Cardiovascular Events In Diabetic Patients Research Articles

Time-frequency analysis reveals an association between the specific nuclear magnetic resonance (NMR) signal properties of serum samples and arteriosclerotic lesion progression in a diabetes mouse model.

Diabetes causes arteriosclerosis, primarily due to persistent hyperglycemia, subsequently leading to various cardiovascular events. No method has been established for directly detecting and evaluating arteriosclerotic lesions from blood samples of diabetic patients, as the mechanism of arteriosclerotic lesion formation, which involves complex molecular biological processes, has not been elucidated. "NMR modal analysis" is a technology that enables visualization of specific nuclear magnetic resonance (NMR) signal properties of blood samples. We hypothesized that this technique could be used to identify changes in blood status associated with the progression of arteriosclerotic lesions in the context of diabetes. The study aimed to assess the possibility of early detection and evaluation of arteriosclerotic lesions by NMR modal analysis of serum samples from diabetes model mice. Diabetes model mice (BKS.Cg db/db) were bred in a clean room and fed a normal diet. Blood samples were collected and centrifuged. Carotid arteries were collected for histological examination by hematoxylin and eosin staining on weeks 10, 14, 18, 22, and 26. The serum was separated and subjected to NMR modal analysis and biochemical examination. Mice typically show hyperglycemia at an early stage (8 weeks old), and pathological findings of a previous study showed that more than half of mice had atheromatous plaques at 18 weeks old, and severe arteriosclerotic lesions were observed in almost all mice after 22 weeks. Partial least squares regression analysis was performed, which showed that the mice were clearly classified into two groups with positive and negative score values within 18 weeks of age. The findings of this study revealed that NMR modal properties of serum are associated with arteriosclerotic lesions. Thus, it may be worth exploring the possibility that the risk of cardiovascular events in diabetic patients could be assessed using serum samples.

Perioperative changes of serum orphanin in diabetic patients and its relationship with sympathetic nervous system

The occurrence of cardiovascular events in diabetic patients during the perioperative period is related to the activation of sympathetic nerves. Basic research shows that serum nociceptin/orphanin FQ (N/OFQ) levels in diabetic neuropathy rats increased, and N/OFQ reduces the release of norepinephrine (NE). We hypothesize that N/OFQ will affect the sympathetic nervous system during perioperative myocardium of diabetic patients. 66 patients with unilateral knee arthroplasty were divided into diabetes group (D group) and non-diabetes group (N group). Measured blood glucose, serum NE, N/OFQ concentrations at the 30 min before anesthesia (T0), 1 h after surgery (T1), 24 h after surgery (T2) and the cardiac troponinI (cTnI) concentration at T0 and T2. Compared with N group, the concentration of blood glucose, N/OFQ and cTnI in D group was higher and the NE was lower at T0 (P < 0.05). At T1, the blood glucose, N/OFQ, NE concentrations of D group increased, only the blood glucose increased in N group (P < 0.05). Serum N/OFQ of D group from T0 to T1 was correlated with the change trend of blood glucose, NE concentration from T0 to T1 and cTnI from T0 to T2(r = 0.386, P = 0.027; r = 0.350, P = 0.046; r = 0.363, P = 0.038). The outcomes demonstrated that the preoperative serum N/OFQ concentration in diabetic patients was increased, and the increase in N/OFQ concentration during the operation was related to the increase in NE and cTnI concentrations, perioperative N/OFQ may mediate myocardial injury through sympathetic nervous system.

The impact of sodium-glucose co-transporter-2 inhibitors on dementia and cardiovascular events in diabetic patients with atrial fibrillation.

The effectiveness of sodium-glucose co-transporter-2 inhibitors (SGLT2i) on incident dementia in patients with diabetes and atrial fibrillation (AF) remains unknown. This study aimed to investigate the association between SGLT2i and the risk of incident dementia in diabetic patients with AF, and to explore the interactions with oral anticoagulants or dipeptidyl peptidase-4 inhibitors (DPP4i). We conducted a cohort study using Taiwan's National Health Insurance Research Database. Patients with diabetes and AFwithout a prior history of established cardiovascular diseases, were identified. Using propensity score matching, 810 patients receiving SGLT2i were matched with 1620 patients not receiving SGLT2i. The primary outcome was incident dementia, and secondary outcomes included composite cardiovascular events and mortality. After up to 5years of follow-up, SGLT2i use was associated with a significantly lower risk of incident dementia (hazard: 0.71, 95% confidence interval: 0.51-0.98), particularly vascular dementia (HR: 0.44, 95% CI: 0.24-0.82). SGLT2i was related to reduced risks of AF-related hospitalisation (HR: 0.72, 95% CI: 0.56-0.93), stroke (HR: 0.75, 95% CI: 0.60-0.94), and all-cause death (HR: 0.33, 95% CI: 0.24-0.44). The protective effects were consistent irrespective of the concurrent use of non-vitamin K antagonist oral anticoagulants (NOACs) or DPP4i. In diabetic patients with AF, SGLT2i was associated with reduced risks of incident dementia, AF-related hospitalisation, stroke, and all-cause death. The protective effects were independent of either concurrent use of NOACs or DPP4i.

Effect of sodium-glucose type 2 cotransporter inhibitors on cardiac structure and function in patients with normal ejection fraction

Abstract Introduction Sodium-glucose cotransporter inhibitors (SGLT2i) have proven a reduction in cardiovascular events in diabetic patients with and without heart failure (HF), as well as in non-diabetic patients with heart failure with reduced and preserved ejection fraction (EF). The mechanisms underlying this benefit are not well known, with contradicting data on the changes that SGLT2i produce on cardiac function and structure. Methods Between October 2020 and October 2021, 31 diabetic patients without prior history of SGLT2i use with normal EF (&amp;gt;50%), glycated hemoglobin &amp;lt;6.5%, renal clearance rate of &amp;gt;60 ml/min/1.73 m2 and sinus rhythm were prospectively included. In all of them, SGLT2i were started. At inclusion and 6-months follow-up, different clinical, ECG, analytical and echocardiographic (standard, 3D and speckle tracking) variables were recorded. Results The average age of our population was 66.4 years (±8.4). 90% were male, 71% were hypertensive, 77.4% were dyslipidemic, 22.6% were obese and 87.1% were current or former smokers. 77.4% of patients had a history of ischemic heart disease, and 10% had vascular disease in other territories. At the time of inclusion, 80.6% of the population was treated with ACEI or ARB, 54.8% with beta-blockers, 29% with diuretics, and 93.5% with statins. After an average follow-up period of 6.6 months (±0.8), medication had to be withdrawn in 5 patients (in 3 of them due to repeated genital or urinary infections, and in 2 of them because of patient choice). An average reduction of 0.89 mm (±0.24, p = 0.001) in myocardial thickness was observed, as well as a reduction in the 3D-estimated left ventricle mass of 9.9 g/m2 (±4.5, p = 0.03), and in the E/é ratio of 1.4 (±4.5, p = 0.02). An increase in absolute left ventricle global longitudinal strain (LVGLS) of 0.74 (±0.35, p = 0.05) was observed, as well as an increase in isovolumetric relaxation time (IVRT) of 9.8 ms (±4.8, p = 0.05). An increase in LA strain and indexed volume was noted, although differences did not achieve statistical significance. No relevant differences in LV dimensions and volumes were observed, as well as in the evaluated RV parameters (picture 1). Conclusions It is necessary to understand the mechanism underlying the clinical benefit of these drugs. This will allow us to better understand its effect in patients with HF. Our data shows that the use of SGLT2i is associated with cardiac improvements, both structural (myocardial mass) and functional (IVRT, LVGLS, E/e'), in a population of patients with normal EF.

GLP1 receptor agonists exhibit antioxidant and anti-inflammatory properties in human heart tissue via the canonical GLP1 receptor expression through a AMPK-mediated pathway

Abstract Background Clinical research has demonstrated that glucagon-like peptide-1 receptor (GLP1R) agonists (GLP1RA) can decrease the occurrence of major cardiovascular events in diabetic patients, regardless of their glycemic control. However, a significant challenge in understanding the positive effects of GLP1RA has been the lack of knowledge regarding the specific cellular types that express GLP1R. Despite the established cardiovascular benefits of GLP1RA, previous studies have been unable to confirm the expression of GLP1R in the heart. Aim The study aimed to investigate the expression and function of GLP1R in heart tissue. Methods We collected human cardiac tissue samples from 30 patients who underwent left ventricle (LV) biopsies (n=21) or right atrial (RA) appendage closure (n=9) at a university hospital. Gene expression levels were assessed using RT-qPCR, protein levels by Western blot analysis, in situ tissue localization of proteins by immunofluorescence (IF) staining, and the level of oxidative stress using dihydroethidium. Results LV biopsies and RA appendages showed a substantial heterogeneity in GLP1R mRNA levels. GLP1R mRNA levels exhibited a positive correlation with IL1B, IL6, TNFα, CCL2, CD68, ACE1, AT1R, and VCAM1 mRNA levels, but a negative correlation with NOS3 mRNA levels. High GLP1R expression in both RA appendages and LV biopsies was associated with increased oxidative stress levels, which were mitigated by the antioxidant N-acetylcysteine (NAC), NADPH oxidase inhibitor (VAS-2870), ACE inhibitor (perindoprilat), AT1R antagonist (losartan), TNF-α receptor neutralizing antibody (infliximab) and by GLP1R agonists (liraglutide and semaglutide) with inhibitory effects amounting to about 50-60 %. Exendin, a GLP1R antagonist reversed the effect of liraglutide and semaglutide which accounted for a receptor-mediated antioxidant effect. H-89, a PKA inhibitor equally reversed liraglutide and semaglutide effect on ROS generation suggesting a canonical GLP1R mediated effect involving the AMPK pathway. Conclusion These findings indicate that human cardiac GLP1R expression levels are correlated to low-grade inflammation and endothelial dysfunction. Increased expression levels of GLP1R were associated with higher levels of oxidative stress sensitive to GLP1RA in a canonical GLP1R AMPK-mediated manner. Therefore, the cardiovascular beneficial effects of GLP1RA might be attributable to their antioxidant and anti-inflammatory properties, specifically within the cardiac system.

High triglyceride-glucose index predicts cardiovascular events in patients with coronary bifurcation lesions: a large-scale cohort study

BackgroundCoronary bifurcation lesion, as a complex coronary lesion, is associated with higher risk of long-term poor prognosis than non-bifurcation lesions. The triglyceride-glucose (TyG) index has been shown to predict cardiovascular (CV) events in patients with coronary artery disease (CAD). However, the prognostic value of the TyG index in patients with bifurcation lesions who are at high risk of CV events remains undetermined. Therefore, this study aimed to investigate the association between the TyG index and CV events in patients with bifurcation lesions.MethodsA total of 4530 consecutive patients with angiography-proven CAD and bifurcation lesions were included in this study from January 2017 to December 2018. The TyG index was calculated as Ln [fasting triglyceride (mg/dL) × fasting plasma glucose (mg/dL)/2]. Patients were assigned into 3 groups according to TyG tertiles (T) (T1: <8.633; T2: 8.633–9.096 and T3: ≥9.096). The primary endpoint was CV events, including CV death, nonfatal myocardial infarction and nonfatal stroke at 3-year follow-up. Restricted cubic spline (RCS) analysis, Kaplan-Meier curves and Cox proportional hazard models were used to investigate the associations between the TyG index and study endpoints.ResultsDuring a median follow-up of 3.1 years, 141 (3.1%) CV events occurred. RCS analysis demonstrated a linear relationship between the TyG index and events after adjusting for age and male sex (non-linear P = 0.262). After multivariable adjustments, elevated TyG index (both T2 and T3) was significantly associated with the risk of CV events (hazard ratio [HR], 1.68; 95% confidence interval [CI],1.06–2.65; HR, 2.10; 95%CI, 1.28–3.47, respectively). When study patients were further stratified according to glycemic status, higher TyG index was associated with significantly higher risk of CV events in diabetic patients after adjusting for confounding factors (T3 vs. T1; HR, 2.68; 95%CI, 1.17–6.11). In addition, subgroup analysis revealed consistent associations of the TyG index with 3-year CV events across various subgroups. Furthermore, adding the TyG index to the original model significantly improved the predictive performance.ConclusionsHigh TyG index was associated with CV events in patients with bifurcation lesions, suggesting the TyG index could help in risk stratification and prognosis in this population.

Treatment effect of canagliflozin for patients on therapy for heart failure: Pooled analysis of the CANVAS program and CREDENCE trial

BackgroundCanagliflozin is a sodium–glucose cotransporter 2 inhibitor that has been shown to reduce cardiovascular events in diabetic patients with and without heart failure (HF). Whether the clinical benefits and safety profile of canagliflozin are different in those on a beta blocker and an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (BB + RAASi) is unknown. MethodsWe pooled participants with HF at baseline from the CANVAS Program and CREDENCE trial and assessed major adverse cardiovascular events and its components; hospitalization for heart failure (HHF); HHF or CV death; all-cause mortality; a renal composite; and a combined renal and CV composite. ResultsOf 14,543 participants, 2113 had HF at baseline, and 1280 were on BB + RAASi. In those with a history of HF, participants on BB + RAASi therapy were more likely to have coronary atherosclerotic disease (82 vs 72%, p < 0.001), history of myocardial infarction (42 vs 29%, p < 0.001), higher mean body mass index (34 vs 32 kg/m2, p < 0.001), and lower mean estimated glomerular filtration rate (67 vs 70 mL/min/1.73 m2, p < 0.01). They were also more likely to be on insulin, a statin, antithrombotic agent, and a diuretic (all p < 0.001). In unadjusted analysis and when adjusted for selected baseline factors, there was no heterogeneity in canagliflozin treatment effect except for HHF/CV death in those on baseline BB + RAASi vs. those not on baseline BB + RAASi (Pheterogeneity = 0.02). ConclusionCanagliflozin mostly improved CV and kidney outcomes in participants with a history of HF irrespective of use of BB + RAASi at baseline, with possible greater benefit on HHF/CV death in participants on BB + RAASi.

Role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in diabetic complications.

Cardiovascular disease (CVD) complications have remained a major cause of death among patients with diabetes. Hence, there is a need for effective therapeutics against diabetes-induced CVD complications. Since its discovery, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been reported to be involved in the pathology of various CVDs, with studies showing a positive association between plasma levels of PCSK9, hyperglycemia, and dyslipidemia. PCSK9 regulates lipid homeostasis by interacting with low-density lipoprotein receptors (LDLRs) present in hepatocytes and subsequently induces LDLR degradation via receptor-mediated endocytosis, thereby reducing LDL uptake from circulation. In addition, PCSK9 also induces pro-inflammatory cytokine expression and apoptotic cell death in diabetic-CVD. Furthermore, therapies designed to inhibit PCSK9 effectively reduces diabetic dyslipidemia with clinical studies reporting reduced cardiovascular events in patients with diabetes and no significant adverse effect on glycemic controls. In this review, we discuss the role of PCSK9 in the pathogenesis of diabetes-induced CVD and the potential mechanisms by which PCSK9 inhibition reduces cardiovascular events in diabetic patients.

Dapagliflozin versus empagliflozin in patients with chronic kidney disease.

Background and Aim: Dapagliflozin and empagliflozin have demonstrated favorable clinical outcomes among patients with chronic kidney disease (CKD). However, their comparative monetary value for improving outcomes in CKD patients is unestablished. We examined the cost-per-outcome implications of utilizing dapagliflozin as compared to empagliflozin for prevention of renal and cardiovascular events in CKD patients. Methods: For calculation of preventable events we divided the allocated budget by the cost needed to treat (CNT) for preventing a single renal or cardiovascular event. CNT was derived by multiplying the annualized number needed to treat (aNNT) by the annual therapy cost. The aNNTs were determined based on data from the DAPA-CKD and EMPEROR-KIDNEY trials. The budget limit was defined based on the threshold recommended by the United States' Institute for Clinical and Economic Review. Results: The aNNT was 42 both dapagliflozin (95% confidence interval [CI]: 34-59) and empagliflozin (CI: 33-66). The CNT estimates for the prevention of one primary event for dapagliflozin and empagliflozin were comparable at $201,911 (CI: $163,452-$283,636) and $209,664 (CI: $164,736-$329,472), respectively. However, diabetic patients had a higher CNT with dapagliflozin ($201,911 [CI: $153,837-$346,133]) than empagliflozin ($134,784 [CI: $109,824-$214,656]), whereas non-diabetic patients had lower CNT for dapagliflozin ($197,103 [CI: $149,029-$346,133]) than empagliflozin ($394,368 [CI: $219,648-$7,093,632]). The CNT for preventing CKD progression was higher for dapagliflozin ($427,858 [CI: $307,673-$855,717]) than empagliflozin ($224,640 [CI: $169,728-$344,448]). For preventing cardiovascular death (CVD), the CNT was lower for dapagliflozin ($1,634,515 [CI: $740,339-∞]) than empagliflozin ($2,990,208 [CI: $1,193,088-∞]). Conclusion: Among patients with CKD, empagliflozin provides a better monetary value for preventing the composite renal and cardiovascular events in diabetic patients while dapagliflozin has a better value for non-diabetic patients. Dapagliflozin provides a better monetary value for the prevention of CVD, whereas empagliflozin has a better value for the prevention of CKD progression.

COMPARISON OF EFFECTS OF BLOOD PRESSURE, BLOOD GLUCOSE AND LIPID VARIABILITY ON CARDIOVASCULAR PROGNOSIS IN DIABETIC PATIENTS

Objective: Metabolic abnormalities such as dyslipidemia, glucose and high blood pressure are common in diabetic patients. Variabilities in these measures have been reported as a potential residual cardiovascular risk factors. This study aimed to analyze the relationship between variabilities of blood pressure, blood glucose, total cholesterol and triglyceride levels (metabolic variability parameters) and their effects on cardiovascular prognosis in diabetic patients. Design and method: A total of 22,310 diabetic patients aged 40 years or older who had their blood pressure, blood glucose, total cholesterol, and triglyceride levels measured three or more times for three years after January 1, 2017 at three tertiary general hospitals were selected. They were divided into high/low groups based on their systolic blood pressure (SBP), blood glucose, total cholesterol (TC) and triglyceride coefficient of variation (CV) over a 3-year period. The incidence of major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke, was compared between groups, and significant risk factors for MACE were estimated by multivariable Cox regression analysis. Results: The number of measurements for 3 years was 15.1 times for SBP, 7.8 times for TC, 6.9 times for triglyceride, and 8.6 times for glucose. The correlation between the CV of SBP and the CV of glucose was highest, and the correlation between the CV of SBP and the CV of triglycerides was the lowest. All groups with high CV had a higher incidence of MACE than those with low CV (2.5% vs 6.0% for SBP CV groups, 3.0% vs 5.5% for TC CV groups, 3.8% vs 4.7% for triglyceride CV groups, 2.7% vs 5.8% for glucose CV groups). Multivariable Cox regression analysis suggested male, creatinine, prior myocardial infarction, SCORE2, SBP CV, TC CV, mean TC, and mean triglyceride as independent risk predictors for MACE in diabetic patients (HR 1.087 (95% CI 1.068 – 1.107) for SBP CV, 1.023 (1.016 – 1.031) for TC CV). Conclusions: Metabolic variability parameters, especially SBP CV and TC CV are important residual risk factors for cardiovascular events in diabetic patients.

Effects of metabolic parameters’ variability on cardiovascular outcomes in diabetic patients

BackgroundMetabolic abnormalities such as dyslipidemia, glucose and high blood pressure are common in diabetic patients. Visit-to-visit variabilities in these measures have been reported as potential residual cardiovascular risk factors. However, the relationship between these variabilities and their effects on cardiovascular prognosis have not been studied.MethodsA total of 22,310 diabetic patients with ≥ 3 measurements of systolic blood pressure (SBP), blood glucose, total cholesterol (TC), and triglyceride (TG) levels during a minimum of three years at three tertiary general hospitals were selected. They were divided into high/low variability groups for each variable based on the coefficient of variation (CV) values. The primary outcome was the incidence of major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke.ResultsAll high CV groups had a higher incidence of MACE than those with low CV (6.0% vs. 2.5% for SBP-CV groups, 5.5% vs. 3.0% for TC-CV groups, 4.7% vs. 3.8% for TG-CV groups, 5.8% vs. 2.7% for glucose-CV groups). In multivariable Cox regression analysis,, high SBP-CV (HR 1.79 [95% CI 1.54–2.07], p < 0.01), high TC-CV (HR 1.54 [95% CI 1.34–1.77], p < 0.01), high TG-CV (HR 1.15 [95% CI 1.01–1.31], p = 0.040) and high glucose-CV (HR 1.61 [95% CI 1.40–1.86], p < 0.01) were independent predictors of MACE.ConclusionVariability of SBP, TC, TG and glucose are important residual risk factors for cardiovascular events in diabetic patients.

CT-derived fractional flow reserve for prediction of major adverse cardiovascular events in diabetic patients

ObjectivesTo investigate the prognostic value of computed tomography fractional flow reserve (CT-FFR) in patients with diabetes and to establish a risk stratification model for major adverse cardiac event (MACE).MethodsDiabetic patients with intermediate pre-test probability of coronary artery disease were prospectively enrolled. All patients were referred for coronary computed tomography angiography and followed up for at least 2 years. In the training cohort comprising of 957 patients, two models were developed: model1 with the inclusion of clinical and conventional imaging parameters, model2 incorporating the above parameters + CT-FFR. An internal validation cohort comprising 411 patients and an independent external test cohort of 429 patients were used to validate the proposed models.Results1797 patients (mean age: 61.0 ± 7.0 years, 1031 males) were finally included in the present study. MACE occurred in 7.18% (129/1797) of the current cohort during follow- up. Multivariate Cox regression analysis revealed that CT-FFR ≤ 0.80 (hazard ratio [HR] = 4.534, p < 0.001), HbA1c (HR = 1.142, p = 0.015) and low attenuation plaque (LAP) (HR = 3.973, p = 0.041) were the independent predictors for MACE. In the training cohort, the Log-likelihood test showed statistical significance between model1 and model2 (p < 0.001). The C-index of model2 was significantly larger than that of model1 (C-index = 0.82 [0.77–0.87] vs. 0.80 [0.75–0.85], p = 0.021). Similar findings were found in internal validation and external test cohorts.ConclusionCT-FFR was a strong independent predictor for MACE in diabetic cohort. The model incorporating CT-FFR, LAP and HbA1c yielded excellent performance in predicting MACE.

Substituent effects of sulfonamide derivatives of metformin that can dually improve cellular glucose utilization and anti-coagulation

Metformin, the most frequently prescribed medicine for the management of type 2 diabetes, has been shown to reduce cardiovascular events in diabetic patients in pre-clinical and clinical studies. The present work reports the design, synthesis, and biological assessment of the impact of six benzenesulfonamide biguanides on various aspects of hemostasis, cell function, red blood cell integrity (RBC), and their ability to uptake glucose in human umbilical endothelial cells (HUVECs). It was found that all synthesized o- and m-benzenesulfonamides, particularly derivatives with nitro (3) and amino groups (4), are characterized by a good safety profile in HUVECs, which was further confirmed in the cellular integrity studies. The biguanide analogues with methoxy group (1, 2) and an amino substituent (5, 6) significantly increased glucose utilization in HUVECs, similarly to the parent drug. Intriguingly, compounds 1, 3, and 6 favourably influenced some of the coagulation parameters. Furthermore, derivative 3 also slowed the process of fibrin polymerization, indicating more beneficial anti-coagulant properties than metformin. None of the novel metformin analogues interact strongly with the erythrocyte lipid-protein bilayer. Our findings indicate that derivative 3 has highly desirable anti-coagulant properties, and compounds 1 and 6 have potential dual-action activity, including anti-hyperglycaemic properties and anti-coagulant activity. As such, these derivatives can be used as lead molecules for further development of anti-diabetic agents with a beneficial effect on hypercoagulability.

Atherosclerotic patients with diabetes mellitus may break through the threshold of healthy TMAO levels formed by long-term statins therapy

BackgroundCardiovascular disease (CVD) is the leading course of disease-related death in both developed and developing countries. Atherosclerosis is main pathology of CVD, and its severity is thought to be related to trimethylamine N-oxide (TMAO) level in plasma. Therefore, it is necessary to deeply understand the synergistic patterns between TMAO and other contribution variables to atherosclerosis, allowing for effective and timely monitoring or intervention. MethodsA total of 359 participants were recruited in our study, including 190 atherosclerosis patients, 82 MI or stroke patients, 68 non-atherosclerosis controls and 19 healthy controls. Information on their risk associated with atherosclerosis and plasma TMAO concentration were collected. LASSO regression, multivariate analysis and univariate analysis were then performed to confirm the correlation between TMAO level and risk factors of atherosclerosis. ResultsCompared to patients and non-atherosclerosis controls, healthy participants had a normal BMI range (lower than 24), lower triglyceride concentration, and healthy lifestyle habits (no smoking and low salt diet). However, under backgrounds of statins treatment and balanced dietary preferences, TMAO levels were not significantly different among patients, non-atherosclerosis controls and healthy controls. Using LASSO regression model, four indicators was identified to have contribution to TMAO levels, including diabetes, atherosclerosis, low-density lipoprotein and total cholesterol. Subsequent univariate analysis further confirmed that the presence or absence of diabetes had a decisive effect on patients' plasma TMAO levels, even though they had been taking statin lipid-lowering drugs for a long time. ConclusionDiabetics have abnormally high plasma TMAO levels even under continuous statins treatment, which may contribute to the development and progression of atherosclerosis. Therefore, it is necessary to focus on monitoring TMAO levels in diabetic patients to reduce adverse cardiovascular events in diabetic patients.

SGLT2 inhibitors reduce adverse kidney and cardiovascular events in patients with advanced diabetic kidney disease: A population-based propensity score-matched cohort study

BackgroundThere were limited data on the efficacy and safety profile on use of sodium–glucose co-transporter 2 receptor (SGLT2) inhibitors in diabetic patients with advanced chronic kidney disease (CKD). We aimed to evaluate the efficacy, in terms of improvement in glycemic profile, kidney function, prevention of adverse kidney and cardiovascular events, and the safety profile of SGLT2 inhibitors in a group of diabetic patients at CKD stage 3B-5 from a real-world population-based cohort. MethodsWe performed a retrospective observational cohort study of type 2 diabetic patients at CKD stage 3B-5 who received SGLT2 inhibitors as compared to control from 1 January 2015 through 31 December 2021. Propensity score assignment by logistic regression and matching with control by the nearest score at 1:3 ratio was done. All patients were followed for 1 year. Outcomes were kidney-related adverse events and major adverse cardiovascular events (MACE), change in estimated glomerular filtration rate (eGFR), glycemic control, and side effects profiling. ResultsWe analyzed 1,450 SGLT2 inhibitor users. They had significantly lower rates of kidney-related adverse events (7.7 % versus 24.1 %, p < 0.001) and MACE (9.6 % versus 15.1 %, p < 0.001) as compared to control group. Their eGFR also significantly improved (0.4 ± 9.3 versus −5.5 ± 10.6 ml/min/1.73 m2, p < 0.001). These patients also had a greater reduction in HbA1c (-0.40 ± 1.13 versus -0.04 ± 1.47 %, p < 0.001), and insulin requirement (-8.8 ± 35.2 versus 4.1 ± 19.4 units/day, p < 0.001). After adjusting for confounders, SGLT2 inhibitors protected against kidney-related adverse events (odds ratio [OR] 0.48, 95 % confidence interval [CI] 0.33 – 0.71, p < 0.001) and MACE (OR 0.47, 95 % CI 0.37 – 0.60, p < 0.001). Apart from a marginally higher rate of fungal urinary tract infection (0.08 ± 0.66 versus 0.03 ± 0.23 episodes per year, p < 0.001), SGLT2 inhibitor use was not associated with other side effects. ConclusionsSGLT2 inhibitor improved kidney function, glycemic profile, and reduced adverse kidney-related and cardiovascular events in diabetic patients with advanced CKD.

Glucagon-like peptide-1 receptor agonists and the risk of cardiovascular events in diabetes patients surviving an acute myocardial infarction – experience from Dubrava University Hospital

Glucagon-like peptide-1 receptor agonists and the risk of cardiovascular events in diabetes patients surviving an acute myocardial infarction – experience from Dubrava University Hospital

GLP-1 receptor expression in human internal thoracic arteries is dependent on low-grade inflammation potentially explaining the cardiovascular protective effect of GLP1-R agonists

Abstract Background Clinical research showed that glucagon-like peptide-1 receptor (GLP1R) agonists (GLP1RA) reduced the incidence of major cardiovascular events in diabetic patients. The protective effect was more noteworthy in patients with established cardiovascular disease, associated with chronic low-grade inflammation resulting in endothelial dysfunction and arterial remodeling and fibrosis. Despite the clinically proven cardiovascular benefit of GLP1RA, the expression pattern of GLP1R and its function in the human vasculature remain poorly studied. Aim This study investigated the expression of GLP1R and its role in internal thoracic arteries (ITA) from patients with coronary artery disease. Methods Human ITA were collected from patients (N=30) undergoing coronary artery bypass surgery at the University Hospital of Strasbourg. Gene expression levels were assessed using RT-qPCR, protein levels by Western blot analysis, in situ tissue localization of proteins by immunofluorescence (IF) staining, and the level of oxidative stress using dihydroethidium. Results ITA showed a substantial difference in GLP1R mRNA levels reaching up to 7-fold among patients. GLP1R mRNA levels were positively correlated with those of SLC5A1, SLC5A2, F3, AT1R, IL1B, IL6, TNFα, VCAM1 and NCF1, and negatively with NOS3 mRNA levels. High GLP1R expressing ITA showed high levels of phosphorylated p65 NF-κB, cell adhesion molecule VCAM1, members of the angiotensin system (ACE1 and AT1R), remodeling and fibrotic markers (MMP9, MMP2, TGFβ) and a low level of eNOS, whereas the contrary was observed for low GLP1R expressing ITA. IF staining showed that GLP1R signals were predominantly observed in the endothelium of low GLP1R expressing ITA and in the vascular smooth muscle of high GLP1R expressing ITA. Prominent CD68 staining associated with the endothelium and the perivascular adipose tissue were observed in high but not low GLP1R expressing ITA. High GLP1R expressing ITA showed increased levels of oxidative stress, which were inhibited by the antioxidant N-acetylcysteine (NAC), NADPH oxidase inhibitor (VAS-2870), ACE inhibitor (perindoprilat), AT1R antagonist (losartan), TNF-α receptor neutralizing antibody (infliximab), selective SGLT2 inhibitor (empagliflozin), dual SGLT1/2 inhibitor (sotagliflozin) and by GLP1R agonists (liraglutide and semaglutide) with inhibitory effects amounting to about 50 to 75%. Conclusion These findings indicate that GLP1R expression levels in human ITA are dependent on low-grade inflammation and linked to endothelial dysfunction, pro-thrombotic, pro-remodeling and pro-fibrotic responses. Furthermore, they were associated with increased level of oxidative stress sensitive to inhibitors of either the local angiotensin system, SGLT2, TNFα and agonists of GLP1R. Thus, the cardiovascular beneficial effects of GLP1R agonists might be attributable to their ability to reduce the pro-oxidant stimulatory signal related to low-grade inflammation. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Frency Society of Vascular Medicine (SFMV)

Dynamic patterns of postprandial metabolic responses to three dietary challenges.

Food intake triggers extensive changes in the blood metabolome. The kinetics of these changes depend on meal composition and on intrinsic, health-related characteristics of each individual, making the assessment of changes in the postprandial metabolome an opportunity to assess someone's metabolic status. To enable the usage of dietary challenges as diagnostic tools, profound knowledge about changes that occur in the postprandial period in healthy individuals is needed. In this study, we characterize the time-resolved changes in plasma levels of 634 metabolites in response to an oral glucose tolerance test (OGTT), an oral lipid tolerance test (OLTT), and a mixed meal (SLD) in healthy young males (n = 15). Metabolite levels for samples taken at different time points (20 per individual) during the challenges were available from targeted (132 metabolites) and non-targeted (502 metabolites) metabolomics. Almost half of the profiled metabolites (n = 308) showed a significant change in at least one challenge, thereof 111 metabolites responded exclusively to one particular challenge. Examples include azelate, which is linked to ω-oxidation and increased only in OLTT, and a fibrinogen cleavage peptide that has been linked to a higher risk of cardiovascular events in diabetes patients and increased only in OGTT, making its postprandial dynamics a potential target for risk management. A pool of 89 metabolites changed their plasma levels during all three challenges and represents the core postprandial response to food intake regardless of macronutrient composition. We used fuzzy c-means clustering to group these metabolites into eight clusters based on commonalities of their dynamic response patterns, with each cluster following one of four primary response patterns: (i) “decrease-increase” (valley-like) with fatty acids and acylcarnitines indicating the suppression of lipolysis, (ii) “increase-decrease” (mountain-like) including a cluster of conjugated bile acids and the glucose/insulin cluster, (iii) “steady decrease” with metabolites reflecting a carryover from meals prior to the study, and (iv) “mixed” decreasing after the glucose challenge and increasing otherwise. Despite the small number of subjects, the diversity of the challenges and the wealth of metabolomic data make this study an important step toward the characterization of postprandial responses and the identification of markers of metabolic processes regulated by food intake.

Protective effects of metformin in various cardiovascular diseases: Clinical evidence and AMPK-dependent mechanisms.

Metformin, a well‐known AMPK agonist, has been widely used as the first‐line drug for treating type 2 diabetes. There had been a significant concern regarding the use of metformin in people with cardiovascular diseases (CVDs) due to its potential lactic acidosis side effect. Currently growing clinical and preclinical evidence indicates that metformin can lower the incidence of cardiovascular events in diabetic patients or even non‐diabetic patients beyond its hypoglycaemic effects. The underlying mechanisms of cardiovascular benefits of metformin largely involve the cellular energy sensor, AMPK, of which activation corrects endothelial dysfunction, reduces oxidative stress and improves inflammatory response. In this minireview, we summarized the clinical evidence of metformin benefits in several widely studied cardiovascular diseases, such as atherosclerosis, ischaemic/reperfusion injury and arrhythmia, both in patients with or without diabetes. Meanwhile, we highlighted the potential AMPK‐dependent mechanisms in in vitro and/or in vivo models.

The clinical impact of serum 1,5-anhydro-D-glucitol levels on coronary artery calcification and adverse outcomes assessed by coronary optical coherence tomography in diabetic patients.

BackgroundSerum 1,5-anhydro-D-glucitol (1,5-AG) is a novel biomarker for short-term glycemic status and postprandial hyperglycemia. The association between serum 1,5-AG levels and coronary artery calcification (CAC) through a quantitative assessment using optical coherence tomography (OCT) is unclear. We aimed to evaluate this association using OCT in patients with diabetes mellitus (DM).MethodsFrom June 2016 to December 2019, we prospectively enrolled 256 patients who underwent OCT-guided percutaneous coronary intervention (PCI). Half of the patients had diabetes. Patients were followed up for a mean period of 1.8 ± 0.8 years (median: 2.2 years). The relative calcium index and relative lipid core index measured by quantitative OCT analysis were used to evaluate the intra-plaque calcium and lipid levels of culprit plaques. We also analyzed the correlation between serum 1,5-AG levels and long-term major adverse cardiovascular events.ResultsSerum 1,5-AG levels were significantly lower in diabetic patients than in non-diabetic patients (DM vs. non-DM: 55.6 ± 27.9 μg/mL vs. 63.7 ± 26.1 μg/mL, p = 0.016), and lower in fibrocalcified lesions than in fibrotic or fibrolipidic lesions (fibrocalcified vs. fibrotic or fibrolipidic: 42.8 ± 19.1 vs. 72.9 ± 25.2 or 66.4 ± 27.5 μg/mL, p < 0.001, respectively). In addition, we found a significant inverse correlation between serum 1,5-AG levels and relative calcium index (r = −0.729, p < 0.001). In multivariate Cox regression analysis, low serum 1,5-AG level was identified as an independent predictor for major adverse cardiovascular events in diabetic patients (p = 0.043), but not in non-diabetic patients (p = 0.748) after adjusting for age and sex.ConclusionThis study revealed that low serum 1,5-AG levels were associated with an increased risk of CAC as assessed by OCT, especially in diabetic patients. Low serum 1,5-AG levels may predict future major adverse cardiovascular events in diabetic patients undergoing OCT-guided PCI.