Cardiovascular Diabetology最新文献

Background: Type 2 diabetes mellitus (T2DM) increases the risk of cardiovascular disease (CVD), largely by alterations in the blood lipids and the metabolism of circulating lipoproteins (LPs). We studied whether the presence of additional risk factors, such as hypertension, or CVD itself, is associated with further alterations in the LP profiles in individuals with T2DM.

Methods: We performed LP profiling using ¹H NMR spectroscopy and quantified 65 parameters in 393 healthy controls (HC) and in 390 T2DM patients with and without cardiovascular comorbidities. Univariate and multivariate analyses were used to assess alterations in LPs in diabetic patients.

Results: Triglycerides in all major LP classes, as well as particle numbers of very low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL) were increased in T2DM compared to HC. In contrast, particle numbers of low-density lipoproteins (LDL) and high-density lipoproteins (HDL) were reduced, suggesting slower lipolytic conversion of IDL to LDL and impaired clearance of triglyceride-enriched HDL. Univariate and multivariate analyses converged in identifying distinct LP profiles associated with T2DM, while differences between patients with and without hypertension or CVD were minor, indicating that T2DM is the primary factor driving LP dysregulation. T2DM, with or without cardiovascular comorbidities, also causes differential disruption of the correlation structure among LPs.

Conclusions: T2DM is associated with major alterations in LP metabolism independent of hypertension or CVD. Thus, early lipid management in T2DM is important to mitigate CVD risk. Further research is needed to elucidate how T2DM progresses to CVD in relation to atherogenic LPs.

Background: To evaluate whether integrating proteomics, metabolomics, and a cardiovascular disease specific polygenic risk score (CVD-PRS) in the SCORE2-Diabetes model improves sex-specific 10-year prediction of major adverse cardiovascular events (MACE) in individuals with type 2 diabetes (T2D).

Methods: Genome-wide association study (GWAS), plasma proteomics (with the Olink Explore 3072 platform), and metabolomics (with nuclear magnetic resonance spectroscopy by Nightingale Health) data were measured in the UK Biobank. A novel sex-specific protein algorithm was developed using bootstrap-LASSO (Least absolute shrinkage and selection operator) regression. The CVD-PRS and sex-specific metabolite algorithms were used from previous UK Biobank projects. In a subset of 990 participants with T2D, age 40-69 years, with no prior MACE, and complete multi-omics data, we evaluated, which omics data improved the SCORE2-Diabetes model performance using Harrell's C-index.

Results: Overall 9 proteins were selected for males and 7 for females and adding them to the SCORE2-Diabetes model significantly improved discrimination in the total population (C-index increase from 0.766 to 0.835 (P < 0.001)). Further adding of metabolites significantly improved model performance (C-index, 0.846, P = 0.035), which was mostly attributable to model improvement among males (∆C-index, 0.012, P = 0.078) but not among females (∆C-index, 0.004, P = 0.723). Further adding the CVD-PRS did not statistically significantly improve the SCORE2-Diabetes + proteomics + metabolomics model further in the total population (C-index, 0.848 (P = 0.070)).

Conclusions: Sex-specific proteomic signatures markedly improved 10-year MACE risk prediction in individuals with T2D. In men but not in women, further integration of metabolomics may enhance model performance whereas adding the CVD-PRS is not needed. External validation is warranted.

Background: Initiation of Glucagon-Like Peptide-1 receptor agonists (GLP-1RA) in patients with type 2 diabetes (T2D) treated with levothyroxine may decrease the required levothyroxine dose due to weight loss or enhance levothyroxine absorption through delayed gastric emptying. These changes may cause thyroid hormone over-replacement and increased risk of atrial fibrillation/flutter (AF/Aflutter) and stroke. Our study aims to investigate the impact of GLP-1RA initiation on risks of AF/Aflutter and stroke in patients with T2D treated with levothyroxine, compared to sodium-glucose cotransporter 2 (SGLT2) inhibitors.

Methods: Leveraging the target trial emulation framework, we conducted a retrospective study using observational data to emulate a new user, active comparator trial examining the effects of initiating GLP-1RA (exposure group) versus SGLT2 inhibitors (control group), with random treatment assignment emulated by propensity score matching with 1:1 ratio. We used a 15% nationally representative sample of U.S. Medicare beneficiaries to identify participants > 65 years, continuously on stable dose of levothyroxine for ≥ 6 months before the index date (i.e., GLP-1RA or SGLT2 inhibitor initiation), with continuous Medicare enrollment, without malignant cancer or palliative care during 1 year before the index date. The primary outcome was AF/Aflutter, and secondary outcome was stroke, including ischemic stroke or transient ischemic attack. We assessed the per-protocol effects of GLP-1RA vs. SGLT2 inhibitors using inverse-probability-censoring weighted Cox proportional hazards models.

Results: After matching, the study cohort included 2,384 participants in both GLP-1RA and SGLT2 groups with mean age (SD): 73.3 (5.9) vs. 73.2 (5.8), and 71.5% and 71.8% of female. The median follow-up time was 1.05 years. Compared to SGLT2 inhibitors, initiation of GLP-1RA was associated with higher risk of AF/Aflutter (HR: 1.46; 95% CI: 1.28-1.67), while no statistically significant difference was observed between the two groups for stroke (HR: 1.17; 95% CI: 0.98-1.39). Sensitivity analyses showed consistent results, including restricting outcomes to inpatient visits, conducting an intention-to-treat analysis, applying a prevalent new user design, and substituting SGLT2 inhibitors with dipeptidyl peptidase-4 (DPP4) inhibitors as the active comparator.

Conclusions: In patients with T2D historically treated with stable doses of levothyroxine, GLP-1RA initiation was associated with a higher risk of AF/Aflutter. Further research is warranted to investigate the potential roles of weight loss, TSH fluctuations, and levothyroxine dose adjustment after GLP-1RA in mediating the cardiovascular risk.

Background: Statins are a cornerstone of cardiovascular disease prevention, but growing evidence suggests they may increase the risk of new-onset type 2 diabetes. The cardiovascular implications of diabetes that develops during statin therapy, however, remain unclear. This study aimed to evaluate whether incident diabetes during statin use is associated with increased risk of major adverse cardiovascular events (MACE) or all-cause mortality, compared with individuals with preexisting diabetes and statin users who remained free of diabetes.

Methods: We conducted two retrospective cohort studies using data from the Korean National Health Insurance Service (KNHIS) database between 2009 and 2020, which includes nationwide, population-based data from both primary and secondary care settings. From a source population of 1,500,959 adults, Study 1 identified 4371 individuals who had used statins continuously for ≥ 730 days before receiving a new diagnosis of type 2 diabetes mellitus (T2DM). These individuals were propensity score-matched 1:1 to individuals who initiated statin therapy after a prior diagnosis of T2DM, matched by age, sex, and low-density lipoprotein cholesterol levels. In Study 2, 4191 statin users who developed T2DM during follow-up were matched 1:1 with statin users who remained diabetes-free during the same period. The primary outcome was MACE, defined as a composite of myocardial infarction and stroke. All-cause mortality was assessed as a secondary outcome.

Results: In Study 1, individuals who developed diabetes during statin therapy had a significantly lower risk of MACE compared with those who initiated statins after diabetes diagnosis (adjusted hazard ratio [aHR] 0.607; 95% confidence interval [CI], 0.458-0.805; p = 0.0005), primarily driven by a reduced stroke risk (aHR 0.504; 95% CI, 0.357-0.711; p < 0.001). In Study 2, incident diabetes during statin use was not associated with increased risk of MACE (aHR 1.122; 95% CI, 0.784-1.605; p = 0.53) or all-cause mortality (aHR 0.555; 95% CI, 0.290-1.063; p = 0.0758), compared with remaining diabetes-free.

Conclusions: Diabetes that develops during statin therapy was associated with a lower risk of MACE compared with initiating statins after diabetes diagnosis and was not linked to increased risk of MACE or all-cause mortality compared with remaining diabetes-free.

Background/objective: Chronic vascular complications are the primary threat in long-standing type 1 diabetes (T1D) patients. We examined the associations between oral-gut microbiome dysbiosis and these complications, offering novel insights into therapeutic strategies and underlying mechanisms.

Methods: This cross-sectional study enrolled 75 T1D participants (disease duration ≥ 10 years) and 43 healthy controls who underwent comprehensive clinical assessment, including blood glucose, lipid profile, and complication-related examinations. Fecal and oral rinse samples were collected for shotgun metagenomic sequencing. T1D participants were stratified by the presence of microvascular (retinopathy, nephropathy, or neuropathy) or macrovascular complications separately. Microbial differences across groups were assessed.

Results: Significant differences in oral and gut microbiota compositions were observed between T1D participants with and without complications (both microvascular and macrovascular). A core set of 26 gut and 8 oral microbial species was specifically associated with vascular complications. Butyrate-producing gut bacteria (Blautia wexlerae, Anaerobutyricum hallii, Roseburia inulinivorans, A. soehngenii) and specific oral Neisseria species were enriched in T1D without complications individuals, suggesting protective effects against complications. Mediation analysis indicated associations consistent with partial mediation between certain microbial species and the relationships of glycemic control or insulin resistance (HbA1c, glucose risk index, estimated glucose disposal rate) with complication risk. Moreover, potential oral-gut microbiome interconnections were implicated in complication development. Finally, classification models integrating both oral and gut microbial features significantly outperformed models based on either site alone in distinguishing T1D patients with complications.

Conclusions: Distinct oral and gut microbiome features are associated with chronic vascular complications in T1D. These findings highlight the potential of microbiome-targeted strategies for understanding and preventing T1D-related complications.

Background: Very long-chain saturated fatty acids (VLCSFA) may influence cardiometabolic health differently from other, often detrimental, saturated fatty acids (SFA). Evidence remains inconclusive, partly because VLCSFA are metabolically derived from SFA, making it difficult to disentangle their individual effects due to potential confounding of correlated lipids. Prior studies rarely accounted for correlations with other lipids or do not consider VLCSFA-specific lipid classes. We investigated prospective associations of circulating VLCSFA (C20:0, C22:0, C24:0) across multiple plasma lipid classes with type 2 diabetes (T2D) and cardiovascular disease (CVD), accounting for confounding by correlated lipids.

Methods: We constructed two nested case-cohort studies within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort: 1911 in the T2D case-cohort (774 cases); 1704 in the CVD case-cohort (547 cases). Plasma concentrations of VLCSFA were measured in 12 lipid classes. A data-driven network including SFA across all lipid classes was used to identify precursors and downstream lipid metabolites for each lipid class of VLCSFA. The correlated lipids were gradually incorporated in multivariable-adjusted Cox regression models between individual lipids and disease risk.

Results: C20:0 was distributed across more lipid classes than C22:0 and C24:0. After including all correlated precursors and downstream lipid metabolites in the model, we observed that higher C22:0 levels were linked to higher T2D risk, while associations for C20:0 and C24:0 varied by class. Ceramides C20:0 (hazard ratio [HR] per SD: 0.52, 95% CI 0.35-0.79) and C24:0 (0.46, 0.27-0.79) were inversely associated with T2D, whereas dihydroceramides C20:0 (1.36, 1.07-1.72) and sphingomyelin C24:0 (1.61, 1.15-2.26) showed positive associations. Monoglycerides and cholesteryl esters containing VLCSFA were associated to higher risk of both outcomes. Most of these relationships were not observed when the confounding or mediation by correlated lipids was not considered.

Conclusions: VLCSFA show different metabolic roles in cardiometabolic diseases and highlight the importance of adjusting for confounding by correlated lipids. These findings challenge the traditional view that SFA exert uniform negative effects and suggest class-specific VLCSFA profiles may improve risk prediction of cardiometabolic diseases, guiding more precise prevention strategies.

Background: The FLOW clinical trial recently demonstrated that the glucagon-like peptide-1 receptor agonist once-weekly semaglutide 1 mg was associated with kidney- and cardio-protective effects (the latter already shown in the SUSTAIN 6 trial) compared with placebo, both in addition to standard of care (SoC), in people with type 2 diabetes (T2D) and chronic kidney disease (CKD). This study assessed the long-term cost-effectiveness of semaglutide versus placebo in people with T2D and CKD in Denmark, based on outcomes from FLOW.

Methods: Life expectancy, quality-adjusted life expectancy, cumulative incidence of diabetes-related complications, and costs were projected over a lifetime time horizon using the PRIME T2D Model. Baseline cohort characteristics and changes in risk factors with semaglutide and placebo were taken from FLOW, with extrapolation over patient lifetimes. Outcomes were assessed for the full population and subgroups receiving/not receiving sodium-glucose cotransporter-2 (SGLT-2) inhibitors at baseline. Quality-of-life disutilities and Denmark-specific costs (expressed in 2023 Danish Kroner [DKK]) were applied to capture the impact of diabetes-related complications and pharmacy costs.

Results: Treatment with semaglutide was projected to improve long-term quality-adjusted life expectancy by 0.60 quality-adjusted life years (QALYs) compared with placebo in the full population and by 0.44 and 0.62 QALYs in subgroups receiving/not receiving SGLT-2 inhibitors at baseline, respectively. Differences were predominantly driven by a reduced incidence of kidney failure with semaglutide versus placebo. Semaglutide was associated with long-term, per-person cost savings of DKK 6,068 in the full population and DKK 9,212 in those not receiving SGLT-2 inhibitors at baseline, leading to semaglutide being a dominant treatment compared with placebo. In patients receiving SGLT-2 inhibitors at baseline, semaglutide was cost-effective with an ICER of DKK 19,167 per QALY gained.

Conclusions: Adding semaglutide to SoC was projected to be highly cost-effective over the long term in people with T2D and CKD in a Danish healthcare setting, based on patient characteristics and treatment effects from FLOW. Trial registration NCT03819153, first submitted on January 18, 2019.

Cardiovascular-Kidney-Metabolic (CKM) syndrome progresses through distinct stages, from early metabolic risk factors to advanced cardiovascular disease and kidney dysfunction. Across these stages, exercise remains a central yet underutilized intervention, offering physiological adaptations that address metabolic dysregulation, vascular dysfunction, and inflammation. This review evaluates the stage-specific effects of moderate-intensity continuous exercise (MICE), high-intensity interval exercise (HIIE), and resistance training (RT) on CKM syndrome. In Stage 0, exercise augments insulin sensitivity, endothelial function, and mitochondrial biogenesis, preserving optimal health in individuals without metabolic risk factors. Stage 1, marked by excess adiposity, sees structured exercise regimens effectively reducing visceral fat, improving lipid profiles, and enhancing glucose regulation. During Stage 2, encompassing metabolic risk factors and early chronic kidney disease (CKD), aerobic and resistance exercise improve endothelial responsiveness, glycemic control, and renal outcomes. In Stage 3, subclinical cardiovascular disease, targeted exercise interventions strengthen vascular integrity, boost cardiac efficiency, and enhance metabolic resilience. Finally, Stage 4 entails clinical CVD, where exercise-based rehabilitation programs (e.g., moderate-intensity continuous training [MICT], high-intensity interval training [HIIT]) raise functional capacity, improve quality of life, and support favorable prognosis. Sex differences in exercise adaptations underscore the importance of individualized prescriptions. Emphasizing a multidisciplinary strategy that integrates lifestyle modifications and clinical measures can mitigate CKM-associated morbidity and mortality. Future research should investigate long-term exercise adherence, sex-specific responses, and the role of digital health tools to optimize CKM management and patient outcomes.

Background: Prior studies have suggested an association between estimated glucose disposal rate (eGDR) and the risk of incident stroke in nondiabetic populations. However, evidence regarding the impact of long-term cumulative exposure to eGDR on stroke risk remains limited. This study aimed to investigate whether cumulative eGDR levels are independently associated with incident stroke among adults aged 50 years and older without diabetes.

Methods: We used data from the China Health and Retirement Longitudinal Study (CHARLS) and included 3,808 participants aged 50 years or older with no history of diabetes. Cumulative eGDR was calculated as the sum of the products of the average eGDR between consecutive survey waves and the corresponding time interval in years. The primary outcome was incident stroke. Associations between cumulative eGDR and stroke risk were assessed using Cox proportional hazards regression and restricted cubic spline (RCS) models. Discriminatory performance was assessed using receiver-operating characteristic (ROC) curves.

Results: The median age at baseline was 61 years, and 48.7% of participants were men. RCS analyses revealed a significant inverse and nonlinear association between cumulative eGDR and incident stroke (P < 0.001; P for nonlinearity = 0.021). After adjustment for potential confounders, higher cumulative eGDR was independently associated with a reduced risk of stroke (per standard deviation increase: HR: 0.69; 95% CI, 0.60-0.80; P < 0.001). Quartile-based analysis of cumulative eGDR further demonstrated that, compared with participants in the lowest quartile, those in the second quartile (Q2: HR: 0.63; 95% CI, 0.46-0.88; P = 0.006), third quartile (Q3: HR: 0.41; 95% CI, 0.28-0.60; P < 0.001) and fourth quartile (Q4: HR: 0.35; 95% CI, 0.23-0.52; P < 0.001) had significantly lower risks of incident stroke.

Conclusions: Among adults aged 50 years or older without diabetes, lower cumulative eGDR levels were significantly associated with an increased risk of incident stroke.