting for comorbidity burden including AF, T2DM, CAD, CKD, CAS and ID [adjusted HR for an increase in 1-log unit (95%CI): NfL 3.28 (1.93-5.57), t-tau 3.96 (2.07-7.57), Aβ40 2.42 (1.34-4.38), Aβ42 3.05 (1.56-5.97); p<0.01 for all]. Conclusion The findings suggest a close connection between elevated levels of markers of neurodegeneration and increased comorbidity burden in HFrEF patients. While this association may indicate the cumulative risk leading to neuronal injury and HFrEF progression, a causal relationship cannot be excluded. The observed accelerated neurodegeneration in HFrEF underscores the need for further investigation into this complex interplay.Figure 1Figure 2

Molecular landscape of the overlap between Alzheimer’s disease and somatic insulin-related diseases

Alzheimer’s disease (AD) is a multifactorial disease with both genetic and environmental factors contributing to its etiology. Previous evidence has implicated disturbed insulin signaling as a key mechanism that plays a role in both neurodegenerative diseases such as AD and comorbid somatic diseases such as diabetes mellitus type 2 (DM2). In this study, we analysed available genome-wide association studies (GWASs) of AD and somatic insulin-related diseases and conditions (SID), i.e., DM2, metabolic syndrome and obesity, to identify genes associated with both AD and SID that could increase our insights into their molecular underpinnings. We then performed functional enrichment analyses of these genes. Subsequently, using (additional) GWAS data, we conducted shared genetic etiology analyses between AD and SID, on the one hand, and blood and cerebrospinal fluid (CSF) metabolite levels on the other hand. Further, integrating all these analysis results with elaborate literature searches, we built a molecular landscape of the overlap between AD and SID. From the landscape, multiple functional themes emerged, including insulin signaling, estrogen signaling, synaptic transmission, lipid metabolism and tau signaling. We also found shared genetic etiologies between AD/SID and the blood/CSF levels of multiple metabolites, pointing towards “energy metabolism” as a key metabolic pathway that is affected in both AD and SID. Lastly, the landscape provided leads for putative novel drug targets for AD (including MARK4, TMEM219, FKBP5, NDUFS3 and IL34) that could be further developed into new AD treatments.

Signature of diabetic cardiomyopathy progression using high-fat diet and streptozotocin mouse model: from subclinical to clinical with three-hit mouse model

Abstract Background Diabetic cardiomyopathy (DbCM) is a pre-heart failure (pre-HF) condition that usually exhibits early diastolic dysfunction and evolving systolic dysfunction, along with left ventricular (LV) remodelling. Although DbCM shows distinct pathophysiology, the transition from the subclinical to the symptomatic stage is not straightforward and usually involves multifaceted processes which are not fully understood. Purpose To define the signature of DbCM progression in a novel mouse model using longitudinal echocardiography and multi-omics approaches. Methods Male mice (C57BL/6) were fed with high-fat diet (HFD) or control diet (CD) for 24 weeks, with single dose of streptozotocin (STZ) or vehicle injection at 8 weeks (n=10 each). Serial functional and metabolic parameters were measured prior to endpoint single nuclei RNA sequencing (snRNA-seq) and mass spectrometry-based proteomics analysis with comparison to cardiac remodelling to define detailed mechanisms underlying DbCM progression. Results HFD/STZ mice developed type 2 diabetes mellitus (T2DM) based on higher fasting blood glucose and HbA1C levels, insulin resistance and decreased beta-cell function (HOMA-IR and HOMA-beta, respectively) compared to controls. Progressive diastolic dysfunction was evident in HFD/STZ mice compared to CD mice based on enlarged LVPW;d from 12 weeks (P<0.05), reduced MV E/A ratio (P<0.01) and IVRT (P<0.05) from 16 weeks, and increased cardiac filling pressure (Left atrial (LA) area and LA volume) at 24 weeks, with preserved systolic function. This was paralleled by elevated collagen deposition (Picrosirius red), myocyte cross-sectional area and Col1a1 expression in HFD/STZ versus CD mice (all P<0.05). snRNA-seq analysis indicated preferential monocyte migration into diabetic hearts (P<0.01) whilst inflammatory pathways were activated across all cardiac cell types. Proteomics analysis revealed elevated expression of the established inflammation marker, plasma C-reactive protein (CRP), in HFD/STZ versus CD mice (P<0.05), which was correlated with worsening diastolic function (MV E/A ratio: r=-0.839, P<0.01) and LV hypertrophy (LVPW;d: r=0.861, P<0.01). Conclusion Our HFD/STZ mouse model offers a ‘three-hit’ approach which effectively captures key stages of clinical DbCM progression: 1) T2DM with insulin resistance, 2) progressive diastolic dysfunction with elevated chronic filling pressure and cardiac remodelling, and 3) systemic inflammation. This improved HFD/STZ mouse model is therefore appropriate to support a detailed study of mechanisms underlying DbCM progression and subsequent translation.

Effect of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors and their combination on carotid intima-media thickness

Abstract Background/Introduction Type 2 diabetes mellitus (T2DM) is an additional factor for exacerbation of atherosclerosis increasing the risk for ischemic attacks such as coronary artery disease and ischemic stroke. Evaluation of carotid artery atherosclerosis through ultrasound techniques is a useful tool for risk stratification in type 2 diabetic patients. Purpose We investigated the effects of insulin, glucagon like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and their combination on carotid intima-media thickness (cIMT) of T2DM patients. Methods A total of 320 T2DM patients were randomized to receive insulin (n = 80), liraglutide (n = 80), empagliflozin (n = 80) or their combination (GLP-1RA+SGLT-2i) (n = 80) as add-on to metformin. At baseline, at 6 and at 12 months of treatment, we measured the maximal thickness of six major points including right and left common carotid, carotid bifurcation and internal carotids. Finally, we calculated the average cIMT of all six segments (three on each side) to get mean cIMT. Results Compared to baseline, all patients had significantly reduced cIMT at 6 and at 12 months of treatment (p < 0.001; Table). A significant interaction of follow-up time with the type of treatment was observed regarding cIMT levels (F = 7.203, p for interaction < 0.001) in a model including age, sex, smoking, baseline body mass index, glucose levels, glycosylated hemoglobin, levels of blood lipids and their changes at 6 and 12 months of treatment as covariates. At 6 months, patients who were treated with GLP-1RA, SGLT-2i and those under the combination GLP-1RA+SGLT-2i showed a greater reduction of cIMT (-2.5%, -2.4% and -5.8%) compared to insulin (-0.8%; p = 0.008, p = 0.022, and p < 0.001, respectively). Moreover, at 12 months patients under GLP-1RA, SGLT-2i and their combination achieved remarkable reduction of cIMT (-7.4%, -4.9% and -10%) than those under insulin (-1.7%, p < 0.001 for all comparisons). Conclusions Twelve-month treatment with GLP-1RA, SGLT-2i and their combination resulted in reduction of cIMT in T2DM. The combined treatment was superior and additive to each regimen separately.Table