Cardiovascular Diabetology最新文献

Background: Patients with low-to-normal body mass index (BMI; < 25.0 kg/m²) were underrepresented in major randomized controlled trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors for type 2 diabetes. The present study aims to investigate the effectiveness of SGLT2 inhibitors for cardiovascular outcomes among patients with type 2 diabetes and low-to-normal BMI, using finer stratification than previous trials.

Methods: This cohort study with a target trial emulation framework was conducted using insurance claims and health screening records of more than 30 million working-age citizens in Japan acquired from April 1, 2015 to March 31, 2022. 139,783 new users of SGLT2 inhibitors matched to 139,783 users of dipeptidyl protease (DPP) 4 inhibitors with stratification by BMI category (< 20.0, 20.0-22.4, 22.5-24.9, 25.0-29.9, 30.0-34.9, and 35.0 ≤ kg/m²). The primary outcome was a composite of all-cause death, myocardial infarction, stroke, or heart failure. Secondary outcomes were the components of the primary outcome. Cox proportional hazard models were used to compare SGLT2 inhibitors with DPP4 inhibitors in the whole population and subgroups defined by the BMI category.

Results: Among participants, 17.3% (n = 48,377) were female and 31.0% (n = 86,536) had low-to-normal BMI (< 20.0 kg/m², 1.9% [n = 5,350]; 20.0-22.4 kg/m², 8.5% [n = 23,818]; and 22.5-24.9 kg/m², 20.5% [n = 57,368]). Over a median follow-up of 24 months, the primary outcome occurred in 2.9% (n = 8,165) of participants. SGLT2 inhibitors were associated with a decreased incidence of the primary outcome in the whole population (HR [95%CI] = 0.92 [0.89 to 0.96]), but not in patients with low-to-normal BMI (< 20.0 kg/m², HR [95%CI] = 1.08 [0.80 to 1.46]; 20.0-22.4 kg/m², HR [95%CI] = 1.04 [0.90 to 1.20]; and 22.5-24.9 kg/m², HR [95%CI] = 0.92 [0.84 to 1.01]).

Conclusions: The protective effect of SGLT2 inhibitors on cardiovascular events among patients with type 2 diabetes appeared to decrease with lower BMI and was not significant among patients with low-to-normal BMI (< 25.0 kg/m2). These findings suggest the importance of considering BMI when initiating SGLT2 inhibitors.

Background: The Steno Type 1 Risk Engine (ST1RE) was developed to aid clinical decisions in primary prevention for individuals with type 1 diabetes (T1D), as existing cardiovascular (CV) risk models for the general population and type 2 diabetes tend to underestimate CV risk in T1D. However, the applicability of ST1RE in different populations remains uncertain, as prediction models developed for one population may not accurately estimate risk in another. This study aimed to evaluate the performance of the ST1RE in predicting CV events among ethnically mixed T1D individuals and its association with the progression of microangiopathy complications.

Methods: A retrospective survey of 435 adults with T1D who were free of CV events at baseline was assessed by ST1RE and chronic diabetes complications at 5 and 10 years of follow-up. The estimated CV risk rates were compared with the observed rates at 5 and 10 years using statistical analyses, including Receiver Operating Characteristic (ROC) curve analysis, Hosmer-Lemeshow test, Kaplan-Meier curves analysis and Cox-regression models.

Results: Among 435 patients (aged 25 years; interquartile range [IQR]: 21-32) with a median T1D duration of 13 years (IQR: 9-18), only 5% were categorized into the high ST1RE group. Within a median follow-up of 9.2 years (IQR 6.0-10.7), 5.5% of patients experienced a CV event (1.6%, 14.9%, and 50% from the low, moderate, and high-risk groups, respectively). The hazard ratios (HRs) for CV events were greater in the high-risk group (HR 52.02; 95% CI 18.60-145.51, p < 0.001) and in the moderate-risk group (HR 8.66; 95% CI 2.90-25.80, p < 0.001) compared to the low-risk group. The ST1RE estimated CV events were similar to the observed at 5 years (3.4% vs. 3.5%; χ² = 10.12, p = 0.899) and 10 years (6.8% vs. 9.9%; χ² = 14.80, p = 0.676) of follow-up. The progression of microangiopathies was greater in the high vs. low for retinopathy (p = 0.008), diabetic kidney disease (p < 0.001), peripheral neuropathy (p = 0.021), and autonomic neuropathy (p = 0.008).

Conclusions: ST1RE performed well in predicting CV events at 5 and 10 years of follow-up. Moreover, higher ST1RE scores were associated with the progression of microangiopathy complications in this genetically heterogeneous T1D population.

Background: Type 2 diabetes mellitus (T2DM) is a major risk factor for heart failure with preserved ejection fraction and cardiac arrhythmias. Precursors of these complications, such as diabetic cardiomyopathy, remain incompletely understood and underdiagnosed. Detection of early signs of cardiac deterioration in T2DM patients is critical for prevention. Our goal is to quantify T2DM-driven abnormalities in ECG and cardiac imaging biomarkers leading to cardiovascular disease.

Methods: We quantified ECG and cardiac magnetic resonance imaging biomarkers in two matched cohorts of 1781 UK Biobank participants, with and without T2DM, and no diagnosed cardiovascular disease at the time of assessment. We performed a pair-matched cross-sectional study to compare cardiac biomarkers in both cohorts, and examined the association between T2DM and these biomarkers. We built multivariate multiple linear regression models sequentially adjusted for socio-demographic, lifestyle, and clinical covariates.

Results: Participants with T2DM had a higher resting heart rate (66 vs. 61 beats per minute, p < 0.001), longer QTc interval (424 vs. 420ms, p < 0.001), reduced T wave amplitude (0.33 vs. 0.37mV, p < 0.001), lower stroke volume (72 vs. 78ml, p < 0.001) and thicker left ventricular wall (6.1 vs. 5.9mm, p < 0.001) despite a decreased Sokolow-Lyon index (19.1 vs. 20.2mm, p < 0.001). T2DM was independently associated with higher heart rate (beta = 3.11, 95% CI = [2.11,4.10], p < 0.001), lower stroke volume (beta = -4.11, 95% CI = [-6.03, -2.19], p < 0.001) and higher left ventricular wall thickness (beta = 0.133, 95% CI = [0.081,0.186], p < 0.001). Trends were consistent in subgroups of different sex, age and body mass index. Fewer significant differences were observed in participants of non-white ethnic background. QRS duration and Sokolow-Lyon index showed a positive association with the development of cardiovascular disease in cohorts with and without T2DM, respectively. A higher left ventricular mass and wall thickness were associated with cardiovascular outcomes in both groups.

Conclusion: T2DM prior to cardiovascular disease was linked with a higher heart rate, QTc prolongation, T wave amplitude reduction, as well as lower stroke volume and increased left ventricular wall thickness. Increased QRS duration and left ventricular wall thickness and mass were most strongly associated with future cardiovascular disease. Although subclinical, these changes may indicate the presence of autonomic dysfunction and diabetic cardiomyopathy.

Background: Reduced red blood cell deformability (RBCD) is associated with diabetic vascular complications, but early pathophysiological RBC changes and predictive demographic and clinical factors in populations with diabetes are unclear. An understanding of early diabetes-specific RBC changes associated with impaired RBCD is essential in investigating mechanisms that predispose to diabetic vascular complications.

Methods: We conducted an outpatient cross-sectional study of participants in a well-controlled diabetes cohort (N81) and nondiabetic controls (N78) at the National Institutes of Health. First, between-group differences in RBCD measures were assessed with shear stress-gradient ektacytometry. Differences in structural RBC parameters were assessed using osmotic gradient ektacytometry and NaCl osmotic fragility. Functional RBC changes were assessed using hemoglobin-oxygen dissociation: p50.

Results: All shear-stress gradient RBCD measures were significantly altered in the diabetes cohort vs. nondiabetic controls, even after adjustment for confounding covariates (p < 0.001). Adjusted for diabetes-status and demographic factors, significant predictors of reduced RBCD included older age, Black race, male gender, hyperglycemia, and vascular complications (all p < 0.05). Reduced RBCD was also associated with aberrant osmotic-gradient parameters, with a left-shift on osmotic gradient profile indicative of dehydrated RBCs in diabetes. A structure-function relationship was observed with reduced RBCD associated with reduced osmotic fragility (P < 0.001) and increased hemoglobin-oxygen dissociation (P < 0.01).

Conclusions: Findings suggest impaired RBCD incurs similar demographic and clinical risk factors as diabetic vascular disease, with early pathophysiological RBC changes indicative of disordered RBC hydration in diabetes. Findings provide strong evidence for disordered oxygen release as a functional consequence of reduced RBCD.

Clinical trial number: NCT00071526.

Background: Non-alcoholic fatty liver diseases (NAFLDs)/non-alcoholic steatohepatitis (NASH) are the most common liver disorders among patients with type 2 diabetes. Newer classes of glucose-lowering agents (GLAs), such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is), have been shown to improve liver-related biomarkers. However, their effects on the development of NAFLD/NASH remain inconclusive.

Methods: A nested case-control study was conducted using Taiwan's National Health Insurance Research Database for 2011-2018. Patients aged ≥ 40 years, diagnosed with type 2 diabetes, having stable non-insulin GLA use, and without NAFLD/NASH history were included. Patients with incident NAFLD/NASH were matched up to 10 randomly sampled controls based on individual's age, gender, cohort entry date, type 2 diabetes diagnosis date, and disease risk score. Conditional logistic regression analyses were employed to estimate the association between liver risk and treatment exposure. Dose-response analysis was also performed.

Results: There were 621,438 study patients included for analysis. During 1.8 years of median follow-up, the incidence of NAFLD/NASH was 2.7 per 1000 person-years. After matching, 5,730 incident NAFLD cases (mean age: 57.6 years, male: 53.2%) and 45,070 controls (57.7 years, 52.7%) were identified. Using GLP-1RAs or SGLT2is was associated with an insignificantly lower NAFLD/NASH risk (i.e., odds ratios [95% CIs]: 0.84 [0.46-1.52] and 0.85 [0.63-1.14], respectively) and increased cumulative SGLT2i doses were significantly associated with a reduced NAFLD/NASH risk (0.61 [0.38-0.97]).

Conclusion: GLP-1RA and SGLT2i therapies in type 2 diabetes patients might prevent NAFLD/NASH development, with a significantly lower risk related to greater treatment exposure.

Introduction: Arterial calcification, an independent predictor of cardiovascular events, increases morbidity and mortality in patients with diabetes mellitus (DM), but its mechanisms remain unclear. Extracellular vesicles (EVs) play an important role in intercellular communication. The study investigates the role and potential mechanisms of EVs derived from endothelial cells (ECs) in regulating vascular smooth muscle cell (VSMC) calcification under high glucose (HG) condition, with a goal of developing effective prevention and treatment strategies for diabetic arterial calcification.

Results: The results showed that EVs derived from HG induced ECs (EC^HG-EVs) exhibited a bilayer structure morphology with a mean diameter of 74.08 ± 31.78 nm, expressing EVs markers including CD9, CD63 and TSG101, but not express calnexin. EC^HG-EVs was internalized by VSMCs and induced VSMC calcification by increasing Runx2 expression and mineralized nodule formation. The circ_0008362 was enriched in EC^HG-EVs, and it can be transmitted to VSMCs to promote VSMC calcification both in vitro and in vivo. Mechanistically, miR-1251-5p might be one of the targets of circ_0008362 and they were co-localization in the cytoplasm of VSMCs. Runx2 was identified as the downstream target of miR-1251-5p, and circ_0008362 acted as a sponge, enhancing Runx2 expression and then promoted VSMC calcification. Besides, circ_0008362 could directly interact with Runx2 to aggravate VSMC calcification. Notably, DiR-labelled EC^HG-EVs was detected in the vessels of mice. Meanwhile, the level of circ_0008362 and Runx2 were increased significantly, while the expression of miR-1251-5p was decreased significantly in calcified artery tissues of mice. However, inhibiting the release of EVs by GW4869 attenuated arterial calcification in diabetic mice. Finally, the level of circulation of plasma EVs circ_0008362 was significantly higher in patients with DM compared with normal controls. Elevated levels of plasma EVs circ_0008362 were associated with more severe coronary and aorta artery calcification in patients with DM.

Conclusions: Our findings suggested that circ_0008362 was enriched in EVs derived from ECs and promoted VSMC calcification under HG conditions, both by sponging miR-1251-5p to upregulate Runx2 expression and through direct interaction with Runx2. Furthermore, elevated levels of plasma EVs circ_0008362 were associated with more severe coronary and aorta artery calcification in patients with DM. These results may serve as a potential prevention and therapeutic target for diabetic arterial calcification.

Aims: The association and co-isolation of low-density lipoproteins (LDL) and extracellular vesicles (EVs) have been shown in blood plasma. Here we explore this relationship to better understand the role of EVs in atherogenesis.

Methods and results: Wild type (WT), PCSK9^-/-, and LDLR^-/- C57BL/6 mice were used in this study. Eleven week-old male mice were fed high-fat diet (HFD) for 12 weeks or kept on normal diet until old age (22-months). Cardiac function was assessed by ultrasound, cholesterol was quantified with a colorimetric kit and circulating EVs were measured using flow cytometry. Plaques were analysed post-mortem using Oil-Red-O staining of the aortic arch. EVs were measured from platelet free blood plasma samples of normal and hypercholesterolaemic clinical patients. Based on annexin V and CD63 staining, we found a significant increase in EV levels in LDLR^-/- and PCSK9^-/- mice after HFD, but CD81 showed no significant change in either group. There was no significant change in plaque formation after HFD. PCSK9^-/- mice show a favourable cardiac function after HFD. Blood cholesterol levels progressively increased during HFD, with LDLR^-/- mice showing high levels while PCSK9^-/- were significantly lowered compared to WT animals. In mice at old age, similar cholesterol levels were observed as in young mice. In old age, LDLR^-/- mice showed significantly increased plaques. At old age, ejection fraction was decreased in all groups of mice, as were CD63⁺ EVs. Similarly to mice, in patients with hypercholesterolaemia, CD63⁺ EVs were significantly depleted.

Conclusions: This research demonstrates an inverse relationship between circulating EVs and cholesterol, making EVs a potential marker for cardiovascular disease (CVD). HFD causes reduced cardiac function, but atherosclerotic development is slowly progressing in hypercholesterolaemic models and only observed with old animals. These results also bring further evidence for the benefit of using of PCSK9 inhibitors as therapeutic agents in CVD.

More than 10% of adults in the United States have type 2 diabetes mellitus (DM) with a 2-4 times higher prevalence of ischemic heart disease than the non-diabetics. Despite extensive research approaches to limit this life-threatening condition have proven unsuccessful, highlighting the need for understanding underlying molecular mechanisms. Long noncoding RNAs (lncRNAs), which regulate gene expression by acting as signals, decoys, guides, or scaffolds have been implicated in diverse cardiovascular conditions. However, their role in ischemic heart disease in DM remains poorly understood. We provide new insights into the lncRNA expression profile after ischemic heart disease in DM mice. We performed unbiased RNA sequencing of well-characterized type 2 DM model db/db mice or its control db/+ subjected to sham or MI surgery. Computational analysis of the RNA sequencing of these LV tissues identified several differentially expressed lncRNAs between (db/db sham vs. db/db MI) including Gm19522 and Gm8075. lncRNA Gm-19522 may regulate DNA replication via DNA protein kinases, while lncRNA Gm-8075 is associated with cancer gene dysregulation and PI3K/Akt pathways. Thus, the downregulation of lncRNAs Gm19522 and Gm8075 post-MI may serve as potential biomarkers or novel therapeutic targets to improve cardiac repair/recovery in diabetic ischemic heart disease.

Background: Cardiovascular disease (CVD), particularly ischemic heart disease, remains the leading cause of death and morbidity in patients with type 1 diabetes. Detecting subclinical atherosclerosis could enhance cardiovascular risk stratification and enable individualised therapies. The aim of this study is to investigate the prevalence and predictors of subclinical atherosclerosis in patients with type 1 diabetes without overt cardiovascular disease (CVD) and to assess its impact on patient survival over a follow-up period of at least 5 years.

Methods: This observational study included 507 patients treated at the Diabetes Unit of the Hospital of Girona Doctor Josep Trueta between 2015 and 2023. The inclusion criteria for patients were as follows: those aged 18 and older with diabetes for a minimum of 10 years or those aged 40 and older with a diabetes for at least 5 years. Subclinical atherosclerosis was identified via ultrasound imaging of the carotid and femoral arteries. Clinical and biochemical evaluations were also conducted. Major cardiovascular events (MACE) and deaths from other causes were monitored, and survival analysis was performed using Kaplan‒Meier methods.

Results: Subclinical atherosclerosis was detected in 218 patients (43%). Multivariate analysis revealed that the male sex, diabetic nephropathy, tobacco exposure, higher HbA1c levels, older age, and longer diabetes duration were significant predictors. During a mean follow-up of 70.64 ± 27.08 months, 19 patients experienced MACE, and 13 died from any cause. The probability of MACE or death was greater in patients with subclinical atherosclerosis, with a hazard ratio (HR) of 25.1 (95% CI 5.81-108, p < 0.001) for MACE and an odds ratio (OR) of 7.57 (95% CI 1.97-53.9, p = 0.004) for death.

Conclusion: Subclinical atherosclerosis is independently associated with increased overall mortality and MACE in patients with type 1 diabetes. Identifying clinical predictors can improve risk stratification and personalised therapeutic strategies to prevent MACEs in this high-risk population.

Background: The association between changes in insulin resistance, reflected by the triglyceride-glucose (TyG) index, and mortality remains unclear. This study investigated whether longitudinal trajectories of TyG index changes are associated with all-cause and cardiovascular disease (CVD) mortality.

Methods: This retrospective cohort study analyzed data from 233,546 adults aged ≥ 19 years from the Korea National Health Insurance Service-National Sample Cohort. Participants were categorized as having increasing, stable, or decreasing TyG index changes during a 4-year exposure period (2009-2014). Mortality outcomes were assessed during an 8.13-year follow-up period (2015-2021). Cox proportional hazards regression and competing risk analysis were used to evaluate all-cause and CVD mortality.

Results: A total of 7918 mortality events, including 651 CVD deaths, were recorded. Compared with the stable group, adjusted hazard ratios for all-cause mortality were 1.09 (95% CI 1.03-1.15) in the increasing group and 1.23 (95% CI 1.01-1.50) for CVD mortality. An increased TyG index was significantly associated with all-cause mortality in individuals aged < 50 years; men; and individuals with obesity, hypertension, diabetes, and/or dyslipidemia. For CVD mortality, significant associations were found in individuals aged 50-69 years, with obesity, with diabetes, or without dyslipidemia.

Conclusion: An increasing TyG index from baseline during follow-up was independently associated with higher risks of all-cause and CVD mortality. Serial monitoring of TyG index changes could enhance risk stratification and inform targeted interventions to reduce insulin resistance, and ultimately lower mortality risk.