Journal: Cardiovasc Diabetol

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Abstract

Alirocumab therapy in individuals with type 2 diabetes mellitus and atherosclerotic cardiovascular disease: analysis of the ODYSSEY DM-DYSLIPIDEMIA and DM-INSULIN studies.

Ray KK, Del Prato S, Müller-Wieland D, Cariou B, ... Bujas-Bobanovic M, Leiter LA
Background
Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778).
Methods
In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C ≥ 100 mg/dL; n = 413) were randomized to open-label alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C ≥ 70 mg/dL; n = 441) were randomized in a double-blind fashion to alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin < 9% (DM-DYSLIPIDEMIA) or < 10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was ≥ 70 mg/dL (DM-INSULIN) or non-HDL-C was ≥ 100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies.
Results
This analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C < 100 mg/dL (64.6% alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% alirocumab/14.9% placebo [DM-INSULIN]) and ApoB < 80 mg/dL (75.1% alirocumab/35.4% UC and 76.8% alirocumab/24.8% placebo, respectively) versus control at week 24 (all P < 0.0001). In pooling these studies, 66.4% (alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with alirocumab versus controls.
Conclusions
Among individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov. NCT02642159. Registered 30 December 2015 and Clinicaltrials.gov. NCT02585778. Registered 23 October 2015.



Cardiovasc Diabetol: 08 Nov 2019; 18:149
Ray KK, Del Prato S, Müller-Wieland D, Cariou B, ... Bujas-Bobanovic M, Leiter LA
Cardiovasc Diabetol: 08 Nov 2019; 18:149 | PMID: 31706300
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Abstract

Incremental role of glycaemic variability over HbA1c in identifying type 2 diabetic patients with high platelet reactivity undergoing percutaneous coronary intervention.

Nusca A, Tuccinardi D, Proscia C, Melfi R, ... Grigioni F, Di Sciascio G
Background
Diabetic patients with on-treatment high platelet reactivity (HPR) show an increased risk of thrombotic events. Whether measuring glycated haemoglobin (HbA1c) levels and/or glycaemic variability (GV) may help identifying diabetic patients at higher risk deserving tailored antiplatelet and/or glucose lowering strategies is unknown. We aimed to investigate the relationship between GV, HbA1c levels and platelet reactivity in patients with type 2 diabetes mellitus (DM) undergoing percutaneous coronary intervention (PCI).
Methods
Platelet reactivity was measured in type 2 DM patients using VerifyNow P2Y12 assay. HPR was defined as P2Y12 Reaction Unit (PRU) > 240. GV was expressed through mean amplitude of glycaemic excursions (MAGE) and coefficient of variance (CV) by using the iPro™ continuous glucose recorder.
Results
Thirty-five patients (age 70 ± 9 years, 86% male, mean HbA1c 7.2 ± 1.0%) on clopidogrel therapy were enrolled. HbA1c was independently associated with HPR (OR 7.25, 95% CI 1.55-33.86, p = 0.012). Furthermore, when factored into the model, GV indexes provided independent (OR 1.094, 95% CI 1.007-1.188, p < 0.034) and additional (p < 0.001) diagnostic significance in identifying diabetic patients with HPR.
Conclusions
Glyco-metabolic state significantly correlates with HPR in well-controlled type 2 DM patients on clopidogrel therapy. HbA1c identifies patients at higher thrombotic risk but the highest diagnostic accuracy is achieved by combining GV and HbA1c. Whether individualized antithrombotic and glucose-lowering therapies based on the assessment of these parameters may reduce the incidence of thrombotic events in patients undergoing PCI should be further investigated.



Cardiovasc Diabetol: 08 Nov 2019; 18:147
Nusca A, Tuccinardi D, Proscia C, Melfi R, ... Grigioni F, Di Sciascio G
Cardiovasc Diabetol: 08 Nov 2019; 18:147 | PMID: 31706305
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Abstract

Liraglutide improves lipid metabolism by enhancing cholesterol efflux associated with ABCA1 and ERK1/2 pathway.

Wu YR, Shi XY, Ma CY, Zhang Y, Xu RX, Li JJ
Background
Reverse cholesterol transport (RCT) is an important cardioprotective mechanism and the decrease in cholesterol efflux can result in the dyslipidemia. Although liraglutide, a glucagon like peptide-1 analogue, has mainly impacted blood glucose, recent data has also suggested a beneficial effect on blood lipid. However, the exact mechanism by which liraglutide modulates lipid metabolism, especially its effect on RCT, remain undetermined. Hence, the aim of the present study was to investigate the potential impacts and potential underlying mechanisms of liraglutide on the cholesterol efflux in both db/db mice and HepG2 cells.
Methods
Six-week old db/db mice with high fat diet (HFD) and wild type mice were administered either liraglutide (200 μg/kg) or equivoluminal saline subcutaneously, twice daily for 8 weeks and body weight was measured every week. After the 8-week treatment, the blood was collected for lipid evaluation and liver was obtained from the mice for hematoxylin-eosin (HE) staining, red O staining and Western blotting. Cholesterol efflux was assessed by measuring the radioactivity in the plasma and feces after intraperitoneal injection of H-labeled cholesterol. HepG2 Cells were treated with different concentrations of glucose (0, 5, 25, and 50 mmol/L) with or without liraglutide (1000 nmol/L) for 24 h. The intracellular cholesterol efflux was detected by BODIPY-cholesterol fluorescence labeling. Real-time PCR or Western blotting was used to examine the expression levels of ABCA1, ABCG1 and SR-B1.
Results
Liraglutide significantly decreased blood glucose, serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C). It also reduced liver lipid deposition in db/db mice fed with HFD. Moreover, the movement of H-cholesterol from macrophages to plasma and feces was significantly enhanced in db/db mice fed with HFD after liraglutide adminstration. In vitro study, liraglutide could promote the cholesterol efflux of HepG2 cells under high glucose, and also increase the expression of ABCA1 by activating the ERK1/2 pathway.
Conclusions
Liraglutide could improve lipid metabolism and hepatic lipid accumulation in db/db mice fed with HFD by promoting reversal of cholesterol transport, which was associated with the up-regulation of ABCA1 mediated by the ERK1/2 phosphorylation.



Cardiovasc Diabetol: 08 Nov 2019; 18:146
Wu YR, Shi XY, Ma CY, Zhang Y, Xu RX, Li JJ
Cardiovasc Diabetol: 08 Nov 2019; 18:146 | PMID: 31706303
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Abstract

Circulating levels of mitochondrial uncoupling protein 2, but not prohibitin, are lower in humans with type 2 diabetes and correlate with brachial artery flow-mediated dilation.

Kakarla M, Puppala VK, Tyagi S, Anger A, ... Ying R, Widlansky ME
Background
Excessive reactive oxygen species from endothelial mitochondria in type 2 diabetes individuals (T2DM) may occur through multiple related mechanisms, including production of mitochondrial reactive oxygen species (mtROS), inner mitochondrial membrane (Δψ) hyperpolarization, changes in mitochondrial mass and membrane composition, and fission of the mitochondrial networks. Inner mitochondrial membrane proteins uncoupling protein-2 (UCP2) and prohibitin (PHB) can favorably impact mtROS and mitochondrial membrane potential (Δψ). Circulating levels of UCP2 and PHB could potentially serve as biomarker surrogates for vascular health in patients with and without T2DM.
Methods
Plasma samples and data from a total of 107 individuals with (N = 52) and without T2DM (N = 55) were included in this study. Brachial artery flow mediated dilation (FMD) was measured by ultrasound. ELISA was performed to measure serum concentrations of PHB1 and UCP2. Mitochondrial membrane potential was measured from isolated leukocytes using JC-1 dye.
Results
Serum UCP2 levels were significantly lower in T2DM subjects compared to control subjects (3.01 ± 0.34 vs. 4.11 ± 0.41 ng/mL, P = 0.04). There were no significant differences in levels of serum PHB. UCP2 levels significantly and positively correlated with FMDmm (r = 0.30, P = 0.03) in T2DM subjects only and remained significant after multivariable adjustment. Within T2DM subjects, serum PHB levels were significantly and negatively correlated with UCP2 levels (ρ = - 0.35, P = 0.03).
Conclusion
Circulating UCP2 levels are lower in T2DM patients and correlate with endothelium-dependent vasodilation in conduit vessels. UCP2 could be biomarker surrogate for overall vascular health in patients with T2DM and merits additional investigation.



Cardiovasc Diabetol: 08 Nov 2019; 18:148
Kakarla M, Puppala VK, Tyagi S, Anger A, ... Ying R, Widlansky ME
Cardiovasc Diabetol: 08 Nov 2019; 18:148 | PMID: 31706320
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Abstract

Glucose and insulin levels are associated with arterial stiffness and concentric remodeling of the heart.

Markus MRP, Rospleszcz S, Ittermann T, Baumeister SE, ... Rathmann W, Dörr M
Background
Mortality attributable to heart failure remains high. The prevalence of heart failure in patients with diabetes mellitus ranges from 19 to 26%. It is estimated that up to 21.1 million adults in the United States have diagnosed diabetes mellitus and around 80.8 million have impaired fasting glucose. We investigated the associations of fasting glucose (FG) and fasting insulin (FI), the homeostasis model assessment-insulin resistance index (HOMA-IR) and 2-h postload glucose (2HG) and insulin (2HI) with parameters of left ventricular geometry and function and arterial stiffness determined by magnetic resonance imaging in individuals without diagnosed type 2 diabetes.
Methods
Cross-sectional analyses of 1001 individuals (453 women, 45.3%), aged 21 to 80 years, from two independent population-based studies, the Study of Health in Pomerania (SHIP-TREND-0) and KORA FF4 Study. FG, FI, HOMA-IR, 2HG and 2HI, as well as glucose tolerance categories, were analyzed for associations with heart and arterial parameters using multivariable-adjusted linear regression models.
Results
In total, 390 individuals (39%) had prediabetes (isolated impaired fasting glucose, isolated glucose tolerance or both), and 49 (4.9%) were found to have unknown type 2 diabetes. In the multivariable-adjusted analysis, positive linear associations of FG, FI, HOMA-IR, 2HG and 2HI with arterial stiffness index and left ventricular wall-thickness and concentricity and inverse linear associations with left ventricular end-diastolic volume were observed. A 1 mmol/l higher FG was associated with a 1.18 ml/m (1.80 to 0.57; p < 0.001) lower left ventricular end-diastolic volume index, a 0.042 mm/m (0.014 to 0.070) higher left ventricular wall-thickness index, a 0.12 mmHg m/ml (0.06 to 0.17; p < 0.001) greater arterial stiffness index and a 0.037 g/ml (0.018 to 0.056; p < 0.001) higher left ventricular concentricity.
Conclusions
Our findings suggest that higher glucose levels in the prediabetic range and insulin resistance might lead to higher arterial stiffness and concentric remodeling of the heart.



Cardiovasc Diabetol: 03 Nov 2019; 18:145
Markus MRP, Rospleszcz S, Ittermann T, Baumeister SE, ... Rathmann W, Dörr M
Cardiovasc Diabetol: 03 Nov 2019; 18:145 | PMID: 31684945
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Abstract

Luseogliflozin attenuates neointimal hyperplasia after wire injury in high-fat diet-fed mice via inhibition of perivascular adipose tissue remodeling.

Mori Y, Terasaki M, Hiromura M, Saito T, ... Tsutomu H, Yamagishi SI
Background
Excess fat deposition could induce phenotypic changes of perivascular adipose tissue (PVAT remodeling), which may promote the progression of atherosclerosis via modulation of adipocytokine secretion. However, it remains unclear whether and how suppression of PVAT remodeling could attenuate vascular injury. In this study, we examined the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitor, luseogliflozin on PVAT remodeling and neointima formation after wire injury in mice.
Methods
Wilt-type mice fed with low-fat diet (LFD) or high-fat diet (HFD) received oral administration of luseogliflozin (18 mg/kg/day) or vehicle. Mice underwent bilateral femoral artery wire injury followed by unilateral removal of surrounding PVAT. After 25 days, injured femoral arteries and surrounding PVAT were analyzed.
Results
In LFD-fed lean mice, neither luseogliflozin treatment or PVAT removal attenuated the intima-to-media (I/M) ratio of injured arteries. However, in HFD-fed mice, luseogliflozin or PVAT removal reduced the I/M ratio, whereas their combination showed no additive reduction. In PVAT surrounding injured femoral arteries of HFD-fed mice, luseogliflozin treatment decreased the adipocyte sizes. Furthermore, luseogliflozin reduced accumulation of macrophages expressing platelet-derived growth factor-B (PDGF-B) and increased adiponectin gene expression. Gene expression levels of Pdgf-b in PVAT were correlated with the I/M ratio.
Conclusions
Our present study suggests that luseogliflozin could attenuate neointimal hyperplasia after wire injury in HFD-fed mice partly via suppression of macrophage PDGF-B expression in PVAT. Inhibition of PVAT remodeling by luseogliflozin may be a novel therapeutic target for vascular remodeling after angioplasty.



Cardiovasc Diabetol: 30 Oct 2019; 18:143
Mori Y, Terasaki M, Hiromura M, Saito T, ... Tsutomu H, Yamagishi SI
Cardiovasc Diabetol: 30 Oct 2019; 18:143 | PMID: 31672147
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Abstract

Predictive and diagnostic biomarkers for gestational diabetes and its associated metabolic and cardiovascular diseases.

Lorenzo-Almorós A, Hang T, Peiró C, Soriano-Guillén L, ... Tuñón J, Lorenzo Ó

Gestational diabetes mellitus (GDM) is defined as the presence of high blood glucose levels with the onset, or detected for the first time during pregnancy, as a result of increased insulin resistance. GDM may be induced by dysregulation of pancreatic β-cell function and/or by alteration of secreted gestational hormones and peptides related with glucose homeostasis. It may affect one out of five pregnancies, leading to perinatal morbidity and adverse neonatal outcomes, and high risk of chronic metabolic and cardiovascular injuries in both mother and offspring. Currently, GDM diagnosis is based on evaluation of glucose homeostasis at late stages of pregnancy, but increased age and body-weight, and familiar or previous occurrence of GDM, may conditionate this criteria. In addition, an earlier and more specific detection of GDM with associated metabolic and cardiovascular risk could improve GDM development and outcomes. In this sense, 1st-2nd trimester-released biomarkers found in maternal plasma including adipose tissue-derived factors such as adiponectin, visfatin, omentin-1, fatty acid-binding protein-4 and retinol binding-protein-4 have shown correlations with GDM development. Moreover, placenta-related factors such as sex hormone-binding globulin, afamin, fetuin-A, fibroblast growth factors-21/23, ficolin-3 and follistatin, or specific micro-RNAs may participate in GDM progression and be useful for its recognition. Finally, urine-excreted metabolites such as those related with serotonin system, non-polar amino-acids and ketone bodies, may complete a predictive or early-diagnostic panel of biomarkers for GDM.



Cardiovasc Diabetol: 29 Oct 2019; 18:140
Lorenzo-Almorós A, Hang T, Peiró C, Soriano-Guillén L, ... Tuñón J, Lorenzo Ó
Cardiovasc Diabetol: 29 Oct 2019; 18:140 | PMID: 31666083
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Abstract

Short-term treatment with high dose liraglutide improves lipid and lipoprotein profile and changes hormonal mediators of lipid metabolism in obese patients with no overt type 2 diabetes mellitus: a randomized, placebo-controlled, cross-over, double-blind clinical trial.

Peradze N, Farr OM, Perakakis N, Lázaro I, Sala-Vila A, Mantzoros CS
Objective
Long-term treatment with up to 1.8 mg liraglutide improves cardiovascular and all-cause mortality in patients with type 2 diabetes at high risk for cardiovascular disease (CVD) and is currently under investigation in subjects without diabetes. Aim of our study was to investigate whether high dose (3 mg) short-term (5 weeks) treatment with liraglutide in obese patients with no overt type 2 diabetes affects metabolites, lipid and lipoprotein profile and components of activin-follistatin axis in cardiovascular beneficial or detrimental way.
Research design and methods
Twenty obese patients participated in a randomized, placebo-controlled, cross-over, double-blind study and were administrated liraglutide 3 mg or placebo for 5 weeks. Metabolites, fatty acids, lipid-lipoprotein profile and concentrations of activins and follistatins (250 parameters) were assessed in serum at start and completion of each treatment.
Results
Concentrations of important cardiovascular markers such as total, free and remnant cholesterol were reduced with liraglutide before and after adjusting for weight loss. Similarly, reductions in number of small and medium size LDL particles and in their total lipid concentration were observed with liraglutide and partially weight-loss related. Tyrosine levels were reduced and behenic acid levels were increased whereas only minor changes were observed in HDL, VLDL and IDL. Concentrations of activin AB and follistatin were significantly reduced in liraglutide-treated group.
Conclusions
Treatment of obese patients without overt type 2 diabetes with high dose of liraglutide for a short period of time induces changes in lipid-lipoprotein and hormonal profile that are suggestive of lower risk of atherosclerosis and CVD. Trial registration ClinicalTrials.gov Identifier: NCT02944500. Study ID Number 2015P000327. Registered November 2016.



Cardiovasc Diabetol: 30 Oct 2019; 18:141
Peradze N, Farr OM, Perakakis N, Lázaro I, Sala-Vila A, Mantzoros CS
Cardiovasc Diabetol: 30 Oct 2019; 18:141 | PMID: 31672146
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Abstract

Relationships of coronary culprit-plaque characteristics with duration of diabetes mellitus in acute myocardial infarction: an intravascular optical coherence tomography study.

Sheng Z, Zhou P, Liu C, Li J, ... Zhao H, Yan H
Background
Diabetes mellitus (DM) or pre-diabetes status is closely associated with features of vulnerable coronary lesions in patients with stable coronary heart disease or acute coronary syndrome. However, the association between duration of diabetes and the morphologies and features of vulnerable plaques has not been fully investigated in patients with acute myocardial infarction (AMI).
Methods
We enrolled a total of 279 patients who presented with AMI between March 2017 and March 2019 and underwent pre-intervention optical coherence tomography imaging of culprit lesions. Patients with DM were divided into two subgroups: a Short-DM group with DM duration of < 10 years and a Long-DM group with DM duration of ≥ 10 years. Baseline clinical data and culprit-plaque characteristics were compared between patients without DM (the non-DM group), those in the Short-DM group, and those in the Long-DM group.
Results
Patients with DM represented 34.1% of the study population (95 patients). The Short- and Long-DM groups included 64 (67.4%) and 31 patients (32.6%), respectively. Glycated hemoglobin A1c (HbA1c) levels were significantly higher in the Long-DM group than the Non- or Short-DM groups (8.4% [Long-DM] versus 5.7% [Non-DM] and 7.6% [Short-DM], P < 0.001). In addition, the highest prevalence of lipid-rich plaques, thin-cap fibroatheroma (TCFA), and plaque ruptures of culprit lesions were observed in the Long-DM group (lipid-rich plaques: 80.6% [Long-DM] versus 52.2% [Non-DM] and 62.5% [Short-DM], P = 0.007; TCFA: 41.9% [Long-DM] versus 19.6% [Non-DM] and 31.3% [Short-DM], P = 0.012; plaque rupture: 74.2% [Long-DM] versus 46.7% [Non-DM] and 48.4% [Short-DM], P = 0.017). The frequency of calcification was significantly higher among patients with DM than among those without (62.1% versus 46.2%, P = 0.016); however, no significant differences were found between the DM subgroups (61.3% [Long-DM] versus 62.5% [Short-DM], P = 0.999).
Conclusions
Increased duration of DM combined with higher HbA1c levels influences culprit-plaque characteristics in patients with DM who suffer AMI. These findings might account for the higher risks of cardiac death in DM patients with long disease duration. Trial registration This study is registered at clinicaltrials.gov as NCT03593928.



Cardiovasc Diabetol: 18 Oct 2019; 18:136
Sheng Z, Zhou P, Liu C, Li J, ... Zhao H, Yan H
Cardiovasc Diabetol: 18 Oct 2019; 18:136 | PMID: 31629406
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Impact:
Abstract

Diabetes and baseline glucose are associated with inflammation, left ventricular function and short- and long-term outcome in acute coronary syndromes: role of the novel biomarker Cyr 61.

Winzap P, Davies A, Klingenberg R, Obeid S, ... von Eckardstein A, Lüscher TF
Background
Hyperglycemia in the setting of an acute coronary syndrome (ACS) impacts short term outcomes, but little is known about longer term effects. We therefore designed this study to firstly determine the association between hyperglycemia and short term and longer term outcomes in patients presenting with ACS and secondly evaluate the prognostic role of diabetes, body mass index (BMI) and the novel biomarker Cyr61 on outcomes.
Methods
The prospective Special Program University Medicine-Acute Coronary Syndrome (SPUM-ACS) cohort enrolled 2168 patients with ACS between December 2009 and October 2012, of which 2034 underwent PCI (93.8%). Patients were followed up for 12 months. Events were independently adjudicated by three experienced cardiologists. Participants were recruited from four tertiary hospitals in Switzerland: Zurich, Geneva, Lausanne and Bern. Participants presenting with acute coronary syndromes and who underwent coronary angiography were included in the analysis. Patients were grouped according to history of diabetes (or HbA1c greater than 6%), baseline blood sugar level (BSL; < 6, 6-11.1 and > 11.1 mmol/L) and body mass index (BMI). The primary outcome was major adverse cardiac events (MACE) which was a composite of myocardial infarction, stroke and all-cause death. Secondary outcomes included the individual components of the primary endpoint, revascularisations, bleeding events (BARC classification) and cerebrovascular events (ischaemic or haemorrhagic stroke or TIA).
Results
Patients with hyperglycemia, i.e. BSL ≥ 11.1 mmol/L, had higher levels of C-reactive protein (CRP), white blood cell count (WBC), creatinine kinase (CK), higher heart rates and lower left ventricular ejection fraction (LVEF) and increased N-terminal pro-brain natriuretic peptide. At 30 days and 12 months, those with BSL ≥ 11.1 mmol/L had more MACE and death compared to those with BSL < 6.0 mmol/L or 6.0-11.1 mmol/L (HR-ratio 4.78 and 6.6; p < 0.001). The novel biomarker Cyr61 strongly associated with high BSL and STEMI and was independently associated with 1 year outcomes (HR 2.22; 95% CI 1.33-3.72; Tertile 3 vs. Tertile 1).
Conclusions and relevance
In this large, prospective, independently adjudicated cohort of in all comers ACS patients undergoing PCI, both a history of diabetes and elevated entry glucose was associated with inflammation and increased risk of MACE both at short and long-term. The mediators might involve increased sympathetic activation, inflammation and ischemia as reflected by elevated Cyr61 levels leading to larger levels of troponin and lower LVEF. Trial registration Clinical Trial registration Number: NCT01000701. Registered October 23, 2009.



Cardiovasc Diabetol: 30 Oct 2019; 18:142
Winzap P, Davies A, Klingenberg R, Obeid S, ... von Eckardstein A, Lüscher TF
Cardiovasc Diabetol: 30 Oct 2019; 18:142 | PMID: 31672144
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Impact:
Abstract

Association of PCSK9 plasma levels with metabolic patterns and coronary atherosclerosis in patients with stable angina.

Caselli C, Del Turco S, Ragusa R, Lorenzoni V, ... De Caterina R, Neglia D
Objective
Aim of this study was to evaluate the relationship of plasma PCSK9 with metabolic and inflammatory profile and coronary atherosclerotic burden in patients with suspected CAD enrolled in the EVINCI study.
Methods
PCSK9 was measured in 539 patients (60.3 ± 8.6 years, 256 males) with symptoms of CAD characterized by risk factors, bio-humoral profiles, and treatment. N = 412 patients underwent coronary computed tomography angiography (CTA) to assess the presence and characteristics of coronary atherosclerosis. A CTA score, combining extent, severity, composition, and location of plaques was computed.
Results
Patients were divided according to PCSK9 quartiles: I (< 136 ng/mL), II-III (136-266 ng/mL), and IV quartile (> 266 ng/mL). Compared with patients in quartile IV, patients in quartile I had a higher prevalence of the metabolic syndrome and higher values of body mass index. LDL- and HDL-cholesterol were significantly lower in patients in the quartile I than in those in quartile IV. Coronary CTA documented normal vessels in 30% and obstructive CAD in 35% of cases without differences among PCSK9 quartiles. Compared with patients with the highest levels, patients with the lowest PCSK9 levels had a higher CTA score mainly due to higher number of mixed non-obstructive coronary plaques. At multivariable analysis including clinical, medications, and lipid variables, PCSK9 was an independent predictor of the CTA score (coefficient - 0.129, SE 0.03, P < 0.0001), together with age, male gender, statins, interleukin-6, and leptin.
Conclusion
In patients with stable CAD, low PCSK9 plasma levels are associated with a particular metabolic phenotype (low HDL cholesterol, the metabolic syndrome, obesity, insulin resistance and diabetes) and diffuse non-obstructive coronary atherosclerosis. Trial registration ClinicalTrials.gov NCT00979199. Registered September 17, 2009.



Cardiovasc Diabetol: 30 Oct 2019; 18:144
Caselli C, Del Turco S, Ragusa R, Lorenzoni V, ... De Caterina R, Neglia D
Cardiovasc Diabetol: 30 Oct 2019; 18:144 | PMID: 31672148
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Impact:
Abstract

Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial.

Clegg LE, Penland RC, Bachina S, Boulton DW, ... Mentz RJ, Holman RR
Background
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes.
Methods
In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses.
Results
In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39-1.17) and EQW alone (0.85, 0.48-1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16-0.90) and compared with EQW (0.41, 0.17-0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94-2.94 mL/min/1.73 m/year) and EQW alone (+ 2.38, 1.40-3.35 mL/min/1.73 m/year).
Conclusions
This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality. Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010.



Cardiovasc Diabetol: 21 Oct 2019; 18:138
Clegg LE, Penland RC, Bachina S, Boulton DW, ... Mentz RJ, Holman RR
Cardiovasc Diabetol: 21 Oct 2019; 18:138 | PMID: 31640705
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Impact:
Abstract

Risk of early mortality and cardiovascular disease in type 1 diabetes: a comparison with type 2 diabetes, a nationwide study.

Lee YB, Han K, Kim B, Lee SE, ... Jin SM, Kim JH
Background
Both type 1 and type 2 diabetes are well-established risk factors for cardiovascular disease and early mortality. However, few studies have directly compared the hazards of cardiovascular outcomes and premature death among people with type 1 diabetes to those among people with type 2 diabetes and subjects without diabetes. Furthermore, information about the hazard of cardiovascular disease and early mortality among Asians with type 1 diabetes is sparse, although the clinical and epidemiological characteristics of Asians with type 1 diabetes are unlike those of Europeans. We estimated the hazard of myocardial infarction (MI), hospitalization for heart failure (HF), atrial fibrillation (AF), and mortality during follow-up in Korean adults with type 1 diabetes compared with those without diabetes and those with type 2 diabetes.
Methods
We used Korean National Health Insurance Service datasets of preventive health check-ups from 2009 to 2016 in this retrospective longitudinal study. The hazard ratios of MI, HF, AF, and mortality during follow-up were analyzed using the Cox regression analyses according to the presence and type of diabetes in ≥ 20-year-old individuals without baseline cardiovascular disease (N = 20,423,051). The presence and type of diabetes was determined based on the presence of type 1 or type 2 diabetes at baseline.
Results
During more than 93,300,000 person-years of follow-up, there were 116,649 MIs, 135,532 AF cases, 125,997 hospitalizations for HF, and 344,516 deaths. The fully-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident MI, hospitalized HF, AF, and all-cause death within the mean follow-up of 4.6 years were higher in the type 1 diabetes group than the type 2 diabetes [HR (95% CI) 1.679 (1.490-1.893) for MI; 2.105 (1.901-2.330) for HF; 1.608 (1.411-1.833) for AF; 1.884 (1.762-2.013) for death] and non-diabetes groups [HR (95% CI) 2.411 (2.138-2.718) for MI; 3.024 (2.730-3.350) for HF; 1.748 (1.534-1.993) for AF; 2.874 (2.689-3.073) for death].
Conclusions
In Korea, the presence of diabetes was associated with a higher hazard of cardiovascular disease and all-cause death. Specifically, people with type 1 diabetes had a higher hazard of cardiovascular disease and all-cause mortality compared to people with type 2 diabetes.



Cardiovasc Diabetol: 15 Nov 2019; 18:157
Lee YB, Han K, Kim B, Lee SE, ... Jin SM, Kim JH
Cardiovasc Diabetol: 15 Nov 2019; 18:157 | PMID: 31733656
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Impact:
Abstract

Cholesterol levels and development of cardiovascular disease in Koreans with type 2 diabetes mellitus and without pre-existing cardiovascular disease.

Kim MK, Han K, Joung HN, Baek KH, Song KH, Kwon HS
Background
The aim of the present study was to identify a threshold for the cholesterol level at which the risk of cardiovascular disease (CVD) begins to increase in people with type 2 diabetes mellitus (DM).
Methods
Using the Korean National Health Insurance Service database, 2,077,135 people aged ≥ 40 years with type 2 DM who underwent regular health checks between 2009 and 2012 were included. Subjects with previous CVD were excluded. Cox regression analyses were performed to estimate the risk of CVD for each low-density lipoprotein cholesterol (LDL-C) group using the < 70 mg/dL as the reference group.
Results
There were 78,560 cases of stroke (3.91%), and 50,791 myocardial infarction (MI, 2.53%) during a median follow-up of 7.1 years. Among participants not taking statins, LDL-C levels of 130-159 mg/dL and ≥ 160 mg/dL were significantly associated with the risk of MI: the hazard ratios (HRs) (95% confidence interval) were 1.19 (1.14-1.25) and 1.53 (1.46-1.62), respectively. Among participants taking statins, all categories of LDL-C level ≥ 70 mg/dL were significantly associated with increased risk of stroke and MI.
Conclusions
We identified an increased risk of CVD in people with an LDL-C level ≥ 130 mg/dL among individuals with type 2 DM not taking statins. The risk of CVD was significantly higher in those taking statins with an LDL-C level ≥ 70 mg/dL.



Cardiovasc Diabetol: 21 Oct 2019; 18:139
Kim MK, Han K, Joung HN, Baek KH, Song KH, Kwon HS
Cardiovasc Diabetol: 21 Oct 2019; 18:139 | PMID: 31640795
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Impact:
Abstract

Meta-analysis of the impact of alpha-glucosidase inhibitors on incident diabetes and cardiovascular outcomes.

Coleman RL, Scott CAB, Lang Z, Bethel MA, Tuomilehto J, Holman RR
Background
Alpha-glucosidase inhibitors (AGIs) have been shown to reduce incident type 2 diabetes but their impact on cardiovascular (CV) disease remains controversial. We sought to identify the overall impact of AGIs with respect to incident type 2 diabetes in individuals with impaired glucose tolerance (IGT), and CV outcomes in those with IGT or type 2 diabetes.
Methods
We used PubMed and SCOPUS to identify randomized controlled trials reporting the incidence of type 2 diabetes and/or CV outcomes that had compared AGIs with placebo in populations with IGT or type 2 diabetes, with or without established CV disease. Eligible studies were required to have ≥ 500 participants and/or ≥ 100 endpoints of interest. Meta-analyses of available trial data were performed using random effects models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident type 2 diabetes and CV outcomes.
Results
Of ten trials identified, three met our inclusion criteria for incident type 2 diabetes and four were eligible for CV outcomes. The overall HR (95% CI) comparing AGI with placebo for incident type 2 diabetes was 0.77 (0.67-0.88), p < 0.0001, and for CV outcomes was 0.98 (0.89-1.10), p = 0.85. There was little to no heterogeneity between studies, with I values of 0.03% (p = 0.43) and 0% (p = 0.79) for the two outcomes respectively.
Conclusions
Allocation of people with IGT to an AGI significantly reduced their risk of incident type 2 diabetes by 23%, whereas in those with IGT or type 2 diabetes the impact on CV outcomes was neutral.



Cardiovasc Diabetol: 16 Oct 2019; 18:135
Coleman RL, Scott CAB, Lang Z, Bethel MA, Tuomilehto J, Holman RR
Cardiovasc Diabetol: 16 Oct 2019; 18:135 | PMID: 31623625
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Impact:
Abstract

Efficacy of visceral fat estimation by dual bioelectrical impedance analysis in detecting cardiovascular risk factors in patients with type 2 diabetes.

Omura-Ohata Y, Son C, Makino H, Koezuka R, ... Kishimoto I, Hosoda K
Background
Visceral fat area (VFA) is a good surrogate marker of obesity-related disorders, such as hypertension, dyslipidemia and glucose intolerance. Although estimating the VFA by X-ray computed tomography (CT) is the primary index for visceral obesity, it is expensive and requires invasive radiation exposure. Dual bioelectrical impedance analysis (BIA) is a simple and reliable method to estimate VFA; however, the clinical usefulness of dual BIA remains unclear in patients with type 2 diabetes (T2D).
Methods
We estimated the VFAs by dual BIA and CT in 98 patients with T2D and assessed anthropometric parameters, blood test results, and the presence of comorbid hypertension and dyslipidemia. We compared the correlation between the VFAs examined by dual BIA and CT. Furthermore, we performed the receiver operating characteristic (ROC) analyses for the VFAs to detect the presence of comorbid hypertension and/or dyslipidemia with T2D, which are major comorbidities of visceral obesity, and estimated the area under the curve (AUC).
Results
The measurement error between the VFAs by dual BIA and CT was significantly higher among patients with brain natriuretic peptide (BNP) ≥ 100 pg/mL than those with BNP < 100 pg/mL (39.2% ± 31.1% vs. 24.1% ± 18.6%, P < 0.05). After excluding patients with BNP ≥ 100 pg/mL, the VFA by dual BIA significantly correlated with the VFA by CT (r = 0.917; P < 0.0001). The AUC in the ROC analysis for the VFA by dual BIA to detect the presence of comorbid hypertension and/or dyslipidemia with T2D was almost equivalent to that for the VFA by CT.
Conclusions
In patients with T2D without elevated BNP > 100 pg/mL as indicator for fluid accumulation interfering with BIA, estimation of the VFA by dual BIA significantly correlated with that by CT and also detected comorbid hypertension and/or dyslipidemia with T2D equivalent to those detected by CT. Hence, dual BIA could be an alternative to CT as a standard method for estimating the VFA in patients with diabetes.



Cardiovasc Diabetol: 21 Oct 2019; 18:137
Omura-Ohata Y, Son C, Makino H, Koezuka R, ... Kishimoto I, Hosoda K
Cardiovasc Diabetol: 21 Oct 2019; 18:137 | PMID: 31640702
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Impact:
Abstract

High triglyceride-glucose index is associated with poor prognosis in patients with acute ST-elevation myocardial infarction after percutaneous coronary intervention.

Luo E, Wang D, Yan G, Qiao Y, ... Hou J, Tang C
Background
Insulin resistance (IR) is considered a pivotal risk factor for cardiometabolic diseases, and the triglyceride-glucose index (TyG index) has emerged as a reliable surrogate marker of IR. Although several recent studies have shown the association of the TyG index with vascular disease, no studies have further investigated the role of the TyG index in acute ST-elevation myocardial infarction (STEMI). The objective of the present study was to evaluate the potential role of the TyG index as a predictor of prognosis in STEMI patients after percutaneous coronary intervention (PCI).
Methods
The study included 1092 STEMI patients who underwent PCI. The patients were divided into 4 quartiles according to TyG index levels. Clinical characteristics, fasting plasma glucose (FPG), triglycerides (TGs), other biochemical parameters, and the incidence of major adverse cardiovascular and cerebral events (MACCEs) during the follow-up period were recorded. The TyG index was calculated using the following formula: ln[fasting TGs (mg/dL) × FPG (mg/dL)/2].
Results
The incidence of MACCEs and all-cause mortality within 30 days, 6 months and 1 year after PCI were higher among STEMI patients with TyG index levels in the highest quartile. The TyG index was significantly associated with an increased risk of MACCEs in STEMI patients within 1 year after PCI, independent of confounding factors, with a value of 1.529 (95% CI 1.001-2.061; P = 0.003) for those in the highest quartile. The area under the curve (AUC) of the TyG index predicting the occurrence of MACCEs in STEMI patients after PCI was 0.685 (95% CI 0.610-0.761; P = 0.001). The results also revealed that Killip class > 1, anaemia, albumin, uric acid, number of stents and left ventricular ejection fraction (LVEF) were independent predictors of MACCEs in STEMI patients after PCI (all P < 0.05).
Conclusions
This study indicated an association between higher TyG index levels and increased risk of MACCEs in STEMI patients for the first time, and the TyG index might be a valid predictor of clinical outcomes in STEMI patients undergoing PCI. Trial registration ChiCTR1900024577.



Cardiovasc Diabetol: 12 Nov 2019; 18:150
Luo E, Wang D, Yan G, Qiao Y, ... Hou J, Tang C
Cardiovasc Diabetol: 12 Nov 2019; 18:150 | PMID: 31722708
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Impact:
Abstract

Microvascular complications burden (nephropathy, retinopathy and peripheral polyneuropathy) affects risk of major vascular events and all-cause mortality in type 1 diabetes: a 10-year follow-up study.

Garofolo M, Gualdani E, Giannarelli R, Aragona M, ... Del Prato S, Penno G
Background
Microvascular complications (MC) have been claimed to increase the risk for cardiovascular disease in diabetic subjects. However, the effect of MC burden on the risk of major vascular outcomes and all-cause mortality in type 1 diabetes is still poorly explored. We evaluated the relationship between microvascular complications burden and incidence of major cardiovascular events and all-cause mortality in subjects with type 1 diabetes.
Methods
We recruited 774 participants with type 1 diabetes in a single-center observational study over a follow-up of 10.8 ± 2.5 years. Hazard ratios (HR) for cardiovascular outcomes and all-cause death associated with microvascular complications were determined by unadjusted and adjusted Cox regression analysis.
Results
Out of 774 individuals, 54.9% had no-MC, 32.3% 1 MC, 9.7% 2 MC and 3.1% 3 MC. A total of 54 deaths (7.0%) occurred. Death rate increased from no-MC 2.1% (Ref) to 1 MC 7.2% (HR 3.54 [95% CI 1.59-7.87]), 2 MC 14.7% (HR 6.41 [95% CI 2.65-15.49]) and 3 MC 66.7% (HR 41.73 [95% CI 18.42-94.57], p < 0.0001). After adjustments, HRs were: 1 MC 2.05 (95% CI 0.88-4.76), 2 MC 1.98 (95% CI 0.75-5.21), 3 MC 7.02 (95% CI 2.44-20.20, p = 0.002). Forty-nine subjects (6.7%) had at least one cardiovascular event, and cumulative incidence went from no-MC 2.2% (Ref) to 1 MC 5.0%; (HR 2.27 [95% CI 0.96-5.38]), 2 MC 26.8% (HR 12.88 [95% CI 5.82-28.50]) and 3 MC 40.9% (HR 29.34 [95% CI 11.59-74.25], p < 0.0001). Upon adjustments, HRs were: 1 MC 1.59 (95% CI 0.65-3.88), 2 MC 4.33 (95% CI 1.75-10.74), 3 MC 9.31 (95% CI 3.18-27.25, p < 0.0001). Thirty-five individuals (4.8%) had at least one coronary event, which cumulative incidence increased with MC burden (p < 0.0001).
Conclusions
In type 1 diabetes, microvascular complications burden increases in an independent dose-dependent manner the risk of major cardiovascular outcomes and all-cause mortality. The presence and number of microvascular complications should be considered in stratifying overall cardiovascular risk in type 1 diabetes.



Cardiovasc Diabetol: 15 Nov 2019; 18:159
Garofolo M, Gualdani E, Giannarelli R, Aragona M, ... Del Prato S, Penno G
Cardiovasc Diabetol: 15 Nov 2019; 18:159 | PMID: 31733651
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Impact:
Abstract

Lysine pathway metabolites and the risk of type 2 diabetes and cardiovascular disease in the PREDIMED study: results from two case-cohort studies.

Razquin C, Ruiz-Canela M, Clish CB, Li J, ... Hu FB, Martínez-González MA
Background
The pandemic of cardiovascular disease (CVD) and type 2 diabetes (T2D) requires the identification of new predictor biomarkers. Biomarkers potentially modifiable with lifestyle changes deserve a special interest. Our aims were to analyze: (a) The associations of lysine, 2-aminoadipic acid (2-AAA) or pipecolic acid with the risk of T2D or CVD in the PREDIMED trial; (b) the effect of the dietary intervention on 1-year changes in these metabolites, and (c) whether the Mediterranean diet (MedDiet) interventions can modify the effects of these metabolites on CVD or T2D risk.
Methods
Two unstratified case-cohort studies nested within the PREDIMED trial were used. For CVD analyses, we selected 696 non-cases and 221 incident CVD cases; for T2D, we included 610 non-cases and 243 type 2 diabetes incident cases. Metabolites were quantified using liquid chromatography-tandem mass spectrometry, at baseline and after 1-year of intervention.
Results
In weighted Cox regression models, we found that baseline lysine (HR = 1.26; 95% CI 1.06-1.51) and 2-AAA (HR = 1.28; 95% CI 1.05-1.55) were both associated with a higher risk of T2D, but not with CVD. A significant interaction (p = 0.032) between baseline lysine and T2D on the risk of CVD was observed: subjects with prevalent T2D and high levels of lysine exhibited the highest risk of CVD. The intervention with MedDiet did not have a significant effect on 1-year changes of the metabolites.
Conclusions
Our results provide an independent prospective replication of the association of 2-AAA with future risk of T2D. We show an association of lysine with subsequent CVD risk, which is apparently diabetes-dependent. No evidence of effects of MedDiet intervention on lysine, 2-AAA or pipecolic acid changes was found. Trial registration ISRCTN35739639; registration date: 05/10/2005; recruitment start date 01/10/2003.



Cardiovasc Diabetol: 12 Nov 2019; 18:151
Razquin C, Ruiz-Canela M, Clish CB, Li J, ... Hu FB, Martínez-González MA
Cardiovasc Diabetol: 12 Nov 2019; 18:151 | PMID: 31722714
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Impact:
Abstract

Phenotyping diabetic cardiomyopathy in Europeans and South Asians.

Paiman EHM, van Eyk HJ, Bizino MB, Dekkers IA, ... Jazet IM, Lamb HJ
Background
The pathogenesis and cardiovascular impact of type 2 diabetes (T2D) may be different in South Asians compared with other ethnic groups. The phenotypic characterization of diabetic cardiomyopathy remains debated and little is known regarding differences in T2D-related cardiovascular remodeling across ethnicities. We aimed to characterize the differences in left ventricular (LV) diastolic and systolic function, LV structure, myocardial tissue characteristics and aortic stiffness between T2D patients and controls and to assess the differences in T2D-related cardiovascular remodeling between South Asians and Europeans.
Methods
T2D patients and controls of South Asian and European descent underwent 3 Tesla cardiovascular magnetic resonance imaging (CMR) and cardiac proton-magnetic resonance spectroscopy (H-MRS). Differences in cardiovascular parameters between T2D patients and controls were examined using ANCOVA and were reported as mean (95% CI). Ethnic group comparisons in the association of T2D with cardiovascular remodeling were made by adding the interaction term between ethnicity and diabetes status to the model.
Results
A total of 131 individuals were included (54 South Asians [50.1 ± 8.7 years, 33% men, 33 patients vs. 21 controls) and 77 Europeans (58.8 ± 7.0 years, 56% men, 48 patients vs. 29 controls)]. The ratio of the transmitral early and late peak filling rate (E/A) was lower in T2D patients compared with controls, in South Asians [- 0.20 (- 0.36; - 0.03), P = 0.021] and Europeans [- 0.20 (- 0.36; - 0.04), P = 0.017], whereas global longitudinal strain and aortic pulse wave velocity were similar. South Asian T2D patients had a higher LV mass [+ 22 g (15; 30), P < 0.001] (P for interaction by ethnicity = 0.005) with a lower extracellular volume fraction [- 1.9% (- 3.4; - 0.4), P = 0.013] (P for interaction = 0.114), whilst European T2D patients had a higher myocardial triglyceride content [+ 0.59% (0.35; 0.84), P = 0.001] (P for interaction = 0.002) than their control group.
Conclusions
Diabetic cardiomyopathy was characterized by impaired LV diastolic function in South Asians and Europeans. Increased LV mass was solely observed among South Asian T2D patients, whereas differences in myocardial triglyceride content between T2D patients and controls were only present in the European cohort. The diabetic cardiomyopathy phenotype may differ between subsets of T2D patients, for example across ethnicities, and tailored strategies for T2D management may be required.



Cardiovasc Diabetol: 10 Oct 2019; 18:133
Paiman EHM, van Eyk HJ, Bizino MB, Dekkers IA, ... Jazet IM, Lamb HJ
Cardiovasc Diabetol: 10 Oct 2019; 18:133 | PMID: 31604432
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Impact:
Abstract

Prospective study of hemoglobin A1c and incident carotid artery plaque in Chinese adults without diabetes.

Xu R, Zhang T, Wan Y, Fan Z, Gao X
Background
Diabetes has been reported to be associated with carotid artery plaque (CAP). However, it remains unclear whether hemoglobin A1c (HbA1c) level, a marker for long-term glycemic status, is associated with altered CAP risk in individuals with fasting blood glucose (FBG) concentrations below the current cutoff for diabetes.
Methods
Included were 16,863 Chinese adults (aged 18 years or more; 9855 men and 7008 women) with fasting blood glucose < 7.0 mmol/L at baseline (2013). Both HbA1c level and CAP (assessed via ultrasound B-mode imaging) were annually assessed during 2014-2018. All the participants were further classified into three groups based on baseline HbA1c level: ≤ 5.6%, 5.7-6.4%, and ≥ 6.5%. We used Cox proportional-hazards model to evaluate the association between HbA1c level and incident CAP, adjusting for a series of potential confounders.
Results
During 5 years of follow up, 3942 incident CAP cases were identified. Individuals with higher baseline HbA1c had higher future risk of CAP (p-trend < 0.001). In the full-adjusted model, each percent increase of HbA1c was associated with a 56% (HR = 1.56, 95% CI 1.37, 1.78) higher risk of CAP. Excluding participants with chronic inflammation, as assessed by high-sensitivity C-reactive protein and white blood cell, and those with FBG ≥ 5.6 mmol/L at baseline generated similar results.
Conclusions
Elevated HbA1c level was associated with high risk of developing CAP in Chinese adults without FBG defined diabetes.



Cardiovasc Diabetol: 13 Nov 2019; 18:153
Xu R, Zhang T, Wan Y, Fan Z, Gao X
Cardiovasc Diabetol: 13 Nov 2019; 18:153 | PMID: 31727070
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Impact:
Abstract

Hypomagnesemia is associated with new-onset diabetes mellitus following heart transplantation.

Peled Y, Ram E, Lavee J, Tenenbaum A, ... Sternik L, Shechter M
Background
Diabetes mellitus (DM) is a major cause of morbidity and mortality following heart transplantation (HT), with 21% and 35% of survivors being affected within 1 and 5 years following HT, respectively. Magnesium deficiency is common among HT patients treated with calcineurin inhibitors and is a known risk factor for DM in non-HT patients. We therefore investigated the association between serum Mg (s-Mg) levels and new-onset diabetes after transplantation (NODAT).
Methods
Between 2002 and 2017, 102 non-DM HT patients were assessed. In accordance with the mean value of all s-Mg levels recorded during the first year post-HT, patients were divided into high s-Mg (≥ 1.8 mg/dL) and low s-Mg (< 1.8 mg/dL) groups. The endpoint was NODAT, defined according to the diagnostic criteria of the American Diabetes Association.
Results
Baseline clinical and demographic characteristics for the high (n = 45) and low s-Mg (n = 57) groups were similar. Kaplan-Meier survival analysis showed that 15-year freedom from NODAT was significantly higher among patients with high vs low s-Mg (85% vs 46% log-rank test, p < 0.001). Consistently, multivariate analysis adjusted for age, gender, immunosuppression therapies, BMI and mean creatinine values in the first year post-HT, showed that low s-Mg was independently associated with a significant > 8-fold increased risk for NODAT (95% CI 2.15-32.63, p = 0.003). Stroke rate was significantly higher in patients with low s-Mg levels vs high s-Mg (14% vs 0, p = 0.025), as well as long term mortality (HR 2.6, 95% CI 1.02-6.77, p = 0.05).
Conclusions
Low s-Mg level post-HT is an independent risk factor for NODAT in HT patients. The implications of interventions, focusing on preventing or correcting low s-Mg, for the risk of NODAT and for clinical outcomes should be evaluated.



Cardiovasc Diabetol: 10 Oct 2019; 18:132
Peled Y, Ram E, Lavee J, Tenenbaum A, ... Sternik L, Shechter M
Cardiovasc Diabetol: 10 Oct 2019; 18:132 | PMID: 31604444
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Impact:
Abstract

Diabetes mellitus and other cardiovascular risk factors in lower-extremity peripheral artery disease versus coronary artery disease: an analysis of 1,121,359 cases from the nationwide databases.

Takahara M, Iida O, Kohsaka S, Soga Y, ... Ikari Y,
Background
Lower-extremity peripheral artery disease (LE-PAD) and coronary artery disease (CAD) are both pathologically rooted in atherosclerosis, and their shared clinical features regarding the exposure to cardiovascular risk factors have been emphasized. However, comparative data of the two cardiovascular diseases (CVDs) were so far lacking. The purpose of this study was to directly compare the clinical profile between cases undergoing endovascular therapy (EVT) for LE-PAD and those undergoing percutaneous coronary intervention (PCI).
Methods
Data were extracted from the nationwide procedural databases of EVT and PCI in Japan (J-EVT and J-PCI) between 2012 and 2017. A total of 1,121,359 cases (103,887 EVT cases for critical limb ischemia [CLI] or intermittent claudication and 1,017,472 PCI cases for acute coronary syndrome [ACS] or stable angina) were analyzed. Heterogeneity in clinical profile between CVDs was evaluated using the C statistic of the logistic regression model for which dependent variable was one CVD versus another, and explanatory variables were clinical profile. When two CVDs were completely discriminated from each other by the developed model, the C statistic (discrimination ability) of the model would be equal to 1, indicating that the two CVDs were completely different in clinical profile. On the other hand, when two CVDs were identical in clinical profile, the developed model would not discriminate them at all, with the C statistic equal to 0.5.
Results
Mean age was 73.5 ± 9.3 years in LE-PAD patients versus 70.0 ± 11.2 years in CAD patients (P < 0.001). The prevalence of diabetes mellitus and end-stage renal disease was 1.96- and 6.39-times higher in LE-PAD patients than in CAD patients (both P < 0.001). The higher prevalence was observed irrespective of age group. The exposure to other cardiovascular risk factors and the likelihood of cardiovascular risk clustering also varied between the diseases. The between-disease heterogeneity in patient profile was particularly evident between CLI and ACS, with the C statistic equal to 0.833 (95% CI 0.831-0.836).
Conclusions
The current study, an analysis based on nationwide procedural databases, confirmed that patient profiles were not identical but rather considerably different between clinically significant LE-PAD and CAD warranting revascularization.



Cardiovasc Diabetol: 14 Nov 2019; 18:155
Takahara M, Iida O, Kohsaka S, Soga Y, ... Ikari Y,
Cardiovasc Diabetol: 14 Nov 2019; 18:155 | PMID: 31730004
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Impact:
Abstract

Genetic predisposition to type 2 diabetes is associated with severity of coronary artery disease in patients with acute coronary syndromes.

Zheng Q, Jiang J, Huo Y, Chen D
Background
Accumulating evidence has shown that type 2 diabetes (T2D) and coronary artery disease (CAD) may stem from a \'common soil\'. The aim of our study was to examine the association between genetic predisposition to T2D and the risk of severe CAD among patients with acute coronary syndromes (ACS) undergoing angiography.
Methods
The current case-control study included 1414 ACS patients with at least one major epicardial vessel stenosis > 50% enrolled in the ACS Genetic Study. The severity of CAD was quantified by the number of coronary arteries involved. Genetic risk score (GRS) was calculated using 41 common variants that robustly associated with increased risk of T2D in East Asians. Logistic regression models were used to estimate the association between GRS and the severity of CAD.
Results
In the age-, sex- and BMI-adjusted model, each additional risk allele was associated with a 6% increased risk of multi-vessel disease (OR = 1.06, 95% CI 1.02-1.09). The OR was 1.43 (95% CI 1.08-1.89) for the risk of severe CAD when comparing the extreme tertiles of T2D-GRS. The association was not reduced after further adjustment for conventional cardiovascular risk factors. Additional adjustment for T2D status in our regression model attenuated the association by approximately one quarter. In subgroup analysis, the strengths of the associations between GRS and the severity of CAD were broadly similar in terms of baseline demographic information and disease characteristics.
Conclusions
Our data indicated that genetic predisposition to T2D is associated with elevated risk of severe CAD. This association revealed a possible causal relationship and is partially mediated through diabetic status.



Cardiovasc Diabetol: 07 Oct 2019; 18:131
Zheng Q, Jiang J, Huo Y, Chen D
Cardiovasc Diabetol: 07 Oct 2019; 18:131 | PMID: 31594547
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Impact:
Abstract

Impact of free fatty acids on prognosis in coronary artery disease patients under different glucose metabolism status.

Jin JL, Cao YX, Liu HH, Zhang HW, ... Dong Q, Li JJ
Background
The aim of the present study is to examine the effects of free fatty acids (FFAs) on major cardiovascular events (MACEs) in patients with stable coronary artery disease (CAD) and different glucose metabolism status.
Methods
In this study, we consecutively enrolled 5443 patients from March 2011 to May 2015. Patients were categorized according to both status of glucose metabolism status [diabetes mellitus (DM), pre-diabetes (Pre-DM), normal glycaemia regulation (NGR)] and FFAs levels. All subjects were followed up for the occurrence of the MACEs.
Results
During a median of 6.7 years\' follow-up, 608 MACEs occurred. A twofold higher FFAs level was independently associated with MACEs after adjusting for confounding factors [Hazard Ratio (HR): 1.242, 95% confidence interval (CI) 1.084-1.424, p value = 0.002]. Adding FFAs to the Cox model increased the C-statistic by 0.015 (0.005-0.027). No significant difference in MACEs was observed between NGR and Pre-DM groups (p > 0.05). When patients were categorized by both status of glucose metabolism and FFAs levels, medium and high FFAs were associated with significantly higher risk of MACEs in Pre-DM [1.736 (1.018-2.959) and 1.779 (1.012-3.126), all p-value < 0.05] and DM [2.017 (1.164-3.494) and 2.795 (1.619-4.824), all p-value < 0.05].
Conclusions
The present data indicated that baseline FFAs levels were associated with the prognosis in DM and Pre-DM patients with CAD, suggesting that FFAs may be a valuable predictor in patients with impaired glucose metabolism.



Cardiovasc Diabetol: 13 Oct 2019; 18:134
Jin JL, Cao YX, Liu HH, Zhang HW, ... Dong Q, Li JJ
Cardiovasc Diabetol: 13 Oct 2019; 18:134 | PMID: 31610783
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Impact:
Abstract

Heart failure with insulin degludec versus glargine U100 in patients with type 2 diabetes at high risk of cardiovascular disease: DEVOTE 14.

Pratley RE, Husain M, Lingvay I, Pieber TR, ... Zinman B,
Background
Heart failure (HF) is a common cardiovascular complication of type 2 diabetes (T2D). This secondary analysis investigated baseline factors and treatment differences associated with risk of hospitalization for HF (hHF), and the possible association between severe hypoglycemia and hHF.
Methods
DEVOTE was a treat-to-target, double-blind cardiovascular outcomes trial in patients (n = 7637) with T2D and high cardiovascular risk randomized to insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100). The main endpoint of this secondary analysis was time to first hHF (standardized MedDRA Query definition). Severe hypoglycemia was adjudicated (American Diabetes Association definition). The main endpoint and the temporal association between severe hypoglycemia and hHF were analyzed with a Cox proportional hazards regression model. Predictors of time to first hHF were identified using baseline variables.
Results
Overall, 372 (4.9%) patients experienced hHF (550 events). There was no significant difference in the risk of hHF between treatments (hazard ratio [HR] 0.88 [0.72;1.08], p = 0.227). Prior HF (HR 4.89 [3.90;6.14], p ≤ 0.0001) was the strongest predictor of future hHF events. The risk of hHF significantly increased after (HR 2.2), and within a week after (HR 11.1), experiencing a severe hypoglycemic episode compared with before an episode.
Conclusions
In patients with T2D and high cardiovascular risk there were no treatment differences in terms of hHF. Prior HF was the strongest predictor of future hHF events, and there was an association between severe hypoglycemia and subsequent hHF. Further research should evaluate whether the risk of hHF can be modified by treatments aimed at reducing hypoglycemia. Trial registration NCT01959529.



Cardiovasc Diabetol: 14 Nov 2019; 18:156
Pratley RE, Husain M, Lingvay I, Pieber TR, ... Zinman B,
Cardiovasc Diabetol: 14 Nov 2019; 18:156 | PMID: 31729990
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Impact:
Abstract

Characteristics of atheromatosis in the prediabetes stage: a cross-sectional investigation of the ILERVAS project.

Sánchez E, Betriu À, López-Cano C, Hernández M, ... Lecube A,
Background
Prediabetes has recently been associated with subclinical atheromatous disease in the middle-aged population. Our aim was to characterize atheromatous plaque burden by the number of affected territories and the total plaque area in the prediabetes stage.
Methods
Atheromatous plaque burden (quantity of plaques and total plaque area) was assessed in 12 territories from the carotid and femoral regions using ultrasonography in 6688 non-diabetic middle-aged subjects without cardiovascular disease. Prediabetes was defined by glycosylated hemoglobin (HbA1c) between 5.7 and 6.4% according to the American Diabetes Association guidelines.
Results
Prediabetes was diagnosed in 33.9% (n = 2269) of the ILERVAS participants. Subjects with prediabetes presented a higher prevalence of subclinical atheromatous disease than participants with HbA1c < 5.7% (70.4 vs. 67.5%, p = 0.017). In the population with prediabetes this was observed at the level of the carotid territory (p < 0.001), but not in the femoral arteries. Participants in the prediabetes stage also presented a significantly higher number of affected territories (2 [1;3] vs. 1 [0;3], p = 0.002), with a positive correlation between HbA1c levels and the number of affected territories (r = 0.068, p < 0.001). However, atheromatosis was only significantly (p = 0.016) magnified by prediabetes in those subjects with 3 or more cardiovascular risk factors. The multivariable logistic regression model showed that the well-established cardiovascular risk factors together with HbA1c were independently associated with the presence of atheromatous disease in participants with prediabetes. When males and females were analyzed separately, we found that only men with prediabetes presented both carotid and femoral atherosclerosis, as well as an increase of total plaque area in comparison with non-prediabetic subjects.
Conclusions
The prediabetes stage is accompanied by an increased subclinical atheromatous disease only in the presence of other cardiovascular risk factors. Prediabetes modulates the atherogenic effect of cardiovascular risk factors in terms of distribution and total plaque area in a sex-dependent manner. Trial registration NCT03228459 (clinicaltrials.gov).



Cardiovasc Diabetol: 14 Nov 2019; 18:154
Sánchez E, Betriu À, López-Cano C, Hernández M, ... Lecube A,
Cardiovasc Diabetol: 14 Nov 2019; 18:154 | PMID: 31729979
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Abstract

The oral glucose tolerance test-derived incremental glucose peak is associated with greater arterial stiffness and maladaptive arterial remodeling: The Maastricht Study.

Foreman YD, Brouwers MCGJ, Berendschot TTJM, van Dongen MCJM, ... Schaper NC, Stehouwer CDA
Background
Daily glucose variability may contribute to vascular complication development irrespective of mean glucose values. The incremental glucose peak (IGP) during an oral glucose tolerance test (OGTT) can be used as a proxy of glucose variability. We investigated the association of IGP with arterial stiffness, arterial remodeling, and microvascular function, independent of HbA and other confounders.
Methods
IGP was calculated as the peak minus baseline plasma glucose value during a seven-point OGTT in 2758 participants (age: 60 ± 8 years; 48% women) of The Maastricht Study, an observational population-based cohort. We assessed the cross-sectional associations between IGP and arterial stiffness (carotid-femoral pulse wave velocity [cf-PWV], carotid distensibility coefficient [carDC]), arterial remodeling (carotid intima-media thickness [cIMT]; mean [CWS] and pulsatile [CWS] circumferential wall stress), and microvascular function (retinal arteriolar average dilatation; heat-induced skin hyperemia) via multiple linear regression with adjustment for age, sex, HbA, cardiovascular risk factors, lifestyle factors, and medication use.
Results
Higher IGP was independently associated with higher cf-PWV (regression coefficient [B]: 0.054 m/s [0.020; 0.089]) and with higher CWS (B: 0.227 kPa [0.008; 0.446]). IGP was not independently associated with carDC (B: - 0.026 10/kPa [- 0.112; 0.060]), cIMT (B: - 2.745 µm [- 5.736; 0.245]), CWS (B: 0.108 kPa [- 0.054; 0.270]), retinal arteriolar average dilatation (B: - 0.022% [- 0.087; 0.043]), or heat-induced skin hyperemia (B: - 1.380% [- 22.273; 19.513]).
Conclusions
IGP was independently associated with aortic stiffness and maladaptive carotid remodeling, but not with carotid stiffness, cIMT, and microvascular function measures. Future studies should investigate whether glucose variability is associated with cardiovascular disease.



Cardiovasc Diabetol: 13 Nov 2019; 18:152
Foreman YD, Brouwers MCGJ, Berendschot TTJM, van Dongen MCJM, ... Schaper NC, Stehouwer CDA
Cardiovasc Diabetol: 13 Nov 2019; 18:152 | PMID: 31727061
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Abstract

Lessons learned from the DAPA-HF trial concerning the mechanisms of benefit of SGLT2 inhibitors on heart failure events in the context of other large-scale trials nearing completion.

Packer M

Four large-scale trials in type 2 diabetes have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent the occurrence of serious heart failure events. Additionally, the DAPA-HF trial demonstrated a benefit of dapagliflozin to reduce major adverse outcomes in patients with established heart failure with a reduced ejection fraction. The trial sheds light on potential mechanisms. In DAPA-HF, the benefits of dapagliflozin on heart failure were seen to a similar extent in both patients with or without diabetes, thus undermining the hypothesis that these drugs mitigate glycemia-related cardiotoxicity. The action of SGLT2 inhibitors to promote ketogenesis is also primarily a feature of the action of these drugs in patients with diabetes, raising doubts that enhanced ketogenesis contributes to the benefit on heart failure. Also, dapagliflozin does not have a meaningful effect to decrease circulating natriuretic peptides, and it did not potentiate the actions of diuretics in DAPA-HF; moreover, intensification of diuretics therapy does not reduce cardiovascular death, questioning a benefit of SGLT2 inhibitors that is mediated by an action on renal sodium excretion. Finally, although hematocrit increases with SGLT2 inhibitors might favorably affect patients with coronary artery disease, in DAPA-HF, the benefit of dapagliflozin was similar in patients with or without an ischemic cardiomyopathy; furthermore, increases in hematocrit do not favorably affect the clinical course of patients with heart failure. Therefore, the results of DAPA-HF do not support many currently-held hypotheses about the mechanism of action of SGLT2 inhibitors in heart failure. Ongoing trials are likely to provide further insights.



Cardiovasc Diabetol: 03 Oct 2019; 18:129
Packer M
Cardiovasc Diabetol: 03 Oct 2019; 18:129 | PMID: 31585532
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Abstract

Comparative effects of lipid lowering, hypoglycemic, antihypertensive and antiplatelet medications on carotid artery intima-media thickness progression: a network meta-analysis.

Huang R, Mills K, Romero J, Li Y, ... Xu Y, Jiang L
Background
Carotid artery intima-media thickness (cIMT) progression is a surrogate marker of atherosclerosis with a high predictive value for future CVD risk. This study evaluates the comparative efficacies of lipid lowering, hypoglycemic, antihypertensive and antiplatelet medications on cIMT progression.
Methods
We conducted a network meta-analysis (NMA) to evaluate the relative efficacies of several drug classes in modifying cIMT progression. After a literature search in several electronic databases, studies were selected by following predetermined eligibility criteria. An inverse variance-heterogeneity model was used for NMA. Sensitivity analyses were performed to check the reliability of the overall NMA, and transitivity analyses were performed to examine the effects of modifiers on the NMA outcomes.
Results
Data were taken from 47 studies (15,721 patients; age: 60.2 years [95% confidence interval (CI) 58.8, 61.6]; BMI: 27.2 kg/m [95% CI 26.4, 28.0]; and gender: 58.3% males [95% CI 48.3, 68.3]). Treatment duration was 25.8 months [95% CI 22.9, 28.7]. Of the 13 drug classes in the network, treatment with phosphodiesterase III inhibitors was the most effective in retarding annual mean cIMT against network placebo (weighted mean difference (WMD) - 0.059 mm [95% CI - 0.099, - 0.020) followed by the calcium channel blockers (WMD - 0.055 mm [95% CI - 0.099, 0.001]) and platelet adenosine diphosphate inhibitors (WMD - 0.033 mm [95% CI - 0.058, 0.008]). These 3 drug classes also attained the same positions when the NMA was conducted by using first-year changes in mean cIMT. In transitivity analyses, longer treatment duration, higher body mass index (BMI), and a higher baseline cIMT were found to be independently associated with a lesser reduction in annual mean cIMT. However, in a multivariate analysis with these 3 modifiers, none of these factors was significantly associated with annual change in mean cIMT. In the placebo group, age was inversely associated with annual change in mean cIMT independently.
Conclusion
Phosphodiesterase III inhibitors and calcium channel blockers are found more effective than other drug classes in retarding cIMT progression. Age, BMI, and baseline cIMT may have some impact on these outcomes.



Cardiovasc Diabetol: 29 Jan 2019; 18:14
Huang R, Mills K, Romero J, Li Y, ... Xu Y, Jiang L
Cardiovasc Diabetol: 29 Jan 2019; 18:14 | PMID: 30700294
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Impact:
Abstract

Comparative risk evaluation for cardiovascular events associated with dapagliflozin vs. empagliflozin in real-world type 2 diabetes patients: a multi-institutional cohort study.

Shao SC, Chang KC, Hung MJ, Yang NI, ... Kao Yang YH, Lai EC
Background
To compare the cardiovascular event risk in type 2 diabetes patients newly receiving dapagliflozin vs. empagliflozin.
Methods
We conducted a retrospective cohort study by analyzing a multi-institutional electronic medical records database (Chang Gung Research Database) in Taiwan and included adult type 2 diabetes patients who were newly receiving sodium-glucose co-transporter 2 (SGLT2) inhibitors from 2016 to 2017. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischemic stroke and heart failure. We followed up patients from initiation of SGLT2 inhibitors until the occurrence of cardiovascular events before December 31, 2018. We performed multivariable Cox proportional hazard modeling, adjusting for patients\' age, sex, laboratory data, co-morbidities, and concomitant medications.
Results
We identified 12,681 new SGLT2 inhibitor users with a mean age of 58.9 (SD 11.8) years, of whom 43.9% were female and 45.8% were new dapagliflozin users. A total of 10,442 person-years of dapagliflozin use and 12,096 person-years of empagliflozin use were included. Compared to empagliflozin users, new users of dapagliflozin were found to have similar risks for primary composite outcome (adjusted HR: 0.91; 95% CI 0.73-1.14), cardiovascular death (adjusted HR: 0.54; 95% CI 0.14-2.12), myocardial infarction (adjusted HR: 0.77, 95% CI 0.49-1.19) and ischemic stroke (adjusted HR: 1.15; 95% CI 0.80-1.65), but a lower risk of heart failure (adjusted HR: 0.68; 95% CI 0.49-0.95).
Conclusion
The risk of cardiovascular events was similar between dapagliflozin and empagliflozin new users, but dapagliflozin may have a better outcome in the reduction of heart failure in type 2 diabetes patients. Future prospective studies are required to confirm the findings.



Cardiovasc Diabetol: 23 Sep 2019; 18:120
Shao SC, Chang KC, Hung MJ, Yang NI, ... Kao Yang YH, Lai EC
Cardiovasc Diabetol: 23 Sep 2019; 18:120 | PMID: 31551068
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Impact:
Abstract

Effects of 1 year of exercise training versus combined exercise training and weight loss on body composition, low-grade inflammation and lipids in overweight patients with coronary artery disease: a randomized trial.

Pedersen LR, Olsen RH, Anholm C, Astrup A, ... Haugaard SB, Prescott E
Background
Dyslipidaemia and low-grade inflammation are central in atherogenesis and linked to overweight and physical inactivity. Lifestyle changes are important in secondary prevention of coronary artery disease (CAD). We compared the effects of combined weight loss and interval training with interval training alone on physical fitness, body composition, dyslipidaemia and low-grade inflammation in overweight, sedentary participants with CAD.
Methods
Seventy CAD patients, BMI 28-40 kg/m and age 45-75 years were randomised to (1) 12 weeks\' aerobic interval training (AIT) at 90% of peak heart rate three times/week followed by 40 weeks\' AIT twice weekly or (2) a low energy diet (LED) (800-1000 kcal/day) for 8-10 weeks followed by 40 weeks\' weight maintenance including AIT twice weekly and a high-protein/low-glycaemic load diet. Effects of the intervention were evaluated by physical fitness, body weight and composition. Dyslipidaemia was described using both biochemical analysis of lipid concentrations and lipoprotein particle subclass distribution determined by density profiling. Low-grade inflammation was determined by C-reactive protein, soluble urokinase-type plasminogen activator receptor and tumour necrosis factor α. Effects on continuous outcomes were tested by mixed-models analysis.
Results
Twenty-six (74%) AIT and 29 (83%) LED + AIT participants completed the study. At baseline subject included 43 (78%) men; subjects averages were: age 63 years (6.2), body weight 95.9 kg (12.2) and VOpeak 20.7 mL O/kg/min (4.9). Forty-six (84%) had pre-diabetes (i.e. impaired fasting glucose and/or impaired glucose tolerance). LED + AIT reduced body weight by 7.2 kg (- 8.4; - 6.1) and waist circumference by 6.6 cm (- 7.7; - 5.5) compared to 1.7 kg (- 0.7; - 2.6) and 3.3 cm (- 5.1; - 1.5) after AIT (within-group p < 0.001, between-group p < 0.001 and p = 0.018, respectively). Treatments caused similar changes in VOpeak and lowering of total cholesterol, triglycerides, non-HDL cholesterol and low-grade inflammation. A shift toward larger HDL particles was seen following LED + AIT while AIT elicited no change.
Conclusions
Both interventions were feasible. Both groups obtained improvements in VOpeak, serum-lipids and inflammation with superior weight loss and greater central fat loss following LED + AIT. Combined LED induced weight loss and exercise can be recommended to CAD patients. Trial registration NCT01724567, November 12, 2012, retrospectively registered (enrolment ended in April 2013).



Cardiovasc Diabetol: 30 Sep 2019; 18:127
Pedersen LR, Olsen RH, Anholm C, Astrup A, ... Haugaard SB, Prescott E
Cardiovasc Diabetol: 30 Sep 2019; 18:127 | PMID: 31575375
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Abstract

Pericoronary fat inflammation and Major Adverse Cardiac Events (MACE) in prediabetic patients with acute myocardial infarction: effects of metformin.

Sardu C, D\'Onofrio N, Torella M, Portoghese M, ... Paolisso G, Marfella R
Background/objectives
Pericoronary adipose tissue inflammation might lead to the development and destabilization of coronary plaques in prediabetic patients. Here, we evaluated inflammation and leptin to adiponectin ratio in pericoronary fat from patients subjected to coronary artery bypass grafting (CABG) for acute myocardial infarction (AMI). Furthermore, we compared the 12-month prognosis of prediabetic patients compared to normoglycemic patients (NG). Finally, the effect of metformin therapy on pericoronary fat inflammation and 12-months prognosis in AMI-prediabetic patients was also evaluated.
Methods
An observational prospective study was conducted on patients with first AMI referred for CABG. Participants were divided in prediabetic and NG-patients. Prediabetic patients were divided in two groups; never-metformin-users and current-metformin-users receiving metformin therapy for almost 6 months before CABG. During the by-pass procedure on epicardial coronary portion, the pericoronary fat was removed from the surrounding stenosis area. The primary endpoints were the assessments of Major-Adverse-Cardiac-Events (MACE) at 12-month follow-up. Moreover, inflammatory tone was evaluated by measuring pericoronary fat levels of tumor necrosis factor-α (TNF-α), sirtuin 6 (SIRT6), and leptin to adiponectin ratio. Finally, inflammatory tone was correlated to the MACE during the 12-months follow-up.
Results
The MACE was 9.1% in all prediabetic patients and 3% in NG-patients. In prediabetic patients, current-metformin-users presented a significantly lower rate of MACE compared to prediabetic patients never-metformin-users. In addition, prediabetic patients showed higher inflammatory tone and leptin to adiponectin ratio in pericoronary fat compared to NG-patients (P < 0.001). Prediabetic never-metformin-users showed higher inflammatory tone and leptin to adiponectin ratio in pericoronary fat compared to current-metformin-users (P < 0.001). Remarkably, inflammatory tone and leptin to adiponectin ratio was significantly related to the MACE during the 12-months follow-up.
Conclusion
Prediabetes increase inflammatory burden in pericoronary adipose tissue. Metformin by reducing inflammatory tone and leptin to adiponectin ratio in pericoronary fat may improve prognosis in prediabetic patients with AMI. Trial registration Clinical Trial NCT03360981, Retrospectively Registered 7 January 2018.



Cardiovasc Diabetol: 29 Sep 2019; 18:126
Sardu C, D'Onofrio N, Torella M, Portoghese M, ... Paolisso G, Marfella R
Cardiovasc Diabetol: 29 Sep 2019; 18:126 | PMID: 31570103
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Abstract

Disease-treatment interactions in the management of patients with obesity and diabetes who have atrial fibrillation: the potential mediating influence of epicardial adipose tissue.

Packer M

Both obesity and type 2 diabetes are important risk factors for atrial fibrillation (AF), possibly because they both cause an expansion of epicardial adipose tissue, which is the source of proinflammatory adipocytokines that can lead to microvascular dysfunction and fibrosis of the underlying myocardium. If the derangement of epicardial fat adjoins the left atrium, the result is an atrial myopathy, which is clinically manifest as AF. In patients with AF, there is a close relationship between epicardial fat volume and the severity of electrophysiological abnormalities in the adjacent myocardial tissues, and epicardial fat mass predicts AF in the general population. The expansion of epicardial adipose tissue in obesity and type 2 diabetes may also affect the left ventricle, impairing its distensibility and leading to heart failure with a preserved ejection fraction (HFpEF). Patients with obesity or type 2 diabetes with AF often have HFpEF, but the diagnosis may be missed, if dyspnea is attributed to increased body mass or to the arrhythmia. The expected response to the treatment for obesity, diabetes or AF may be influenced by their effects on epicardial inflammation and the underlying atrial and ventricular myopathy. Bariatric surgery and metformin reduce epicardial fat mass and ameliorate AF, whereas insulin promotes adipogenesis and cardiac fibrosis, and its use is accompanied by an increased risk of AF. Rate control strategies for AF may impair exercise tolerance, because they allow for greater time for ventricular filling in patients who cannot tolerate volume loading because of cardiac fibrosis and HFpEF. At the same time, both obesity and diabetes decrease the expected success rate of rhythm control strategies for AF (e.g., electrical cardioversion or catheter ablation), because increased epicardial adipose tissue volumes and cardiac fibrosis are important determinants of AF recurrence following these procedures.



Cardiovasc Diabetol: 23 Sep 2019; 18:121
Packer M
Cardiovasc Diabetol: 23 Sep 2019; 18:121 | PMID: 31551089
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Abstract

Greater glucagon-like peptide-1 responses to oral glucose are associated with lower central and peripheral blood pressures.

Lundgren JR, Færch K, Witte DR, Jonsson AE, ... Torekov SS, Johansen NB
Background and aim
Cardiovascular diseases (CVDs) are globally the leading cause of death and hypertension is a significant risk factor. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with decreases in blood pressure and CVD risk. Our aim was to investigate the association between endogenous GLP-1 responses to oral glucose and peripheral and central haemodynamic measures in a population at risk of diabetes and CVD.
Methods
This cross-sectional study included 837 Danish individuals from the ADDITION-PRO cohort (52% men, median (interquartile range) age 65.5 (59.8 to 70.7) years, BMI 26.1 (23.4 to 28.5) kg/m, without antihypertensive treatment and known diabetes). All participants received an oral glucose tolerance test with measurements of GLP-1 at 0, 30 and 120 min. Aortic stiffness was assessed by pulse wave velocity (PWV). The associations between GLP-1 response and central and brachial blood pressure (BP) and PWV were assessed in linear regression models adjusting for age and sex.
Results
A greater GLP-1 response was associated with lower central systolic and diastolic BP of - 1.17 mmHg (95% confidence interval (CI) - 2.07 to - 0.27 mmHg, P = 0.011) and - 0.74 mmHg (95% CI - 1.29 to - 0.18 mmHg, P = 0.009), respectively, as well as lower brachial systolic and diastolic BP of - 1.27 mmHg (95% CI - 2.20 to - 0.33 mmHg, P = 0.008) and - 1.00 (95% CI - 1.56 to - 0.44 mmHg, P = 0.001), respectively. PWV was not associated with GLP-1 release (P = 0.3). Individuals with the greatest quartile of GLP-1 response had clinically relevant lower BP measures compared to individuals with the lowest quartile of GLP-1 response (central systolic BP: - 4.94 (95% CI - 8.56 to - 1.31) mmHg, central diastolic BP: - 3.05 (95% CI - 5.29 to - 0.80) mmHg, brachial systolic BP: - 5.18 (95% CI - 8.94 to - 1.42) mmHg, and brachial diastolic BP: - 2.96 (95% CI - 5.26 to - 0.67) mmHg).
Conclusion
Greater glucose-stimulated GLP-1 responses were associated with clinically relevant lower central and peripheral blood pressures, consistent with beneficial effects on the cardiovascular system and reduced risk of CVD and mortality. Trial registration ClinicalTrials.gov Identifier: NCT00237549. Retrospectively registered 10 October 2005.



Cardiovasc Diabetol: 04 Oct 2019; 18:130
Lundgren JR, Færch K, Witte DR, Jonsson AE, ... Torekov SS, Johansen NB
Cardiovasc Diabetol: 04 Oct 2019; 18:130 | PMID: 31586493
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Impact:
Abstract

Searching for optimal blood pressure targets in type 2 diabetic patients with coronary artery disease.

Shen Y, Dai Y, Wang XQ, Zhang RY, ... Ding FH, Shen WF
Background
Controversies exist regarding the optimal blood pressure (BP) level that is safe and provides cardiovascular protection in patients with type 2 diabetes mellitus (T2DM) and coexistent coronary artery disease. Several new glucose-lowering agents have been found to lower BP as well, making the interaction between BP and T2DM even more complex.
Methods
With the reference to recent literature, this review article describes the potential mechanisms of increased risk of hypertension in T2DM and outlines the possible optimal BP levels based upon recommendations on the management of hypertension by the current guidelines, in combination with our research findings, for type 2 diabetic patients with coronary artery disease.
Results
The development of hypertension in T2DM involves multiple processes, including enhanced sympathetic output, inappropriate activation of renin-angiotensin- aldosterone system, endothelial dysfunction induced through insulin resistance, and abnormal sodium handling by the kidney. Both AGE-RAGE axis and adipokine dysregulation activate intracellular signaling pathways, increase oxidative stress, and aggravate vascular inflammation. Pancreatic β-cell specific microRNAs are implicated in gene expression and diabetic complications. Non-pharmacological intervention with lifestyle changes improves BP control, and anti-hypertensive medications with ACEI/ARB, calcium antagonists, β-blockers, diuretics and new hypoglycemic agent SGLT2 inhibitors are effective to decrease mortality and prevent major adverse cardiovascular events. For hypertensive patients with T2DM and stable coronary artery disease, control of BP < 130/80 mmHg but not < 120/70 mmHg is reasonable, whereas for those with chronic total occlusion or acute coronary syndromes, an ideal BP target may be somewhat higher (< 140/90 mmHg). Caution is advised with aggressive lowering of diastolic BP to a critical threshold (< 60 mmHg).
Conclusions
Hypertension and T2DM share certain similar aspects of pathophysiology, and BP control should be individualized to minimize adverse events and maximize benefits especially for patients with T2DM and coronary artery disease.



Cardiovasc Diabetol: 15 Nov 2019; 18:160
Shen Y, Dai Y, Wang XQ, Zhang RY, ... Ding FH, Shen WF
Cardiovasc Diabetol: 15 Nov 2019; 18:160 | PMID: 31733658
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Abstract

Differences in lipid metabolism between anagliptin and sitagliptin in patients with type 2 diabetes on statin therapy: a secondary analysis of the REASON trial.

Chihara A, Tanaka A, Morimoto T, Sakuma M, ... Ueda S, Node K
Background
Anagliptin, a dipeptidyl peptidase-4 inhibitor, is reported to reduce the level of low-density lipoprotein cholesterol (LDL-C). The underlying mechanism of this effect and effect on lipid metabolism however remains uncertain.
Aim and methods
We therefore evaluate the effects of anagliptin on lipid metabolism-related markers compared with those of sitagliptin. The study was a secondary analysis using data obtained from the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. This trial in patients with type 2 diabetes at a high risk of cardiovascular events and on statin therapy showed that anagliptin reduced LDL-C levels to a greater extent than sitagliptin. Cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol) markers were measured at baseline and 52 weeks in the study cohort (n = 353).
Results
There was no significant difference in the changes of campesterol or sitosterol between the two treatment groups (p = 0.85 and 0.55, respectively). Lathosterol concentration was increased significantly at 52 weeks with sitagliptin treatment (baseline, 1.2 ± 0.7 μg/mL vs. 52 weeks, 1.4 ± 1.0 μg/mL, p = 0.02), whereas it did not change in the anagliptin group (baseline, 1.3 ± 0.8 μg/mL vs. 52 weeks, 1.3 ± 0.7 μg/mL, p = 0.99). The difference in absolute change between the two groups showed a borderline significance (p = 0.06).
Conclusion
These findings suggest that anagliptin reduces LDL-C level by suppressing excess cholesterol synthesis, even in combination with statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. https://clinicaltrials.gov/ct2/show/NCT02330406; registered January 5, 2015.



Cardiovasc Diabetol: 15 Nov 2019; 18:158
Chihara A, Tanaka A, Morimoto T, Sakuma M, ... Ueda S, Node K
Cardiovasc Diabetol: 15 Nov 2019; 18:158 | PMID: 31733647
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Impact:
Abstract

Staged complete revascularization or culprit-only percutaneous coronary intervention for multivessel coronary artery disease in patients with ST-segment elevation myocardial infarction and diabetes.

Cui K, Lyu S, Liu H, Song X, ... Zhang D, Tian J
Background
Recently, several randomized trials have noted improved outcomes with staged percutaneous coronary intervention (PCI) of nonculprit vessels in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease. However, it remains unclear whether diabetes status affects the outcomes after different revascularization strategies. This study thus compared the impact of diabetes status on long-term outcomes after staged complete revascularization with that after culprit-only PCI.
Methods
From January 2006 to December 2015, 371 diabetic patients (staged PCI: 164, culprit-only PCI: 207) and 834 nondiabetic patients (staged PCI: 412, culprit-only PCI: 422) with STEMI and multivessel disease were enrolled. The primary endpoint was 5-year major adverse cardiac and cerebrovascular event (MACCE), defined as a composite of all-cause death, myocardial infarction (MI), stroke or unplanned revascularization.
Results
The rate of the 5-year composite primary endpoint for diabetic patients was close to that for nondiabetic patients (34.5% vs. 33.7%; adjusted hazard ratio [HR] 1.012, 95% confidence interval [CI] 0.815-1.255). In nondiabetic patients, the 5-year risks of MACCE (31.8% vs. 35.5%; adjusted HR 0.638, 95% CI 0.500-0.816), MI (4.6% vs. 9.2%; adjusted HR 0.358, 95% CI 0.200-0.641), unplanned revascularization (19.9% vs. 24.9%; adjusted HR 0.532, 95% CI 0.393-0.720), and the composite of cardiac death, MI or stroke (11.4% vs. 15.2%; adjusted HR 0.621, 95% CI 0.419-0.921) were significantly lower after staged PCI than after culprit-only PCI. In contrast, no significant difference was found between the two groups with respect to MACCE, MI, unplanned revascularization, and the composite of cardiac death, MI or stroke in diabetic patients. Significant interactions were found between diabetes status and revascularization assignment for the composite of cardiac death, MI or stroke (P = 0.013), MI (P = 0.005), and unplanned revascularization (P = 0.013) at 5 years. In addition, the interaction tended to be significant for the primary endpoint of MACCE (P = 0.053). Moreover, the results of propensity score-matching analysis were concordant with the overall analysis in both diabetic and nondiabetic population.
Conclusions
In patients with STEMI and multivessel disease, diabetes is not an independent predictor of adverse cardiovascular events at 5 years. In nondiabetic patients, an approach of staged complete revascularization is superior to culprit-only PCI, whereas the advantage of staged PCI is attenuated in diabetic patients. Trial registration This study was not registered in an open access database.



Cardiovasc Diabetol: 16 Sep 2019; 18:119
Cui K, Lyu S, Liu H, Song X, ... Zhang D, Tian J
Cardiovasc Diabetol: 16 Sep 2019; 18:119 | PMID: 31530274
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Impact:
Abstract

Significance of circulating microRNAs in diabetes mellitus type 2 and platelet reactivity: bioinformatic analysis and review.

Pordzik J, Jakubik D, Jarosz-Popek J, Wicik Z, ... Czajka P, Postula M

In the light of growing global epidemic of type 2 diabetes mellitus (T2DM), significant efforts are made to discover next-generation biomarkers for early detection of the disease. Multiple mechanisms including inflammatory response, abnormal insulin secretion and glucose metabolism contribute to the development of T2DM. Platelet activation, on the other hand, is known to be one of the underlying mechanisms of atherosclerosis, which is a common T2DM complication that frequently results in ischemic events at later stages of the disease. Available data suggest that platelets contain large amounts of microRNAs (miRNAs) that are found in circulating body fluids, including the blood. Since miRNAs have been illustrated to play an important role in metabolic homeostasis through regulation of multiple genes, they attracted substantial scientific interest as diagnostic and prognostic biomarkers in T2DM. Various miRNAs, as well as their target genes are implicated in the complex pathophysiology of T2DM. This article will first review the different miRNAs studied in the context of T2DM and platelet reactivity, and subsequently present original results from bioinformatic analyses of published reports, identifying a common gene (PRKAR1A) linked to glucose metabolism, blood coagulation and insulin signalling and targeted by miRNAs in T2DM. Moreover, miRNA-target gene interaction networks built upon Gene Ontology information from electronic databases were developed. According to our results, miR-30a-5p, miR-30d-5p and miR-30c-5p are the most widely regulated miRNAs across all specified ontologies, hence they are the most promising biomarkers of T2DM to be investigated in future clinical studies.



Cardiovasc Diabetol: 29 Aug 2019; 18:113
Pordzik J, Jakubik D, Jarosz-Popek J, Wicik Z, ... Czajka P, Postula M
Cardiovasc Diabetol: 29 Aug 2019; 18:113 | PMID: 31470851
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Impact:
Abstract

The impact of body weight and diabetes on new-onset atrial fibrillation: a nationwide population based study.

Kim YG, Han KD, Choi JI, Boo KY, ... Kim JS, Kim YH
Background
Being obese or underweight, and having diabetes are important risk factors for new-onset atrial fibrillation (AF). However, it is unclear whether there is any interaction between body weight and diabetes in regard to development of new-onset AF. We aimed to evaluate the role of body weight status and various stage of diabetes on new-onset AF.
Methods
This was a nationwide population based study using National Health Insurance Service (NHIS) data. A total of 9,797,418 patients who underwent national health check-ups were analyzed. Patients were classified as underweight [body mass index (BMI) < 18.5], normal reference group (18.5 ≤ BMI < 23.0), upper normal (23.0 ≤ BMI < 25.0), overweight (25.0 ≤ BMI < 30.0), or obese (BMI ≥ 30.0) based on BMI. Diabetes were categorized as non-diabetic, impaired fasting glucose (IFG), new-onset diabetes, diabetes < 5 years, and diabetes ≥ 5 years. Primary outcome end point was new-onset AF. New-onset AF was defined as one inpatient or two outpatient records of International Classification of Disease, Tenth Revision (ICD-10) codes in patients without prior AF diagnosis.
Results
During 80,130,161 patient*years follow-up, a total of 196,136 new-onset AF occurred. Obese [hazard ration (HR) = 1.327], overweight (HR = 1.123), upper normal (HR = 1.040), and underweight (HR = 1.055) patients showed significantly increased risk of new-onset AF compared to the normal reference group. Gradual escalation in the risk of new-onset AF was observed along with advancing diabetic stage. Body weight status and diabetes were independently associated with new-onset AF and at the same time, had synergistic effects on the risk of new-onset AF with obese diabetic patients having the highest risk (HR = 1.823).
Conclusions
Patients with obesity, overweight, underweight, and diabetes had significantly increased risk of new-onset AF. Body weight status and diabetes had synergistic effects on the risk of new-onset AF. The risk of new-onset AF increased gradually with advancing diabetic stage. This study suggests that maintaining optimal body weight and glucose homeostasis might prevent new-onset AF.



Cardiovasc Diabetol: 30 Sep 2019; 18:128
Kim YG, Han KD, Choi JI, Boo KY, ... Kim JS, Kim YH
Cardiovasc Diabetol: 30 Sep 2019; 18:128 | PMID: 31575379
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Impact:
Abstract

Atrial fibrillation and its arrhythmogenesis associated with insulin resistance.

Chan YH, Chang GJ, Lai YJ, Chen WJ, ... Kuo CT, Yeh YH
Background
Insulin resistance (IR) is considered as a risk factor for atrial fibrillation (AF) even before diabetes develops. The pathophysiology and underlying mechanism are largely unclear.
Methods
We investigated the corresponding mechanism in two IR models of rats fed 15-week high-fat (HFa) and high-fructose/cholesterol (HFr) diets. AF was evaluated and induced by burst atrial pacing. Isolated atrial myocytes were used for whole-cell patch clamp and calcium assessment. Ex vivo whole heart was used for optical mapping. Western blot and immunofluorescence were used for quantitative protein evaluation.
Results
Both HFa and HFr rat atria were vulnerable to AF evaluated by burst atrial pacing. Isolated atrial myocytes from HFa and HFr rats revealed significantly increased sarcoplasmic reticulum calcium content and diastolic calcium sparks. Whole-heart mapping showed prolonged calcium transient duration, conduction velocity reduction, and repetitive ectopic focal discharge in HFa and HFr atria. Protein analysis revealed increased TGF-β1 and collagen expression; increased superoxide production; abnormal upregulation of calcium-homeostasis-related proteins, including oxidized CaMKIIδ, phosphorylated-phospholamban, phosphorylated-RyR-2, and sodium-calcium exchanger; and increased Rac1 activity in both HFa and HFr atria. We observed that inhibition of CaMKII suppressed AF in both HF and HFr diet-fed rats. In vitro palmitate-induced IR neonatal cardiomyocytes and atrial fibroblasts expressed significantly more TGF-β1 than did controls, suggesting paracrine and autocrine effects on both myocytes and fibroblasts.
Conclusions
IR engenders both atrial structural remodeling and abnormal intracellular calcium homeostasis, contributing to increased AF susceptibility. The inhibition of CaMKII may be a potential therapeutic target for AF in insulin resistance.



Cardiovasc Diabetol: 25 Sep 2019; 18:125
Chan YH, Chang GJ, Lai YJ, Chen WJ, ... Kuo CT, Yeh YH
Cardiovasc Diabetol: 25 Sep 2019; 18:125 | PMID: 31558158
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Impact:
Abstract

Renal glucosuria is associated with lower body weight and lower rates of elevated systolic blood pressure: results of a nationwide cross-sectional study of 2.5 million adolescents.

Fishman B, Shlomai G, Twig G, Derazne E, ... Leiba A, Grossman E
Background
Gene coding mutations found in sodium glucose co-transporters (SGLTs) are known to cause renal glucosuria. SGLT2 inhibitors have recently been shown to be effective hypoglycemic agents as well as possessing cardiovascular and renal protective properties. These beneficial effects have to some extent, been attributed to weight loss and reduced blood pressure. The aim of the current study was to evaluate the prevalence of renal glucosuria amongst a large cohort of Israeli adolescents and to investigate whether renal glucosuria is associated with lower body weight and lower blood pressure values.
Methods
Medical and socio-demographic data were collected from the Israeli Defense Force\'s conscription center\'s database. A cross-sectional study to evaluate the association between conscripts diagnosed as overweight [BMI percentiles of ≥ 85 and < 95 and obesity (≥ 95 BMI percentile)] and afflicted with renal glucosuria was conducted. In addition, we assessed the association of renal glucosuria with elevated diastolic and systolic blood pressure. Multinomial regression models were used.
Results
The final study cohort comprised 2,506,830 conscripts of whom 1108 (0.044%) were diagnosed with renal glucosuria, unrelated to diabetes mellitus, with males twice as affected compared to females. The adjusted odds ratio for overweight and obesity was 0.66 (95% CI 0.50-0.87) and 0.62 (95% CI 0.43-0.88), respectively. Adolescents afflicted with renal glucosuria were also less likely to have an elevated systolic blood pressure of 130-139 mmHg with an adjusted odds ratio of 0.74 (95% CI 0.60-0.90).
Conclusions
Renal glucosuria is associated with lower body weight and obesity as well as with lower rates of elevated systolic blood pressure.



Cardiovasc Diabetol: 24 Sep 2019; 18:124
Fishman B, Shlomai G, Twig G, Derazne E, ... Leiba A, Grossman E
Cardiovasc Diabetol: 24 Sep 2019; 18:124 | PMID: 31554505
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Impact:
Abstract

Intrinsic calcification angle: a novel feature of the vulnerable coronary plaque in patients with type 2 diabetes: an optical coherence tomography study.

Reith S, Milzi A, Lemma ED, Dettori R, ... Marx N, Burgmaier M
Background
Coronary calcification is associated with high risk for cardiovascular events. However, its impact on plaque vulnerability is incompletely understood. In the present study we defined the intrinsic calcification angle (ICA) as the angle externally projected by a vascular calcification and analyzed its role as novel feature of coronary plaque vulnerability in patients with type 2 diabetes.
Methods
Optical coherence tomography was used to determine ICA in 219 calcifications from 56 patients with stable coronary artery disease (CAD) and 143 calcifications from 36 patients with acute coronary syndrome (ACS). We then used finite elements analysis to gain mechanistic insight into the effects of ICA.
Results
Minimal (139.8 ± 32.8° vs. 165.6 ± 21.6°, p < 0.001) and mean ICA (164.1 ± 14.3° vs. 176.0 ± 8.4°, p < 0.001) were lower in ACS vs. stable CAD patients. Mean ICA predicted ACS with very good diagnostic efficiency (AUC = 0.840, 95% CI 0.797-0.882, p < 0.001, optimal cut-off 175.9°); younger age (OR 0.95 per year, 95% CI 0.92-0.98, p = 0.002), male sex (OR 2.18, 95% CI 1.41-3.38, p < 0.001), lower HDL-cholesterol (OR 0.82 per 10 mg/dl, 95% CI 0.68-0.98, p = 0.029) and ACS (OR 14.71, 95% CI 8.47-25.64, p < 0.001) were determinants of ICA < 175.9°. A lower ICA predicted ACS (OR for 10°-variation 0.25, 95% CI 0.13-0.52, p < 0.001) independently from fibrous cap thickness, presence of macrophages or extension of lipid core. In finite elements analysis we confirmed that lower ICA causes increased stress on a lesion\'s fibrous cap; this effect was potentiated in more superficial calcifications and adds to the destabilizing role of smaller calcifications.
Conclusion
Our clinical and mechanistic data for the first time identify ICA as a novel feature of coronary plaque vulnerability.



Cardiovasc Diabetol: 23 Sep 2019; 18:122
Reith S, Milzi A, Lemma ED, Dettori R, ... Marx N, Burgmaier M
Cardiovasc Diabetol: 23 Sep 2019; 18:122 | PMID: 31551093
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Impact:
Abstract

Serial coronary computed tomography angiography-verified coronary plaque progression: comparison of stented patients with or without diabetes.

Shi R, Shi K, Yang ZG, Guo YK, ... Zhang Y, Huang S
Background
Patients with Diabetes mellitus (DM) are susceptible to coronary artery disease (CAD). However, the impact of DM on plaque progression in the non-stented segments of stent-implanted patients has been rarely reported. This study aimed to evaluate the impact of DM on the prevalence, characteristics and severity of coronary computed tomography angiography (CCTA) verified plaque progression in stented patients. A comparison between diabetic and non-diabetic patients was performed.
Methods
A total of 98 patients who underwent clinically indicated serial CCTAs arranged within 1 month before and at least 6 months after percutaneous coronary intervention (PCI) were consecutively included. All the subjects were categorized into diabetic group (n = 36) and non-diabetic groups (n = 62). Coronary stenosis extent scores, segment involvement scores (SIS), segment stenosis scores (SSS) at baseline and follow-up CCTA were quantitatively assessed. The prevalence, characteristics and severity of plaque progression was evaluated blindly to the clinical data and compared between the groups.
Results
During the median 1.5 year follow up, a larger number of patients (72.2% vs 40.3%, P = 0.002), more non-stented vessels (55.7% vs 23.2%, P < 0.001) and non-stented segments (10.3% vs 4.4%, P < 0.001) showed plaque progression in DM group, compared to non-DM controls. More progressive lesions in DM patients were found to be non-calcified plaques (31.1% vs 12.8%, P = 0.014) or non-stenotic segments (6.6% vs 3.0%, p = 0.005) and were more widely distributed on left main artery (24.2% vs 5.2%, p = 0.007), the right coronary artery (50% vs 21.1%, P = 0.028) and the proximal left anterior artery (33.3% vs 5.1%, P = 0.009) compared to non-DM patients. In addition, DM patients possessed higher numbers of progressive segments per patient, ΔSIS and ΔSSS compared with non-DM individuals (P < 0.001, P = 0.029 and P < 0.001 respectively). A larger number of patients with at least two progressive lesions were found in the DM group (P = 0.006). Multivariate logistic regression analysis demonstrated that DM (OR: 4.81; 95% CI 1.64-14.07, P = 0.004) was independently associated with plaque progression.
Conclusions
DM is closely associated with the prevalence and severity of CCTA verified CAD progression. These findings suggest that physicians should pay attention to non-stent segments and the management of non-stent segment plaque progression, particularly to DM patients.



Cardiovasc Diabetol: 23 Sep 2019; 18:123
Shi R, Shi K, Yang ZG, Guo YK, ... Zhang Y, Huang S
Cardiovasc Diabetol: 23 Sep 2019; 18:123 | PMID: 31551077
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Impact:
Abstract

Sitagliptin does not reduce the risk of cardiovascular death or hospitalization for heart failure following myocardial infarction in patients with diabetes: observations from TECOS.

Nauck MA, McGuire DK, Pieper KS, Lokhnygina Y, ... Scott R, Holman RR
Background
To examine the effects of the DPP-4i sitagliptin on CV outcomes during and after incident MI in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).
Methods
TECOS randomized 14,671 participants with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) to sitagliptin or placebo, in addition to usual care. For those who had a within-trial MI, we analyzed case fatality, and for those with a nonfatal MI, we examined a composite cardiovascular (CV) outcome (CV death or hospitalization for heart failure [hHF]) by treatment group, using Cox proportional hazards models left-censored at the time of the first within-trial MI, without and with adjustment for potential confounders, in intention-to-treat analyses.
Results
During TECOS, 616 participants had ≥ 1 MI (sitagliptin group 300, placebo group 316, HR 0.95, 95% CI 0.81-1.11, P = 0.49), of which 25 were fatal [11 and 14, respectively]). Of the 591 patients with a nonfatal MI, 87 (15%) died subsequently, with 66 (11%) being CV deaths, and 57 (10%) experiencing hHF. The composite outcome occurred in 58 (20.1%; 13.9 per 100 person-years) sitagliptin group participants and 50 (16.6%; 11.7 per 100 person-years) placebo group participants (HR 1.21, 95% CI 0.83-1.77, P = 0.32, adjusted HR 1.23, 95% CI 0.83-1.82, P = 0.31). On-treatment sensitivity analyses also showed no significant between-group differences in post-MI outcomes.
Conclusions
In patients with type 2 diabetes and ASCVD experiencing an MI, sitagliptin did not reduce subsequent risk of CV death or hHF, contrary to expectations derived from preclinical animal models. Trial registration clinicaltrials.gov no. NCT00790205.



Cardiovasc Diabetol: 02 Sep 2019; 18:116
Nauck MA, McGuire DK, Pieper KS, Lokhnygina Y, ... Scott R, Holman RR
Cardiovasc Diabetol: 02 Sep 2019; 18:116 | PMID: 31481069
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Impact:
Abstract

Epicardial adipose tissue predicts incident cardiovascular disease and mortality in patients with type 2 diabetes.

Christensen RH, von Scholten BJ, Hansen CS, Jensen MT, ... Rossing P, Jørgensen PG
Background
Cardiac fat is a cardiovascular biomarker but its importance in patients with type 2 diabetes is not clear. The aim was to evaluate the predictive potential of epicardial (EAT), pericardial (PAT) and total cardiac (CAT) fat in type 2 diabetes and elucidate sex differences.
Methods
EAT and PAT were measured by echocardiography in 1030 patients with type 2 diabetes. Follow-up was performed through national registries. The end-point was the composite of incident cardiovascular disease (CVD) and all-cause mortality. Analyses were unadjusted (model 1), adjusted for age and sex (model 2), plus systolic blood pressure, body mass index (BMI), low-density lipoprotein (LDL), smoking, diabetes duration and glycated hemoglobin (HbA) (model 3).
Results
Median follow-up was 4.7 years and 248 patients (191 men vs. 57 women) experienced the composite end-point. Patients with high EAT (> median level) had increased risk of the composite end-point in model 1 [Hazard ratio (HR): 1.46 (1.13; 1.88), p = 0.004], model 2 [HR: 1.31 (1.01; 1.69), p = 0.038], and borderline in model 3 [HR: 1.32 (0.99; 1.77), p = 0.058]. For men, but not women, high EAT was associated with a 41% increased risk of CVD and mortality in model 3 (p = 0.041). Net reclassification index improved when high EAT was added to model 3 (19.6%, p = 0.035). PAT or CAT were not associated with the end-point.
Conclusion
High levels of EAT were associated with the composite of incident CVD and mortality in patients with type 2 diabetes, particularly in men, after adjusting for CVD risk factors. EAT modestly improved risk prediction over CVD risk factors.



Cardiovasc Diabetol: 29 Aug 2019; 18:114
Christensen RH, von Scholten BJ, Hansen CS, Jensen MT, ... Rossing P, Jørgensen PG
Cardiovasc Diabetol: 29 Aug 2019; 18:114 | PMID: 31470858
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Impact:
Abstract

Metformin therapy in patients with diabetes mellitus is associated with a reduced risk of vasculopathy and cardiovascular mortality after heart transplantation.

Ram E, Lavee J, Tenenbaum A, Klempfner R, ... Sternik L, Peled Y
Background
Cardiac allograft vasculopathy (CAV) is a major cause of morbidity and mortality following heart transplantation (HT). Reduced cardiovascular mortality and morbidity have been reported in non-HT patients treated with metformin. Given the high prevalence of type 2 diabetes mellitus (T2DM) in HT patients, we investigated the association between metformin therapy and cardiovascular outcomes after HT.
Methods
The study population comprised 103 DM patients who had undergone HT between 1994 and 2018 and were prospectively followed-up. We excluded from the study patients with type 1 diabetes mellitus. Fifty-five HT patients (53%) in the cohort were treated with metformin. Clinical data were recorded on prospectively designed forms. The primary outcomes included CAV, survival, and the combined end-point of CAV or cardiovascular mortality.
Results
Kaplan-Meier survival analysis showed that the CAV rate at 20 years of follow-up was lower in DM patients treated with metformin than in those who were not (30 vs. 65%; log-rank p = 0.044). Similarly, the combined risk of CAV or cardiovascular mortality was lower in the metformin-treated patients than in those not receiving metformin (32 vs. 68%; log rank p = 0.01). Consistently, multivariate analysis adjusted for age and comorbidities showed that metformin therapy was independently associated with a significant 90% reduction (95% confidence interval 0.02-0.46, p = 0.003) in the risk for the development of CAV, and a 91% reduction (95% confidence interval 0.02-0.42; p = 0.003) in the risk for CAV or cardiovascular mortality.
Conclusions
In diabetic HT patients, metformin therapy is independently associated with a significant reduction in the long-term risk for CAV and the combined end-point of CAV or cardiovascular mortality after HT.



Cardiovasc Diabetol: 15 Sep 2019; 18:118
Ram E, Lavee J, Tenenbaum A, Klempfner R, ... Sternik L, Peled Y
Cardiovasc Diabetol: 15 Sep 2019; 18:118 | PMID: 31526382
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Impact:
Abstract

Improved long-term cardiovascular outcomes after intensive versus standard screening of diabetic complications: an observational study.

Morieri ML, Longato E, Mazzucato M, Di Camillo B, ... Fadini GP, Vigili de Kreutzenberg S
Background
Complication screening is recommended for patients with type 2 diabetes (T2D), but the optimal screening intensity and schedules are unknown. In this study, we evaluated whether intensive versus standard complication screening affects long-term cardiovascular outcomes.
Methods
In this observational study, we included 368 T2D patients referred for intensive screening provided as a 1-day session of clinical-instrumental evaluation of diabetic complications, followed by dedicated counseling. From a total of 4906 patients, we selected control T2D patients who underwent standard complication screening at different visits, by 2:1 propensity score matching. The primary endpoint was the 4p-MACE, defined as cardiovascular mortality, or non-fatal myocardial infarction, stroke, or heart failure. The Cox proportional regression analyses was used to compare outcome occurrence in the two groups, adjusted for residual confounders.
Results
357 patients from the intensive screening group (out of 368) were matched with 683 patients in the standard screening group. Clinical characteristics were well balanced between the two groups, except for a slightly higher prevalence of microangiopathy in the intensive group (56% vs 50%; standardized mean difference 0.11, p = 0.1). Median follow-up was 5.6 years. The adjusted incidence of 4p-MACE was significantly lower in the intensive versus standard screening group (HR 0.70; 95% CI 0.52-0.95; p = 0.02). All components of the primary endpoint had nominally lower rates in the intensive versus standard screening group, which was particularly significant for heart failure (HR 0.43; 95% CI 0.22-0.83; p = 0.01).
Conclusion
Among T2D patients attending a specialist outpatient clinic, intensive complication screening is followed by better long-term cardiovascular outcomes. No significant effect was noted for cardiovascular and all-cause mortality and the benefit was mainly driven by a reduced rate of hospitalization for heart failure.



Cardiovasc Diabetol: 15 Sep 2019; 18:117
Morieri ML, Longato E, Mazzucato M, Di Camillo B, ... Fadini GP, Vigili de Kreutzenberg S
Cardiovasc Diabetol: 15 Sep 2019; 18:117 | PMID: 31526380
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Impact:
Abstract

Positive association between baseline brachial-ankle pulse wave velocity and the risk of new-onset diabetes in hypertensive patients.

Zhang Y, He P, Li Y, Zhang Y, ... Xu X, Qin X
Background
There is no clearly defined temporal relationship between arterial stiffness and diabetes. We aimed to investigate the prospective association between baseline brachial-ankle pulse wave velocity (baPWV) and the risk of new-onset diabetes during follow-up, and examined whether there were effect modifiers, in hypertensive patients.
Methods
We included 2429 hypertensive patients with all the pertinent data but without diabetes at the baseline, who were part of the China Stroke Primary Prevention Trial (CSPPT), a randomized, double-blind, actively controlled trial conducted in 32 communities in Anhui and Jiangsu provinces in China. The primary outcome was new-onset diabetes, defined as physician-diagnosed diabetes or use of glucose-lowering drugs during follow-up, or fasting glucose (FG) ≥ 126.0 mg/dL at the exit visit.
Results
During a median follow-up duration of 4.5 years, 287 (11.8%) participants developed diabetes. There was a significant positive association between baseline baPWV and the risk of new-onset diabetes (per SD increment; OR, 1.33; 95% CI 1.13, 1.56). Consistently, when baPWV was assessed as quartiles, a significantly higher risk of new-onset diabetes was found in participants in quartiles 2-4 (≥ 15.9 m/s; OR, 1.80; 95% CI 1.22, 2.65) compared with those in quartile 1 (< 15.9 m/s). The positive association was consistent in participants with (per SD increment; OR, 1.29; 95% CI 1.06, 1.56) or without (per SD increment; OR, 1.40; 95% CI 1.15, 1.71) impaired fasting glucose (IFG, FG ≥ 100.8 and < 126.0 mg/dL, P-interaction = 0.486).
Conclusions
In this sample of hypertensive patients, we found a significant positive association between baseline baPWV and the risk of new-onset diabetes. Clinical trial registration Trial registration: NCT00794885 (clinicaltrials.gov). Retrospectively registered November 20, 2008.



Cardiovasc Diabetol: 27 Aug 2019; 18:111
Zhang Y, He P, Li Y, Zhang Y, ... Xu X, Qin X
Cardiovasc Diabetol: 27 Aug 2019; 18:111 | PMID: 31462258
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Impact:
Abstract

Metformin in patients with and without diabetes: a paradigm shift in cardiovascular disease management.

Luo F, Das A, Chen J, Wu P, Li X, Fang Z

With an increasing global burden of coronary artery disease (CAD), early detection and timely management of risk factors are crucial to reduce morbidity and mortality in such patients. Diabetes mellitus (DM) is considered an independent risk factor for the development of CAD. Metformin, an anti-diabetic drug, has been shown in pre-clinical and clinical studies, to lower the cardiovascular events in the DM patients. Growing evidence suggests that metformin has a protective effect on coronary artery beyond its hypoglycemic effects. Given its global availability, route of administration and cost, metformin provides an alternate/additional therapeutic option for primary and secondary prevention of CAD in DM and non-diabetics alike. Future prospective cohort-based studies and randomized clinical trials are needed to identify \'at-risk\' population who may potentially benefit from metformin.



Cardiovasc Diabetol: 26 Jan 2019; 18:54
Luo F, Das A, Chen J, Wu P, Li X, Fang Z
Cardiovasc Diabetol: 26 Jan 2019; 18:54 | PMID: 31029144
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Impact:
Abstract

Evidence from routine clinical practice: EMPRISE provides a new perspective on CVOTs.

Schernthaner G, Karasik A, Abraitienė A, Ametov AS, ... Tkáč I, Trušinskis K

EMPA-REG OUTCOME is recognised by international guidelines as a landmark study that showed a significant cardioprotective benefit with empagliflozin in patients with type 2 diabetes (T2D) and cardiovascular disease. To assess the impact of empagliflozin in routine clinical practice, the ongoing EMPRISE study is collecting real-world evidence to compare effectiveness, safety and health economic outcomes between empagliflozin and DPP-4 inhibitors. A planned interim analysis of EMPRISE was recently published, confirming a substantial reduction in hospitalisation for heart failure with empagliflozin across a diverse patient population. In this commentary article, we discuss the new data in the context of current evidence and clinical guidelines, as clinicians experienced in managing cardiovascular risk in patients with T2D. We also look forward to what future insights EMPRISE may offer, as evidence is accumulated over the next years to complement the important findings of EMPA-REG OUTCOME.



Cardiovasc Diabetol: 30 Aug 2019; 18:115
Schernthaner G, Karasik A, Abraitienė A, Ametov AS, ... Tkáč I, Trušinskis K
Cardiovasc Diabetol: 30 Aug 2019; 18:115 | PMID: 31472683
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Impact:
Abstract

Comparison of outcomes after carotid endarterectomy between type 2 diabetic and non-diabetic patients with significant carotid stenosis.

Jeong MJ, Kwon H, Jung CH, Kwon SU, ... Kwon TW, Cho YP
Background
We aimed to compare early and late outcomes after carotid endarterectomy (CEA) between Korean type 2 diabetic and non-diabetic patients and to investigate the impact of diabetes on the overall incidence of cardiovascular events after CEA.
Methods
We retrospectively analyzed 675 CEAs, which were performed on 613 patients with significant carotid stenosis between January 2007 and December 2014. The CEAs were divided into a type 2 diabetes mellitus (DM) group (n = 265, 39.3%) and a non-DM group (n = 410, 60.7%). The study outcomes included the incidence of major adverse events (MAEs), defined as fatal or nonfatal stroke or myocardial infarction or all-cause mortality, during the perioperative period and within 4 years after CEA.
Results
Patients in the DM and non-DM groups did not differ significantly in the incidence of MAEs or any of the individual MAE manifestations during the perioperative period. However, within 4 years after CEA, the difference in the MAE incidence was significantly greater in the DM group (P = 0.040). Analysis of the individual MAE manifestations indicated a significantly higher risk of stroke in the DM group (P = 0.006). Multivariate analysis indicated that diabetes was not associated with MAEs or individual MAE manifestations during the perioperative period, whereas within 4 years after CEA, diabetes was an independent risk factor for MAEs overall (hazard ratio [HR], 1.62; 95% confidence interval [CI] 1.06-2.48; P = 0.026) and stroke (HR, 2.55; 95% CI 1.20-5.41; P = 0.015) in particular.
Conclusions
Diabetic patients were not at greater risk of perioperative MAEs after CEA; however, the risk of late MAE occurrence was significantly greater in these patients. Within 4 years after CEA, DM was an independent risk factor for the occurrence of MAEs overall and stroke in particular.



Cardiovasc Diabetol: 24 Jan 2019; 18:41
Jeong MJ, Kwon H, Jung CH, Kwon SU, ... Kwon TW, Cho YP
Cardiovasc Diabetol: 24 Jan 2019; 18:41 | PMID: 30909911
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Impact:
Abstract

Temporal relationship between inflammation and insulin resistance and their joint effect on hyperglycemia: the Bogalusa Heart Study.

Yan Y, Li S, Liu Y, Bazzano L, ... Mi J, Chen W
Background
Inflammation and insulin resistance play crucial roles in the development of type 2 diabetes mellitus (T2DM). We aim to examine the temporal relationship between high-sensitivity C-reactive protein (hsCRP) and insulin resistance in non-diabetic adults and their joint effect on the development of hyperglycemia.
Methods
The longitudinal cohort from the Bogalusa Heart Study consisted of 509 non-diabetic adults (360 whites and 149 blacks, mean age = 42.8 years at follow-up) who had hsCRP, fasting glucose and insulin measured twice at baseline and follow-up over 6.8 years. Cross-lagged panel model was used to examine the temporal relationship between hsCRP and homeostasis model assessment for insulin resistance (HOMA-IR). Information on incident T2DM was collected in a survey in 6.1 years after the follow-up survey.
Results
After adjusting for race, sex, age, body mass index, smoking, alcohol drinking and follow-up years, the path coefficient from baseline hsCRP to follow-up HOMA-IR (β = 0.105, p = 0.009) was significant and greater than the path from baseline HOMA-IR to follow-up hsCRP (β = 0.005, p = 0.903), with p = 0.011 for the difference between β and β. This one-directional path from baseline hsCRP to follow-up HOMA-IR was significant in the hyperglycemia group but not in the normoglycemia group. In addition, participants with high levels of baseline hsCRP and follow-up HOMA-IR had greater risks of T2DM (odds ratio, OR = 2.38, p = 0.035), pre-T2DM (OR = 2.27, p = 0.006) and hyperglycemia (OR = 2.18, p = 0.003) than those with low-low levels.
Conclusions
These findings suggest that elevated hsCRP is associated with future insulin resistance in non-diabetic adults, and their joint effect is predictive of the development of T2DM.



Cardiovasc Diabetol: 22 Aug 2019; 18:109
Yan Y, Li S, Liu Y, Bazzano L, ... Mi J, Chen W
Cardiovasc Diabetol: 22 Aug 2019; 18:109 | PMID: 31443647
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Impact:
Abstract

Cardiovascular outcomes in trials of new antidiabetic drug classes: a network meta-analysis.

Fei Y, Tsoi MF, Cheung BMY
Background
Recent trials suggested that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter-2 (SGLT-2) inhibitors reduced cardiovascular events. Comparative effectiveness of these new antidiabetic drug classes remains unclear. We therefore performed a network meta-analysis to compare the effect on cardiovascular outcomes among GLP-1 RAs, SGLT-2 and dipeptidyl peptidase-4 (DPP-4) inhibitors.
Methods
MEDLINE, EMBASE, Cochrane database, ClinicalTrials.gov, and congress proceedings from recent cardiology conferences were searched up to April 20, 2019. Cardiovascular outcome trials and renal outcome trials reporting cardiovascular outcomes on GLP-1 RAs, SGLT-2 and DPP-4 inhibitors in patients with type 2 diabetes mellitus were included. The primary outcome was major adverse cardiovascular events (MACE). Secondary outcomes were nonfatal myocardial infarction, nonfatal stroke, cardiovascular mortality, all-cause mortality, hospitalisation for heart failure (HF), and renal composite outcome. ORs and 95% CI were calculated using random-effects models.
Results
Fourteen trials enrolling 121,047 patients were included. SGLT-2 inhibitors reduced cardiovascular deaths and all-cause deaths compared to placebo (OR 0.82, 95% CI 0.73-0.93 and OR 0.84, 95% CI 0.77-0.92) and DPP-4 inhibitors (OR 0.83, 95% CI 0.70-0.99 and OR 0.83, 95% CI 0.73-0.94), respectively. SGLT-2 inhibitors and GLP-1 RAs significantly reduced MACE (OR 0.88, 95% CI 0.82-0.95 and OR 0.87, 95% CI 0.82-0.93), hospitalisation for HF (OR 0.68, 95% CI 0.61-0.77 and OR 0.87, 95% CI 0.82-0.93), and renal composite outcome (OR 0.59, 95% CI 0.52-0.67 and OR 0.86, 95% CI 0.78-0.94) compared to placebo, but SGLT-2 inhibitors reduced hospitalisation for HF (OR 0.79, 95% CI 0.69-0.90) and renal composite outcome (OR 0.69, 95% CI 0.59-0.80) more than GLP-1 RAs. Only GLP-1 RAs reduced nonfatal stroke (OR 0.88, 95% CI 0.77-0.99). DPP-4 inhibitors did not lower the risk of these outcomes when compared to placebo and were associated with higher risks of MACE, hospitalisation for HF, and renal composite outcome when compared to the other two drug classes.
Conclusions
SGLT-2 inhibitors show clear superiority in reducing cardiovascular and all-cause deaths, hospitalisation for HF, and renal events among new antidiabetic drug classes. GLP-1 RAs also have cardiovascular and renal protective effects. DPP-4 inhibitors have no beneficial cardiovascular effects and are therefore inferior to the other two drug classes. SGLT-2 inhibitors should now be the preferred treatment for type 2 diabetes mellitus.



Cardiovasc Diabetol: 27 Aug 2019; 18:112
Fei Y, Tsoi MF, Cheung BMY
Cardiovasc Diabetol: 27 Aug 2019; 18:112 | PMID: 31462224
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Impact:
Abstract

Improved home BP profile with dapagliflozin is associated with amelioration of albuminuria in Japanese patients with diabetic nephropathy: the Yokohama add-on inhibitory efficacy of dapagliflozin on albuminuria in Japanese patients with type 2 diabetes study (Y-AIDA study).

Kinguchi S, Wakui H, Ito Y, Kondo Y, ... Terauchi Y, Tamura K
Background
The Y-AIDA study was designed to investigate the renal- and home blood pressure (BP)-modulating effects of add-on dapagliflozin treatment in Japanese individuals with type 2 diabetes mellitus (T2DM) and albuminuria.
Methods
We conducted a prospective, multicenter, single-arm study. Eighty-six patients with T2DM, HbA1c 7.0-10.0%, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m, and urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine (gCr) were enrolled, and 85 of these patients were administered add-on dapagliflozin for 24 weeks. The primary and key secondary endpoints were change from baseline in the natural logarithm of UACR over 24 weeks and change in home BP profile at week 24.
Results
Baseline median UACR was 181.5 mg/gCr (interquartile range 47.85, 638.0). Baseline morning, evening, and nocturnal home systolic/diastolic BP was 137.6/82.7 mmHg, 136.1/79.3 mmHg, and 125.4/74.1 mmHg, respectively. After 24 weeks, the logarithm of UACR decreased by 0.37 ± 0.73 (P < 0.001). In addition, changes in morning, evening, and nocturnal home BP from baseline were as follows: morning systolic/diastolic BP - 8.32 ± 11.42/- 4.18 ± 5.91 mmHg (both P < 0.001), evening systolic/diastolic BP - 9.57 ± 12.08/- 4.48 ± 6.45 mmHg (both P < 0.001), and nocturnal systolic/diastolic BP - 2.38 ± 7.82/- 1.17 ± 5.39 mmHg (P = 0.0079 for systolic BP, P = 0.0415 for diastolic BP). Furthermore, the reduction in UACR after 24 weeks significantly correlated with an improvement in home BP profile, but not with changes in other variables, including office BP. Multivariate linear regression analysis also revealed that the change in morning home systolic BP was a significant contributor to the change in log-UACR.
Conclusions
In Japanese patients with T2DM and diabetic nephropathy, dapagliflozin significantly improved albuminuria levels and the home BP profile. Improved morning home systolic BP was associated with albuminuria reduction. Trial registration The study is registered at the UMIN Clinical Trials Registry (UMIN000018930; http://www.umin.ac.jp/ctr/index-j.htm ). The study was conducted from July 1, 2015 to August 1, 2018.



Cardiovasc Diabetol: 26 Aug 2019; 18:110
Kinguchi S, Wakui H, Ito Y, Kondo Y, ... Terauchi Y, Tamura K
Cardiovasc Diabetol: 26 Aug 2019; 18:110 | PMID: 31455298
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Impact:
Abstract

Successful revascularization versus medical therapy in diabetic patients with stable right coronary artery chronic total occlusion: a retrospective cohort study.

Yan Y, Zhang M, Yuan F, Liu H, ... Zhao Q, Lyu S
Background
The territory of the right coronary artery (RCA) is smaller than that of the left anterior descending artery. Previous studies have reported conflicting results when considering whether stable RCA-chronic total occlusion (CTO) should be reopened. The coexistence of diabetic and coronary artery diseases represents a severe situation. Therefore, we aimed to determine if stable RCA-CTO in diabetic patients was necessary to be reopened. To our knowledge, no studies have focused on this topic to date.
Methods
We enrolled diabetic patients with RCA-CTO who had clinical presentations of symptomatic stable angina or silent ischemia. RCA-CTO was treated with either successful revascularization (the CTO-SR group) or medical therapy (the CTO-MT group). The primary endpoint was all-cause death. Both Cox regression and propensity score matching analyses were used. Sensitivity analysis was performed based on subgroup populations and relevant baseline variables.
Results
A total of 943 patients were included: 443 (46.98%) patients in the CTO-MT group and 500 (53.02%) patients in the CTO-SR group. After a mid-term follow-up (CTO-SR: 48 months; CTO-MT: 42 months), we found that CTO-SR was superior to CTO-MT in terms of all-cause death (adjusted hazard ratio [HR] [model 1]: 0.429, 95% conference interval [CI] 0.269-0.682; adjusted HR [model 2]: 0.445, 95% CI 0.278-0.714). The superiority of CTO-SR was consistent for cardiac death, possible/definite cardiac death, repeat revascularization, target vessel revascularization (TVR) and repeat nonfatal myocardial infarction. Subgroup analysis confirmed the mortality benefit of CTO-SR by percutaneous coronary intervention (the successful CTO-PCI subgroup, 309 patients in total). While CTO-SR by coronary artery bypass grafting (the CTO-CABG subgroup, 191 patients in total) offered patients more benefit from repeat revascularization and TVR than that offered by successful CTO-PCI.
Conclusions
For stable RCA-CTO patients with diabetes, successful revascularization offered patients more clinical benefits than medical therapy. CTO-CABG might be a more recommended way to accomplish revascularization. Trial registration This study was not registered in an open access database.



Cardiovasc Diabetol: 20 Aug 2019; 18:108
Yan Y, Zhang M, Yuan F, Liu H, ... Zhao Q, Lyu S
Cardiovasc Diabetol: 20 Aug 2019; 18:108 | PMID: 31434572
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Impact:
Abstract

How does empagliflozin improve arterial stiffness in patients with type 2 diabetes mellitus? Sub analysis of a clinical trial.

Bosch A, Ott C, Jung S, Striepe K, ... Dienemann T, Schmieder RE
Background
Empagliflozin has been shown to reduce cardiovascular mortality, but the underlying pathogenetic mechanisms are poorly understood. It was previously demonstrated that empagliflozin improved arterial stiffness.
Methods
Our analysis comprising 58 patients with type 2 diabetes mellitus identifies factors triggering the improvement of arterial stiffness. All patients participated in an investigator-initiated, prospective, double-blind, randomized, placebo-controlled, interventional clinical trial ( http://www.ClinicalTrials.gov : NCT02471963, registered 15th June 2015, retrospectively registered) and received either 6-weeks treatment with 25 mg empagliflozin orally once daily or placebo (crossover). Central systolic pressure and central pulse pressure were recorded by the SphygmoCor System (AtCor Medical). Now, we investigated the impact of parameters of glucose metabolism, volume status, sympathetic activation, lipids, uric acid, blood pressure and inflammation on vascular parameters of arterial stiffness using multivariate regression analysis.
Results
As previously reported, therapy with empagliflozin improved arterial stiffness as indicated by reduced central systolic blood pressure (113.6 ± 12.1 vs 118.6 ± 12.9 mmHg, p < 0.001), central pulse pressure (39.1 ± 10.2 vs 41.9 ± 10.7 mmHg, p = 0.027) forward (27.1 ± 5.69 vs 28.7 ± 6.23 mmHg, p = 0.031) as well as reflected wave amplitude (18.9 ± 5.98 vs 20.3 ± 5.97 mmHg, p = 0.045) compared to placebo. The multivariate regression analysis included age, sex and change between empagliflozin and placebo therapy of the following parameters: HbA1c, copeptin, hematocrit, heart rate, LDL-cholesterol, uric acid, systolic 24-h ambulatory blood pressure and high sensitive CRP (hsCRP). Besides the influence of age (beta = - 0.259, p = 0.054), sex (beta = 0.292, p = 0.040) and change in systolic 24-h ambulatory blood pressure (beta = 0.364, p = 0.019), the change of hsCRP (beta = 0.305, p = 0.033) emerged as a significant determinant of the empagliflozin induced reduction in arterial stiffness (placebo corrected). When replacing HbA1c with fasting plasma glucose in the multivariate regression analysis, a similar effect of the change in hsCRP (beta = 0.347, p = 0.017) on arterial stiffness parameters was found.
Conclusion
Besides age and sex, change in systolic 24-h ambulatory blood pressure and change in hsCRP were determinants of the empagliflozin induced improvement of vascular parameters of arterial stiffness, whereas parameters of change in glucose metabolism and volume status had no significant influence. Our analysis suggests that empagliflozin exerts, at least to some extent, its beneficial vascular effects via anti-inflammatory mechanisms. Trial registration http://www.ClinicalTrials.gov : NCT02471963, registered 15th June 2015, retrospectively registered.



Cardiovasc Diabetol: 28 Jan 2019; 18:44
Bosch A, Ott C, Jung S, Striepe K, ... Dienemann T, Schmieder RE
Cardiovasc Diabetol: 28 Jan 2019; 18:44 | PMID: 30922297
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Impact:
Abstract

Cardiovascular events, diabetes and guidelines: the virtue of simplicity.

Esper RJ, Nordaby RA

Cardiovascular (CV) events or their minor syndromes, as various forms of ischemia, are medical emergencies that do not allow enough time for a guiding anamnesis or proper clinical examination, and lead to relying on Treatment Guidelines, but in many situations it is appropriate to deviate from them. Pathological studies have associated 75% of coronary artery events with atherosclerotic plaque rupture; it is now known that rupture alone is not enough for obstruction or occlusion of the vessel lumen. Concomitant conditions are required for the clinical manifestation of cardiovascular disease, including prothrombogenic and dysfunctional endothelium, less fibrinolytic capacity to protect it, increased platelet activation, increased adrenergic tone, microcirculation vasoconstriction, and other countless factors that contribute to thrombus formation, causing ischemia or infarction. But in most cases, repair of plaque rupture and re endothelization of the lesion are asymptomatic and silent. Atherosclerotic process is a chronic and progressive immune inflammation. Most of the therapeutic indications include statins, which cause side effects in 10% of patients, with a range varying between 7 and 21%, according to different authors. Many investigators have proved that statin use contribute to the genesis of diabetes, reports vary between 1 and 46%, where marked elevation of blood glucose fasting levels and glycosylated hemoglobin have been observed, be it by increased tissue resistance to insulin or by reduced β-cell insulin secretion. Physicians should base their indications on the recommendations provided by Guidelines, but they should not forget that every patient is different, and they should not get confused due to lack of time in an emergency nor be influenced by the latest publications or techniques until they have been properly tested.



Cardiovasc Diabetol: 27 Jan 2019; 18:42
Esper RJ, Nordaby RA
Cardiovasc Diabetol: 27 Jan 2019; 18:42 | PMID: 30922303
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Impact:
Abstract

Relationship between frailty and mortality, hospitalization, and cardiovascular diseases in diabetes: a systematic review and meta-analysis.

Ida S, Kaneko R, Imataka K, Murata K
Background
In patients with diabetes, death and cardiovascular diseases are attributed to classical risk factors such as hypertension, dyslipidemia, and smoking habit, whereas these events are attributed to frailty in the remaining patients. In this meta-analysis, we examined the relationship between frailty and mortality, hospitalization, and cardiovascular diseases in patients with diabetes.
Methods
Literature search was conducted using databases such as MEDLINE, Cochrane Controlled Trials Registry, and ClinicalTrials.gov. Studies that examined the relationship between frailty and mortality, hospitalization, and cardiovascular disease and included hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (CIs) were included. Statistical analysis was performed using a random effects model, and pooled HRs, pooled ORs, and 95% CIs were calculated.
Results
The literature search extracted 8 studies (565,039 patients) that met our inclusion criteria, which were included in this meta-analysis. The pooled HR of prefrailty and frailty related to mortality was 1.09 (95% CI 1.01-1.17; P = 0.02) and 1.35 (95% CI 1.05-1.74; P = 0.02), respectively, indicating a significant relationship between them. The pooled OR of prefrailty and frailty related to hospitalization was 2.15 (95% CI 1.30-3.54; P = 0.003) and 5.18 (95% CI 2.68-9.99; P < 0.001), respectively, indicating a significant relationship. Although a significant relationship was found between frailty and cardiovascular diseases, we found only few related studies; thus, robust results could not be obtained.
Conclusions
In patients with diabetes, a significant relationship was observed between frailty and mortality and hospitalization. However, only few heterogeneous studies were included, warranting further examination.



Cardiovasc Diabetol: 17 Jun 2019; 18:81
Ida S, Kaneko R, Imataka K, Murata K
Cardiovasc Diabetol: 17 Jun 2019; 18:81 | PMID: 31215496
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Impact:
Abstract

Early dysregulation of cardiac-specific microRNA-208a is linked to maladaptive cardiac remodelling in diabetic myocardium.

Rawal S, Nagesh PT, Coffey S, Van Hout I, ... Williams MJA, Katare R
Background
The diabetic heart undergoes remodelling contributing to an increased incidence of heart failure in individuals with diabetes at a later stage. The molecular regulators that drive this process in the diabetic heart are still unknown.
Methods
Real-time (RT) PCR analysis was performed to determine the expression of cardiac specific microRNA-208a in right atrial appendage (RAA) and left ventricular (LV) biopsy tissues collected from diabetic and non-diabetic patients undergoing coronary artery bypass graft surgery. To determine the time-dependent changes, cardiac tissue were collected from type 2 diabetic mice at different age groups. A western blotting analysis was conducted to determine the expression of contractile proteins α- and β-myosin heavy chain (MHC) and thyroid hormone receptor-α (TR-α), the negative regulator of β-MHC. To determine the beneficial effects of therapeutic modulation of miR-208a, high glucose treated adult mouse HL-1 cardiomyocytes were transfected with anti-miR-208a.
Results
RT-PCR analysis showed marked upregulation of miR-208a from early stages of diabetes in type 2 diabetic mouse heart, which was associated with a marked increase in the expression of pro-hypertrophic β-MHC and downregulation of TR-α. Interestingly, upregulation of miR-208a preceded the switch of α-/β-MHC isoforms and the development of diastolic and systolic dysfunction. We also observed significant upregulation of miR-208a and modulation of miR-208a associated proteins in the type 2 human diabetic heart. Therapeutic inhibition of miR-208a activity in high glucose treated HL-1 cardiomyocytes prevented the activation of β-MHC and hence the hypertrophic response.
Conclusion
Our results provide the first evidence that early modulation of miR-208a in the diabetic heart induces alterations in the downstream signaling pathway leading to cardiac remodelling and that therapeutic inhibition of miR-208a may be beneficial in preventing diabetes-induced adverse remodelling of the heart.



Cardiovasc Diabetol: 28 Jan 2019; 18:13
Rawal S, Nagesh PT, Coffey S, Van Hout I, ... Williams MJA, Katare R
Cardiovasc Diabetol: 28 Jan 2019; 18:13 | PMID: 30696455
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Impact:
Abstract

The association between serum adiponectin and 3-month outcome after ischemic stroke.

Wang Z, Li B, Wang Y, Maimaitili A, ... Dangmurenjiafu G, Wang S
Background
Although adiponectin is a major adipocytokine that affects the pathogenesis of various cardiovascular diseases, its clinical significance in stroke remains controversial. The purpose of this study was to assess the impact of serum adiponectin levels on functional prognosis in patients with ischemic stroke.
Methods
This was a prospective, observational cohort study. Consecutive first-ever ischemic stroke patients without any pre-morbid handicap admitted to our hospital were identified from December 2017 to December 2018. Serum concentration of adiponectin was routinely measured within the first 24 h after admission by a commercially available sandwich ELISA. Associations between adiponectin and either clinical severity at admission, poor outcomes or mortality at 3-month after admission were analyzed using logistic regression to obtain odds ratios (OR) and 95% confidence intervals (CI).
Results
The serum level of adiponectin was obtained in 227 patients with a median value of 7.0 μg/ml, which was significantly higher (P < 0.001) than in those heathy control. Adiponectin levels were associated with moderate-to-high stroke, and risk increased by 12% (OR = 1.12; 95% CI 1.03-1.25; P = 0.002). Patients with a poor outcome and nonsurvivors had significantly increased adiponectin levels on admission (P < 0.001, all). In multivariate logistic regression analysis, adiponectin was an independent predictor of functional outcome and mortality, and risk increased by 24% (OR = 1.24, 95% CI 1.13-1.37; P < 0.001) and 31% (1.31 [1.18-1.46], P < 0.001), respectively. Kaplan-Meier analysis suggested that the patients with high serum adiponectin levels had a higher risk of death than those patients with low levels (log-rank test P < 0.001).
Conclusions
Our results show that high adiponectin is associated with stroke severity and support the hypothesis that adiponectin can be serve as a biomarker of poor outcome after stroke, independent of baseline variables. Trial registration ChiCTR-OPC-17013501. Retrospectively Registered 21 September 2017.



Cardiovasc Diabetol: 13 Aug 2019; 18:105
Wang Z, Li B, Wang Y, Maimaitili A, ... Dangmurenjiafu G, Wang S
Cardiovasc Diabetol: 13 Aug 2019; 18:105 | PMID: 31412946
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Impact:
Abstract

Effects of the SGLT2 inhibitor dapagliflozin on cardiac function evaluated by impedance cardiography in patients with type 2 diabetes. Secondary analysis of a randomized placebo-controlled trial.

Bonora BM, Vigili de Kreutzenberg S, Avogaro A, Fadini GP
Background and aims
Cardiovascular outcome trials have documented a strong benefit of sodium glucose cotransporter-2 inhibitors (SGLT2i) on the risk of hospitalization for heart failure (HF) in patients with type 2 diabetes (T2D) with or without established cardiovascular disease or prior history of HF. The mechanisms, however, are not entirely clear. We aimed to evaluate whether treatment with SGLT2i affected cardiac function using impedance cardiography (ICG) in a randomized placebo-controlled trial.
Materials and methods
Thirty-three patients with T2D were randomized to receive blind dapagliflozin 10 mg or matching placebo for 12-week on top of their ongoing glucose lowering medication regimen. Cardiac function was evaluated by resting ICG at baseline and at the end of the 12-week treatment period. ICG is a non-invasive technology based on the continuous measurement of thoracic electrical conductivity to process a cardiodynamic parameters related to fluid content, blood flow, cardiac function, and circulatory function. We also evaluated changes in glycaemic control, blood pressure, and body weight.
Results
Thirty-one patients completed the study, 1 was excluded because ICG data was missing. Patients included in the final analysis were on average 63.4-year-old, with a known diabetes duration of 14.1 years and a baseline HbA1c of 8.2% (66 mmol/mol). 63.3% of patients had established cardiovascular disease (symptomatic or asymptomatic) and 36.7% had microangiopathy, but none had a prior history of HF. After 12 weeks, patients randomized to dapagliflozin, as compared to those randomized to placebo, showed improvements in HbA1c (- 1.2%; 13 mmol/mol), systolic blood pressure (- 3.7 mmHg), and body weight (- 3.3 kg). Based on ICG, in both groups, we detected no significant change in parameters of blood flow (stroke volume, cardiac output, cardiac index), systolic function (ejection fraction, acceleration and velocity indexes, systolic time ratio), circulatory function (systemic vascular resistance index), and fluid status (thoracic fluid content) after treatment.
Conclusion
This is the first study exploring cardiac effects of SGLT2i using ICG in T2D. We observed no change in cardiac function parameters estimated by ICG in T2D patients who received dapagliflozin versus placebo for 12 weeks. Trial registration ClinicalTrial.gov NCT02327039. Registered 30 December 2014.



Cardiovasc Diabetol: 13 Aug 2019; 18:106
Bonora BM, Vigili de Kreutzenberg S, Avogaro A, Fadini GP
Cardiovasc Diabetol: 13 Aug 2019; 18:106 | PMID: 31412874
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Impact:
Abstract

Severe hypoglycemia and the risk of cardiovascular disease and mortality in type 2 diabetes: a nationwide population-based cohort study.

Yun JS, Park YM, Han K, Cha SA, Ahn YB, Ko SH
Background
We investigated the association regarding severe hypoglycemia episodes with cardiovascular disease risk and all-cause mortality in patients with type 2 diabetes.
Methods
Baseline and follow-up data (n = 1,568,097) from patients with type 2 diabetes were retrieved from the National Health Insurance System database (covering the entire Korean population). Type 2 diabetes, severe hypoglycemia, and major comorbidities were identified using International Classification of Diseases 10 codes and medication information. Individuals who were classified as type 2 diabetes in the year of 2009 were screened, and we counted severe hypoglycemia episodes from 2007 to 2009. The primary outcome was newly developed myocardial infarction (MI), stroke, heart failure, or all-cause mortality. Participants were followed from the baseline index date to the date of death or until December 31, 2015.
Results
In total, 19,660 (1.2%) patients developed at least one severe hypoglycemia event during the period from 2007 to 2009. Mean follow-up was 5.7 years. After adjustment for confounding factors, the hazard ratio (HR) of MI significantly and sequentially increased: 0 vs. 1 episode, HR 1.56, 95% CI 1.46-1.64; 0 vs. 2 episodes, HR 1.86, 95% CI 1.61-2.15; 0 vs. 3 or more episodes, HR 1.86, 95% CI 1.48-2.35, P for trend < 0.001. Similar findings were noted regarding the relationship of severe hypoglycemia episodes with stroke, heart failure, and all-cause mortality. Risks for all outcomes were highest within 1 year from the index date and showed decreasing trends with follow-up. Sensitivity analyses of the data from the subgroup population and 797,544 subjects who received a national health examination did not change the significance of the main findings.
Conclusion
Among adult Korean patients with type 2 diabetes, a severe hypoglycemia episode is associated with increased risk for cardiovascular outcomes and all-cause mortality. Significant results from dose-response, temporal, and sensitivity analyses may suggest the possibility of direct causality between severe hypoglycemia and cardiovascular outcomes and mortality.



Cardiovasc Diabetol: 13 Aug 2019; 18:103
Yun JS, Park YM, Han K, Cha SA, Ahn YB, Ko SH
Cardiovasc Diabetol: 13 Aug 2019; 18:103 | PMID: 31412855
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Impact:
Abstract

Dapagliflozin improves left ventricular remodeling and aorta sympathetic tone in a pig model of heart failure with preserved ejection fraction.

Zhang N, Feng B, Ma X, Sun K, Xu G, Zhou Y
Background
Heart failure with preserved ejection fraction (HFpEF) is a difficult disease with high morbidity and mortality rates and lacks an effective treatment. Here, we report the therapeutic effect of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), on hypertension + hyperlipidemia-induced HFpEF in a pig model.
Methods
HFpEF pigs were established by infusing a combination of deoxycorticosterone acetate (DOCA) and angiotensin II (Ang II), and Western diet (WD) feeding for 18 weeks. In the 9th week, half of the HFpEF pigs were randomly assigned to receive additional dapagliflozin treatment (10 mg/day) by oral gavage daily for the next 9 weeks. Blood pressure, lipid levels, echocardiography and cardiac hemodynamics for cardiac structural and functional changes, as well as epinephrine and norepinephrine concentrations in the plasma and tissues were measured. After sacrifice, cardiac fibrosis, the distribution of tyrosine hydroxylase (TH), inflammatory factors (IL-6 and TNF-α) and NO-cGMP-PKG pathway activity in the cardiovascular system were also determined.
Results
Blood pressure, total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) were markedly increased in HFpEF pigs, but only blood pressure was significantly decreased after 9 weeks of dapagliflozin treatment. By echocardiographic and hemodynamic assessment, dapagliflozin significantly attenuated heart concentric remodeling in HFpEF pigs, but failed to improve diastolic function and compliance with the left ventricle (LV). In the dapagliflozin treatment group, TH expression and norepinephrine concentration in the aorta were strongly mitigated compared to that in the HFpEF group. Moreover, inflammatory cytokines such as IL-6 and TNF-α in aortic tissue were markedly elevated in HFpEF pigs and inhibited by dapagliflozin. Furthermore, the reduced expression of eNOS and the PKG-1 protein and the cGMP content in the aortas of HFpEF pigs were significantly restored after 9 weeks of dapagliflozin treatment.
Conclusion
9 weeks of dapagliflozin treatment decreases hypertension and reverses LV concentric remodeling in HFpEF pigs partly by restraining sympathetic tone in the aorta, leading to inhibition of the inflammatory response and NO-cGMP-PKG pathway activation.



Cardiovasc Diabetol: 19 Aug 2019; 18:107
Zhang N, Feng B, Ma X, Sun K, Xu G, Zhou Y
Cardiovasc Diabetol: 19 Aug 2019; 18:107 | PMID: 31429767
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Impact:
Abstract

Class effects of SGLT2 inhibitors on cardiorenal outcomes.

Kluger AY, Tecson KM, Lee AY, Lerma EV, ... Cobble ME, McCullough PA
Background
To summarize the four recent sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials: Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58), CANagliflozin CardioVascular Assessment Study (CANVAS) Program, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME), Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), and explore the potential determinants for their cardiovascular, renal, and safety outcomes.
Results
The composite renal outcome event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 3.7, 7.0, 47%; 5.5, 9.0, 40%; 6.3, 11.5, 46%; 43.2, 61.2, 30% for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively (event definitions varied across trials). The major adverse cardiovascular (CV) event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 22.6, 24.2, 7%; 26.9, 31.5, 14%; 37.4, 43.9, 14%; 38.7, 48.7, 20% for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively. DECLARE-TIMI 58 had the fewest cardiorenal events and CREDENCE the most. These differences were presumably due to varying inclusion criteria resulting in DECLARE-TIMI 58 having the best baseline renal filtration function and CREDENCE the worst (mean estimated glomerular filtration rate 85.2, 76.5, 74, 56.2 mL/min/1.73 m for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively). Additionally, CREDENCE had considerably higher rates of albuminuria (median urinary albumin-creatinine ratios (UACR) were 927, 12.3, and 13.1 mg/g for CREDENCE, CANVAS, and DECLARE-TIMI 58, respectively; EMPA-REG OUTCOME had 59.4% UACR < 30, 28.6% UACR > 30-300, 11.0% UACR > 300 mg/g).
Conclusions
Dapagliflozin, empagliflozin, and canagliflozin have internally and externally consistent and biologically plausible class effects on cardiorenal outcomes. Baseline renal filtration function and degree of albuminuria are the most significant indicators of risk for both CV and renal events. Thus, these two factors also anticipate the greatest clinical benefit for SGLT2i.



Cardiovasc Diabetol: 04 Aug 2019; 18:99
Kluger AY, Tecson KM, Lee AY, Lerma EV, ... Cobble ME, McCullough PA
Cardiovasc Diabetol: 04 Aug 2019; 18:99 | PMID: 31382965
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Impact:
Abstract

Class effect for SGLT-2 inhibitors: a tale of 9 drugs.

Giugliano D, Esposito K

The definition of class effect for SGLT-2 inhibitors may be based on three concepts: a similar chemical structure, a similar mechanism of action and similar pharmacological effects. We have also assumed that a class effect does exist when an effect on a particular outcome is present and is significant for each drug within the class of SGLT-2 inhibitors. For major cardiovascular events (MACE), there is no class effect for SGLT-2 inhibitors, as the 7% reduction of MACE risk observed with dapagliflozin in the DECLARE trial was not significant; on the other hand, a class effect is evident for both heart failure and diabetic kidney disease, as in all four trials so far completed (EMPAREG-OUTCOME, CANVAS, DECLARE, CREDENCE) the risk of hospitalization for heart failure and progression of diabetic kidney disease was significantly reduced by all SGLT-2 inhibitors.



Cardiovasc Diabetol: 22 Jul 2019; 18:94
Giugliano D, Esposito K
Cardiovasc Diabetol: 22 Jul 2019; 18:94 | PMID: 31337395
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Impact:
Abstract

Carotid ultrasound investigation as a prognostic tool for patients with diabetes mellitus.

Hoke M, Schillinger M, Minar E, Goliasch G, Binder CJ, Mayer FJ
Background
Experimental and clinical data indicate a major influence of diabetes on atherogenesis. We aimed to assess whether the effect of diabetes on long-term mortality in asymptomatic patient with carotid stenosis is contingent upon the degree of the carotid atherosclerotic burden.
Methods
1065 patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex sonography were prospectively followed for cause-specific mortality.
Results
During a median of 11.8 years, a total of 549 deaths, including 362 cardiovascular deaths, were recorded. Diabetes and glycohemoglobin A1c (Hba1c) levels were significantly associated with mortality. Diabetes displayed an independent risk for all-cause (adjusted HR 1.62; 95% CI 1.35-1.94) and cardiovascular death (adjusted HR 1.75, 95% CI 1.40-2.19). The adjusted hazard ratio per increase of 1% of Hba1c levels was 1.21 (P < 0.01) for all-cause and 1.31 (P < 0.01) for cardiovascular mortality, respectively. Patients with diabetes mellitus and a higher degree of carotid stenosis and were at great risk of adverse outcome. Only 21% of the asymptomatic diabetic patients with carotid narrowing over 50% survived, whereas 62% of the patients without diabetes and with carotid atherosclerosis below 50% were still alive after 12-years of follow-up. The high risk for all-cause and cardiovascular death of these patients remained significant after adjustment for various established cardiovascular risk factors in multivariable regression analysis (adjusted hazard ratio 2.4, P < 0.001; compared to patients without diabetes and < 50% carotid atherosclerosis).
Conclusion
Diabetic patients with carotid stenosis ≥ 50% are at exceptional high risk for all-cause and cardiovascular death. Thus, routinely ultrasound investigation of the carotid arteries might be a valuable prognostic tool for patients with diabetes mellitus.



Cardiovasc Diabetol: 11 Jul 2019; 18:90
Hoke M, Schillinger M, Minar E, Goliasch G, Binder CJ, Mayer FJ
Cardiovasc Diabetol: 11 Jul 2019; 18:90 | PMID: 31299990
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Impact:
Abstract

Heart failure and the prognostic impact and incidence of new-onset of diabetes mellitus: a nationwide cohort study.

Zareini B, Rørth R, Holt A, Mogensen UM, ... Lamberts M, Kristensen SL
Background
Prevalent diabetes at the time of heart failure (HF) diagnosis is associated with a higher risk of death, but the incidence and prognostic importance of new-onset diabetes in patients with established HF remains unknown.
Methods
Patients with a first hospitalization for HF in the period 2003-2014 were included and stratified according to history of diabetes. Annual incidence rates of new-onset diabetes were calculated and time-dependent multivariable Cox regression models were used to compare the risk of death in patients with prevalent and new-onset diabetes with patients without diabetes as reference. The model was adjusted for age, sex, duration of HF, educational level and comorbidity. Covariates were continuously updated throughout follow-up.
Results
A total of 104,522 HF patients were included in the study, of which 21,216 (19%) patients had diabetes at baseline, and 8164 (10%) developed new-onset diabetes during a mean follow-up of 3.9 years. Patients with new-onset diabetes and prevalent diabetes were slightly younger than patients without diabetes (70 vs. 74 and 77, respectively), more likely to be men (62% vs. 60% and 54%), and had more comorbidities expect for ischemic heart disease, hypertension and chronic kidney disease which were more prevalent among patients with prevalent diabetes. Incidence rates of new-onset diabetes increased from around 2 per 100 person-years in the first years following HF hospitalization up to 3 per 100 person-years after 5 years of follow-up. A total of 61,424 (59%) patients died during the study period with event rates per 100 person-years of 21.5 for new-onset diabetes, 17.9 for prevalent diabetes and 13.9 for patients without diabetes. Compared to patients without diabetes, new-onset diabetes was associated with a higher risk of death (adjusted HR 1.47; 95% CI 1.42-1.52) and prevalent diabetes was associated with an intermediate risk (HR 1.19; 95% CI, 1.16-1.21).
Conclusion
Following the first HF hospitalization, the incidence of new-onset diabetes was around 2% per year, rising to 3% after 5 years of follow-up. New-onset diabetes was associated with an increased risk of death, compared to HF patients with prevalent diabetes (intermediate risk) and HF patients without diabetes.



Cardiovasc Diabetol: 11 Jun 2019; 18:79
Zareini B, Rørth R, Holt A, Mogensen UM, ... Lamberts M, Kristensen SL
Cardiovasc Diabetol: 11 Jun 2019; 18:79 | PMID: 31189473
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Impact:
Abstract

High-intensity interval training improves metabolic syndrome and body composition in outpatient cardiac rehabilitation patients with myocardial infarction.

Dun Y, Thomas RJ, Smith JR, Medina-Inojosa JR, ... Liu S, Olson TP
Background
To examine the effect of high-intensity interval training (HIIT) on metabolic syndrome (MetS) and body composition in cardiac rehabilitation (CR) patients with myocardial infarction (MI).
Methods
We retrospectively screened 174 consecutive patients with MetS enrolled in CR following MI between 2015 and 2018. We included 56 patients who completed 36 CR sessions and pre-post dual-energy X-ray absorptiometry. Of these patients, 42 engaged in HIIT and 14 in moderate-intensity continuous training (MICT). HIIT included 4-8 intervals of high-intensity (30-60 s at RPE 15-17 [Borg 6-20]) and low-intensity (1-5 min at RPE < 14), and MICT included 20-45 min of exercise at RPE 12-14. MetS and body composition variables were compared between MICT and HIIT groups.
Results
Compared to MICT, HIIT demonstrated greater reductions in MetS (relative risk = 0.5, 95% CI 0.33-0.75, P < .001), MetS z-score (- 3.6 ± 2.9 vs. - 0.8 ± 3.8, P < .001) and improved MetS components: waist circumference (- 3 ± 5 vs. 1 ± 5 cm, P = .01), fasting blood glucose (- 25.8 ± 34.8 vs. - 3.9 ± 25.8 mg/dl, P < .001), triglycerides (- 67.8 ± 86.7 vs. - 10.4 ± 105.3 mg/dl, P < .001), and diastolic blood pressure (- 7 ± 11 vs. 0 ± 13 mmHg, P = .001). HIIT group demonstrated greater reductions in body fat mass (- 2.1 ± 2.1 vs. 0 ± 2.2 kg, P = .002), with increased body lean mass (0.9 ± 1.9 vs. - 0.9 ± 3.2 kg, P = .01) than the MICT. After matching for exercise energy expenditure, HIIT-induced improvements persisted for MetS z-score (P < .001), MetS components (P < .05), body fat mass (P = .002), body fat (P = .01), and lean mass (P = .03).
Conclusions
Our data suggest that, compared to MICT, supervised HIIT results in greater improvements in MetS and body composition in MI patients with MetS undergoing CR.



Cardiovasc Diabetol: 13 Aug 2019; 18:104
Dun Y, Thomas RJ, Smith JR, Medina-Inojosa JR, ... Liu S, Olson TP
Cardiovasc Diabetol: 13 Aug 2019; 18:104 | PMID: 31412869
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Impact:
Abstract

A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with myocardial infarction in type 2 diabetic patients.

Mannino GC, Pezzilli S, Averta C, Fuoco A, ... Andreozzi F, Sesti G
Background
Myocardial infarction is the main mortality cause in patients with type 2 diabetes (T2DM). Endothelial dysfunction due to reduced bioavailability of nitric oxide (NO) is an early step of atherogenesis. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and it is metabolized by the enzymes dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2. The functional variant rs9267551 C, in the promoter region of DDAH2, has been linked to increased DDAH2 expression, and lower ADMA plasma levels, and was associated with lower risk of coronary artery disease in large-scale genome-wide association studies (GWAS) performed in the general population. However, it is unknown whether this association holds true in T2DM patients. To address this issue, we investigated whether rs9267551 is associated with risk of myocardial infarction in two cohorts of T2DM patients.
Methods
SNP rs9267551 was genotyped in 1839 White T2DM patients from the Catanzaro Study (CZ, n = 1060) and the Gargano Heart Study-cross sectional design (GHS, n = 779). Cases were patients with a previous myocardial infarction, controls were asymptomatic patients with neither previous myocardial ischemia nor signs of it at resting and during a maximal symptom limited stress electrocardiogram.
Results
Carriers of allele rs9267551 C showed a dose dependent reduction in the risk of myocardial infarction [(CZ = OR 0.380, 95% CI 0.175-0.823, p = 0.014), (GHS = 0.497, 0.267-0.923, p = 0.027), (Pooled = 0.458, 0.283-0.739, p = 0.001)] which remained significant after adjusting for sex, age, BMI, smoking, HbA1c, total cholesterol HDL, and triglyceride levels [(CZ = 0.307, 0.106-0.885, p = 0.029), (GHS = 0.512, 0.270-0.970, p = 0.040), (Pooled = 0.458, 0.266-0.787, p = 0.005)].
Conclusions
We found that rs9267551 polymorphism is significantly associated with myocardial infarction in T2DM patients of European ancestry from two independent cohorts. It is possible that in subjects carrying the protective C allele less ADMA accumulates in endothelial cells causing vascular protection as a consequence of higher nitric oxide availability.



Cardiovasc Diabetol: 12 Aug 2019; 18:102
Mannino GC, Pezzilli S, Averta C, Fuoco A, ... Andreozzi F, Sesti G
Cardiovasc Diabetol: 12 Aug 2019; 18:102 | PMID: 31409409
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Impact:
Abstract

Insulin resistance and dysglycemia are associated with left ventricular remodeling after myocardial infarction in non-diabetic patients.

Yang CD, Shen Y, Lu L, Ding FH, ... Jin W, Wang XQ
Background
Adverse cardiac remodeling after ST-segment elevation myocardial infarction (STEMI) is a major cause for poor cardiovascular outcomes such as heart failure. The predisposing factors and underlying mechanisms remain not fully understood. This study investigates the association of insulin resistance and dysglycemia with left ventricular (LV) remodeling after STEMI in non-diabetic patients.
Methods
A total of 485 non-diabetic subjects with STEMI who underwent primary percutaneous coronary intervention were consecutively enrolled and followed up for 12 months. Relation of homeostasis model assessment-estimated insulin resistance (HOMA-IR) and glucose levels to changes in echocardiography parameters was studied.
Results
Left ventricular dilation was detected in 49.1% of subjects at 12-month follow-up after STEMI, and was more severe in subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and high HOMA-IR levels. HOMA-IR remained correlated to changes in LV dimensions after adjusting for confounding risk factors. Multivariate regression analysis demonstrated that higher HOMA-IR was independently associated with greater LV dilation after STEMI. A significant interaction term was present between HOMA-IR and IGT in the model (P = 0.001).
Conclusions
Our study reveals that insulin resistance and dysglycemia are prevalent in non-diabetic patients with STEMI and are predictors of the post-infarction LV dilation. Trial registration Trials number, NCT02089360; registered on March 17, 2014.



Cardiovasc Diabetol: 06 Aug 2019; 18:100
Yang CD, Shen Y, Lu L, Ding FH, ... Jin W, Wang XQ
Cardiovasc Diabetol: 06 Aug 2019; 18:100 | PMID: 31391045
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Impact:
Abstract

Novel associations between sex hormones and diabetic vascular complications in men and postmenopausal women: a cross-sectional study.

Wang C, Zhang W, Wang Y, Wan H, ... Wang N, Lu Y
Background
Associations between sex hormones and vascular remodeling have been extensively studied, but the results vary widely among different races and sex. We aimed to investigate whether total testosterone (TT), estrogen (E2), and dehydroepiandrosterone (DHEA) associate with macrovascular complications and diabetic kidney disease (DKD) among community-dwelling patients with diabetes.
Methods
A total of 4720 participants with type 2 diabetes were recruited from Shanghai, China. Common carotid artery (CCA) plaques and diameter were assessed by ultrasound. Cardiovascular disease (CVD) was defined by prior diagnosis of coronary heart disease, myocardial infarction or stroke. DKD was defined according to the ADA Guidelines.
Results
(1) In men, TT was negatively associated with CCA diameter (regression coefficient (β) - 0.044, 95% CI - 0.087, 0). E2 levels were positively associated with CVD and CCA plaque prevalence (OR 1.151, 95% CI 1.038, 1.277 and OR 1.13, 95% CI 1.017, 1.255, respectively). DHEA was negatively associated with CVD (OR 0.809, 95% CI 0.734, 0.893). In postmenopausal women, TT levels were negatively associated with CCA diameter (β - 0.046, 95% CI - 0.083, - 0.010) and positively associated with CVD (OR 1.154, 95% CI 1.038, 1.284). (2) In both men and postmenopausal women, TT levels were negatively associated with the albumin/creatinine ratio and DKD (β - 0.098, 95% CI - 0.154, - 0.043 and OR 0.887, 95% CI 0.790, 0.997 vs. β - 0.084, 95% CI - 0.137, - 0.031 and OR 0.822, 95% CI 0.731, 0.924, respectively) and DHEA levels were positively associated with DKD (OR 1.167, 95% CI 1.038, 1.313 vs. OR 1.251, 95% CI 1.104, 1.418, respectively).
Conclusions
Our study indicates that macrovascular complications were associated with low TT, DHEA and high E2 in men and with high TT in postmenopausal women. DKD was associated with low TT and high DHEA levels in both genders. Sex hormone replacement therapy requires careful and comprehensive consideration. Trial registration ChiCTR1800017573, http://www.chictr.org.cn . Registered 04 August 2018.



Cardiovasc Diabetol: 30 Jul 2019; 18:97
Wang C, Zhang W, Wang Y, Wan H, ... Wang N, Lu Y
Cardiovasc Diabetol: 30 Jul 2019; 18:97 | PMID: 31366359
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Impact:
Abstract

Association between macro- and microvascular damage and the triglyceride glucose index in community-dwelling elderly individuals: the Northern Shanghai Study.

Zhao S, Yu S, Chi C, Fan X, ... Zhang Y, Xu Y
Background
It has been reported that the triglyceride-glucose (TyG) index may serve as a simple and credible surrogate marker of insulin resistance (IR). However, its association with macrovascular and microvascular damage is unclear. Accordingly, the objective of the present study is to investigate the association of macrovascular and microvascular damage with the TyG index.
Methods
A total of 2830 elderly participants from the Northern Shanghai Study (NSS) were enrolled. The TyG index was calculated as ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. Parameters of vascular damage, including carotid-femoral pulse wave velocity (cf-PWV), brachial-ankle pulse wave velocity (ba-PWV), ankle-brachial index (ABI), carotid intima-media thickness (CMT), carotid plaque, estimated glomerular filtration rate (eGFR) and the urine albumin-to-creatinine ratio (UACR), were measured and calculated.
Results
In univariate logistic regression, an increased TyG index was associated with a higher risk of cf-PWV > 10 m/s, ba-PWV > 1800 cm/s, ABI < 0.9, microalbuminuria (MAU) and chronic kidney disease (CKD). In multivariable logistic regression, there was a significant increase in the risk of cf-PWV > 10 m/s (OR = 1.86, 95% confidence interval [95% CI] 1.37-2.53, P < 0.001), ba-PWV > 1800 cm/s (OR = 1.39, [95% CI] 1.05-1.84, P= 0.02), MAU (OR = 1.61, [95% CI] 1.22-2.13, P < 0.001) and CKD (OR = 1.67, [95% CI] 1.10-1.50, P= 0.02) after adjustment for age, sex, BMI, waist circumference, smoking habit, hypertension, family history of premature CVD, diabetes, HDL-C, LDL-C, insulin therapy and statin therapy. However, no significant relationship was observed between the TyG index and lower extremity atherosclerosis, carotid hypertrophy or carotid plaque.
Conclusion
An elevated TyG index was significantly associated with a higher risk of arterial stiffness and nephric microvascular damage. This conclusion lends support to the clinical significance of the TyG index for the assessment of vascular damage.



Cardiovasc Diabetol: 24 Jul 2019; 18:95
Zhao S, Yu S, Chi C, Fan X, ... Zhang Y, Xu Y
Cardiovasc Diabetol: 24 Jul 2019; 18:95 | PMID: 31345238
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Impact:
Abstract

Depressed systemic arterial compliance and impaired left ventricular midwall performance in aortic stenosis with concomitant type 2 diabetes: a retrospective cross-sectional study.

Czestkowska E, Rożanowska A, Długosz D, Bolt K, ... Chyrchel B, Surdacki A
Background
Degenerative aortic stenosis (AS), a disease of the elderly, frequently coexists with concomitant diseases, including type 2 diabetes (T2DM) which amplifies the cardiovascular (CV) risk. T2DM affects left ventricular (LV) structure and function via hemodynamic and metabolic factors. In concentric LV geometry, typical for AS, indices of LV midwall mechanics are better estimates of LV function than ejection fraction (EF). Effects of T2DM coexisting with AS on circumferential LV midwall systolic function and large artery properties have not been reported so far. Our aim was to compare characteristics of AS patients with and without T2DM, with a focus on LV midwall systolic function and arterial compliance.
Methods
Medical records of 130 electively hospitalized patients with moderate or severe isolated degenerative AS were retrospectively analyzed. Exclusion criteria included clinical instability, atrial fibrillation, coronary artery disease and relevant non-cardiac diseases. From in-hospital echocardiography and blood pressure, we calculated LV midwall fractional shortening (mwFS), circumferential end-systolic LV wall stress (cESS) and valvulo-arterial impedance (Zva), estimates of LV afterload, as well as systemic arterial compliance.
Results
Patients with (n = 50) and without T2DM (n = 80) did not differ in age, AS severity, LV mass and LV diastolic diameter. T2DM patients exhibited elevated cESS (247 ± 105 vs. 209 ± 84 hPa, p = 0.025) and Zva (5.8 ± 2.2 vs. 5.1 ± 1.8 mmHg per mL/m, p = 0.04), and lower stroke volume index (33 ± 10 vs. 38 ± 12 mL/m, p = 0.01) and systemic arterial compliance (0.53 ± 0.16 vs. 0.62 ± 0.22 mL/m per mmHg, p = 0.01). mwFS (11.9 ± 3.9 vs. 14.1 ± 3.7%, p = 0.001), but not EF (51 ± 14 vs. 54 ± 13%, p = n.s.), was reduced in T2DM. mwFS and cESS were inversely interrelated in patients both with (r = - 0.59, p < 0.001) and without T2DM (r = - 0.53, p < 0.001) By multiple regression, higher cESS (p < 0.001) and T2DM (p = 0.02) were independent predictors of depressed mwFS.
Conclusions
In AS, coexistent T2DM appears associated with reduced systemic arterial compliance and LV dysfunction at the midwall level, corresponding to slightly depressed myocardial contractility.



Cardiovasc Diabetol: 16 Jul 2019; 18:92
Czestkowska E, Rożanowska A, Długosz D, Bolt K, ... Chyrchel B, Surdacki A
Cardiovasc Diabetol: 16 Jul 2019; 18:92 | PMID: 31315620
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Impact:
Abstract

Triglyceride-glucose index is associated with symptomatic coronary artery disease in patients in secondary care.

da Silva A, Caldas APS, Hermsdorff HHM, Bersch-Ferreira ÂC, ... Weber B, Bressan J
Background
The triglyceride-glucose index (TyG index) is a tool for insulin resistance evaluation, however, little is known about its association with coronary artery disease (CAD), which is the major cardiovascular death cause, and what factors may be associated with TyG index.
Objective
To evaluate the association between the TyG index and the prevalence of CAD phases, as well as cardiovascular risk factors.
Methods
The baseline data of patients in secondary care in cardiology from Brazilian Cardioprotective Nutritional Program Trial (BALANCE Program Trial) were analyzed. Anthropometric, clinical, socio-demographic and food consumption data were collected by trained professionals. The TyG index was calculated by the formula: Ln (fasting triglycerides (mg/dl) × fasting blood glucose (mg/dl)/2) and regression models were used to evaluate the associations.
Results
We evaluated 2330 patients, which the majority was male (58.1%) and elderly (62.1%). The prevalence of symptomatic CAD was 1.16 times higher in patients classified in the last tertile of the TyG index (9.9 ± 0.5) compared to those in the first tertile (8.3 ± 0.3). Cardiometabolic risk factors were associated with TyG index, with the highlight for higher carbohydrate and lower lipid consumption in relation to recommendations that reduced the chance of being in the last TyG index tertile.
Conclusion
The TyG index was positively associated with a higher prevalence of symptomatic CAD, with metabolic and behavioral risk factors, and could be used as a marker for atherosclerosis. Trial registration ClinicalTrials.gov identifier: NCT01620398. Registered 15 June, 2012.



Cardiovasc Diabetol: 10 Jul 2019; 18:89
da Silva A, Caldas APS, Hermsdorff HHM, Bersch-Ferreira ÂC, ... Weber B, Bressan J
Cardiovasc Diabetol: 10 Jul 2019; 18:89 | PMID: 31296225
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Impact:
Abstract

A double-blind, placebo-controlled, randomised trial to assess the effect of liraglutide on ectopic fat accumulation in South Asian type 2 diabetes patients.

van Eyk HJ, Paiman EHM, Bizino MB, de Heer P, ... Rensen PCN, Jazet IM
Background
South Asians have a high risk to develop type 2 diabetes, which may be related to substantial ectopic fat deposition. Since glucagon-like peptide-1 analogues can reduce ectopic fat accumulation, the aim of the present study was to assess the effect of treatment with liraglutide for 26 weeks on ectopic fat deposition and HbA1c in South Asian patients with type 2 diabetes.
Methods
In a placebo-controlled trial, 47 South Asian patients with type 2 diabetes were randomly assigned to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after 26 weeks of treatment we assessed abdominal subcutaneous, visceral, epicardial and paracardial adipose tissue volume using MRI. Furthermore, myocardial and hepatic triglyceride content were examined with proton magnetic resonance spectroscopy.
Results
In the intention-to-treat analysis, liraglutide decreased body weight compared to placebo (- 3.9 ± 3.6 kg vs - 0.6 ± 2.2 kg; mean change from baseline (liraglutide vs placebo): - 3.5 kg; 95% CI [- 5.3, - 1.8]) without significant effects on the different adipose tissue compartments. HbA1c was decreased in both groups without between group differences. In the per-protocol analysis, liraglutide did decrease visceral adipose tissue volume compared to placebo (- 23 ± 27 cm vs - 2 ± 17 cm; mean change from baseline (liraglutide vs placebo): - 17 cm; 95% CI [- 32, - 3]). Furthermore, HbA1c was decreased by liraglutide compared to placebo (- 1.0 ± 0.8% (- 10.5 ± 9.1 mmol/mol)) vs (- 0.6 ± 0.8% (- 6.1 ± 8.8 mmol/mol)), with a between group difference (mean change from baseline (liraglutide vs placebo): - 0.6% (- 6.5 mmol/mol); 95% CI [- 1.1, - 0.1 (- 11.5, - 1.5)]). Interestingly, the decrease of visceral adipose tissue volume was associated with the reduction of HbA1c (β: 0.165 mmol/mol (0.015%) per 1 cm decrease of visceral adipose tissue volume; 95% CI [0.062, 0.267 (0.006, 0.024%)]).
Conclusions
While the intention-to-treat analysis did not show effects of liraglutide on ectopic fat and HbA1c, per-protocol analysis showed that liraglutide decreases visceral adipose tissue volume, which was associated with improved glycaemic control in South Asians. Trial registration NCT02660047 (clinicaltrials.gov). Registered 21 January 2016.



Cardiovasc Diabetol: 08 Jul 2019; 18:87
van Eyk HJ, Paiman EHM, Bizino MB, de Heer P, ... Rensen PCN, Jazet IM
Cardiovasc Diabetol: 08 Jul 2019; 18:87 | PMID: 31288820
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Impact:
Abstract

The role of blood pressure in risk of ischemic and hemorrhagic stroke in type 1 diabetes.

Hägg-Holmberg S, Dahlström EH, Forsblom CM, Harjutsalo V, ... Thorn LM,
Background
Hypertension is one of the strongest risk factors for stroke in the general population, while systolic blood pressure has been shown to independently increase the risk of stroke in type 1 diabetes. The aim of this study was to elucidate the association between different blood pressure variables and risk of stroke in type 1 diabetes, and to explore potential nonlinearity of this relationship.
Methods
We included 4105 individuals with type 1 diabetes without stroke at baseline, participating in the nationwide Finnish Diabetic Nephropathy Study. Mean age at baseline was 37.4 ± 11.9 years, median duration of diabetes 20.9 (interquartile range 11.5-30.4) years, and 52% were men. Office systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured. Based on these pulse pressure (PP) and mean arterial pressure (MAP) were calculated. Strokes were classified based on medical and autopsy records, as well as neuroimaging. Cox proportional hazard models were performed to study how the different blood pressure variables affected the risk of stroke and its subtypes.
Results
During median follow-up time of 11.9 (9.21-13.9) years, 202 (5%) individuals suffered an incident stroke; 145 (72%) were ischemic and 57 (28%) hemorrhagic. SBP, DBP, PP, and MAP all independently increased the risk of any stroke. SBP, PP, and MAP increased the risk of ischemic stroke, while SBP, DBP, and MAP increased the risk of hemorrhagic stroke. SBP was strongly associated with stroke with a hazard ratio of 1.20 (1.11-1.29)/10 mmHg. When variables were modeled using restricted cubic splines, the risk of stroke increased linearly for SBP, MAP, and PP, and non-linearly for DBP.
Conclusions
The different blood pressure variables are all independently associated with increased risk of stroke in individuals with type 1 diabetes. The risk of stroke, ischemic stroke, and hemorrhagic stroke increases linearly at blood pressure levels less than the current recommended treatment guidelines.



Cardiovasc Diabetol: 08 Jul 2019; 18:88
Hägg-Holmberg S, Dahlström EH, Forsblom CM, Harjutsalo V, ... Thorn LM,
Cardiovasc Diabetol: 08 Jul 2019; 18:88 | PMID: 31288813
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Impact:
Abstract

Impaired branched chain amino acid oxidation contributes to cardiac insulin resistance in heart failure.

Uddin GM, Zhang L, Shah S, Fukushima A, ... Oudit GY, Lopaschuk GD
Background
Branched chain amino acids (BCAA) can impair insulin signaling, and cardiac insulin resistance can occur in the failing heart. We, therefore, determined if cardiac BCAA accumulation occurs in patients with dilated cardiomyopathy (DCM), due to an impaired catabolism of BCAA, and if stimulating cardiac BCAA oxidation can improve cardiac function in mice with heart failure.
Method
For human cohorts of DCM and control, both male and female patients of ages between 22 and 66 years were recruited with informed consent from University of Alberta hospital. Left ventricular biopsies were obtained at the time of transplantation. Control biopsies were obtained from non-transplanted donor hearts without heart disease history. To determine if stimulating BCAA catabolism could lessen the severity of heart failure, C57BL/6J mice subjected to a transverse aortic constriction (TAC) were treated between 1 to 4-week post-surgery with either vehicle or a stimulator of BCAA oxidation (BT2, 40 mg/kg/day).
Result
Echocardiographic data showed a reduction in ejection fraction (54.3 ± 2.3 to 22.3 ± 2.2%) and an enhanced formation of cardiac fibrosis in DCM patients when compared to the control patients. Cardiac BCAA levels were dramatically elevated in left ventricular samples of patients with DCM. Hearts from DCM patients showed a blunted insulin signalling pathway, as indicated by an increase in P-IRS1ser636/639 and its upstream modulator P-p70S6K, but a decrease in its downstream modulators P-AKT ser473 and in P-GSK3β ser9. Cardiac BCAA oxidation in isolated working hearts was significantly enhanced by BT2, compared to vehicle, following either acute or chronic treatment. Treatment of TAC mice with BT2 significantly improved cardiac function in both sham and TAC mice (63.0 ± 1.8 and 56.9 ± 3.8% ejection fraction respectively). Furthermore, P-BCKDH and BCKDK expression was significantly decreased in the BT2 treated groups.
Conclusion
We conclude that impaired cardiac BCAA catabolism and insulin signaling occur in human heart failure, while enhancing BCAA oxidation can improve cardiac function in the failing mouse heart.



Cardiovasc Diabetol: 04 Jul 2019; 18:86
Uddin GM, Zhang L, Shah S, Fukushima A, ... Oudit GY, Lopaschuk GD
Cardiovasc Diabetol: 04 Jul 2019; 18:86 | PMID: 31277657
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Impact:
Abstract

Cardiac ischemia-reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity.

Yoshii A, Nagoshi T, Kashiwagi Y, Kimura H, ... Tanaka TD, Yoshimura M
Background
Recent large-scale clinical trials have shown that SGLT2-inhibitors reduce cardiovascular events in diabetic patients. However, the regulation and functional role of cardiac sodium-glucose cotransporter (SGLT1 is the dominant isoform) compared with those of other glucose transporters (insulin-dependent GLUT4 is the major isoform) remain incompletely understood. Given that glucose is an important preferential substrate for myocardial energy metabolism under conditions of ischemia-reperfusion injury (IRI), we hypothesized that SGLT1 contributes to cardioprotection during the acute phase of IRI via enhanced glucose transport, particularly in insulin-resistant phenotypes.
Methods and results
The hearts from mice fed a high-fat diet (HFD) for 12 weeks or a normal-fat diet (NFD) were perfused with either the non-selective SGLT-inhibitor phlorizin or selective SGLT2-inhibitors (tofogliflozin, ipragliflozin, canagliflozin) during IRI using Langendorff model. After ischemia-reperfusion, HFD impaired left ventricular developed pressure (LVDP) recovery compared with the findings in NFD. Although phlorizin-perfusion impaired LVDP recovery in NFD, a further impaired LVDP recovery and a dramatically increased infarct size were observed in HFD with phlorizin-perfusion. Meanwhile, none of the SGLT2-inhibitors significantly affected cardiac function or myocardial injury after ischemia-reperfusion under either diet condition. The plasma membrane expression of GLUT4 was significantly increased after IRI in NFD but was substantially attenuated in HFD, the latter of which was associated with a significant reduction in myocardial glucose uptake. In contrast, SGLT1 expression at the plasma membrane remained constant during IRI, regardless of the diet condition, whereas SGLT2 was not detected in the hearts of any mice. Of note, phlorizin considerably reduced myocardial glucose uptake after IRI, particularly in HFD.
Conclusions
Cardiac SGLT1 but not SGLT2 plays a compensatory protective role during the acute phase of IRI via enhanced glucose uptake, particularly under insulin-resistant conditions, in which IRI-induced GLUT4 upregulation is compromised.



Cardiovasc Diabetol: 30 Jun 2019; 18:85
Yoshii A, Nagoshi T, Kashiwagi Y, Kimura H, ... Tanaka TD, Yoshimura M
Cardiovasc Diabetol: 30 Jun 2019; 18:85 | PMID: 31262297
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Impact:
Abstract

Cardiovascular, electrophysiologic, and hematologic effects of omega-3 fatty acids beyond reducing hypertriglyceridemia: as it pertains to the recently published REDUCE-IT trial.

Sheikh O, Vande Hei AG, Battisha A, Hammad T, Pham S, Chilton R

Heart disease continues to affect health outcomes globally, accounting for a quarter of all deaths in the United States. Despite the improvement in the development and implementation of guideline-directed medical therapy, the risk of adverse cardiac events remains substantially high. Historically, it has been debated whether omega-3 polyunsaturated fatty acids provide clinical benefit in cardiac disease. The recently published REDUCE-IT trial demonstrated a statistically significant absolute risk reduction of 4.8% in its primary endpoint (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina) with the use of icosapent ethyl, which is a highly purified eicosapentaenoic acid (EPA) ethyl ester. However, the mechanism of action of omega-3 fatty acids is not commonly discussed. Moreover, the use of EPA was not without risk, as the incidence of atrial fibrillation was increased along with a trend towards increased bleeding risk. Thus, our aim is to help explain the function of purified EPA ethyl ester, especially at the molecular level, which will ultimately lead to a better understanding of their clinically observable effects.



Cardiovasc Diabetol: 23 Jun 2019; 18:84
Sheikh O, Vande Hei AG, Battisha A, Hammad T, Pham S, Chilton R
Cardiovasc Diabetol: 23 Jun 2019; 18:84 | PMID: 31234885
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Impact:
Abstract

Lipoprotein (a) interactions with cholesterol-containing lipids on angiographic coronary collateralization in type 2 diabetic patients with chronic total occlusion.

Shen Y, Chen S, Dai Y, Wang XQ, ... Ding FH, Shen WF
Background
We investigated whether or to what extent the interaction of lipoprotein (a) [Lp(a)] with cholesterol-containing lipids was associated with angiographic coronary collateralization in type 2 diabetic patients with chronic total occlusion.
Methods
Serum levels of Lp(a), total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), and triglyceride were determined and non-HDL-C was calculated in 706 type 2 diabetic and 578 non-diabetic patients with stable coronary artery disease and angiographic total occlusion of at least one major coronary artery. The degree of collaterals supplying the distal aspect of a total occlusion from the contra-lateral vessel was graded as poor (Rentrop score of 0 or 1) or good coronary collateralization (Rentrop score of 2 or 3).
Results
For diabetic and non-diabetic patients, Lp(a), total cholesterol, LDL-C, and non-HDL-C levels were higher in patients with poor coronary collateralization than in those with good collateralization, whereas HDL-C and triglyceride levels were similar. After adjustment for potential confounding factors, tertiles of Lp(a), total cholesterol, LDL-C and non-HDL-C remained independent determinants for poor collateralization. A significant interaction between Lp(a) and total cholesterol, LDL-C or non-HDL-C was observed in diabetic patients (all P interaction < 0.001) but not in non-diabetics. At high tertile of total cholesterol (≥ 5.35 mmol/L), LDL-C (≥ 3.36 mmol/L) and non-HDL-C (≥ 4.38 mmol/L), diabetic patients with high tertile of Lp(a) (≥ 30.23 mg/dL) had an increased risk of poor collateralization compared with those with low tertile of Lp(a) (< 12.66 mg/dL) (adjusted OR = 4.300, 3.970 and 4.386, respectively, all P < 0.001).
Conclusions
Increased Lp(a) confers greater risk for poor coronary collateralization when total cholesterol, LDL-C or non-HDL-C are elevated especially for patients with type 2 diabetes.



Cardiovasc Diabetol: 23 Jun 2019; 18:82
Shen Y, Chen S, Dai Y, Wang XQ, ... Ding FH, Shen WF
Cardiovasc Diabetol: 23 Jun 2019; 18:82 | PMID: 31234867
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Impact:
Abstract

Ipragliflozin-induced adipose expansion inhibits cuff-induced vascular remodeling in mice.

Mori K, Tsuchiya K, Nakamura S, Miyachi Y, ... Ogawa Y, Kitamura K
Background
Perivascular adipose tissue (PVAT) plays a critical role in the pathogenesis of cardiovascular disease. It is unclear whether inhibition of sodium glucose cotransporter 2 (SGLT2) in subjects with type 2 diabetes (T2DM) could affect PVAT characters, and whether the SGLT2 inhibitors-induced changes of adipose tissue, especially the alternation of adipose tissue-derived secretory factors, affect vascular pathophysiology.
Methods
Western-type diet (WD) fed wild-type mice were treated with or without an SGLT2 inhibitor ipragliflozin (Ipra) for 10 weeks. WEHI 274.1 and primary vascular smooth muscle cells were incubated with conditioned media (CM) of epididymal adipose tissue (Epi) or abdominal PVAT of Ipra- or vehicle-treated mice fed a WD. Epi of Ipra- or vehicle-treated mice fed a WD was implanted onto cuff-placed femoral arteries of apoE-deficient mice.
Results
Ipra increased adipocyte size associated with decreased expression of pro-inflammatory and fibrosis-related genes in abdominal PVAT of WD-fed mice. Ipra also suppressed WD-induced macrophages accumulation, fibrosis, and adipocyte death in abdominal PVAT. In CM of abdominal PVAT from Ipra-treated mice, concentration of leptin was significantly lower than that from vehicle-treated mice. In vitro, migration of WEHI 274.1 and primary vascular smooth muscle cells were more enhanced by CM of Epi or abdominal PVAT from vehicle-treated mice than that from Ipra-treated mice. Perivascular implantation of Epi from Ipra-treated mice to apolipoprotein E-deficient mice attenuated cuff-induced neointimal hyperplasia and vascular remodeling compared to that from vehicle-treated mice.
Conclusions
The Ipra-induced changes of abdominal PVAT will lead to a better understanding of unveiled mechanisms by which SGLT2 inhibitors prevent cardiovascular complications in T2DM, and the development of new therapeutic strategies targeting PVAT.



Cardiovasc Diabetol: 23 Jun 2019; 18:83
Mori K, Tsuchiya K, Nakamura S, Miyachi Y, ... Ogawa Y, Kitamura K
Cardiovasc Diabetol: 23 Jun 2019; 18:83 | PMID: 31234839
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Impact:
Abstract

Proteomic alterations of HDL in youth with type 1 diabetes and their associations with glycemic control: a case-control study.

Gourgari E, Ma J, Playford MP, Mehta NN, ... Remaley AT, Gordon SM
Background
Patients with type 1 diabetes (T1DM) typically have normal or even elevated plasma high density lipoprotein (HDL) cholesterol concentrations; however, HDL protein composition can be altered without a change in cholesterol content. Alteration of the HDL proteome can result in dysfunctional HDL particles with reduced ability to protect against cardiovascular disease (CVD). The objective of this study was to compare the HDL proteomes of youth with T1DM and healthy controls (HC) and to evaluate the influence of glycemic control on HDL protein composition.
Methods
This was a cross-sectional case-control study. Blood samples were obtained from patients with T1DM and HC. HDL was isolated from plasma by size-exclusion chromatography and further purified using a lipid binding resin. The HDL proteome was analyzed by mass spectrometry using label-free SWATH peptide quantification.
Results
Samples from 26 patients with T1DM and 13 HC were analyzed and 78 HDL-bound proteins were measured. Youth with T1DM had significantly increased amounts of complement factor H related protein 2 (FHR2; adjusted P < 0.05), compared to HC. When patients were analyzed based on glucose control, several trends emerged. Some proteins were altered in T1DM and not influenced by glycemic control (e.g. FHR2) while others were partially or completely corrected with optimal glucose control (e.g. alpha-1-beta glycoprotein, A1BG). In a subgroup of poorly controlled T1DM patients, inter alpha trypsin inhibitor 4 (ITIH4) was dramatically elevated (P < 0.0001) and this was partially reversed in patients with optimal glucose control. Some proteins including complement component C3 (CO3) and albumin (ALB) were significantly different only in T1DM patients with optimal glucose control, suggesting a possible effect of exogenous insulin.
Conclusions
Youth with T1DM have proteomic alterations of their HDL compared to HC, despite similar concentration of HDL cholesterol. The influence of these compositional changes on HDL function are not yet known. Future efforts should focus on investigating the role of these HDL associated proteins in regard to HDL function and their role in CVD risk in patients with T1DM. Trial registration NCT02275091.



Cardiovasc Diabetol: 27 Jan 2019; 18:43
Gourgari E, Ma J, Playford MP, Mehta NN, ... Remaley AT, Gordon SM
Cardiovasc Diabetol: 27 Jan 2019; 18:43 | PMID: 30922315
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Impact:
Abstract

Potential relation between soluble growth differentiation factor-15 and testosterone deficiency in male patients with coronary artery disease.

Liu H, Lyu Y, Li D, Cui Y, ... Dai W, Li Y
Background
There is a mutual interaction between inflammation and endocrine disorders in the development of coronary artery disease (CAD). Growth differentiation factor-15 (GDF-15) is associated with CAD, and the effects of testosterone on CAD as reported in literature have been considered as anti-atherosclerotic. The present study aimed to examine the possible association between serum GDF-15 and testosterone in male CAD patients.
Methods
GDF-15 and testosterone concentrations were determined in blood samples of 426 male patients with CAD and 220 male controls. Serum concentrations of hs-CRP, and other baseline characteristics were also measured.
Results
Serum levels of GDF-15 were higher in CAD patients when compared to controls, and testosterone concentrations were lower (p < 0.001). Patients with low testosterone levels had higher concentrations of GDF-15 (p < 0.001). In stratified analyses, inverse relations between GDF-15 levels and testosterone were noted for almost all strata, stratified by categories of hs-CRP, leukocytes, neutrophils, neutrophil to lymphocyte ratio, glucose, HDL-c, and LDL-c, and whether had hypertension, diabetes, and underwent percutaneous coronary intervention (PCI). Furthermore, in the linear regression models with bootstrap resampling with 1000 replications, high GDF-15 levels were independently associated with testosterone deficiency in male patients with CAD.
Conclusions
In male patients with CAD, high GDF-15 levels were associated with testosterone deficiency. These results support that upregulation of GDF-15 in the presence of low testosterone levels during CAD progression is a potential mechanism by which GDF-15 affects CAD.



Cardiovasc Diabetol: 27 Jan 2019; 18:21
Liu H, Lyu Y, Li D, Cui Y, ... Dai W, Li Y
Cardiovasc Diabetol: 27 Jan 2019; 18:21 | PMID: 30819257
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Impact:
Abstract

New dual peroxisome proliferator activated receptor agonist-Saroglitazar in diabetic dyslipidemia and non-alcoholic fatty liver disease: integrated analysis of the real world evidence.

Kaul U, Parmar D, Manjunath K, Shah M, ... Patil KP, Jaiswal A
Background
Saroglitazar, a novel dual peroxisome proliferator activated receptor (PPAR) agonist, in clinical trials, has shown an improvement in lipid and glycemic parameters through the PPAR-α and γ agonist actions, respectively. It was granted marketing authorization in India in 2013 for diabetic dyslipidemia. This review was conducted to summarize the effects of Saroglitazar in patients with diabetic dyslipidemia in real world clinical studies conducted after marketing authorization in India.
Methods
In this review, we selected real world clinical studies of Saroglitazar published as manuscripts and abstracts presented at scientific conferences. In all these studies, patients with diabetic dyslipidemia were treated with Saroglitazar 4 mg once daily for at least 12 weeks and different lipid and glycemic parameters were measured at the baseline and end of the study.
Results
In 18 selected studies (5 published manuscripts and 13 abstracts), a total of 5824 patients with diabetic dyslipidemia were prescribed Saroglitazar 4 mg for a duration ranging from 12 to 58 weeks. Across all the studies, mean age of patients ranged from 49.6 to 59.1 years and the proportion of female patients ranged from 22% to 42%. Across all the studies, there was a consistent mean reduction in triglyceride levels (~ 45% to 62%), total cholesterol levels (~ 17% to 26%), non-high-density lipoprotein cholesterol levels (~ 21% to 36%), low-density lipoprotein cholesterol levels (~ 11% to 27%), and glycosylated hemoglobin levels (~ 0.7% to 1.6%) with an increase in mean high-density lipoprotein cholesterol levels (up to 9%) from baseline to end of the study. Saroglitazar also improved alanine aminotransferase levels and fatty liver (evaluated by FibroScan™) in non-alcoholic fatty liver disease patients with diabetic dyslipidemia. Body weight remained unchanged and no significant adverse events (AEs) were reported in the studies.
Conclusion
Saroglitazar effectively improved lipid and glycemic parameters without significant AEs in patients with diabetic dyslipidemia in real-world clinical studies of up to 58 weeks duration.



Cardiovasc Diabetol: 16 Jun 2019; 18:80
Kaul U, Parmar D, Manjunath K, Shah M, ... Patil KP, Jaiswal A
Cardiovasc Diabetol: 16 Jun 2019; 18:80 | PMID: 31208414
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Impact:
Abstract

Machine-learning to stratify diabetic patients using novel cardiac biomarkers and integrative genomics.

Hathaway QA, Roth SM, Pinti MV, Sprando DC, ... Allen JL, Hollander JM
Background
Diabetes mellitus is a chronic disease that impacts an increasing percentage of people each year. Among its comorbidities, diabetics are two to four times more likely to develop cardiovascular diseases. While HbA1c remains the primary diagnostic for diabetics, its ability to predict long-term, health outcomes across diverse demographics, ethnic groups, and at a personalized level are limited. The purpose of this study was to provide a model for precision medicine through the implementation of machine-learning algorithms using multiple cardiac biomarkers as a means for predicting diabetes mellitus development.
Methods
Right atrial appendages from 50 patients, 30 non-diabetic and 20 type 2 diabetic, were procured from the WVU Ruby Memorial Hospital. Machine-learning was applied to physiological, biochemical, and sequencing data for each patient. Supervised learning implementing SHapley Additive exPlanations (SHAP) allowed binary (no diabetes or type 2 diabetes) and multiple classification (no diabetes, prediabetes, and type 2 diabetes) of the patient cohort with and without the inclusion of HbA1c levels. Findings were validated through Logistic Regression (LR), Linear Discriminant Analysis (LDA), Gaussian Naïve Bayes (NB), Support Vector Machine (SVM), and Classification and Regression Tree (CART) models with tenfold cross validation.
Results
Total nuclear methylation and hydroxymethylation were highly correlated to diabetic status, with nuclear methylation and mitochondrial electron transport chain (ETC) activities achieving superior testing accuracies in the predictive model (~ 84% testing, binary). Mitochondrial DNA SNPs found in the D-Loop region (SNP-73G, -16126C, and -16362C) were highly associated with diabetes mellitus. The CpG island of transcription factor A, mitochondrial (TFAM) revealed CpG24 (chr10:58385262, P = 0.003) and CpG29 (chr10:58385324, P = 0.001) as markers correlating with diabetic progression. When combining the most predictive factors from each set, total nuclear methylation and CpG24 methylation were the best diagnostic measures in both binary and multiple classification sets.
Conclusions
Using machine-learning, we were able to identify novel as well as the most relevant biomarkers associated with type 2 diabetes mellitus by integrating physiological, biochemical, and sequencing datasets. Ultimately, this approach may be used as a guideline for future investigations into disease pathogenesis and novel biomarker discovery.



Cardiovasc Diabetol: 10 Jun 2019; 18:78
Hathaway QA, Roth SM, Pinti MV, Sprando DC, ... Allen JL, Hollander JM
Cardiovasc Diabetol: 10 Jun 2019; 18:78 | PMID: 31185988
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Impact:
Abstract

Ticagrelor improves blood viscosity-dependent microcirculatory flow in patients with lower extremity arterial disease: the Hema-kinesis clinical trial.

Rosenson RS, Chen Q, Najera SD, Krishnan P, Lee ML, Cho DJ
Background
Microvascular blood flow (MBF) impairment in patients with lower extremity arterial disease (LEAD) is associated with more severe major adverse limb events (MALE). The contribution of ticagrelor, a P2Y12 antagonist and an adenosine enhancer, on blood viscosity (BV) and BV-dependent MBF in LEAD is unknown. The aim of the trial is to investigate the effects of ticagrelor on BV, and explore the association of BV-dependent MBF in participants with LEAD and type 2 diabetes (T2DM).
Methods
Randomized, double-blind, double-dummy, crossover trial design that compares treatment with aspirin 81 mg/ticagrelor placebo, aspirin 81 mg/ticagrelor 90 mg twice daily and aspirin placebo/ticagrelor 90 mg twice daily on high-shear (300 s) and low-shear (5 s) BV, and laser Doppler flowmetry (LDF) in the dorsum of the feet of participants with T2DM.
Results
We randomized 70 (45% female) participants aged (mean ± SD) 72 ± 9 years. The duration of LEAD was 12.3 ± 10.3 years, and 96.9% reported intermittent claudication symptoms. Use of statins was 93% (high-intensity 43%, moderate intensity 49%), renin-angiotensin-aldosterone system inhibitors (75%) and beta-blockers (61%). Treatment with ticagrelor with or without aspirin reduced high-shear BV by 5%, in both cases, while aspirin monotherapy increased high-shear BV by 3.4% (p < 0.0001). Ticagrelor with or without aspirin reduced low-shear BV by 14.2% and 13.9% respectively, while aspirin monotherapy increased low-shear BV by 9.3% (p < 0.0001). The combination of ticagrelor and aspirin increased MBF in the left foot compared to the other two treatments (p = 0.02), but not in the right foot (p = 0.25).
Conclusions
Ticagrelor should be considered in the treatment of microvascular disease in patients with LEAD and T2DM. Trial registration Registration number: NCT02325466, registration date: December 25, 2014.



Cardiovasc Diabetol: 06 Jun 2019; 18:77
Rosenson RS, Chen Q, Najera SD, Krishnan P, Lee ML, Cho DJ
Cardiovasc Diabetol: 06 Jun 2019; 18:77 | PMID: 31174526
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Impact:
Abstract

Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial.

Leiter LA, Bain SC, Hramiak I, Jódar E, ... Holst I, Lingvay I
Background
The SUSTAIN 6 trial demonstrated that once-weekly semaglutide (0.5 and 1.0 mg) significantly reduced major adverse cardiovascular (CV) events (MACE) vs placebo in subjects with type 2 diabetes (T2D) and high CV risk. The effects of gender, age and baseline CV risk on outcomes are important considerations for further study.
Methods
Subjects were grouped according to gender, age (50-65 years and > 65 years), and CV risk profile at baseline (prior myocardial infarction [MI] or stroke vs no prior MI or stroke, and established CV disease [CVD] vs CV risk factors alone, including subjects with chronic kidney disease). Time to MACE and its individual components (CV death, nonfatal MI, nonfatal stroke), hospitalization for unstable angina or heart failure, and revascularization (coronary and peripheral) were analyzed for all subgroups. Additional analyses were performed for gender and age to investigate change from baseline in HbA and body weight, as well as tolerability.
Results
A total of 3297 subjects were included. The majority of subjects (60.7%) were male; 43% were > 65 years of age; 41.5% had a history of MI or stroke; and 76.8% had established CVD. Compared with placebo, semaglutide reduced the risk of the first occurrence of MACE and each MACE component consistently across all subgroups (gender, age, and baseline CV risk profile). Revascularizations, HbA and body weight were also reduced consistently across all subgroups compared with placebo. Gastrointestinal adverse events in all treatment groups were more common among women than men, but rates of premature treatment discontinuation were similar for both genders.
Conclusions
In this post hoc analysis of SUSTAIN 6, once-weekly semaglutide vs placebo reduced the risk of MACE in all subjects included in the trial, regardless of gender, age, or baseline CV risk profile. Trial registry Clinicaltrials.gov, Identifying number: NCT01720446, Date of registration: October 29, 2012.



Cardiovasc Diabetol: 05 Jun 2019; 18:73
Leiter LA, Bain SC, Hramiak I, Jódar E, ... Holst I, Lingvay I
Cardiovasc Diabetol: 05 Jun 2019; 18:73 | PMID: 31167654
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Impact:
Abstract

Good glycemic control of gestational diabetes mellitus is associated with the attenuation of future maternal cardiovascular risk: a retrospective cohort study.

Yefet E, Schwartz N, Sliman B, Ishay A, Nachum Z
Background
To examine whether glycemic control of gestational diabetes mellitus (GDM) could modify the risk for future maternal metabolic and cardiovascular morbidities.
Methods
A retrospective cohort study of women with a first diagnosis of GDM who delivered between 1991 and 2011. Women were divided into groups of good and poor glycemic control, defined as a mean daily glucose of up to 95 mg/dL (N = 230) and more than 95 mg/dL (N = 216), respectively. In addition, a control group of women without GDM (N = 352) was also analyzed. The primary outcomes were the development of type 2 diabetes mellitus (T2DM), obesity, hypertension, or dyslipidemia.
Results
Mean follow-up time was 15.8 ± 5.1 years. Assessment was performed at a maternal age of 45 ± 7 years. The rates of the study outcomes in the control, GDM with good glycemic control and GDM with poor glycemic control were as follows: T2DM [19 (5.4%), 87 (38%), 127 (57%)]; hypertension [44 (13%), 42 (18%), 44 (20%)]; obesity [111 (32%), 112 (48%), 129 (58%)]; and dyslipidemia [49 (14%), 67 (29%), 106 (48%)]. Glycemic control was an independent risk factor for T2DM in multivariate Cox regression analysis (hazard ratio (HR) for poor glycemic control vs. controls 10.7 95% CI [6.0-19.0], good glycemic control vs. control HR 6.0 [3.3-10.8], and poor glycemic control vs. good glycemic control HR 1.8 [1.3-2.4]). Glycemic control was also an independent risk factor for dyslipidemia (poor glycemic control vs. controls HR 3.7 [2.3-5.8], good glycemic control vs. controls HR 2.0 [1.2-3.2], and poor glycemic control vs. good glycemic control HR 1.8 1.8 [1.3-2.6]). The fasting glucose level during oral glucose tolerance test (OGTT) was also an independent risk factor for these complications. The interaction term between glycemic control and the fasting value of the OGTT was not statistically significant, suggesting that the effect of glycemic control on the rate of future T2DM and dyslipidemia was not modified by the baseline severity of GDM.
Conclusion
GDM and especially poor glycemic control are associated with T2DM and dyslipidemia. Strict glycemic control for reducing that risk should be evaluated in prospective trials.



Cardiovasc Diabetol: 04 Jun 2019; 18:75
Yefet E, Schwartz N, Sliman B, Ishay A, Nachum Z
Cardiovasc Diabetol: 04 Jun 2019; 18:75 | PMID: 31167664
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Impact:
Abstract

Canagliflozin for Japanese patients with chronic heart failure and type II diabetes.

Sezai A, Sekino H, Unosawa S, Taoka M, Osaka S, Tanaka M
Background
Reports that sodium glucose cotransporter 2 inhibitors decrease cardiovascular death and events in patients with diabetes have attracted attention in the cardiology field. We conducted a study of canagliflozin in patients with chronic heart failure and type II diabetes.
Methods
Thirty-five Japanese patients with chronic heart failure and type II diabetes were treated with canagliflozin for 12 months. The primary endpoints were the changes of subcutaneous, visceral, and total fat areas at 12 months determined by computed tomography. Secondary endpoints included markers of glycemic control, renal function, and oxidative stress, as well as lipid parameters, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), flow-mediated dilation (FMD), and echocardiographic left ventricular function.
Results
All fat areas (subcutaneous, visceral, and total) showed a significant decrease at 12 months. ANP and BNP also decreased significantly, along with improvement of renal function, oxidized LDL, and E/e\', FMD increased significantly after canagliflozin treatment.
Conclusion
Canagliflozin demonstrated cardiac and renal protective effects as well as improving oxidative stress, diastolic function, and endothelial function. This drug was effective in patients who had heart failure with preserved ejection fraction and could become first-line therapy for such patients with diabetes. Trial registration UMIN ( http://www.umin.ac.jp/ ), Study ID: UMIN000021239.



Cardiovasc Diabetol: 04 Jun 2019; 18:76
Sezai A, Sekino H, Unosawa S, Taoka M, Osaka S, Tanaka M
Cardiovasc Diabetol: 04 Jun 2019; 18:76 | PMID: 31167663
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Impact:

This program is still in alpha version.