<div><h4>The impact of diabetes on the relationship of coronary artery disease and outcome: a study using multimodality imaging.</h4><i>Mäenpää M, Kujala I, Harjulahti E, Stenström I, ... Saraste A, Maaniitty T</i><br /><b>Background</b><br />Patients with prediabetes or diabetes are at increased risk of developing cardiovascular disease and adverse outcomes. First-line coronary computed tomography angiography (CTA) followed by selective use of positron emission tomography (PET) myocardial perfusion imaging is a feasible strategy to diagnose and risk-stratify patients with suspected coronary artery disease (CAD). The aim of the present study was to study whether diabetes changes the relationship of CAD and long-term outcome.<br /><b>Methods</b><br />We retrospectively identified consecutive symptomatic patients who underwent coronary CTA for suspected CAD. In patients with suspected obstructive CAD on CTA, myocardial ischemia was evaluated by <sup>15</sup>O-water PET myocardial perfusion imaging. The relationship of the phenotype of CAD and long-term outcome in patients with no diabetes, prediabetes, or type 2 diabetes was investigated. A composite endpoint included all-cause mortality, myocardial infarction (MI), and unstable angina pectoris (UAP).<br /><b>Results</b><br />A total of 1743 patients were included: 1214 (70%) non-diabetic, 259 (15%) prediabetic, and 270 (16%) type 2 diabetic patients. During 6.43 years of median follow-up, 164 adverse events occurred (106 deaths, 41 MIs, 17 UAPs). The prevalence of normal coronary arteries on CTA was highest in the non-diabetic patients (39%). The prevalence of hemodynamically significant CAD (abnormal perfusion) increased from 14% in non-diabetic patients to 20% in prediabetic and 27% in diabetic patients. The event rate was lowest in patients with normal coronary arteries and highest in patients with concomitant type 2 diabetes and hemodynamically significant CAD (annual event rate 0.2% vs. 4.7%). However, neither prediabetes nor diabetes were independent predictors of the composite adverse outcome after adjustment for the clinical risk factors and imaging findings.<br /><b>Conclusions</b><br />Coronary CTA followed by selective downstream use of PET myocardial perfusion imaging predicts long-term outcome similarly in non-diabetic and diabetic patients.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 31 May 2023; 22:129</small></div>

<div><h4>Association between triglyceride-glucose index trajectories and carotid atherosclerosis progression.</h4><i>Yu H, Tao L, Li YG, Yang L, ... Zhao W, Gao W</i><br /><b>Background</b><br />The triglyceride-glucose (TyG) index has been recognized as being an alternative cardiometabolic biomarker for insulin resistance associated with the development and prognosis of cardiovascular disease (CVD). However, the prospective relationship between baseline and long-term trajectories of the TyG index and carotid atherosclerosis (CAS) progression has yet to be investigated.<br /><b>Methods</b><br />This longitudinal prospective cohort study included 10,380 adults with multiple general health checks at Peking University Third Hospital from January 2011 to December 2020. The TyG index was calculated as ln (fasting triglyceride [mg/dL] × fasting glucose [mg/dL]/2). The latent class trajectory modeling method was used to analyze the TyG index trajectories over the follow-up. Based on univariate and multivariate Cox proportional hazards analyses, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for the baseline and trajectory of the TyG index.<br /><b>Results</b><br />During a median follow-up period of 757 days, 1813 participants developed CAS progression. Each 1-standard deviation (SD) increase in the TyG index was associated with a 7% higher risk of CAS progression after adjusting for traditional CVD risk factors (HR = 1.067, 95% CI 1.006-1.132). Similar results were observed when the TyG index was expressed as quartiles. According to different trajectory patterns, participants were categorized into low-stable, moderate-stable, and high-increasing groups. After multivariate adjustment, the moderate-stable group had a 1.139-fold (95% CI 1.021-1.272) risk of CAS progression. The high-increasing trajectory of the TyG index tended to be associated with CAS progression (HR = 1.206, 95% CI 0.961-1.513).<br /><b>Conclusions</b><br />Participants with higher baseline and moderate-stable trajectory of the TyG index were associated with CAS progression. Long-term trajectories of the TyG index can help to identify individuals at a higher risk of CAS progression who deserve specific preventive and therapeutic approaches.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 31 May 2023; 22:130</small></div>

<div><h4>Evidence for a lack of inotropic and chronotropic effects of glucagon and glucagon receptors in the human heart.</h4><i>Aranda-Domene R, Orenes-Piñero E, Arribas-Leal JM, Canovas-Lopez S, Hernández-Cascales J</i><br /><b>Background</b><br />Glucagon is thought to increase heart rate and contractility by stimulating glucagon receptors and increasing 3\',5\'-cyclic adenosine monophosphate (cAMP) production in the myocardium. This has been confirmed in animal studies but not in the human heart. The cardiostimulatory effects of glucagon have been correlated with the degree of cardiac dysfunction, as well as with the enzymatic activity of phosphodiesterase (PDE), which hydrolyses cAMP. In this study, the presence of glucagon receptors in the human heart and the inotropic and chronotropic effects of glucagon in samples of failing and nonfailing (NF) human hearts were investigated.<br /><b>Methods</b><br />Concentration‒response curves for glucagon in the absence and presence of the PDE inhibitor IBMX were performed on samples obtained from the right (RA) and left atria (LA), the right (RV) and left ventricles (LV), and the sinoatrial nodes (SNs) of failing and NF human hearts. The expression of glucagon receptors was also investigated. Furthermore, the inotropic and chronotropic effects of glucagon were examined in rat hearts.<br /><b>Results</b><br />In tissues obtained from failing and NF human hearts, glucagon did not exert inotropic or chronotropic effects in the absence or presence of IBMX. IBMX (30 µM) induced a marked increase in contractility in NF hearts (RA: 83 ± 28% (n = 5), LA: 80 ± 20% (n = 5), RV: 75 ± 12% (n = 5), and LV: 40 ± 8% (n = 5), weaker inotropic responses in the ventricular myocardium of failing hearts (RV: 25 ± 10% (n = 5) and LV: 10 ± 5% (n = 5) and no inotropic responses in the atrial myocardium of failing hearts. IBMX (30 µM) increased the SN rate in failing and NF human hearts (27.4 ± 3.0 beats min<sup>-1</sup>, n = 10). In rat hearts, glucagon induced contractile and chronotropic responses, but only contractility was enhanced by 30 µM IBMX (maximal inotropic effect of glucagon 40 ± 8% vs. 75 ± 10%, in the absence or presence of IBMX, n = 5, P < 0.05; maximal chronotropic response 77.7 ± 6.4 beats min<sup>-1</sup> vs. 73 ± 11 beats min<sup>-1</sup>, in the absence or presence of IBMX, n = 5, P > 0.05). Glucagon receptors were not detected in the human heart samples.<br /><b>Conclusions</b><br />Our results conflict with the view that glucagon induces inotropic and chronotropic effects and that glucagon receptors are expressed in the human heart.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 30 May 2023; 22:128</small></div>

<div><h4>The atherogenic index of plasma and carotid atherosclerosis in a community population: a population-based cohort study in China.</h4><i>Huang Q, Liu Z, Wei M, Huang Q, ... Liu Z, Xia J</i><br /><b>Background</b><br />The atherogenic index of plasma (AIP) is an important alternative metabolic biomarker of atherosclerosis and cardiovascular diseases. Nevertheless, the correlation between the AIP and carotid atherosclerosis is unknown among the general population.<br /><b>Methods</b><br />A total of 52,380 community residents, aged ≥ 40 years who underwentcervical vascular ultrasound from December 2017 to December 2020 in Hunan China, were selected for retrospective analysis. The AIP was calculated as a logarithmically converted ratio of triglycerides (TG) to high-density lipoprotein-cholesterol (HDL-C). The participants were divided into AIP quartile groups (Q1-Q4). Logistic regression models and restricted cubic spline analyses were used to examine the association of the AIP with carotid atherosclerosis. Stratified analyses were applied to control for confounding factors. The incremental predictive value of the AIP was further assessed.<br /><b>Results</b><br />After adjusting for traditional risk factors, an increased AIP was associated with a higher rate of carotid atherosclerosis (CA), increased carotid intima-media thickness (CIMT), and plaques [odds ratio, OR (95% confidence interval, CI): 1.06 (1.04, 1.08), 1.07 (1.05, 1.09), and 1.04 (1.02, 1.06) per 1-SD increase in the AIP, respectively]. Compared with those participants in the quartile 1 group, those in the quartile 4 group had a greater risk of CA [OR 1.18, 95% CI (1.12, 1.25)], increased CIMT [OR 1.20, 95% CI (1.13, 1.26)], and plaques [OR 1.13, 95% CI (1.06, 1.19)]. However, we did not observe an association between the AIP and stenosis [0.97 (0.77, 1.23), p for trend = 0.758]. Restricted cubic spline analyses also showed a cumulative increase in the risk of CA, increased CIMT, and plaques but not stenosis severity (> 50%) with an increase of the AIP. Subgroup analyses showed that a more significant association between the AIP and the prevalence of increased CA was detected in younger subjects (aged < 60 years) with a body mass index (BMI) of ≥ 24 and fewer comorbidities. Additionally, the AIP provided incremental predictive capacity over established risk factors for CA, as shown by an improvement in the net reclassification index (NRI) and integrated discrimination index (IDI) (all P < 0.05).<br /><b>Conclusions</b><br />An elevated AIP in a community-based population is associated with a higher rate of CA. the AIP could serve as a potential biomarker for CA risk assessment.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 27 May 2023; 22:125</small></div>

<div><h4>Kidney function loss and albuminuria progression with GLP-1 receptor agonists versus basal insulin in patients with type 2 diabetes: real-world evidence.</h4><i>Schechter M, Melzer Cohen C, Fishkin A, Rozenberg A, ... Karasik A, Mosenzon O</i><br /><b>Background</b><br />In clinical trials enrolling patients with type 2 diabetes (T2D) at high cardiovascular risk, many glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improved albuminuria status and possibly mitigated kidney function loss. However, limited data are available regarding the effects of GLP-1 RAs on albuminuria status and kidney function in real-world settings, including populations with a lower baseline cardiovascular and kidney risk. We assessed the association of GLP-1 RAs initiation with long-term kidney outcomes in the Maccabi Healthcare Services database, Israel.<br /><b>Methods</b><br />Adults with T2D treated with  ≥ 2 glucose-lowering agents who initiated GLP-1 RAs or basal insulin from 2010 to 2019 were propensity-score matched (1:1) and followed until October 2021 (intention-to-treat [ITT]). In an as-treated (AT) analysis, follow-up was also censored at study-drug discontinuation or comparator-initiation. We assessed the risk of a composite kidney outcome, including confirmed  ≥ 40% eGFR loss or end-stage kidney disease, and the risk of new macroalbuminuria. Treatment-effect on eGFR slopes was assessed by fitting a linear regression model per patient, followed by a t-test to compare the slopes between the groups.<br /><b>Results</b><br />Each propensity-score matched group constituted 3424 patients, 45% women, 21% had a history of cardiovascular disease, and 13.9% were treated with sodium-glucose cotransporter-2 inhibitors at baseline. Mean eGFR was 90.6 mL/min/1.73 m<sup>2</sup> (SD 19.3) and median UACR was 14.6 mg/g [IQR 0.0-54.7]. Medians follow-up were 81.1 months (ITT) and 22.3 months (AT). The hazard-ratios [95% CI] of the composite kidney outcome with GLP-1 RAs versus basal insulin were 0.96 [0.82-1.11] (p = 0.566) and 0.71 [0.54-0.95] (p = 0.020) in the ITT and AT analyses, respectively. The respective HRs for first new macroalbuminuria were 0.87 [0.75-0.997] and 0.80 [0.64-0.995]. The use of GLP-1 RA was associated with a less steep eGFR slope compared with basal insulin in the AT analysis (mean annual between-group difference of 0.42 mL/min/1.73 m<sup>2</sup>/year [95%CI 0.11-0.73]; p = 0.008).<br /><b>Conclusion</b><br />Initiation of GLP-1 RAs in a real-world setting is associated with a reduced risk of albuminuria progression and possible mitigation of kidney function loss in patients with T2D and mostly preserved kidney function.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 27 May 2023; 22:126</small></div>

<div><h4>Cardiovascular complications of diabetes: role of non-coding RNAs in the crosstalk between immune and cardiovascular systems.</h4><i>Spinetti G, Mutoli M, Greco S, Riccio F, ... Devaux Y, Martelli F</i><br /><AbstractText>Diabetes mellitus, a group of metabolic disorders characterized by high levels of blood glucose caused by insulin defect or impairment, is a major risk factor for cardiovascular diseases and related mortality. Patients with diabetes experience a state of chronic or intermittent hyperglycemia resulting in damage to the vasculature, leading to micro- and macro-vascular diseases. These conditions are associated with low-grade chronic inflammation and accelerated atherosclerosis. Several classes of leukocytes have been implicated in diabetic cardiovascular impairment. Although the molecular pathways through which diabetes elicits an inflammatory response have attracted significant attention, how they contribute to altering cardiovascular homeostasis is still incompletely understood. In this respect, non-coding RNAs (ncRNAs) are a still largely under-investigated class of transcripts that may play a fundamental role. This review article gathers the current knowledge on the function of ncRNAs in the crosstalk between immune and cardiovascular cells in the context of diabetic complications, highlighting the influence of biological sex in such mechanisms and exploring the potential role of ncRNAs as biomarkers and targets for treatments. The discussion closes by offering an overview of the ncRNAs involved in the increased cardiovascular risk suffered by patients with diabetes facing Sars-CoV-2 infection.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 24 May 2023; 22:122</small></div>

<div><h4>Sodium-glucose cotransporter 2 inhibitor may not prevent atrial fibrillation in patients with heart failure: a systematic review.</h4><i>Ouyang X, Wang J, Chen Q, Peng L, Li S, Tang X</i><br /><b>Background</b><br />Atrial fibrillation (AF) and heart failure (HF) frequently coexist because of their similar pathological basis. However, whether sodium-glucose cotransporter 2 inhibitor (SGLT2i), a novel class of anti-HF medication, decreases the risk of AF in HF patients remains unclear.<br /><b>Objectives</b><br />The aim of this study was to assess the relationship between SGLT2i and AF in HF patients.<br /><b>Methods</b><br />A meta-analysis of randomized controlled trails evaluating the effects of SGLT2i on AF in HF patients was performed. PubMed and ClinicalTrails.gov were searched for eligible studies until 27 November 2022. The risk of bias and quality of evidence were assessed through the Cochrane tool. Pooled risk ratio of AF for SGLT2i versus placebo in eligible studies was calculated.<br /><b>Results</b><br />A total of 10 eligible RCTs examining 16,579 patients were included in the analysis. AF events occurred in 4.20% (348/8292) patients treated with SGLT2i, and in 4.57% (379/8287) patients treated with placebo. Meta-analysis showed that SGLT2i did not significantly reduce the risk of AF (RR 0.92; 95% CI 0.80-1.06; p = 0.23) in HF patients when compared to placebo. Similar results remained in the subgroup analyses, regardless of the type of SGLT2i, the type of HF, and the duration of follow-up.<br /><b>Conclusions</b><br />Current evidences showed that SGLT2i may have no preventive effects on the risk of AF in patients with HF.<br /><b>Translational perspective</b><br />Despite HF being one of the most common heart diseases and conferring increased risk for AF, affective prevention of AF in HF patients is still unresolved. The present meta-analysis demonstrated that SGLT2i may have no preventive effects on reducing AF in patients with HF. How to effectively prevent and early detect the occurrence of AF is worth discussing.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 24 May 2023; 22:124</small></div>

<div><h4>Exploring new insights in coronary lesion assessment and treatment in patients with diabetes mellitus: the impact of optical coherence tomography.</h4><i>Hommels TM, Hermanides RS, Fabris E, Kedhi E</i><br /><AbstractText>In this review, we summarise new insights into diagnostic approaches and treatment strategies for coronary artery disease (CAD) in patients with diabetes mellitus (DM). Despite the improvements in therapy, the clinical management of DM patients remains challenging as they develop more extensive CAD at a younger age and consistently have worse clinical outcomes than non-DM patients. Current diagnostic modalities as well as revascularisation treatments mainly focus on ischemic lesions. However, the impact of plaque morphology and composition are emerging as strong predictors of adverse cardiac events even in the absence of identified ischemia. In particular, the presence of vulnerable plaques such as thin-cap fibroatheroma (TCFA) lesions has been identified as a very strong predictor of future adverse events. This emphasises the need for an approach combining both functional and morphological methods in the assessment of lesions. In particular, optical coherence tomography (OCT) has proven to be a valuable asset by truly identifying TCFAs. New treatment strategies should consist of individualised and advanced medical regimens and may evolve towards plaque sealing through percutaneous treatment.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 24 May 2023; 22:123</small></div>

<div><h4>Evolocumab attenuate pericoronary adipose tissue density via reduction of lipoprotein(a) in type 2 diabetes mellitus: a serial follow-up CCTA study.</h4><i>Yu MM, Zhao X, Chen YY, Tao XW, ... Jin H, Zeng MS</i><br /><b>Background</b><br />Pericoronary adipose tissue (PCAT) density is a biomarker of vessel inflammation, which is supposed to be increased in patients with type 2 diabetes mellitus (T2DM). However, whether the coronary inflammation revealed by this novel index could be alleviated after evolocumab treatment in T2DM remains unknown.<br /><b>Methods</b><br />From January 2020 to December 2022, consecutive T2DM patients with low-density lipoprotein cholesterol ≥ 70 mg/dL on maximally tolerated statin and taking evolocumab were prospectively included. In addition, patients with T2DM who were taking statin alone were recruited as control group. The eligible patients underwent baseline and follow-up coronary CT angiography with an interval of 48-week. To render patients with evolocumab as comparable to those controls, a propensity-score matching design was used to select the matched pairs with a 1:1 ratio. Obstructive lesion was defined as the extent of coronary artery stenosis ≥ 50%; the numbers inside the brackets were interquartile ranges.<br /><b>Results</b><br />A total of 170 T2DM patients with stable chest pain were included [(mean age 64 ± 10.6 [range 40-85] years; 131 men). Among those patients, 85 were in evolocumab group and 85 were in control group. During follow-up, low-density lipoprotein cholesterol (LDL-C) level (2.02 [1.26, 2.78] vs. 3.34 [2.53, 4.14], p < 0.001), and lipoprotein(a) (12.1 [5.6, 21.8] vs. 18.9 [13.2, 27.2], p = 0.002) were reduced after evolocumab treatment. The prevalence of obstructive lesions and high-risk plaque features were significantly decreased (p < 0.05 for all). Furthermore, the calcified plaque volume were significantly increased (188.3 [115.7, 361.0] vs. 129.3 [59.5, 238.3], p = 0.015), while the noncalcified plaque volume and necrotic volume were diminished (107.5 [40.6, 180.6] vs. 125.0 [65.3, 269.7], p = 0.038; 0 [0, 4.7] vs. 0 [0, 13.4], p < 0.001, respectively). In addition, PCAT density of right coronary artery was significantly attenuated in evolocumab group (- 85.0 [- 89.0, - 82.0] vs. - 79.0 [- 83.5, - 74.0], p < 0.001). The change in the calcified plaque volume inversely correlated with achieved LDL-C level (r =  - 0.31, p < 0.001) and lipoprotein(a) level (r =  - 0.33, p < 0.001). Both the changes of noncalcified plaque volume and necrotic volume were positively correlated with achieved LDL-C level and Lp(a) (p < 0.001 for all). However, the change of PCAT<sub>RCA</sub> density only positively correlated with achieved lipoprotein(a) level (r = 0.51, p < 0.001). Causal mediation analysis revealed Lp(a) level mediated 69.8% (p < 0.001) for the relationship between evolocumab and changes of PCAT<sub>RCA</sub>.<br /><b>Conclusions</b><br />In patients with T2DM, evolocumab is an effective therapy to decrease noncalcified plaque volume necrotic volume, and increase calcified plaque volume. Furthermore, evolocumab could attenuate PCAT density, at least in part, via the reduction of lipoprotein(a).<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 22 May 2023; 22:121</small></div>

<div><h4>Drug-coated balloon-based versus drug-eluting stent-only revascularization in patients with diabetes and multivessel coronary artery disease.</h4><i>Her AY, Shin ES, Kim S, Kim B, ... Cho JR, Jeong YH</i><br /><b>Background</b><br />Data on drug-coated balloon (DCB) treatment in the context of diabetes mellitus (DM) and multivessel coronary artery disease (CAD) are limited. We aimed to investigate the clinical impact of DCB-based revascularization on percutaneous coronary intervention (PCI) in patients with DM and multivessel CAD.<br /><b>Methods</b><br />A total of 254 patients with multivessel disease (104 patients with DM) successfully treated with DCB alone or combined with drug-eluting stent (DES) were retrospectively enrolled (DCB-based group) and compared with 254 propensity-matched patients treated with second-generation DES from the PTRG-DES registry (n = 13,160 patients) (DES-only group). Major adverse cardiovascular events (MACE) comprised cardiac death, myocardial infarction, stroke, stent or target lesion thrombosis, target vessel revascularization, and major bleeding at 2 years.<br /><b>Results</b><br />The DCB-based group was associated with a reduced risk of MACE in patients with DM (hazard ratio [HR] 0.19, 95% confidence interval [CI] 0.05-0.68, p = 0.003], but not in those without DM (HR 0.52, 95% CI 0.20-1.38, p = 0.167) at the 2-year follow-up. In patients with DM, the risk of cardiac death was lower in the DCB-based group than the DES-only group, but not in those without DM. In both patients with or without DM, the burdens of DES and small DES (less than 2.5 mm) used were lower in the DCB-based group than in the DES-only group.<br /><b>Conclusions</b><br />In multivessel CAD, the clinical benefit of a DCB-based revascularization strategy appears to be more evident in patients with DM than in those without DM after 2 years of follow-up. (Impact of Drug-Coated Balloon Treatment in De Novo Coronary Lesion; NCT04619277).<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 20 May 2023; 22:120</small></div>

<div><h4>Lack of impact of ipragliflozin on endothelial function in patients with type 2 diabetes: sub-analysis of the PROTECT study.</h4><i>Kishimoto S, Higashi Y, Imai T, Eguchi K, ... Node K, PROTECT investigators</i><br /><b>Background</b><br />We assessed the impact of 24 months of treatment with ipragliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on endothelial function in patients with type 2 diabetes as a sub-analysis of the PROTECT study.<br /><b>Methods</b><br />In the PROTECT study, patients were randomized to receive either standard antihyperglycemic treatment (control group, n = 241 ) or add-on ipragliflozin treatment (ipragliflozin group, n = 241) in a 1:1 ratio. Among the 482 patients in the PROTECT study, flow-mediated vasodilation (FMD) was assessed in 32 patients in the control group and 26 patients in the ipragliflozin group before and after 24 months of treatment.<br /><b>Results</b><br />HbA1c levels significantly decreased after 24 months of treatment compared to the baseline value in the ipragliflozin group, but not in the control group. However, there was no significant difference between the changes in HbA1c levels in the two groups (7.4 ± 0.8% vs. 7.0 ± 0.9% in the ipragliflozin group and 7.4 ± 0.7% vs. 7.3 ± 0.7% in the control group; P = 0.08). There was no significant difference between FMD values at baseline and after 24 months in both groups (5.2 ± 2.6% vs. 5.2 ± 2.6%, P = 0.98 in the ipragliflozin group; 5.4 ± 2.9% vs. 5.0 ± 3.2%, P = 0.34 in the control group). There was no significant difference in the estimated percentage change in FMD between the two groups (P = 0.77).<br /><b>Conclusions</b><br />Over a 24-month period, the addition of ipragliflozin to standard therapy in patients with type 2 diabetes did not change endothelial function assessed by FMD in the brachial artery.<br /><b>Trial registration</b><br />Registration Number for Clinical Trial: jRCT1071220089 ( https://jrct.niph.go.jp/en-latest-detail/jRCT1071220089 ).<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 20 May 2023; 22:119</small></div>

<div><h4>Impact of mental disorders on the risk of heart failure among Korean patients with diabetes: a cohort study.</h4><i>Yoo TK, Han KD, Rhee EJ, Lee WY</i><br /><b>Background</b><br />Few studies have assessed the correlation between coexisting mental disorders in participants with diabetes mellitus (DM) and the risk of heart failure (HF). Herein, we conducted a cohort study to determine the association between the accumulation of mental disorders in participants with DM and the risk of HF.<br /><b>Methods</b><br />The Korean National Health Insurance Service records were assessed. 2,447,386 adults with DM who underwent health screening between 2009 and 2012 were analyzed. Participants with major depressive disorder, bipolar disorder, schizophrenia, insomnia, or anxiety disorders were included. In addition, participants were categorized based on the number of coexisting mental disorders. Each participant was followed until December 2018 or until the onset of HF. Cox proportional hazard modelling with confounding factors adjustment was conducted. In addition, a competing risk analysis was conducted. Subgroup analysis assessed the impact of clinical variables on the association between the accumulation of mental disorders and the risk of HF.<br /><b>Results</b><br />The median follow-up duration was 7.09 years. The accumulation of mental disorders was associated with a risk of HF (zero mental disorder (0), reference; 1 mental disorder, adjusted hazard ratio (aHR): 1.222, 95% confidence intervals (CI): 1.207-1.237; 2 mental disorders, aHR: 1.426, CI: 1.403-1.448; ≥3 mental disorders, aHR: 1.667, CI: 1.632-1.70. In the subgroup analysis, the strength of association was the strongest in the younger age group (< 40 years, 1 mental disorder, aHR 1.301, CI 1.143-1.481; ≥2 mental disorders, aHR 2.683, CI 2.257-3.190; 40-64 years, 1 mental disorder, aHR 1.289, CI 1.265-1.314; ≥2 mental disorders, aHR 1.762, CI 1.724-1.801; ≥65 years, 1 mental disorder, aHR 1.164, CI 1.145-1.183; ≥2 mental disorders, aHR 1.353, CI 1.330-1.377; P<sub>inter</sub><0.001). In addition, income, BMI, hypertension, chronic kidney disease, history of cardiovascular disease, insulin use, and duration of DM showed significant interactions.<br /><b>Conclusions</b><br />Comorbid mental disorders in participants with DM are associated with an increased risk of HF. In addition, the association was stronger in a younger age group. Participants with DM and mental disorders should be monitored with increased frequency for signs of HF; for which they have a higher risk than the general population.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 18 May 2023; 22:115</small></div>

<div><h4>U-shaped association between the triglyceride-glucose index and atrial fibrillation incidence in a general population without known cardiovascular disease.</h4><i>Liu X, Abudukeremu A, Jiang Y, Cao Z, ... Zhang Y, Wang J</i><br /><b>Objective</b><br />The triglyceride-glucose (TyG) index has been shown to be a new alternative measure for insulin resistance. However, no study has attempted to investigate the association of the TyG index with incident atrial fibrillation (AF) in the general population without known cardiovascular diseases.<br /><b>Methods</b><br />Individuals without known cardiovascular diseases (heart failure, coronary heart disease, or stroke) from the Atherosclerosis Risk in Communities (ARIC) cohort were recruited. The baseline TyG index was calculated as the Ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. The association between the baseline TyG index and incident AF was examined using Cox regression.<br /><b>Results</b><br />Of 11,851 participants, the mean age was 54.0 years; 6586 (55.6%) were female. During a median follow-up of 24.26 years, 1925 incidents of AF cases (0.78/per 100 person-years) occurred. An increased AF incidence with a graded TyG index was found by Kaplan‒Meier curves (P < 0.001). In multivariable-adjusted analysis, both < 8.80 (adjusted hazard ratio [aHR] = 1.15, 95% confidence interval [CI] 1.02, 1.29) and > 9.20 levels (aHR 1.18, 95% CI 1.03, 1.37) of the TyG index were associated with an increased risk of AF compared with the middle TyG index category (8.80-9.20). The exposure-effect analysis confirmed the U-shaped association between the TyG index and AF incidence (P = 0.041). Further sex-specific analysis showed that a U-shaped association between the TyG index and incident AF still existed in females but not in males.<br /><b>Conclusions</b><br />A U-shaped association between the TyG index and AF incidence is observed in Americans without known cardiovascular diseases. Female sex may be a modifier in the association between the TyG index and AF incidence.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 18 May 2023; 22:118</small></div>

<div><h4>Effects of metabolic parameters\' variability on cardiovascular outcomes in diabetic patients.</h4><i>Lim S, Chung SH, Kim JH, Kim YH, Kim EJ, Joo HJ</i><br /><b>Background</b><br />Metabolic abnormalities such as dyslipidemia, glucose and high blood pressure are common in diabetic patients. Visit-to-visit variabilities in these measures have been reported as potential residual cardiovascular risk factors. However, the relationship between these variabilities and their effects on cardiovascular prognosis have not been studied.<br /><b>Methods</b><br />A total of 22,310 diabetic patients with ≥ 3 measurements of systolic blood pressure (SBP), blood glucose, total cholesterol (TC), and triglyceride (TG) levels during a minimum of three years at three tertiary general hospitals were selected. They were divided into high/low variability groups for each variable based on the coefficient of variation (CV) values. The primary outcome was the incidence of major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke.<br /><b>Results</b><br />All high CV groups had a higher incidence of MACE than those with low CV (6.0% vs. 2.5% for SBP-CV groups, 5.5% vs. 3.0% for TC-CV groups, 4.7% vs. 3.8% for TG-CV groups, 5.8% vs. 2.7% for glucose-CV groups). In multivariable Cox regression analysis,, high SBP-CV (HR 1.79 [95% CI 1.54-2.07], p < 0.01), high TC-CV (HR 1.54 [95% CI 1.34-1.77], p < 0.01), high TG-CV (HR 1.15 [95% CI 1.01-1.31], p = 0.040) and high glucose-CV (HR 1.61 [95% CI 1.40-1.86], p < 0.01) were independent predictors of MACE.<br /><b>Conclusion</b><br />Variability of SBP, TC, TG and glucose are important residual risk factors for cardiovascular events in diabetic patients.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 15 May 2023; 22:114</small></div>

<div><h4>Association between triglyceride glucose index and arterial stiffness and coronary artery calcification: a systematic review and exposure-effect meta-analysis.</h4><i>Liu F, Ling Q, Xie S, Xu Y, ... Luo J, Liu X</i><br /><b>Background</b><br />The triglyceride and glucose (TyG) index has been linked to various cardiovascular diseases. However, it\'s still unclear whether the TyG index is associated with arterial stiffness and coronary artery calcification (CAC).<br /><b>Methods</b><br />We conducted a systematic review and meta-analysis of relevant studies until September 2022 in the PubMed, Cochrane Library, and Embase databases. We used a random-effects model to calculate the pooled effect estimate and the robust error meta-regression method to summarize the exposure-effect relationship.<br /><b>Results</b><br />Twenty-six observational studies involving 87,307 participants were included. In the category analysis, the TyG index was associated with the risk of arterial stiffness (odds ratio [OR]: 1.83; 95% CI 1.55-2.17, I<sup>2</sup> = 68%) and CAC (OR: 1.66; 95% CI 1.51-1.82, I<sup>2</sup> = 0). The per 1-unit increment in the TyG index was also associated with an increased risk of arterial stiffness (OR: 1.51, 95% CI 1.35-1.69, I<sup>2</sup> = 82%) and CAC (OR: 1.73, 95% CI 1.36-2.20, I<sup>2</sup> = 51%). Moreover, a higher TyG index was shown to be a risk factor for the progression of CAC (OR = 1.66, 95% CI 1.21-2.27, I<sup>2</sup> = 0, in category analysis, OR = 1.47, 95% CI 1.29-1.68, I<sup>2</sup> = 41% in continuity analysis). There was a positive nonlinear association between the TyG index and the risk of arterial stiffness (P<sub>nonlinearity</sub> < 0.001).<br /><b>Conclusion</b><br />An elevated TyG index is associated with an increased risk of arterial stiffness and CAC. Prospective studies are needed to assess causality.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 13 May 2023; 22:111</small></div>

<div><h4>Diabetes is accompanied by secretion of pro-atherosclerotic exosomes from vascular smooth muscle cells.</h4><i>Yu H, Douglas HF, Wathieu D, Braun RA, ... Khismatullin DB, Woods TC</i><br /><b>Background</b><br />Atherosclerosis is a common co-morbidity of type 2 diabetes mellitus. Monocyte recruitment by an activated endothelium and the pro-inflammatory activity of the resulting macrophages are critical components of atherosclerosis. Exosomal transfer of microRNAs has emerged as a paracrine signaling mechanism regulating atherosclerotic plaque development. MicroRNAs-221 and -222 (miR-221/222) are elevated in vascular smooth muscle cells (VSMCs) of diabetic patients. We hypothesized that the transfer of miR-221/222 via VSMC-derived exosomes from diabetic sources (DVEs) promotes increased vascular inflammation and atherosclerotic plaque development.<br /><b>Methods</b><br />Exosomes were obtained from VSMCs, following exposure to non-targeting or miR-221/-222 siRNA (-KD), isolated from diabetic (DVEs) and non-diabetic (NVEs) sources and their miR-221/-222 content was measured using droplet digital PCR (ddPCR). Expression of adhesion molecules and the adhesion of monocytes was measured following exposure to DVEs and NVEs. Macrophage phenotype following exposure to DVEs was determined by measuring mRNA markers and secreted cytokines. Age-matched apolipoprotein-E-deficient mice null (ApoE<sup>-/-</sup>) mice were maintained on Western diet for 6 weeks and received injections of saline, NVEs, NVE-KDs, DVEs or DVE-KDs every other day. Atherosclerotic plaque formation was measured using Oil Red Oil staining.<br /><b>Results</b><br />Exposure of human umbilical vein and coronary artery endothelial cells to DVEs, but not NVEs, NVE-KDs, or DVE-KDs promoted increased intercellular adhesion molecule-1 expression and monocyte adhesion. DVEs but not NVEs, NVE-KDs, or DVE-KDs also promoted pro-inflammatory polarization of human monocytes in a miR-221/222 dependent manner. Finally, intravenous administration of DVEs, but not NVEs, resulted in a significant increase in atherosclerotic plaque development.<br /><b>Conclusion</b><br />These data identify a novel paracrine signaling pathway that promotes the cardiovascular complications of diabetes mellitus.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 13 May 2023; 22:112</small></div>

<div><h4>Association between the triglyceride glucose index and in-hospital and 1-year mortality in patients with chronic kidney disease and coronary artery disease in the intensive care unit.</h4><i>Ye Z, An S, Gao Y, Xie E, ... Shen N, Zheng J</i><br /><b>Objective</b><br />This study aimed to explore the association between the triglyceride glucose index (TyG) and the risk of in-hospital and one-year mortality in patients with chronic kidney disease (CKD) and cardiovascular disease (CAD) admitted to the intensive care unit (ICU).<br /><b>Methods</b><br />The data for the study were taken from the Medical Information Mart for Intensive Care-IV database which contained over 50,000 ICU admissions from 2008 to 2019. The Boruta algorithm was used for feature selection. The study used univariable and multivariable logistic regression analysis, Cox regression analysis, and 3-knotted multivariate restricted cubic spline regression to evaluate the association between the TyG index and mortality risk.<br /><b>Results</b><br />After applying inclusion and exclusion criteria, 639 CKD patients with CAD were included in the study with a median TyG index of 9.1 [8.6,9.5]. The TyG index was nonlinearly associated with in-hospital and one-year mortality risk in populations within the specified range.<br /><b>Conclusion</b><br />This study shows that TyG is a predictor of one-year mortality and in-hospital mortality in ICU patients with CAD and CKD and inform the development of new interventions to improve outcomes. In the high-risk group, TyG might be a valuable tool for risk categorization and management. Further research is required to confirm these results and identify the mechanisms behind the link between TyG and mortality in CAD and CKD patients.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 13 May 2023; 22:110</small></div>

<div><h4>Association between the triglyceride-glucose index and the presence and prognosis of coronary microvascular dysfunction in patients with chronic coronary syndrome.</h4><i>Zhang W, Liu L, Chen H, Li S, ... Abdu FA, Che W</i><br /><b>Background</b><br />Coronary microvascular dysfunction (CMD) is a strong determinant of prognosis in patients with chronic coronary syndrome (CCS). The triglyceride-glucose index (TyG index), an alternative method to evaluate insulin resistance, is positively correlated with the incidence and adverse outcomes of cardiovascular diseases. However, the relationship between the TyG index and the presence and prognosis of CMD in CCS patients has not been investigated. Therefore, we aimed to evaluate the association between the TyG index and the presence and clinical outcomes of CMD among CCS patients.<br /><b>Methods</b><br />CCS patients who underwent coronary angiography between June 2015 to June 2019 were included. The TyG index was calculated as Ln[fasting triglycerides (mg/dL) × fasting blood glucose (mg/dL)/2]. Coronary angiography‑derived index of microvascular resistance (caIMR) was used to measure microvascular function, and CMD was defined as caIMR ≥ 25U. Patients with CMD were divided into three groups (T1, T2, and T3 groups) according to TyG tertiles. The primary endpoint was major adverse cardiac event (MACE).<br /><b>Results</b><br />Of 430 CCS patients, 221 patients had CMD. CMD patients had significantly higher TyG index than those without CMD. Sixty-three MACE was recorded during the follow-up duration among CMD patients, and the incidence rate of MACE was higher in the T3 group compared to T1/T2 groups (39.2% vs. 20.5% vs. 25.7%; P = 0.035). Multivariable logistic regression analysis showed that the TyG index was an independent predictor of CMD (OR, 1.436; 95% CI, 1.014-2.034; P = 0.042). Compared to the T1 group, the T3 group strongly correlated with the risk of MACE in CMD patients even after adjusting for additional confounding risk factors (HR, 2.132; 95%CI, 1.066-4.261; P = 0.032).<br /><b>Conclusion</b><br />TyG index is significantly associated with the risk of CMD, and it is an independent predictor of MACE among CMD patients with CCS. This study suggests that the TyG index has important clinical significance for the early prevention and risk stratification of CMD.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 13 May 2023; 22:113</small></div>

<div><h4>Impact of individual microvascular disease on the risks of macrovascular complications in type 2 diabetes: a nationwide population-based cohort study.</h4><i>Yen FS, Wei JC, Shih YH, Hsu CC, Hwu CM</i><br /><b>Background</b><br />This study compared the risks of cardiovascular morbidity and mortality between patients with type 2 diabetes (T2D) with and without microvascular diseases, and between matched patients with microvascular diseases.<br /><b>Methods</b><br />We identified newly diagnosed type 2 diabetes patients from National Health Insurance Research Database in Taiwan from January 1, 2008, to December 31, 2019. Propensity score matching was applied to construct matched pairs of patients with diabetic kidney disease, retinopathy, or neuropathy. Multivariable Cox proportional-hazard models were adopted to compare the risks of cardiovascular morbidity and mortality.<br /><b>Results</b><br />Patients with microvascular disease had a significantly higher risk of cardiovascular morbidities and mortality than those without microvascular disease. Among the matched cohorts, patients with diabetic retinopathy had a significantly higher risk of stroke development than those with diabetic kidney disease (aHR 1.11, 95%CI 1.03-1.2). Diabetic neuropathy showed a significantly higher risk of stroke development than diabetic kidney disease (aHR 1.17, 95%CI 1.1-1.25) and diabetic retinopathy (aHR 1.12, 95%CI 1.03-1.21). Diabetic retinopathy had a significantly higher risk of incident heart failure than diabetic kidney disease (aHR 1.43, 95%CI 1.3-1.57), and diabetic neuropathy had a significantly lower risk of incident heart failure than diabetic retinopathy (aHR 0.79, 95%CI 0.71-0.87).<br /><b>Conclusions</b><br />T2D patients with microvascular disease have a significantly higher risk of cardiovascular morbidities and mortality than those without microvascular disease. In the matched cohorts, diabetic neuropathy was significantly associated with stroke development, and diabetic retinopathy had a significant association with heart failure compared to other microvascular diseases.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 09 May 2023; 22:109</small></div>

<div><h4>An analysis of DPV and DIVE registry patients with chronic kidney disease according to the finerenone phase III clinical trial selection criteria.</h4><i>Bramlage P, Lanzinger S, Mühldorfer S, Milek K, ... Holl RW, Seufert J</i><br /><b>Background</b><br />The FIDELIO-DKD and FIGARO-DKD randomized clinical trials (RCTs) showed finerenone, a novel non-steroidal mineralocorticoid receptor antagonist (MRA), reduced the risk of renal and cardiovascular events in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Using RCT inclusion and exclusion criteria, we analyzed the RCT coverage for patients with T2DM and CKD in routine clinical practice in Germany.<br /><b>Methods</b><br />German patients from the DPV/DIVE registries who were ≥ 18 years, had T2DM and CKD (an estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m<sup>2</sup> OR eGFR ≥ 60 mL/min/1.73m<sup>2</sup> and albuminuria [≥ 30 mg/g]) were included. RCT inclusion and exclusion criteria were then applied, and the characteristics of the two populations compared.<br /><b>Results</b><br />Overall, 65,168 patients with T2DM and CKD were identified from DPV/DIVE. Key findings were (1) Registry patients with CKD were older, less often male, and had a lower eGFR, but more were normoalbuminuric vs the RCTs. Cardiovascular disease burden was higher in the RCTs; diabetic neuropathy, lipid metabolism disorders, and peripheral arterial disease were more frequent in the registry. CKD-specific drugs (e.g., angiotensin-converting enzyme inhibitors [ACEi] and angiotensin receptor blocker [ARBs]) were used less often in clinical practice; (2) Due to the RCT\'s albuminuric G1/2 to G4 CKD focus, they did not cover 28,147 (43.2%) normoalbuminuric registry patients, 4,519 (6.9%) albuminuric patients with eGFR < 25, and 6,565 (10.1%) patients with microalbuminuria but normal GFR (≥ 90 ml/min); 3) As RCTs required baseline ACEi or ARB treatment, the number of comparable registry patients was reduced to 28,359. Of these, only 12,322 (43.5%) registry patients fulfilled all trial inclusion and exclusion criteria. Registry patients that would have been eligible for the RCTs were more often male, had higher eGFR values, higher rates of albuminuria, more received metformin, and more SGLT-2 inhibitors than patients that would not be eligible.<br /><b>Conclusions</b><br />Certain patient subgroups, especially non-albuminuric CKD-patients, were not included in the RCTs. Although recommended by guidelines, there was an undertreatment of CKD-patients with renin-angiotensin system (RAS) blockers. Further research into patients with normoalbuminuric CKD and a wider prescription of RAS blocking agents for CKD patients in clinical practice appears warranted.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 08 May 2023; 22:108</small></div>

<div><h4>Down-regulation of WWP2 aggravates Type 2 diabetes mellitus-induced vascular endothelial injury through modulating ubiquitination and degradation of DDX3X.</h4><i>You S, Xu J, Yin Z, Wu B, ... Sun Y, Zhang N</i><br /><b>Background</b><br />Endothelial injury caused by Type 2 diabetes mellitus (T2DM) is considered as a mainstay in the pathophysiology of diabetic vascular complications (DVCs). However, the molecular mechanism of T2DM-induced endothelial injury remains largely unknown. Here, we found that endothelial WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) act as a novel regulator for T2DM-induced vascular endothelial injury through modulating ubiquitination and degradation of DEAD-box helicase 3 X-linked (DDX3X).<br /><b>Methods</b><br />Single-cell transcriptome analysis was used to evaluate WWP2 expression in vascular endothelial cells of T2DM patients and healthy controls. Endothelial-specific Wwp2 knockout mice were used to investigate the effect of WWP2 on T2DM-induced vascular endothelial injury. In vitro loss- and gain-of-function studies were performed to assess the function of WWP2 on cell proliferation and apoptosis of human umbilical vein endothelial cells. The substrate protein of WWP2 was verified using mass spectrometry, coimmunoprecipitation assays and immunofluorescence assays. The mechanism of WWP2 regulation on substrate protein was investigated by pulse-chase assay and ubiquitination assay.<br /><b>Results</b><br />The expression of WWP2 was significantly down-regulated in vascular endothelial cells during T2DM. Endothelial-specific Wwp2 knockout in mice significantly aggravated T2DM-induced vascular endothelial injury and vascular remodeling after endothelial injury. Our in vitro experiments showed that WWP2 protected against endothelial injury by promoting cell proliferation and inhibiting apoptosis in ECs. Mechanically, we found that WWP2 is down-regulated in high glucose and palmitic acid (HG/PA)-induced ECs due to c-Jun N-terminal kinase (JNK) activation, and uncovered that WWP2 suppresses HG/PA-induced endothelial injury by catalyzing K63-linked polyubiquitination of DDX3X and targeting it for proteasomal degradation.<br /><b>Conclusion</b><br />Our studies revealed the key role of endothelial WWP2 and the fundamental importance of the JNK-WWP2-DDX3X regulatory axis in T2DM-induced vascular endothelial injury, suggesting that WWP2 may serve as a new therapeutic target for DVCs.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 06 May 2023; 22:107</small></div>

<div><h4>Lobeglitazone, a novel thiazolidinedione, for secondary prevention in patients with ischemic stroke: a nationwide nested case-control study.</h4><i>Yoo J, Jeon J, Baik M, Kim J</i><br /><b>Introduction</b><br />Ischemic stroke patients with diabetes are at high risk for recurrent stroke and cardiovascular complications. Pioglitazone, a type of thiazolidinedione, has been shown to reduce cardiovascular complications in patients with ischemic stroke and type 2 diabetes (T2D) or insulin resistance. Lobeglitazone is a novel thiazolidinedione agent that improves insulin resistance and has similar glycemic efficacy to pioglitazone. Using population-based health claims data, we evaluated whether lobeglitazone has secondary cardiovascular preventive effects in patients with ischemic stroke and T2D.<br /><b>Methods</b><br />This study has a nested case-control design. From nationwide health claims data in Korea, we identified patients with T2D admitted for acute ischemic stroke in 2014-2018. Cases were defined who suffered the primary outcome (a composite of recurrent stroke, myocardial infarction, and all-cause death) before December 2020. Three controls were selected by incidence density sampling for each case from those who were at risk at the time of their case occurrence with exact matching on sex, age, the presence of comorbidities, and medications. As a safety outcome, we also evaluated the risk of heart failure (HF) according to the use of lobeglitazone.<br /><b>Results</b><br />From the cohort of 70,897 T2D patients with acute ischemic stroke, 20,869 cases and 62,607 controls were selected. In the multivariable conditional logistic regression, treatment with lobeglitazone (adjusted OR 0.74; 95% CI 0.61-0.90; p = 0.002) and pioglitazone (adjusted OR 0.71; 95% CI 0.64-0.78; p < 0.001) were significantly associated with a lower risk for the primary outcome. In a safety outcome analysis for HF, treatment with lobeglitazone did not increase the risk of HF (adjusted OR 0.90; 95% CI 0.66-1.22; p = 0.492).<br /><b>Conclusions</b><br />In T2D patients with ischemic stroke, lobeglitazone reduced the risk of cardiovascular complications similar to that of pioglitazone without an increased risk of HF. There is a need for further studies on the cardioprotective role of lobeglitazone, a novel thiazolidinedione.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 05 May 2023; 22:106</small></div>

<div><h4>Liraglutide reduces plasma dihydroceramide levels in patients with type 2 diabetes.</h4><i>Denimal D, Bergas V, Pais-de-Barros JP, Simoneau I, ... Duvillard L, Vergès B</i><br /><b>Background</b><br />Emerging evidence supports that dihydroceramides (DhCer) and ceramides (Cer) contribute to the pathophysiology of insulin resistance and liver steatosis, and that their circulating concentrations are independently associated with cardiovascular outcomes. Circulating DhCer levels are increased in patients with type 2 diabetes (T2D). On the other hand, the GLP-1 receptor agonist liraglutide reduces major adverse cardiac events, insulin resistance and liver steatosis in T2D patients. The main purpose of the present study was therefore to investigate whether liraglutide decreases circulating levels of DhCer and Cer in T2D patients, which could be a mechanism involved in its cardiometabolic benefits. The secondary purpose was to assess the relationship between liraglutide-induced changes in DhCer/Cer levels and insulin resistance and liver steatosis.<br /><b>Methods</b><br />Plasma concentrations of 11 DhCer and 15 Cer species were measured by a highly-sensitive mass spectrometry system in 35 controls and 86 T2D patients before and after 6 months of liraglutide (1.2 mg/day). Insulin resistance was estimated by the triglyceride-glucose (TyG) index. Liver fat content (LFC) was assessed in 53 patients by proton magnetic resonance spectroscopy.<br /><b>Results</b><br />Plasma levels of total DhCer, 7 DhCer and 7 Cer species were increased in T2D patients compared to controls. Liraglutide decreased total DhCer by 15.1% (p = 0.005), affecting 16:0 (p = 0.037), 18:0 (p < 0.0001), 18:1 (p = 0.0005), 20:0 (p = 0.0003), 23:0 (p = 0.005) and 24:1 (p = 0.04) species. Total plasma Cer did not significantly change after liraglutide (p = 0.18), but 5 Cer species decreased significantly, i.e. 18:0 and 18:1 (both p < 0.0001), 19:0 and 24:1 (both p < 0.01) and 26:1 (p = 0.04). In multivariate analysis, the reduction in DhCer after liraglutide was independently associated with the reduction in LFC (p = 0.0005) and in TyG index (p = 0.05).<br /><b>Conclusions</b><br />Liraglutide reduces plasma levels of numerous DhCer and Cer species in T2D patients, which may contribute to the cardiovascular benefit observed in the LEADER trial. The independent association between the decrease in plasma DhCer level with the reduction in LFC and TyG index adds new insights regarding the relationship between DhCer, liver steatosis and insulin resistance. Trial registration ClinicalTrials.gov identifier: NCT02721888.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 04 May 2023; 22:104</small></div>

<div><h4>Lower heart rate variability, an index of worse autonomic function, is associated with worse beta cell response to a glycemic load in vivo-The Maastricht Study.</h4><i>Rinaldi E, van der Heide FC, Bonora E, Trombetta M, ... van Greevenbroek MM, Stehouwer CD</i><br /><b>Objective</b><br />We investigated, using population-based data, whether worse autonomic function, estimated from lower 24-hour heart rate variability (HRV), was associated with beta cell function, assessed from beta cell response during an oral glucose tolerance test (OGTT).<br /><b>Research design and methods</b><br />We used cross-sectional data from The Maastricht Study, a population-based cohort study (N = 2,007; age, mean ± SD:60 ± 8 years; 52% men; and 24% with type 2 diabetes). We used linear regression analyses with adjustment for potential confounders (demographic, cardiovascular, and lifestyle factors) to study the associations of time- and frequency-domain HRV (composite scores) with overall beta cell response (estimated from a composite score calculated from: C-peptidogenic index, overall insulin secretion, beta cell glucose sensitivity, beta cell potentiation factor, and beta cell rate sensitivity). In addition, we tested for interaction by sex and glucose metabolism status.<br /><b>Results</b><br />After full adjustment, lower time- and frequency-domain HRV was significantly associated with lower overall beta cell response composite score (standardized beta, -0.055 [-0.098; -0.011] and - 0.051 [-0.095; -0.007], respectively). These associations were not modified by sex and there was no consistent pattern of interaction by glucose metabolism status.<br /><b>Conclusion</b><br />The present etiological study found that worse autonomic function, estimated from lower HRV, was associated with worse beta cell function, estimated from a composite score in a population-based sample which covered the entire spectrum of glucose metabolism. Hence, autonomic dysfunction may contribute to beta cell dysfunction and, ultimately, to the alteration of glucose metabolism status from normal glucose metabolism to prediabetes and type 2 diabetes.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 04 May 2023; 22:105</small></div>

<div><h4>The degree of cortisol secretion is associated with diabetes mellitus and hypertension in patients with nonfunctioning adrenal tumors.</h4><i>Favero V, Aresta C, Parazzoli C, Cairoli E, ... Morelli V, Chiodini I</i><br /><b>Background</b><br />Similarly to cortisol-secreting adrenal tumors, also non-functioning adrenal tumors (NFAT) may be associated with an increased cardiovascular risk. We assessed in NFAT patients: (i) the association between hypertension (HT), diabetes mellitus (DM), obesity (OB), dyslipidemia (DL) and cardiovascular events (CVE) and cortisol secretion; (ii) the cut-off of the cortisol secretion parameters for identifying NFAT patients with a worse cardiometabolic profile.<br /><b>Patients and methods</b><br />In 615 NFAT patients (with cortisol levels after 1 mg overnight dexamethasone suppression test, F-1mgDST < 1.8 µg/dL [50 nmol/L]) F-1mgDST and adrenocorticotroph hormone (ACTH) levels and data on HT, DM, OB, DL and CVEs prevalence were retrospectively collected.<br /><b>Results</b><br />HT, DM and HT plus DM were associated with F-1mgDST levels (area under the ROC curve: 0.588 ± 0.023, 0.610 ± 0.028, 0.611 ± 0.033, respectively, p < 0.001 for all comparisons) but not with ACTH. The cut-off for identifying patients with either HT or DM or HT plus DM was set at ≥ 1.2 µg/dL (33 nmol/L). As compared with patients with F-1mgDST < 1.2 µg/dL (n = 289), patients with F-1mgDST 1.2-1.79 µg/dL (33-49.4 nmol/L) (n = 326) had lower ACTH levels (17.7 ± 11.9 vs 15.3 ± 10.1 pg/mL, respectively, p = 0.008), older age (57.5 ± 12.3 vs 62.5 ± 10.9 years, respectively, p < 0.001), and higher prevalence of HT (38.1% vs 52.5% respectively p < 0.001), DM (13.1% vs 23.3%, respectively, p = 0.001), HT plus DM (8.3% vs 16.9%, respectively, p < 0.002) and CVE (3.2% vs 7.3%, respectively, p = 0.028). F-1mgDST 1.2-1.79 µg/dL was associated with either HT (odd ratio, OR, 1.55, 95% confidence interval, 95% CI 1.08-2.23, p = 0.018) or DM (OR 1.60, 95% CI 1.01-2.57, p = 0.045) after adjusting for age, gender, OB, DL, and DM (for HT) or HT (for DM), and with the presence of HT plus DM (OR 1.96, 95% CI 1.12-3.41, p = 0.018) after adjusting for age, gender, OB and DL.<br /><b>Conclusions</b><br />In NFAT patients, F-1mgDST 1.2-1.79 µg/dL seems to be associated with a higher prevalence of HT and DM and a worse cardiometabolic profile, even if the poor accuracy of these associations suggests caution in interpreting these results.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 02 May 2023; 22:102</small></div>

<div><h4>The synergistic effect of the triglyceride-glucose index and serum uric acid on the prediction of major adverse cardiovascular events after coronary artery bypass grafting: a multicenter retrospective cohort study.</h4><i>Wu Z, Cheng C, Sun X, Wang J, ... Zhang C, Yang J</i><br /><b>Background</b><br />Elevated serum uric acid (SUA) is regarded as a risk factor for the development of cardiovascular diseases. Triglyceride-glucose (TyG) index, a novel surrogate for insulin resistance (IR), has been proven to be an independent predictor for adverse cardiac events. However, no study has specifically focused on the interaction between the two metabolic risk factors. Whether combining the TyG index and SUA could achieve more accurate prognostic prediction in patients undergoing coronary artery bypass grafting (CABG) remains unknown.<br /><b>Methods</b><br />This was a multicenter, retrospective cohort study. A total of 1225 patients who underwent CABG were included in the final analysis. The patients were grouped based on the cut-off value of the TyG index and the sex-specific criteria of hyperuricemia (HUA). Cox regression analysis was conducted. The interaction between the TyG index and SUA was estimated using relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI). The improvement of model performance yielded by the inclusion of the TyG index and SUA was examined by C-statistics, net reclassification improvement (NRI) and integrated discrimination improvement (IDI). The goodness-of-fit of models was evaluated using the Akaike information criterion (AIC), Bayesian information criterion (BIC) and χ<sup>2</sup> likelihood ratio test.<br /><b>Results</b><br />During follow-up, 263 patients developed major adverse cardiovascular events (MACE). The independent and joint associations of the TyG index and SUA with adverse events were significant. Patients with higher TyG index and HUA were at higher risk of MACE (Kaplan-Meier analysis: log-rank P < 0.001; Cox regression: HR = 4.10; 95% CI 2.80-6.00, P < 0.001). A significant synergistic interaction was found between the TyG index and SUA [RERI (95% CI): 1.83 (0.32-3.34), P = 0.017; AP (95% CI): 0.41 (0.17-0.66), P = 0.001; SI (95% CI): 2.13 (1.13-4.00), P = 0.019]. The addition of the TyG index and SUA yielded a significant improvement in prognostic prediction and model fit [change in C-statistic: 0.038, P < 0.001; continuous NRI (95% CI): 0.336 (0.201-0.471), P < 0.001; IDI (95% CI): 0.031 (0.019-0.044), P < 0.001; AIC: 3534.29; BIC: 3616.45; likelihood ratio test: P < 0.001).<br /><b>Conclusions</b><br />The TyG index interacts synergistically with SUA to increase the risk of MACE in patients undergoing CABG, which emphasizes the need to use both measures concurrently when assessing cardiovascular risk.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 02 May 2023; 22:103</small></div>

<div><h4>Serum triglyceride glucose index is a valuable predictor for visceral obesity in patients with type 2 diabetes: a cross-sectional study.</h4><i>Yang Q, Xu H, Zhang H, Li Y, ... Zhang M, Liu F</i><br /><b>Background</b><br />Since the triglyceride glucose (TyG) index can reflect insulin resistance, it has been proven to be an efficient predictor of glycolipid-metabolism-related diseases. Therefore, this study aimed to investigate the predictive value of the TyG index for visceral obesity (VO) and body fat distribution in patients with type 2 diabetes mellitus (T2DM).<br /><b>Methods</b><br />Abdominal adipose tissue characteristics in patients with T2DM, including visceral adipose area (VAA), subcutaneous adipose area (SAA), VAA-to-SAA ratio (VSR), visceral adipose density (VAD), and subcutaneous adipose density (SAD), were obtained through analyses of computed tomography images at the lumbar 2/3 level. VO was diagnosed according to the VAA (> 142 cm<sup>2</sup> for males and > 115 cm<sup>2</sup> for females). Logistic regression was performed to identify independent factors of VO, and receiver operating characteristic (ROC) curves were used to compare the diagnostic performance according to the area under the ROC curve (AUC).<br /><b>Results</b><br />A total of 976 patients were included in this study. VO patients showed significantly higher TyG values than non-VO patients in males (9.74 vs. 8.88) and females (9.59 vs. 9.01). The TyG index showed significant positive correlations with VAA, SAA, and VSR and negative correlations with VAD and SAD. The TyG index was an independent factor for VO in both males (odds ratio [OR] = 2.997) and females (OR = 2.233). The TyG index ranked second to body mass index (BMI) for predicting VO in male (AUC = 0.770) and female patients (AUC = 0.720). Patients with higher BMI and TyG index values showed a significantly higher risk of VO than the other patients. TyG-BMI, the combination index of TyG and BMI, showed significantly higher predictive power than BMI for VO in male patients (AUC = 0.879 and 0.835, respectively) but showed no significance when compared with BMI in female patients (AUC = 0.865 and 0.835, respectively).<br /><b>Conclusions</b><br />. TyG is a comprehensive indicator of adipose volume, density, and distribution in patients with T2DM and is a valuable predictor for VO in combination with anthropometric indices, such as BMI.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 29 Apr 2023; 22:98</small></div>

<div><h4>Redox-driven cardioprotective effects of sodium-glucose co-transporter-2 inhibitors: comparative review.</h4><i>Hoehlschen J, Hofreither D, Tomin T, Birner-Gruenberger R</i><br /><AbstractText>Sodium-glucose co-transporter-2 inhibitors are used in the treatment of diabetes but are also emerging as cardioprotective agents in heart diseases even in the absence of type 2 diabetes. In this paper, upon providing a short overview of common pathophysiological features of diabetes, we review the clinically reported cardio- and nephroprotective potential of sodium-glucose co-transporter-2 inhibitors currently available on the market, including Dapagliflozin, Canagliflozin, and Empagliflozin. To that end, we summarize findings of clinical trials that have initially drawn attention to the drugs\' organ-protective potential, before providing an overview of their proposed mechanism of action. Since we particularly expect that their antioxidative properties will broaden the application of gliflozins from therapeutic to preventive care, special emphasis was put on this aspect.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 29 Apr 2023; 22:101</small></div>

<div><h4>Extremes of both weight gain and weight loss are associated with increased incidence of heart failure and cardiovascular death: evidence from the CANVAS Program and CREDENCE.</h4><i>Ferrannini G, Pollock C, Natali A, Yavin Y, Mahaffey KW, Ferrannini E</i><br /><b>Background</b><br />Obesity is an independent risk factor for cardiovascular disease (CVD) in patients with type 2 diabetes (T2D). However, it is not known to what extent weight fluctuations might be associated with adverse outcomes. We aimed at assessing the associations between extreme weight changes and cardiovascular outcomes in two large randomised controlled trials of canagliflozin in patients with T2D and high cardiovascular (CV) risk.<br /><b>Methods</b><br />In the study populations of the CANVAS Program and CREDENCE trials, weight change was evaluated between randomization and week 52-78, defining subjects in the top 10% of the entire distribution of weight changes as gainers, subjects in the bottom 10% as losers and the remainder as stable. Univariate and multivariate Cox proportional hazards models were used to test the associations between weight changes categories, randomised treatment and covariates with heart failure hospitalisation (hHF) and the composite of hHF and CV death.<br /><b>Results</b><br />Median weight gain was 4.5 kg in gainers and median weight loss was 8.5 kg in losers. The clinical phenotype of gainers as well as that of losers were similar to that of stable subjects. Weight change within each category was only slightly larger with canagliflozin than placebo. In both trials, gainers and losers had a higher risk of hHF and of hHF/CV death compared with stable at univariate analysis. In CANVAS, this association was still significant by multivariate analysis for hHF/CV death in both gainers and losers vs. stable (hazard ratio - HR 1.61 [95% confidence interval - CI: 1.20-2.16] and 1.53 [95% CI 1.14-2.03] respectively). Results were similar in CREDENCE for gainers vs. stable (adjusted HR for hHF/CV death 1.62 [95% CI 1.19-2.16]) <br /><b>Conclusions:</b><br/>Extremes of weight gain or loss were independently associated with a higher risk of the composite of hHF and CV death. In patients with T2D and high CV risk, large changes in body weight should be carefully assessed in view of individualised management.<br /><b>Trials registration</b><br />CANVAS ClinicalTrials.gov number: NCT01032629. CREDENCE ClinicalTrials.gov number: NCT02065791.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 29 Apr 2023; 22:100</small></div>

<div><h4>Association of abdominal adiposity, hepatic shear stiffness with subclinical left-ventricular remodeling evaluated by magnetic resonance in adults free of overt cardiovascular diseases: a prospective study.</h4><i>Qu Y, Liu J, Li J, Shen S, ... Peng L, Song B</i><br /><b>Background</b><br />Abdominal ectopic fat deposition and excess visceral fat depots in obesity may be related to cardiovascular disease (CVD) as both are involved in the metabolic syndrome (MetS). The awareness of the link between abdominal adiposity and subclinical cardiac remodeling would help improve treatment and outcome. Besides, liver fibrosis has also shown a potential relationship with cardiac dysfunction. Thus, we aimed to investigate the associations of magnetic resonance (MR)-based abdominal adiposity and hepatic shear stiffness with subclinical left ventricular (LV) remodeling while taking account of MetS-related confounders in adults free of overt CVD.<br /><b>Methods</b><br />This was an exploratory, prospective study of 88 adults (46 subjects with obesity, 42 healthy controls) who underwent 3 T cardiac and body MR exams. Measures of abdominal MR included hepatic and pancreatic proton density fat fraction (H-PDFF and P-PDFF), hepatic shear stiffness by MR elastography, and subcutaneous and visceral adipose tissue (SAT and VAT). Cardiac measures included epicardial adipose tissue (EAT) and parameters of LV geometry and function. Associations were assessed using Pearson correlation and multivariable linear regression analyses, in which age, sex, and MetS-related confounders were adjusted for.<br /><b>Results</b><br />The LV ejection fractions of all participants were within the normal range. Higher H-PDFF, P-PDFF, SAT and VAT were independently associated with lower LV global myocardial strain parameters (radial, circumferential and longitudinal peak strain [PS], longitudinal peak systolic strain rate and diastolic strain rate) (β = - 0.001 to - 0.41, p < 0.05), and P-PDFF, SAT and VAT were independently and positively associated with LV end-diastolic volume and stroke volume (β = 0.09 to 3.08, p ≤ 0.02) in the over-all cohort. In the obesity subgroup, higher P-PDFF and VAT were independently associated with lower circumferential and longitudinal PS, respectively (β = - 0.29 to - 0.05, p ≤ 0.01). No independent correlation between hepatic shear stiffness and EAT or LV remodeling was found (all p ≥ 0.05).<br /><b>Conclusions</b><br />Ectopic fat depositions in the liver and pancreas, and excess abdominal adipose tissue pose a risk of subclinical LV remodeling beyond MetS-related CVD risk factors in adults without overt CVD. VAT may play a more considerable role as a risk factor for subclinical LV dysfunction than does SAT in individuals with obesity. The underlying mechanisms of these associations and their longitudinal clinical implications need further investigation.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 29 Apr 2023; 22:99</small></div>

<div><h4>Association of complication of type 2 diabetes mellitus with hemodynamics and exercise capacity in patients with heart failure with preserved ejection fraction: a case-control study in individuals aged 65-80 years.</h4><i>Sugita Y, Ito K, Yoshioka Y, Sakai S</i><br /><b>Background</b><br />Type 2 diabetes mellitus (T2DM) is a frequently observed complication in patients with heart failure with preserved ejection fraction (HFpEF). Although a characteristic finding in such patients is a decrease in objective exercise capacity represented by peak oxygen uptake (peakVO<sub>2</sub>), exercise capacity and its predictors in HFpEF with T2DM remain not clearly understood. This case-control study aimed to investigate the association between exercise capacity and hemodynamics indicators and T2DM comorbidity in patients with HFpEF aged 65-80 years.<br /><b>Methods</b><br />Ninety-nine stable outpatients with HFpEF and 50 age-and-sex-matched controls were enrolled. Patients with HFpEF were classified as HFpEF with T2DM (n = 51, median age, 76 years) or without T2DM (n = 48, median age, 76 years). The peakVO<sub>2</sub> and ventilatory equivalent versus carbon dioxide output slope (VE vs VCO<sub>2</sub> slope) were measured by cardiopulmonary exercise testing. The peak heart rate (HR) and peak stroke volume index (SI) were measured using impedance cardiography, and the estimated arteriovenous oxygen difference (peak a-vO<sub>2</sub> diff) was calculated with Fick\'s equation. The obtained data were compared among the three groups using analysis of covariance adjusted for the β-blocker medication, presence or absence of sarcopenia, and hemoglobin levels in order to determine the T2DM effects on exercise capacity and hemodynamics in patients with HFpEF.<br /><b>Results</b><br />In HFpEF with T2DM compared with HFpEF without T2DM and the controls, the prevalence of sarcopenia, chronotropic incompetence, and anemia were significantly higher (p < 0.001). The peakVO<sub>2</sub> (Controls 23.5 vs. without T2DM 15.1 vs. with T2DM 11.6 mL/min/kg), peak HR (Controls 164 vs. without T2DM 132 vs. with T2DM 120 bpm/min), peak a-vO<sub>2</sub> (Controls 13.1 vs without T2DM 10.6 vs with T2DM 8.9 mL/100 mL), and VE vs VCO<sub>2</sub> slope (Controls 33.2 vs without T2DM 35.0 vs with T2DM 38.2) were significantly worsened in patients with HFpEF with T2DM (median, p < 0.001). There was no significant difference in peak SI among the three groups.<br /><b>Conclusions</b><br />Our results suggested that comorbid T2DM in patients with HFpEF may reduce exercise capacity, HR response, peripheral oxygen extraction, and ventilation efficiency. These results may help identify cardiovascular phenotypes of HFpEF complicated with T2DM and intervention targets for improving exercise intolerance.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 28 Apr 2023; 22:97</small></div>

<div><h4>Effect of dual residual risk of cholesterol and inflammation on all-cause mortality in patients with cardiovascular disease.</h4><i>Yang L, Yue Q, Fang F, Zhang Y, ... Wu S, Yang X</i><br /><b>Background</b><br />Randomized controlled trials confirm that risks of residual cholesterol and residual inflammation remains in patients with cardiovascular disease (CVD) even after lipid-lowering therapy. This study aims to investigate the association between dual residual risk of cholesterol and inflammation and all-cause mortality in a real-world population with CVD.<br /><b>Methods</b><br />Patients with a CVD history who first took statins between 1 January 2010 and 31 December 2017 in the Kailuan Study were selected as study participants. According to low-density lipoprotein cholesterol (LDL-C) and hypersensitive C-reactive protein levels, patients were divided into those with no residual risk, residual inflammatory risk (RIR), residual cholesterol risk (RCR), and residual cholesterol and inflammatory risk (RCIR). Cox proportional hazard model was conducted to determine hazard ratio (HR) of all-cause mortality for RIR, RCR, and RCIR. Stratified analysis was conducted according to good medication adherence and 75% of the percentage LDL-C decline, high SMART 2 risk score, and blood pressure and blood glucose at standard levels.<br /><b>Results</b><br />After 6.10 years of follow-up, 377 all-cause deaths occurred in 3509 participants (mean age 63.69 ± 8.41 years, 86.78% men). After adjusting for related risk factors, the HR and (95% confidence interval [CI]) of all-cause mortality in the RIR, RCR, and RCIR was 1.63 (1.05, 2.52), 1.37 (0.98, 1.90), and 1.75 (1.25, 2.46), compared with no residual risk. Similar associations were observed in participants with moderate or low statin compliance, a lower percentage of LDL-C decline, high SMART 2 risk score, uncontrolled blood pressure, and uncontrolled blood glucose, in the RCIR had a 1.66-fold, 2.08-fold, 1.69-fold, 2.04-fold, and 2.05-fold higher risk of all-cause mortality, respectively, than the reference.<br /><b>Conclusion</b><br />Risks of residual cholesterol and residual inflammation remain in patients with CVD after receiving statins, and their combined effect significantly increases the risk of all-cause mortality. Here, this increased risk was dependent on statin compliance, LDL-C reduction, SMART 2 risk score, and blood pressure and blood glucose control.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 24 Apr 2023; 22:96</small></div>

<div><h4>The right ventricular dysfunction and ventricular interdependence in patients with DM: assessment using cardiac MR feature tracking.</h4><i>Shi R, Yang ZG, Guo YK, Qian WL, ... Xu HY, Li Y</i><br /><b>Background</b><br />To investigate the difference of right ventricular (RV) structural and functional alteration in patients with diabetes mellitus (DM) with preserved left ventricular ejection fraction (LVEF), and the ventricular interdependence in these patients, using cardiac MR (CMR) feature tracking.<br /><b>Methods</b><br />From December 2016 to February 2022, 148 clinically diagnosed patients with DM who underwent cardiac MR (CMR) in our hospital were consecutively recruited. Fifty-four healthy individuals were included as normal controls. Biventricular strains, including left/right ventricular global longitudinal strain (LV-/RVGLS), left/right ventricular global circumferential strain (LV-/RVGCS), left/right ventricular global radial strain (LV-/RVGRS) were evaluated, and compared between patients with DM and healthy controls. Multiple linear regression and mediation analyses were used to evaluate DM\'s direct and indirect effects on RV strains.<br /><b>Results</b><br />No differences were found in age (56.98 ± 10.98 vs. 57.37 ± 8.41, p = 0.985), sex (53.4% vs. 48.1%, p = 0.715), and body surface area (BSA) (1.70 ± 0.21 vs. 1.69 ± 0.17, p = 0.472) between DM and normal controls. Patients with DM had decreased RVGLS (- 21.86 ± 4.14 vs. - 24.49 ± 4.47, p = 0.001), RVGCS (- 13.16 ± 3.86 vs. - 14.92 ± 3.08, p = 0.011), and no decrease was found in RVGRS (22.62 ± 8.11 vs. 23.15 ± 9.05, p = 0.743) in patients with DM compared with normal controls. The difference in RVGLS between normal controls and patients with DM was totally mediated by LVGLS (indirect effecting: 0.655, bootstrapped 95%CI 0.138-0.265). The difference in RVGCS between normal controls and DM was partly mediated by the LVGLS (indirect effecting: 0.336, bootstrapped 95%CI 0.002-0.820) and LVGCS (indirect effecting: 0.368, bootstrapped 95%CI 0.028-0.855).<br /><b>Conclusions</b><br />In the patients with DM and preserved LVEF, the difference in RVGLS between DM and normal controls was totally mediated by LVGLS. Although there were partly mediating effects of LVGLS and LVGCS, the decrease in RVGCS might be directly affected by the DM.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 21 Apr 2023; 22:93</small></div>

<div><h4>Extended-release metformin improves cognitive impairment in frail older women with hypertension and diabetes: preliminary results from the LEOPARDESS Study.</h4><i>Mone P, Martinelli G, Lucariello A, Leo AL, ... Cobellis L, Santulli G</i><br /><b>Background</b><br />Women have a high risk of frailty independently of age and menopause state. Diabetes and hypertension increase the risk of frailty and cognitive impairment. Metformin has been employed in post-menopausal women and some reports have shown encouraging effects in terms of attenuated frailty. However, the impact on cognitive performance of a recently introduced extended-release formulation of metformin has never been explored.<br /><b>Methods</b><br />We studied consecutive frail hypertensive and diabetic older women presenting at the ASL (local health authority of the Italian Ministry of Health) Avellino, Italy, from June 2021 to August 2022, who were treated or not with extended-release metformin. We included a control group of frail older males with diabetes and hypertension treated with extended-release metformin and a control group of frail older women with diabetes and hypertension treated with regular metformin.<br /><b>Results</b><br />A total of 145 patients successfully completed the study. At the end of the 6-month follow-up, we observed a significantly different cognitive performance compared to baseline in the group of frail women treated with extended-release metformin (p: 0.007). Then, we compared the follow-up groups and we observed significant differences between frail women treated vs. untreated (p: 0.041), between treated frail women and treated frail men (p: 0.016), and between women treated with extended-release metformin vs. women treated with regular metformin (p: 0.048). We confirmed the crucial role of extended-release metformin applying a multivariable logistic analysis to adjust for potential confounders.<br /><b>Conclusions</b><br />We evidenced, for the first time to the best of our knowledge, the favorable effects on cognitive impairment of extended-release metformin in frail women with diabetes and hypertension.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 21 Apr 2023; 22:94</small></div>

<div><h4>Long- and very long-chain ceramides are predictors of acute kidney injury in patients with acute coronary syndrome: the PEACP study.</h4><i>Liang L, Li D, Zeng R, Zhang H, ... Wei W, Wan Z</i><br /><b>Background</b><br />Acute kidney injury (AKI) can be caused by multiple factors/events, including acute coronary syndrome (ACS). Ceramides are involved in atherosclerosis progression, cardiovascular events, and renal damage. Almost no studies have been conducted on the relationship between ceramide concentrations and AKI events. Therefore, we evaluated the association between plasma ceramide level at admission and AKI in patients with ACS undergoing percutaneous coronary intervention.<br /><b>Methods</b><br />We enrolled 842 ACS patients from the Prospective Multicenter Study for Early Evaluation of Acute Chest Pain. AKI was defined using the criteria from the 2012 Kidney Disease: Improving Global Outcomes. Eleven C16-C26 ceramides were measured using the high-performance liquid chromatography interfaced to tandem mass spectrometer procedure. Logistic regression models were used to evaluate relationships between ceramides and AKI risk. The area under the receiver operating characteristic curves (AUC) was used to evaluate differences between ceramides.<br /><b>Results</b><br />Overall, 139 (16.5%) patients developed AKI during hospitalisation. Patients who developed AKI had higher levels of Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/21:0), Cer(d18:1/24:1), and Cer(d18:1/24:2) than patients who did not (P < 0.05). In risk-factor adjusted logistic regression models, these ceramides were independently associated with AKI risk (P < 0.05). Cer(d18:1/24:2) had the highest odds ratio of 3.503 (Q4 vs. Q1, 95% confidence interval: 1.743-7.040, P < 0.001). Ceramides had AUCs of 0.581-0.661 (P < 0.001) for AKI. Each ceramide combined with the Mehran risk score (AUC: 0.780) had AUCs of 0.802-0.808, greater than the Mehran risk score alone.<br /><b>Conclusion</b><br />Long-chain and very-long-chain ceramide levels may help determine the high AKI risk beyond traditional assessments.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 20 Apr 2023; 22:92</small></div>

<div><h4>Predictive value of high sensitivity C-reactive protein in three-vessel disease patients with and without type 2 diabetes.</h4><i>Guo L, Lv H, Wang J, Zhang B, ... Zhou X, Xia Y</i><br /><b>Background</b><br />Diabetes mellitus (DM) and atherosclerosis are multifactorial conditions and share a common inflammatory basis. Three-vessel disease (TVD) represents a major challenge for coronary intervention. Nonetheless, the predictive value of high-sensitivity C-reactive protein (hs-CRP) for TVD patients with or without type 2 DM remains unknown. Herein, we aimed to ascertain the long-term predictive value of hs-CRP in TVD patients according to type 2 DM status from a large cohort.<br /><b>Methods</b><br />A total of 2734 TVD patients with (n = 1040, 38%) and without (n = 1694, 62%) type 2 diabetes were stratified based on the hs-CRP (< 2 mg/L vs. ≥ 2 mg/L). Three multivariable analysis models were performed to evaluate the effect of potential confounders on the relationship between hs-CRP level and clinical outcomes. The Concordance index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were calculated to assess the added effect of hs-CRP and the baseline model with established risk factors on the discrimination of clinical outcomes. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE).<br /><b>Results</b><br />The median follow-up duration was 2.4 years. Multivariate Cox regression analyses showed that the incidence of MACCE (adjusted hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.01-1.35, p = 0.031) and all-cause death (HR 1.82, 95% CI 1.07-3.11, p = 0.026) were significantly higher in the diabetic group compared to the non-diabetic group. In the diabetic group, the incidence of MACCE (adjusted HR 1.51, 95% CI 1.09-2.10, p = 0.013) was significantly higher in the high hs-CRP group than in the low hs-CRP group; no significant difference was found for all-cause death (HR 1.63; 95% CI 0.58-4.58, p = 0.349). In the non-diabetic group, the prevalence of MACCE (adjusted HR 0.93, 95% CI 0.71-1.22, p = 0.613) was comparable between the two groups. Finally, the NRI (0.2074, p = 0.001) and IDI (0.0086, p = 0.003) for MACCE were also significantly increased after hs-CRP was added to the baseline model in the diabetic group.<br /><b>Conclusions</b><br />Elevated hs-CRP is an independent prognostic factor for long-term outcomes of MACCE in TVD patients with type 2 diabetes but not in those without type 2 diabetes. Compared to traditional risk factors, hs-CRP improved the risk prediction of adverse cardiovascular events in TVD patients with type 2 diabetes.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 20 Apr 2023; 22:91</small></div>

<div><h4>Triglyceride-glucose index, symptomatic intracranial artery stenosis and recurrence risk in minor stroke patients with hypertension.</h4><i>Wang Y, Liu T, Li Y, Zhang K, ... Liu Y, Niu X</i><br /><b>Background</b><br />The triglyceride-glucose (TyG) index, a simple measure of insulin resistance, is associated with intracranial atherosclerosis (ICAS) and stroke. In hypertensive populations, this association may be pronounced. The aim was to investigate the relationship between TyG and symptomatic intracranial atherosclerosis (sICAS) and recurrence risk in ischemic stroke patients with hypertension.<br /><b>Methods</b><br />This prospective, multicenter cohort study included patients with acute minor ischemic stroke with a preadmission diagnosis of hypertension from September 2019 to November 2021 with a 3-month follow-up. The presence of sICAS was determined by a combination of clinical manifestations, the location of the infarction, and the corresponding artery with moderate-to-severe stenosis. ICAS burden was determined by the degree and number of ICAS occurrences. Fasting blood glucose (FBG) and triglyceride (TG) were measured to calculate TyG. The main outcome was ischemic stroke recurrence during the 90-day follow-up. Multivariate regression models were used to explore the association of TyG, sICAS, and ICAS burden with stroke recurrence.<br /><b>Results</b><br />There were 1281 patients with a mean age of 61.6 ± 11.6 years; 70.1% were male, and 26.4% were diagnosed with sICAS. There were 117 patients who experienced stroke recurrence during follow-up. Patients were categorized according to quartiles of TyG. After adjusting for confounders, the risk of sICAS was greater (OR 1.59, 95% CI 1.04-2.43, p = 0.033) and the risk of stroke recurrence was significantly higher (HR 2.02, 95% CI 1.07-3.84, p = 0.025) in the fourth TyG quartile than in the first quartile. The restricted cubic spline (RCS) plot revealed a linear relationship between TyG and sICAS, and the threshold value for TyG was 8.4. Patients were then dichotomized into low and high TyG groups by the threshold. Patients with high TyG combined with sICAS had a higher risk of recurrence (HR 2.54, 95% CI 1.39-4.65) than patients with low TyG without sICAS. An interaction effect on stroke recurrence between TyG and sICAS was found (p = 0.043).<br /><b>Conclusion</b><br />TyG is a significant risk factor for sICAS in hypertensive patients, and there is a synergistic effect of sICAS and higher TyG on ischemic stroke recurrence.<br /><b>Trial registration number</b><br />The study was registered on 16 August 2019 at https://www.chictr.org.cn/showprojen.aspx?proj=41160 (No. ChiCTR1900025214).<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 19 Apr 2023; 22:90</small></div>

<div><h4>Dysregulation of hypoxia-inducible factor 1α in the sympathetic nervous system accelerates diabetic cardiomyopathy.</h4><i>Hrabalova P, Bohuslavova R, Matejkova K, Papousek F, ... Kolar F, Pavlinkova G</i><br /><b>Background</b><br />An altered sympathetic nervous system is implicated in many cardiac pathologies, ranging from sudden infant death syndrome to common diseases of adulthood such as hypertension, myocardial ischemia, cardiac arrhythmias, myocardial infarction, and heart failure. Although the mechanisms responsible for disruption of this well-organized system are the subject of intensive investigations, the exact processes controlling the cardiac sympathetic nervous system are still not fully understood. A conditional knockout of the Hif1a gene was reported to affect the development of sympathetic ganglia and sympathetic innervation of the heart. This study characterized how the combination of HIF-1α deficiency and streptozotocin (STZ)-induced diabetes affects the cardiac sympathetic nervous system and heart function of adult animals.<br /><b>Methods</b><br />Molecular characteristics of Hif1a deficient sympathetic neurons were identified by RNA sequencing. Diabetes was induced in Hif1a knockout and control mice by low doses of STZ treatment. Heart function was assessed by echocardiography. Mechanisms involved in adverse structural remodeling of the myocardium, i.e. advanced glycation end products, fibrosis, cell death, and inflammation, was assessed by immunohistological analyses.<br /><b>Results</b><br />We demonstrated that the deletion of Hif1a alters the transcriptome of sympathetic neurons, and that diabetic mice with the Hif1a-deficient sympathetic system have significant systolic dysfunction, worsened cardiac sympathetic innervation, and structural remodeling of the myocardium.<br /><b>Conclusions</b><br />We provide evidence that the combination of diabetes and the Hif1a deficient sympathetic nervous system results in compromised cardiac performance and accelerated adverse myocardial remodeling, associated with the progression of diabetic cardiomyopathy.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 18 Apr 2023; 22:88</small></div>

<div><h4>L-Arginine in diabetes: clinical and preclinical evidence.</h4><i>Forzano I, Avvisato R, Varzideh F, Jankauskas SS, ... Trimarco V, Santulli G</i><br /><AbstractText>L-Arginine (L-Arg), is a semi-essential amino acid involved in the formation of nitric oxide. The functional relevance of L-Arg in diabetes mellitus has been evaluated both in animal models and in human subjects. In the literature there are several lines of evidence indicating that L-Arg has beneficial effects in diabetes and numerous studies advocate its administration to attenuate glucose intolerance in diabetic patients. Here we present a comprehensive overview of the main studies exploring the effects of L-Arg in diabetes, including preclinical and clinical reports on this topic.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 18 Apr 2023; 22:89</small></div>

<div><h4>Predicting long-term prognosis after percutaneous coronary intervention in patients with new onset ST-elevation myocardial infarction: development and external validation of a nomogram model.</h4><i>Ye Z, Xu Y, Tang L, Wu M, ... Zhu T, Wang J</i><br /><b>Background</b><br />The triglyceride glucose (TyG) index is a well-established biomarker for insulin resistance (IR) that shows correlation with poor outcomes in patients with coronary artery disease. We aimed to integrate the TyG index with clinical data in a prediction nomogram for the long-term prognosis of new onset ST-elevation myocardial infarction (STEMI) following primary percutaneous coronary intervention (PCI) .<br /><b>Methods</b><br />This retrospective study included new-onset STEMI patients admitted at two heart centers for emergency PCI from December 2015 to March 2018 in development and independent validation cohorts. Potential risk factors were screened applying least absolute shrinkage and selection operator (LASSO) regression. Multiple Cox regression was employed to identify independent risk factors for prediction nomogram construction. Nomogram performance was assessed based on receiver operating characteristic curve analysis, calibration curves, Harrell\'s C-index and decision curve analysis (DCA).<br /><b>Results</b><br />In total, 404 patients were assigned to the development cohort and 169 to the independent validation cohort. The constructed nomogram included four clinical variables: age, diabetes mellitus, current smoking, and TyG index. The Harrell\'s C-index values for the nomogram were 0.772 (95% confidence interval [CI]: 0.721-0.823) in the development cohort and 0.736 (95%CI: 0.656-0.816) in the independent validation cohort. Significant correlation was found between the predicted and actual outcomes in both cohorts, indicating that the nomogram is well calibrated. DCA confirmed the clinical value of the development prediction nomogram.<br /><b>Conclusions</b><br />Our validated prediction nomogram based on the TyG index and electronic health records data was shown to provide accurate and reliable discrimination of new-onset STEMI patients at high- and low-risk for major adverse cardiac events at 2, 3 and 5 years following emergency PCI.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 13 Apr 2023; 22:87</small></div>

<div><h4>Insights into SGLT2 inhibitor treatment of diabetic cardiomyopathy: focus on the mechanisms.</h4><i>Huang K, Luo X, Liao B, Li G, Feng J</i><br /><AbstractText>Among the complications of diabetes, cardiovascular events and cardiac insufficiency are considered two of the most important causes of death. Experimental and clinical evidence supports the effectiveness of SGLT2i for improving cardiac dysfunction. SGLT2i treatment benefits metabolism, microcirculation, mitochondrial function, fibrosis, oxidative stress, endoplasmic reticulum stress, programmed cell death, autophagy, and the intestinal flora, which are involved in diabetic cardiomyopathy. This review summarizes the current knowledge of the mechanisms of SGLT2i for the treatment of diabetic cardiomyopathy.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 13 Apr 2023; 22:86</small></div>

<div><h4>Adipose tissue specific CCL18 associates with cardiometabolic diseases in non-obese individuals implicating CD4 T cells.</h4><i>Subramanian N, Hofwimmer K, Tavira B, Massier L, ... Arner P, Laurencikiene J</i><br /><b>Aim</b><br />Obesity is linked to cardiometabolic diseases, however non-obese individuals are also at risk for type 2 diabetes (T2D) and cardiovascular disease (CVD). White adipose tissue (WAT) is known to play a role in both T2D and CVD, but the contribution of WAT inflammatory status especially in non-obese patients with cardiometabolic diseases is less understood. Therefore, we aimed to find associations between WAT inflammatory status and cardiometabolic diseases in non-obese individuals.<br /><b>Methods</b><br />In a population-based cohort containing non-obese healthy (n = 17), T2D (n = 16), CVD (n = 18), T2D + CVD (n = 19) individuals, seventeen different cytokines were measured in WAT and in circulation. In addition, 13-color flow cytometry profiling was employed to phenotype the immune cells. Human T cell line (Jurkat T cells) was stimulated by rCCL18, and conditioned media (CM) was added to the in vitro cultures of human adipocytes. Lipolysis was measured by glycerol release. Blocking antibodies against IFN-γ and TGF-β were used in vitro to prove a role for these cytokines in CCL18-T-cell-adipocyte lipolysis regulation axis.<br /><b>Results</b><br />In CVD, T2D and CVD + T2D groups, CCL18 and CD4<sup>+</sup> T cells were upregulated significantly compared to healthy controls. WAT CCL18 secretion correlated with the amounts of WAT CD4<sup>+</sup> T cells, which also highly expressed CCL18 receptors suggesting that WAT CD4<sup>+</sup> T cells are responders to this chemokine. While direct addition of rCCL18 to mature adipocytes did not alter the adipocyte lipolysis, CM from CCL18-treated T cells increased glycerol release in in vitro cultures of adipocytes. IFN-γ and TGF-β secretion was significantly induced in CM obtained from T cells treated with CCL18. Blocking these cytokines in CM, prevented CM-induced upregulation of adipocyte lipolysis.<br /><b>Conclusion</b><br />We suggest that in T2D and CVD, increased production of CCL18 recruits and activates CD4<sup>+</sup> T cells to secrete IFN-γ and TGF-β. This, in turn, promotes adipocyte lipolysis - a possible risk factor for cardiometabolic diseases.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 12 Apr 2023; 22:84</small></div>

<div><h4>Association of stress hyperglycemia with clinical outcomes in patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention: a cohort study.</h4><i>Wei QC, Chen YW, Gao QY, Ren KD, ... Shi JT, Jiang J</i><br /><b>Background</b><br />In recent years, several studies have demonstrated that stress hyperglycemia is significantly associated with poor prognosis in patients diagnosed with acute coronary syndrome (ACS). In the present study, we aimed to investigate the potential associations between various markers of stress hyperglycemia, such as admission blood glucose (ABG), fasting blood sugar (FBS), and stress hyperglycemia ratio (SHR) with different definitions, and the occurrence of adverse cardiovascular events in patients diagnosed with ST-elevation myocardial infarction (STEMI) who have undergone percutaneous coronary intervention (PCI).<br /><b>Methods</b><br />Our study enrolled a total of 1099 patients diagnosed with STEMI who underwent PCI from 2016 to 2021. The primary outcomes of this study were in-hospital death and all-cause mortality.<br /><b>Results</b><br />Stress hyperglycemia was associated with a higher incidence of in-hospital death (ABG OR: 1.27 95% CI 1.19-1.36; FBS OR: 1.25 95% CI 1.16-1.35; SHR1 OR: 1.61 95% CI 1.21-2.14; SHR2 OR: 1.57, 95%CI 1.22-2.01; SHR3 OR: 1.59, 95%CI 1.24-2.05) and all-cause mortality (ABG HR: 1.10, 95% CI 1.07-1.14; FBS HR: 1.12, 95 CI 1.07-1.17; SHR1 HR: 1.19 95% CI 1.03-1.39; SHR2 HR: 1.28, 95%CI 1.14-1.44; SHR3 HR: 1.29, 95%CI 1.14-1.45) after adjusting for ischemic time, age, gender, BMI, hypertension, hyperlipidemia, diabetes mellitus (DM), current smoking history, chronic kidney disease (CKD), previous history of coronary artery disease (CAD), atrial fibrillation (AF), heart failure (HF), stroke, cancer, culprit vessel, multi-vessel disease. These associations exhibited a non-linear, J-shaped pattern, wherein the risk significantly increased when the ABG and FBS levels exceeded 5mmol/L. Moreover, the inflection point for SHR was estimated to be 1.2.<br /><b>Conclusions</b><br />Stress hyperglycemia was significantly associated with an increased risk of in-hospital death and all-cause mortality in STEMI patients treated with PCI. Stress hyperglycemia should be considered a high-risk prognostic marker in all STEMI patients, regardless of with or without diabetes.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 12 Apr 2023; 22:85</small></div>

<div><h4>Cardiovascular risk of metabolically healthy obesity in two european populations: Prevention potential from a metabolomic study.</h4><i>Wei D, González-Marrachelli V, Melgarejo JD, Liao CT, ... Monleon D, Zhang ZY</i><br /><b>Background</b><br />A new definition of metabolically healthy obesity (MHO) has recently been proposed to stratify the heterogeneous mortality risk of obesity. Metabolomic profiling provides clues to metabolic alterations beyond clinical definition. We aimed to evaluate the association between MHO and cardiovascular events and assess its metabolomic pattern.<br /><b>Methods</b><br />This prospective study included Europeans from two population-based studies, the FLEMENGHO and the Hortega study. A total of 2339 participants with follow-up were analyzed, including 2218 with metabolomic profiling. Metabolic health was developed from the third National Health and Nutrition Examination Survey and the UK biobank cohorts and defined as systolic blood pressure < 130 mmHg, no antihypertensive drugs, waist-to-hip ratio < 0.95 for women or 1.03 for men, and the absence of diabetes. BMI categories included normal weight, overweight, and obesity (BMI < 25, 25-30, ≥ 30 kg/m<sup>2</sup>). Participants were classified into six subgroups according to BMI category and metabolic healthy status. Outcomes were fatal and nonfatal composited cardiovascular events.<br /><b>Results</b><br />Of 2339 participants, the mean age was 51 years, 1161 (49.6%) were women, 434 (18.6%) had obesity, 117 (5.0%) were classified as MHO, and both cohorts had similar characteristics. Over a median of 9.2-year (3.7-13.0) follow-up, 245 cardiovascular events occurred. Compared to those with metabolically healthy normal weight, individuals with metabolic unhealthy status had a higher risk of cardiovascular events, regardless of BMI category (adjusted HR: 3.30 [95% CI: 1.73-6.28] for normal weight, 2.50 [95% CI: 1.34-4.66] for overweight, and 3.42 [95% CI: 1.81-6.44] for obesity), whereas those with MHO were not at increased risk of cardiovascular events (HR: 1.11 [95% CI: 0.36-3.45]). Factor analysis identified a metabolomic factor mainly associated with glucose regulation, which was associated with cardiovascular events (HR: 1.22 [95% CI: 1.10-1.36]). Individuals with MHO tended to present a higher metabolomic factor score than those with metabolically healthy normal weight (0.175 vs. -0.057, P = 0.019), and the score was comparable to metabolically unhealthy obesity (0.175 vs. -0.080, P = 0.91).<br /><b>Conclusions</b><br />Individuals with MHO may not present higher short-term cardiovascular risk but tend to have a metabolomic pattern associated with higher cardiovascular risk, emphasizing a need for early intervention.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 07 Apr 2023; 22:82</small></div>

<div><h4>Visceral adipose tissue is an independent predictor and mediator of the progression of coronary calcification: a prospective sub-analysis of the GEA study.</h4><i>Antonio-Villa NE, Juárez-Rojas JG, Posadas-Sánchez R, Reyes-Barrera J, Medina-Urrutia A</i><br /><b>Background</b><br />Coronary artery calcium (CAC) improves cardiovascular event prediction. Visceral adipose tissue (VAT) is a cardiometabolic risk factor that may directly or through its related comorbidities determine the obesity-related risk. A clinical VAT estimator could allow an efficient evaluation of obesity-related risk. We aimed to analyze the effect of VAT and its related cardiometabolic risk factors on CAC progression.<br /><b>Methods</b><br />CAC was quantified at baseline and after 5 years by computed tomography (CT), determining its progression. VAT and pericardial fat were measured by CT and estimated by a clinical surrogate (METS-VF). Considered cardiometabolic risk factors were: peripheral insulin resistance (IR), HOMA-IR, adipose tissue IR (ADIPO-IR), and adiponectin. Factors independently associated to CAC progression were analyzed by adjusted Cox proportional hazard models, including statin use and ASCVD risk score as covariates. We performed interaction and mediation models to propose possible pathways for CAC progression.<br /><b>Results</b><br />The study included 862 adults (53 ± 9 years, 53% women), incidence CAC progression rate: 30.2 (95% CI 25.3-35.8)/1000 person-years. VAT (HR: 1.004, 95% CI 1.001-1.007, p < 0.01) and METS-VF (HR: 1.001, 95% CI 1.0-1.001, p < 0.05) independently predicted CAC progression. VAT-associated CAC progression risk was evident among low-risk ASCVD subjects, and attenuated among medium-high-risk subjects, suggesting that traditional risk factors overcome adiposity in the latter. VAT mediates 51.8% (95% CI 44.5-58.8%) of the effect attributable to IR together with adipose tissue dysfunction on CAC progression.<br /><b>Conclusions</b><br />This study supports the hypothesis that VAT is a mediator of the risk conferred by subcutaneous adipose tissue dysfunction. METS-VF is an efficient clinical surrogate that could facilitate the identification of at-risk adiposity subjects in daily clinical practice.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 03 Apr 2023; 22:81</small></div>

<div><h4>SGLT2-inhibitors effects on the coronary fibrous cap thickness and MACEs in diabetic patients with inducible myocardial ischemia and multi vessels non-obstructive coronary artery stenosis.</h4><i>Sardu C, Trotta MC, Sasso FC, Sacra C, ... Paolisso G, Marfella R</i><br /><b>Background</b><br />Sodium-glucose transporter 2 inhibitors (SGLT2-I) could modulate atherosclerotic plaque progression, via down-regulation of inflammatory burden, and lead to reduction of major adverse cardiovascular events (MACEs) in type 2 diabetes mellitus (T2DM) patients with ischemic heart disease (IHD). T2DM patients with multivessel non-obstructive coronary stenosis (Mv-NOCS) have over-inflammation and over-lipids\' plaque accumulation. This could reduce fibrous cap thickness (FCT), favoring plaque rupture and MACEs. Despite this, there is not conclusive data about the effects of SGLT2-I on atherosclerotic plaque phenotype and MACEs in Mv-NOCS patients with T2DM. Thus, in the current study, we evaluated SGLT2-I effects on Mv-NOCS patients with T2DM in terms of FCT increase, reduction of systemic and coronary plaque inflammation, and MACEs at 1 year of follow-up.<br /><b>Methods</b><br />In a multi-center study, we evaluated 369 T2DM patients with Mv-NOCS divided in 258 (69.9%) patients that did not receive the SGLT2-I therapy (Non-SGLT2-I users), and 111 (30.1%) patients that were treated with SGLT2-I therapy (SGLT2-I users) after percutaneous coronary intervention (PCI) and optical coherence tomography (OCT) evaluation. As the primary study endpoint, we evaluated the effects of SGLT2-I on FCT changes at 1 year of follow-up. As secondary endpoints, we evaluated at baseline and at 12 months follow-up the inflammatory systemic and plaque burden and rate of MACEs, and predictors of MACE through multivariable analysis.<br /><b>Results</b><br />At 6 and 12 months of follow-up, SGLT2-I users vs. Non-SGLT2-I users showed lower body mass index (BMI), glycemia, glycated hemoglobin, B-type natriuretic peptide, and inflammatory cells/molecules values (p < 0.05). SGLT2-I users vs. Non-SGLT2-I users, as evaluated by OCT, evidenced the highest values of minimum FCT, and lowest values of lipid arc degree and macrophage grade (p < 0.05). At the follow-up end, SGLT2-I users vs. Non-SGLT2-I users had a lower rate of MACEs [n 12 (10.8%) vs. n 57 (22.1%); p < 0.05]. Finally, Hb1Ac values (1.930, [CI 95%: 1.149-2.176]), macrophage grade (1.188, [CI 95%: 1.073-1.315]), and SGLT2-I therapy (0.342, [CI 95%: 0.180-0.651]) were independent predictors of MACEs at 1 year of follow-up.<br /><b>Conclusions</b><br />SGLT2-I therapy may reduce about 65% the risk to have MACEs at 1 year of follow-up, via ameliorative effects on glucose homeostasis, and by the reduction of systemic inflammatory burden, and local effects on the atherosclerotic plaque inflammation, lipids\' deposit, and FCT in Mv-NOCS patients with T2DM.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 01 Apr 2023; 22:80</small></div>

<div><h4>Combining glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) in patients with type 2 diabetes mellitus (T2DM).</h4><i>Gourdy P, Darmon P, Dievart F, Halimi JM, Guerci B</i><br /><AbstractText>Due to their cardiovascular protective effect, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) represent breakthrough therapies for type 2 diabetes mellitus (T2DM). In this review article, we discuss the mechanistic and clinical synergies that make the combined use of GLP-1RAs and SGLT2is appealing in patients with T2DM. Overall, the presented cumulative evidence supports the benefits of GLP-1RA plus SGLT2i combination therapy on metabolic-cardiovascular-renal disease in patients with T2DM, with a low hypoglycemia risk. Accordingly, we encourage the adoption of GLP-1RA plus SGLT2i combination therapy in patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD (i.e., age ≥ 55 years, overweight/obesity, dyslipidemia, hypertension, current tobacco use, left ventricular hypertrophy, and/or proteinuria). Regarding renal effects, the evidence of SGLT2is in preventing kidney failure is more abundant than for GLP-1RAs, which showed a beneficial effect on albuminuria but not on hard kidney endpoints. Hence, in case of persistent albuminuria and/or uncontrolled metabolic risks (i.e., inadequate glycemic control, hypertension, overweight/obesity) on SGLT2i therapy, GLP-1RAs should be considered as the preferential add-on therapy in T2DM patients with chronic kidney disease. Despite the potential clinical benefits of GLP-1RA plus SGLT2i combination therapy in patients with T2DM, several factors may delay this combination to become a common practice soon, such as reimbursement and costs associated with polypharmacy. Altogether, when administering GLP-1RA plus SGLT2i combination therapy, it is important to adopt an individualized approach to therapy taking into account individual preferences, costs and coverage, toxicity profile, consideration of kidney function and glucose-lowering efficacy, desire for weight loss, and comorbidities.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 01 Apr 2023; 22:79</small></div>

<div><h4>The independent association of myocardial extracellular volume and myocardial blood flow with cardiac diastolic function in patients with type 2 diabetes: a prospective cross-sectional cohort study.</h4><i>Bojer AS, Sørensen MH, Madsen SH, Broadbent DA, ... Gæde P, Madsen PL</i><br /><b>Background</b><br />Diffuse myocardial fibrosis and microvascular dysfunction are suggested to underlie cardiac dysfunction in patients with type 2 diabetes, but studies investigating their relative impact are lacking. We aimed to study imaging biomarkers of these and hypothesized that fibrosis and microvascular dysfunction would affect different phases of left ventricular (LV) diastole.<br /><b>Methods</b><br />In this cross-sectional study myocardial blood flow (MBF) at rest and adenosine-stress and perfusion reserve (MPR), as well as extracellular volume fraction (ECV), were determined with cardiovascular magnetic resonance (CMR) imaging in 205 patients with type 2 diabetes and 25 controls. Diastolic parameters included echocardiography-determined lateral e\' and average E/e\', and CMR-determined (rest and chronotropic-stress) LV early peak filling rate (ePFR), LV peak diastolic strain rate (PDSR), and left atrial (LA) volume changes.<br /><b>Results</b><br />In multivariable analysis adjusted for possible confounders including each other (ECV for blood flow and vice versa), a 10% increase of ECV was independently associated with ePFR/EDV (rest: β = - 4.0%, stress: β = - 7.9%), LA<sub>max</sub> /BSA (rest: β = 4.8%, stress: β = 5.8%), and circumferential (β = - 4.1%) and radial PDSR (β = 0.07%/sec). A 10% stress MBF increase was associated with lateral e\' (β = 1.4%) and average E/e\' (β = - 1.4%) and a 10% MPR increase to lateral e\' (β = 2.7%), and average E/e\' (β = - 2.8%). For all the above, p < 0.05. No associations were found with longitudinal PDSR or left atrial total emptying fraction.<br /><b>Conclusion</b><br />In patients with type 2 diabetes, imaging biomarkers of microvascular dysfunction and diffuse fibrosis impacts diastolic dysfunction independently of each other. Microvascular dysfunction primarily affects early left ventricular relaxation. Diffuse fibrosis primarily affects diastasis. Trial registration https://www.<br /><b>Clinicaltrials</b><br />gov . Unique identifier: NCT02684331. Date of registration: February 18, 2016.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 31 Mar 2023; 22:78</small></div>

<div><h4>Positive association between stress hyperglycemia ratio and pulmonary infection in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention.</h4><i>Lin Z, Liang X, Zhang Y, Dai Y, ... Duan C, Liu Y</i><br /><b>Background</b><br />Previous studies have shown that the stress hyperglycemia ratio (SHR), a parameter of relative stress-induced hyperglycemia, is an excellent predictive factor for all-cause mortality and major adverse cardiovascular events (MACEs) among patients with ST-segment elevation myocardial infarction (STEMI). However, its association with pulmonary infection in patients with STEMI during hospitalization remains unclear.<br /><b>Methods</b><br />Patients with STEMI undergoing percutaneous coronary intervention (PCI) were consecutively enrolled from 2010 to 2020. The primary endpoint was the occurrence of pulmonary infection during hospitalization, and the secondary endpoint was in-hospital MACEs, composed of all-cause mortality, stroke, target vessel revascularization, or recurrent myocardial infarction.<br /><b>Results</b><br />A total of 2,841 patients were finally included, with 323 (11.4%) developing pulmonary infection and 165 (5.8%) developing in-hospital MACEs. The patients were divided into three groups according to SHR tertiles. A higher SHR was associated with a higher rate of pulmonary infection during hospitalization (8.1%, 9.9%, and 18.0%, P < 0.001) and in-hospital MACEs (3.7%, 5.1%, and 8.6%, P < 0.001). Multivariate logistic regression analysis demonstrated that SHR was significantly associated with the risk of pulmonary infection during hospitalization (odds ratio [OR] = 1.46, 95% confidence interval [CI] 1.06-2.02, P = 0.021) and in-hospital MACEs (OR = 1.67, 95% CI 1.17-2.39, P = 0.005) after adjusting for potential confounding factors. The cubic spline models demonstrated no significant non-linear relationship between SHR and pulmonary infection (P = 0.210) and MACEs (P = 0.743). In receiver operating characteristic curve, the best cutoff value of SHR for pulmonary infection was 1.073.<br /><b>Conclusions</b><br />The SHR is independently associated with the risk of pulmonary infection during hospitalization and in-hospital MACEs for patients with STEMI undergoing PCI.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 31 Mar 2023; 22:76</small></div>

<div><h4>Surgical ablation for atrial fibrillation: impact of Diabetes Mellitus type 2.</h4><i>Kogan A, Grupper A, Sabbag A, Ram E, ... Raanani E, Sternik L</i><br /><b>Background</b><br />Diabetes mellitus (DM) type 2 is an independent risk factor for atrial fibrillation (AF). Surgical ablation or \"maze procedure\" is an option for patients with AF undergoing concomitant or isolated cardiac surgery. The aim of this study was to evaluate the impact of DM type 2 on early and long-term outcomes of patients following surgical AF ablation.<br /><b>Methods</b><br />We performed an observational cohort study in Israel\'s largest tertiary care center. All data of patients who underwent surgical AF ablation, between 2006 and 2021 were extracted from our departmental database. Patients were divided into Group I (non-diabetic patients) and Group II (DM type 2 patients). We compared the two groups with respect to freedom from recurrent atrial arrhythmia, and mortality rate.<br /><b>Results</b><br />The study population included 606 patients. Group I (non-DM patients), consisting of 484 patients, and Group II (DM type 2 patients), comprised 122 patients. Patients with DM were older, had more hypertension and incidence of cerebrovascular accident (CVA)/transient ischemic attack (TIA), higher EuroSCORE (p < .05 for all), and a longer bypass time-130 ± 40 vs. 122 ± 36 min (p = 0.028). The mean follow-up duration was 39.0 ± 22.7 months. Freedom from atrial fibrillation was similar between the non-DM and DM type 2 groups after a 1-year follow-up, 414 (88.2%) vs. 101 (87.1%) (p = 0.511), after a 3-year follow-up, 360 (86.3%) vs. 84 (79.9%) (p = 0.290) and after a 5-year follow-up, 226 (74.1%) vs. 55 (71.5%) (p = 0.622) respectively. Furthermore, 1- and 3-year mortality was similar between non-DM and DM type 2 groups, 2.5% vs. 4.9%, (p = 0.226) and 5.6% vs. 10.5% (p = 0.076) respectively. 5-year mortality was higher in Group II (DM type 2 patients) compared with Group I (non-DM patients), 11.1% vs. 23.4% (p = 0.009).<br /><b>Conclusion</b><br />Surgical ablation had a high success rate, with freedom from recurrent atrial arrhythmia at 1- 3- and 5- years follow-up in both the DM type 2 and non-DM groups. Furthermore,1- and 3-year mortality after surgical ablation was also similar in both groups. However, 5-year mortality was higher in the DM type 2 group.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 31 Mar 2023; 22:77</small></div>

<div><h4>Association between triglyceride glucose-body mass index and cardiovascular outcomes in patients undergoing percutaneous coronary intervention: a retrospective study.</h4><i>Cheng Y, Fang Z, Zhang X, Wen Y, ... He S, Xu B</i><br /><b>Background</b><br />The triglyceride glucose-body mass index (TyG-BMI index) has been considered a reliable surrogate measure of insulin resistance; however, its ability to predict the incidence of cardiovascular disease in individuals with coronary artery disease (CAD) remains uncertain. The aim of this study was to demonstrate the correlation between the TyG-BMI index and cardiovascular incidence.<br /><b>Methods</b><br />A total of 2533 consecutive participants who underwent percutaneous coronary intervention (PCI) and drug-eluting stent (DES) implantation were included. Data from 1438 patients was analyzed in the study. The endpoint was defined as a composite of acute myocardial infarction, repeat revascularization, stroke, and all-cause mortality (major adverse cardiac and cerebrovascular events, MACCEs) at 34-month follow-up. The formula for calculating the TyG-BMI index is ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2] × BMI.<br /><b>Results</b><br />Among the 1438 participants, 195 incident patient cases of MACCEs were ascertained. The incidence of MACCEs showed no statistically significant differences in the TyG-BMI index tertiles in the overall population. Further exploratory subgroup analysis and multivariable logistic regression analysis revealed a linear relationship between the TyG-BMI index (per 1 SD increased) and MACCEs in the elderly patients (OR = 1.22, 95% CI 1.011-1.467, p = 0.038) and in the female patients (OR = 1.33, 95% CI 1.004-1.764, p = 0.047). The addition of the TyG-BMI index to traditional risk factor models in elderly and female patients did not improve risk prediction for MACCEs.<br /><b>Conclusion</b><br />A higher TyG-BMI index was proportionally related to an increased incidence of MACCEs in the elderly or female patients. However, the inclusion of the TyG-BMI index did not provide better predictive performance for MACCEs in the elderly, specifically in female patients.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 30 Mar 2023; 22:75</small></div>

<div><h4>Different roles of protein biomarkers predicting eGFR trajectories in people with chronic kidney disease and diabetes mellitus: a nationwide retrospective cohort study.</h4><i>Kammer M, Heinzel A, Hu K, Meiselbach H, ... Oberbauer R, BEAt-DKD consortium</i><br /><b>Background</b><br />Chronic kidney disease (CKD) is a common comorbidity in people with diabetes mellitus, and a key risk factor for further life-threatening conditions such as cardiovascular disease. The early prediction of progression of CKD therefore is an important clinical goal, but remains difficult due to the multifaceted nature of the condition. We validated a set of established protein biomarkers for the prediction of trajectories of estimated glomerular filtration rate (eGFR) in people with moderately advanced chronic kidney disease and diabetes mellitus. Our aim was to discern which biomarkers associate with baseline eGFR or are important for the prediction of the future eGFR trajectory.<br /><b>Methods</b><br />We used Bayesian linear mixed models with weakly informative and shrinkage priors for clinical predictors (n = 12) and protein biomarkers (n = 19) to model eGFR trajectories in a retrospective cohort study of people with diabetes mellitus (n = 838) from the nationwide German Chronic Kidney Disease study. We used baseline eGFR to update the models\' predictions, thereby assessing the importance of the predictors and improving predictive accuracy computed using repeated cross-validation.<br /><b>Results</b><br />The model combining clinical and protein predictors had higher predictive performance than a clinical only model, with an [Formula: see text] of 0.44 (95% credible interval 0.37-0.50) before, and 0.59 (95% credible interval 0.51-0.65) after updating by baseline eGFR, respectively. Only few predictors were sufficient to obtain comparable performance to the main model, with markers such as Tumor Necrosis Factor Receptor 1 and Receptor for Advanced Glycation Endproducts being associated with baseline eGFR, while Kidney Injury Molecule 1 and urine albumin-creatinine-ratio were predictive for future eGFR decline.<br /><b>Conclusions</b><br />Protein biomarkers only modestly improve predictive accuracy compared to clinical predictors alone. The different protein markers serve different roles for the prediction of longitudinal eGFR trajectories potentially reflecting their role in the disease pathway.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 29 Mar 2023; 22:74</small></div>

<div><h4>Changes in high-density lipoprotein cholesterol with risk of Cardiovascular Disease among initially high-density lipoprotein-high participants.</h4><i>Kim HJ, Jeong S, Oh YH, Park SJ, Cho Y, Park SM</i><br /><b>Background</b><br />High-density lipoprotein cholesterol\'s (HDL-C) long-held status as a cardiovascular disease (CVD) preventative has been called into question. Most of the evidence, however, focused on either the risk of death from CVD, or on single time point level of HDL-C. This study aimed to determine the association between changes in HDL-C levels and incident CVD in individuals with high baseline HDL-C levels (≥ 60 mg/dL).<br /><b>Methods</b><br />77,134 people from the Korea National Health Insurance Service-Health Screening Cohort were followed for 517,515 person-years. Cox proportional hazards regression was used to evaluate the association between change in HDL-C levels and the risk of incident CVD. All participants were followed up until 31 December 2019, CVD, or death.<br /><b>Results</b><br />Participants with the greatest increase in their HDL-C levels had higher risks of CVD (adjusted hazard ratio [aHR], 1.15; 95% confidence interval [CI], 1.05-1.25) and CHD (aHR 1.27, CI 1.11-1.46) after adjusting for age, sex, household income, body mass index, hypertension, diabetes mellitus, dyslipidemia, smoking, alcohol consumption, moderate-to-vigorous physical activity, Charlson comorbidity index, and total cholesterol than those with the lowest increase in HDL-C levels. Such association remained significant even among participants with decreased low-density lipoprotein cholesterol (LDL-C) levels for CHD (aHR 1.26, CI 1.03-1.53).<br /><b>Conclusions</b><br />In people with already high HDL-C levels, additional increases in HDL-C levels may be associated with an increased risk of CVD. This finding held true irrespective of the change in their LDL-C levels. Increasing HDL-C levels may lead to unintentionally elevated risk of CVD.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 28 Mar 2023; 22:71</small></div>

<div><h4>Time-dependent event accumulation in a cardiovascular outcome trial of patients with type 2 diabetes and established atherosclerotic cardiovascular disease.</h4><i>Bethel MA, Sourij H, Stevens SR, Hannan K, ... Holman RR, Lopes RD</i><br /><b>Background</b><br />Estimating cardiovascular (CV) event accrual is important for outcome trial planning. Limited data exist describing event accrual patterns in patients with type 2 diabetes (T2D). We compared apparent CV event accrual patterns with true event rates in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).<br /><b>Methods</b><br />Centrally adjudicated event dates and accrual rates for a 4-point major adverse CV event composite (MACE-4; includes CV death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina hospitalization), MACE-4 components, all-cause mortality (ACM), and heart failure hospitalization were compiled. We used three graphical methods (Weibull probability plot, plot of negative log of the Kaplan-Meier survival distribution estimate, and the Epanechnikov kernel-smoothed estimate of the hazard rate) to examine hazard rate morphology over time for the 7 outcomes.<br /><b>Results</b><br />Plots for all outcomes showed real-time constant event hazard rates for the duration of the follow-up, confirmed by Weibull shape parameters. The Weibull shape parameters for ACM (1.14, 95% CI 1.08-1.21) and CV death (1.08, 95% CI 1.01-1.16) were not sufficiently > 1 as to require non-constant hazard rate models to accurately depict the data. The time lag between event occurrence and event adjudication being completed, the adjudication gap, improved over the course of the trial.<br /><b>Conclusions</b><br />In TECOS, the nonfatal event hazard rates were constant over time. Small increases over time in the hazard rate for fatal events would not require complex modelling to predict event accrual, providing confidence in traditional modelling methods for predicting CV outcome trial event rates in this population. The adjudication gap provides a useful metric to monitor within-trial event accrual patterns.<br /><b>Clinical trial registration</b><br />Clinicaltrials.gov NCT00790205.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 28 Mar 2023; 22:72</small></div>

<div><h4>Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation.</h4><i>Gopal K, Karwi QG, Tabatabaei Dakhili SA, Wagg CS, ... Ussher JR, Lopaschuk GD</i><br /><b>Background</b><br />Cardiovascular diseases, including diabetic cardiomyopathy, are major causes of death in people with type 2 diabetes. Aldose reductase activity is enhanced in hyperglycemic conditions, leading to altered cardiac energy metabolism and deterioration of cardiac function with adverse remodeling. Because disturbances in cardiac energy metabolism can promote cardiac inefficiency, we hypothesized that aldose reductase inhibition may mitigate diabetic cardiomyopathy via normalization of cardiac energy metabolism.<br /><b>Methods</b><br />Male C57BL/6J mice (8-week-old) were subjected to experimental type 2 diabetes/diabetic cardiomyopathy (high-fat diet [60% kcal from lard] for 10 weeks with a single intraperitoneal injection of streptozotocin (75 mg/kg) at 4 weeks), following which animals were randomized to treatment with either vehicle or AT-001, a next-generation aldose reductase inhibitor (40 mg/kg/day) for 3 weeks. At study completion, hearts were perfused in the isolated working mode to assess energy metabolism.<br /><b>Results</b><br />Aldose reductase inhibition by AT-001 treatment improved diastolic function and cardiac efficiency in mice subjected to experimental type 2 diabetes. This attenuation of diabetic cardiomyopathy was associated with decreased myocardial fatty acid oxidation rates (1.15 ± 0.19 vs 0.5 ± 0.1 µmol min<sup>-1</sup> g dry wt<sup>-1</sup> in the presence of insulin) but no change in glucose oxidation rates compared to the control group. In addition, cardiac fibrosis and hypertrophy were also mitigated via AT-001 treatment in mice with diabetic cardiomyopathy.<br /><b>Conclusions</b><br />Inhibiting aldose reductase activity ameliorates diastolic dysfunction in mice with experimental type 2 diabetes, which may be due to the decline in myocardial fatty acid oxidation, indicating that treatment with AT-001 may be a novel approach to alleviate diabetic cardiomyopathy in patients with diabetes.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 28 Mar 2023; 22:73</small></div>

<div><h4>HbA1c-based rather than fasting plasma glucose-based definitions of prediabetes identifies high-risk patients with angiographic coronary intermediate lesions: a prospective cohort study.</h4><i>Song C, Yuan S, Cui K, Cai Z, ... Dong Q, Dou K</i><br /><b>Background</b><br />Prediabetes is common and associated with poor prognosis in patients with acute coronary syndrome and those undergoing revascularization. However, the impact of prediabetes on prognosis in patients with coronary intermediate lesions remains unclear. The objective of the current study is to explore the impact of prediabetes and compare the prognostic value of the different definitions of prediabetes in patients with coronary intermediate lesions.<br /><b>Methods</b><br />A total of 1532 patients attending Fuwai hospital (Beijing, China), with intermediate angiographic coronary lesions, not undergoing revascularization, were followed-up from 2013 to 2021. Patients were classified as normal glucose tolerance (NGT), prediabetes and diabetes according to various definitions based on HbA1c or admission fasting plasma glucose (FPG). The primary endpoint was defined as major adverse cardiovascular events (MACE), the composite endpoint of all-cause death, non-fatal myocardial infarction and repeated revascularization therapy. Multivariate cox regression model was used to explore the association between categories of abnormal glucose category and MACE risk.<br /><b>Results</b><br />The proportion of patients defined as prediabetes ranged from 3.92% to 47.06% depending on the definition used. A total of 197 MACE occurred during a median follow-up time of 6.1 years. Multivariate cox analysis showed that prediabetes according to the International Expert Committee (IEC) guideline (6.0 ≤ HbA1c < 6.5%) was associated with increased risk of MACE compared with NGT (hazard ratio [HR]: 1.705, 95% confidence interval [CI] 1.143-2.543) and after confounding adjustment (HR: 1.513, 95%CI 1.005-2.277). Consistently, the best cut-off point of glycated haemoglobin (HbA1c) identified based on the Youden\'s index was also 6%. Restricted cubic spline analysis delineated a linear positive relationship between baseline HbA1c and MACE risk. Globally, FPG or FPG-based definition of prediabetes was not associated with patients\' outcome.<br /><b>Conclusions</b><br />In this cohort of patients with intermediate coronary lesions not undergoing revascularization therapy, prediabetes based on the IEC-HbA1c definition was associated with increased MACE risk compared with NGT, and may assist in identifying high-risk patients who can benefit from early lifestyle intervention.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 25 Mar 2023; 22:68</small></div>

<div><h4>Elevated urine albumin-to-creatinine ratio increases the risk of new-onset heart failure in patients with type 2 diabetes.</h4><i>Tao J, Sang D, Zhen L, Zhang X, ... Wu S, Zhang W</i><br /><b>Background</b><br />Although albuminuria has been linked to heart failure in the general population, the relationship between urine albumin-to-creatinine ratio (uACR) and heart failure in type 2 diabetes patients is not well understood. We aimed to investigate the relationship between uACR and new-onset heart failure (HF) in type 2 diabetics.<br /><b>Methods</b><br />We included 9287 Chinese participants with type 2 diabetes (T2D) but no heart failure (HF) who were assessed with uACR between 2014 and 2016. The participants were divided into three groups based on their baseline uACR: normal (< 3 mg/mmol), microalbuminuria (3-30 mg/mmol), and macroalbuminuria (≥ 30 mg/mmol). The relationship between uACR and new-onset HF was studied using Cox proportional hazard models and restricted cubic spline. The area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to see if incorporating uACR into existing models could improve performance.<br /><b>Results</b><br />216 new-onset HF cases (2.33%) were recorded after a median follow-up of 4.05 years. When compared to normal uACR, elevated uACR was associated with a progressively increased risk of new-onset HF, ranging from microalbuminuria (adjusted HR, 2.21; 95% CI 1.59-3.06) to macroalbuminuria (adjusted HR, 6.02; 95% CI 4.11-8.80), and 1 standard deviation (SD) in ln (uACR) (adjusted HR, 1.89; 95% CI 1.68-2.13). The results were consistent across sex, estimated glomerular filtration rate, systolic blood pressure, and glycosylated hemoglobin subgroups. The addition of uACR to established HF risk models improved the HF risk prediction efficacy.<br /><b>Conclusions</b><br />Increasing uACR, even below the normal range, is an independent risk factor for new-onset HF in a type 2 diabetic population. Furthermore, uACR may improve HF risk prediction in community-based T2D patients.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 25 Mar 2023; 22:70</small></div>

<div><h4>Time-dependent effect of GLP-1 receptor agonists on cardiovascular benefits: a real-world study.</h4><i>Piccini S, Favacchio G, Panico C, Morenghi E, ... Lania AG, Mirani M</i><br /><b>Background</b><br />Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown cardiovascular benefits in cardiovascular outcome trials in type 2 diabetes mellitus. However, the most convincing evidence was obtained in subjects with established cardiovascular (CV) disease. We analyzed the determinants of GLP-1 RA-mediated CV protection in a real-world population of persons with type 2 diabetes with and without a history of CV events with long-term follow-up.<br /><b>Methods</b><br />Retrospective cohort study of 550 individuals with type 2 diabetes (395 in primary CV prevention, 155 in secondary CV prevention), followed at a single center after the first prescription of a GLP-1 RA between 2009 and 2019. CV and metabolic outcomes were assessed.<br /><b>Results</b><br />Median duration of follow-up was 5.0 years (0.25-10.8) in primary prevention and 3.6 years (0-10.3) in secondary prevention, with a median duration of treatment of 3.2 years (0-10.8) and 2.5 years (0-10.3) respectively. In the multivariable Cox regression model considering GLP-1 RA treatment as a time-dependent covariate, in the primary prevention group, changes in BMI and glycated hemoglobin did not have an impact on MACE risk, while age at the time of GLP-1 initiation (HR 1.08, 95% CI 1.03-1.14, p = 0.001) and GLP-1 RA cessation by time (HR 3.40, 95% CI 1.82-6.32, p < 0.001) increased the risk of MACE. Regarding the secondary prevention group, only GLP-1 RA cessation by time (HR 2.71, 95% CI 1.46-5.01, p = 0.002) increased the risk of MACE. With respect to those who withdrew treatment, subjects who continued the GLP-1 RA had significantly greater weight loss and lower glycated hemoglobin levels during follow-up.<br /><b>Conclusions</b><br />In this real-world type 2 diabetes population, discontinuation of GLP-1 RA treatment was associated to a higher risk of major cardiovascular events, in both subjects with and without a history of CV events.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 25 Mar 2023; 22:69</small></div>

<div><h4>Alcohol consumption and microvascular dysfunction: a J-shaped association: The Maastricht Study.</h4><i>van der Heide FCT, Eussen SJPM, Houben AJHM, Henry RMA, ... Beulens JWJ, Stehouwer CDA</i><br /><b>Background</b><br />Microvascular dysfunction (MVD) is an important contributor to major clinical disease such as stroke, dementia, depression, retinopathy, and chronic kidney disease. Alcohol consumption may be a determinant of MVD.<br /><b>Objective</b><br />Main objectives were (1) to study whether alcohol consumption was associated with MVD as assessed in the brain, retina, skin, kidney and in the blood; and (2) to investigate whether associations differed by history of cardiovascular disease or sex.<br /><b>Design</b><br />We used cross-sectional data from The Maastricht Study (N = 3,120 participants, 50.9% men, mean age 60 years, and 27.5% with type 2 diabetes [the latter oversampled by design]). We used regression analyses to study the association between total alcohol (per unit and in the categories, i.e. none, light, moderate, high) and MVD, where all measures of MVD were combined into a total MVD composite score (expressed in SD). We adjusted all associations for potential confounders; and tested for interaction by sex, and history of cardiovascular disease. Additionally we tested for interaction with glucose metabolism status.<br /><b>Results</b><br />The association between total alcohol consumption and MVD was non-linear, i.e. J-shaped. Moderate versus light total alcohol consumption was significantly associated with less MVD, after full adjustment (beta [95% confidence interval], -0.10 [-0.19; -0.01]). The shape of the curve differed with sex (P<sub>interaction</sub> = 0.03), history of cardiovascular disease (P<sub>interaction</sub> < 0.001), and glucose metabolism status (P<sub>interaction</sub> = 0.02).<br /><b>Conclusions</b><br />The present cross-sectional, population-based study found evidence that alcohol consumption may have an effect on MVD. Hence, although increasing alcohol consumption cannot be recommended as a policy, this study suggests that prevention of MVD may be possible through dietary interventions.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 24 Mar 2023; 22:67</small></div>

<div><h4>Systolic blood pressure reduction with tirzepatide in patients with type 2 diabetes: insights from SURPASS clinical program.</h4><i>Lingvay I, Mosenzon O, Brown K, Cui X, ... Fernández Landó L, Patel H</i><br /><b>Background</b><br />Tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide/ glucagon-like peptide-1 receptor agonist, is approved in the United States, Europe and Japan for the treatment of type 2 diabetes. Across the SURPASS-1 to -5 clinical studies, tirzepatide 5, 10 and 15 mg demonstrated significant improvements in glycated haemoglobin A1c (HbA1c) (- 1.9 to - 2.6%), body weight (- 6.6 to - 13.9%) and systolic blood pressure (SBP) (- 2.8 to - 12.6 mmHg) at the end of study treatment.<br /><b>Methods</b><br />Post-hoc mediation analyses were conducted to evaluate weight-loss dependent and weight-loss independent effects of tirzepatide on SBP reductions across the 5 SURPASS studies. The safety population (all randomized patients who took at least 1 dose of study drug) of each study was analyzed. Additional analyses were conducted at individual study level or pooled across 5 SURPASS trials.<br /><b>Results</b><br />The difference in mean SBP change from baseline at 40 weeks (total effect) between the tirzepatide and comparator groups was - 1.3 to - 5.1 mmHg (tirzepatide 5 mg), - 1.7 to - 6.5 mmHg (tirzepatide 10 mg) and - 3.1 to - 11.5 mmHg (tirzepatide 15 mg). These SBP reductions were primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. In the SURPASS-4 study, which enrolled patients with established cardiovascular disease, weight-loss independent effects explained 33% to 57% of difference in SBP change between tirzepatide and insulin glargine groups. In a pooled analysis of the SURPASS-1 to -5 studies, there was a significant (p < 0.001) but weak correlation (r = 0.18 to 0.22) between change in body weight and SBP. Reductions in SBP with tirzepatide were not dependent on concomitant antihypertensive medications at baseline as similar reductions were observed whether participants were receiving them or not (interaction p = 0.77). The largest SBP reductions were observed in the highest baseline category (> 140 mmHg), while those in the first quartile of baseline SBP category (< 122 mmHg) observed no further decrease in SBP.<br /><b>Conclusions</b><br />Tirzepatide-induced SBP reduction was primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. SBP reduction was not dependent on antihypertensive medication use but dependent on baseline SBP value, alleviating theoretical concerns of hypotension.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 24 Mar 2023; 22:66</small></div>

<div><h4>Prognostic implication of stress hyperglycemia in patients with acute coronary syndrome undergoing percutaneous coronary intervention.</h4><i>Wang M, Su W, Cao N, Chen H, Li H</i><br /><b>Background</b><br />It is now understood that stress hyperglycemia is associated with adverse outcomes in hospitalized patients. Herein, we aimed to investigate the association between stress hyperglycemia and mortality risk in acute coronary syndrome (ACS) patients who underwent percutaneous coronary intervention (PCI).<br /><b>Methods</b><br />This cohort study comprised 5190 ACS patients who underwent PCI from the Cardiovascular Center Beijing Friendship Hospital Database Bank (CBDBANK) from January 2013 to January 2021. Stress hyperglycemia was defined by the glucose/glycated albumin (GA) ratio, calculated as admission fasting plasma glucose divided by GA. The patients were divided into four groups according to glucose/GA ratio quartiles (Q1-Q4). Cox proportional hazards regression and restricted cubic spline were used to evaluate the association between glucose/GA ratio and all-cause and cardiovascular mortality.<br /><b>Results</b><br />During a median follow-up of 4.0 years, the number of all-cause deaths was 313 (6.0%) and cardiovascular-associated deaths was 177 (3.4%). After adjustment for potential confounders, the risk of all-cause mortality increased in the lowest (HR, 1.43; 95% CI, 1.01-2.03) and highest (HR, 1.51; 95% CI, 1.03-2.21) glucose/GA ratio quartiles compared to Q2. The restricted cubic splines showed that the association between glucose/GA ratio and all-cause mortality was U-shaped after full adjustment (P <sub>nonlinear</sub> = 0.008). Similar results were observed for cardiovascular mortality. In subgroup analyses according to diabetes status, the U-shaped relationship was only significant in patients with diabetes mellitus.<br /><b>Conclusion</b><br />In ACS patients undergoing PCI, low and high glucose/GA ratio values were associated with an increased all-cause and cardiovascular mortality, especially in those with diabetes mellitus.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 21 Mar 2023; 22:63</small></div>

<div><h4>PNPLA3 rs738409 risk genotype decouples TyG index from HOMA2-IR and intrahepatic lipid content.</h4><i>Nádasdi Á, Gál V, Masszi T, Somogyi A, Firneisz G</i><br /><b>Background</b><br />Recent reports suggested a different predictive value for TyG index compared to HOMA-IR in coronary artery calcification (CAC) and other atherosclerotic outcomes, despite that both indices are proposed as surrogate markers of insulin resistance. We hypothesized a key role for liver pathology as an explanation and therefore assessed the relationship among the two indices and the intrahepatic lipid content stratified by PNPLA3 rs738409 genotypes as a known non-alcoholic fatty liver disease (NAFLD) genetic risk.<br /><b>Methods</b><br />Thirty-nine women from a prior GDM-genetic study were recalled with PNPLA3 rs738409 CC and GG genotypes for metabolic phenotyping and to assess hepatic triglyceride content (HTGC). 75 g OGTT was performed, fasting lipid, glucose, insulin levels and calculated insulin resistance indices (TyG and HOMA2-IR) were used. HTGC was measured by MR based methods. Mann-Whitney-U, χ<sup>2</sup> and for the correlation analysis Spearman rank order tests were applied.<br /><b>Results</b><br />The PNPLA3 rs738409 genotype had a significant effect on the direct correlation between the HOMA2-IR and TyG index: the correlation (R = 0.52, p = 0.0054) found in the CC group was completely abolished in those with the GG (NAFLD) risk genotype. In addition, the HOMA2-IR correlated with HTGC in the entire study population (R = 0.69, p < 0.0001) and also separately in both genotypes (CC R = 0.62, p = 0.0006, GG: R = 0.74, p = 0.0058). In contrast, the correlation between TyG index and HTGC was only significant in rs738409 CC genotype group (R = 0.42, p = 0.0284) but not in GG group. A similar pattern was observed in the correlation between TG and HTGC (CC: R = 0.41, p = 0.0335), when the components of the TyG index were separately assessed.<br /><b>Conclusions</b><br />PNPLA3 rs738409 risk genotype completely decoupled the direct correlation between two surrogate markers of insulin resistance: TyG and HOMA2-IR confirming our hypothesis. The liver lipid content increased in parallel with the HOMA2-IR independent of genotype, in contrast to the TyG index where the risk genotype abolished the correlation. This phenomenon seems to be related to the nature of hepatic fat accumulation and to the different concepts establishing the two insulin resistance markers.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 21 Mar 2023; 22:64</small></div>

<div><h4>CT-derived fractional flow reserve for prediction of major adverse cardiovascular events in diabetic patients.</h4><i>Lan Z, Ding X, Yu Y, Yu L, ... Yang W, Zhang J</i><br /><b>Objectives</b><br />To investigate the prognostic value of computed tomography fractional flow reserve (CT-FFR) in patients with diabetes and to establish a risk stratification model for major adverse cardiac event (MACE).<br /><b>Methods</b><br />Diabetic patients with intermediate pre-test probability of coronary artery disease were prospectively enrolled. All patients were referred for coronary computed tomography angiography and followed up for at least 2 years. In the training cohort comprising of 957 patients, two models were developed: model1 with the inclusion of clinical and conventional imaging parameters, model2 incorporating the above parameters + CT-FFR. An internal validation cohort comprising 411 patients and an independent external test cohort of 429 patients were used to validate the proposed models.<br /><b>Results</b><br />1797 patients (mean age: 61.0 ± 7.0 years, 1031 males) were finally included in the present study. MACE occurred in 7.18% (129/1797) of the current cohort during follow- up. Multivariate Cox regression analysis revealed that CT-FFR ≤ 0.80 (hazard ratio [HR] = 4.534, p < 0.001), HbA1c (HR = 1.142, p = 0.015) and low attenuation plaque (LAP) (HR = 3.973, p = 0.041) were the independent predictors for MACE. In the training cohort, the Log-likelihood test showed statistical significance between model1 and model2 (p < 0.001). The C-index of model2 was significantly larger than that of model1 (C-index = 0.82 [0.77-0.87] vs. 0.80 [0.75-0.85], p = 0.021). Similar findings were found in internal validation and external test cohorts.<br /><b>Conclusion</b><br />CT-FFR was a strong independent predictor for MACE in diabetic cohort. The model incorporating CT-FFR, LAP and HbA1c yielded excellent performance in predicting MACE.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 21 Mar 2023; 22:65</small></div>

<div><h4>Efficacy of antihyperglycemic therapies on cardiovascular and heart failure outcomes: an updated meta-analysis and meta-regression analysis of 35 randomized cardiovascular outcome trials.</h4><i>Hasebe M, Yoshiji S, Keidai Y, Minamino H, ... Hamasaki A, Inagaki N</i><br /><b>Background</b><br />Effects of antihyperglycemic therapies on cardiovascular and heart failure (HF) risks have varied widely across cardiovascular outcome trials (CVOTs), and underlying factors remain incompletely understood. We aimed to determine the relationships of glycated hemoglobin (HbA1c) or bodyweight changes with these outcomes in all CVOTs of antihyperglycemic therapies.<br /><b>Methods</b><br />We searched PubMed and EMBASE up to 25 January 2023 for all randomized controlled CVOTs of antihyperglycemic therapies reporting both major adverse cardiovascular events (MACE) and HF outcomes in patients with type 2 diabetes or prediabetes. We performed meta-regression analyses following random-effects meta-analyses to evaluate the effects of HbA1c or bodyweight reductions on each outcome.<br /><b>Results</b><br />Thirty-five trials comprising 256,524 patients were included. Overall, antihyperglycemic therapies reduced MACE by 9% [risk ratio (RR): 0.91; 95% confidence interval (CI) 0.88-0.94; P < 0.001; I<sup>2</sup> = 36.5%]. In meta-regression, every 1% greater reduction in HbA1c was associated with a 14% reduction in the RR of MACE (95% CI 4-24; P = 0.010), whereas bodyweight change was not associated with the RR of MACE. The magnitude of the reduction in MACE risk associated with HbA1c reduction was greater in trials with a higher baseline prevalence of atherosclerotic cardiovascular disease. On the other hand, antihyperglycemic therapies showed no overall significant effect on HF (RR: 0.95; 95% CI 0.87-1.04; P = 0.28; I<sup>2</sup> = 75.9%). In a subgroup analysis based on intervention type, sodium-glucose cotransporter-2 inhibitors (SGLT2i) conferred the greatest HF risk reduction (RR: 0.68; 95% CI 0.62-0.75; P < 0.001; I<sup>2</sup> = 0.0%). In meta-regression, every 1 kg bodyweight reduction, but not HbA1c reduction, was found to reduce the RR of HF by 7% (95% CI 4-10; P < 0.001); however, significant residual heterogeneity (P < 0.001) was observed, and SGLT2i reduced HF more than could be explained by HbA1c or bodyweight reductions.<br /><b>Conclusions</b><br />Antihyperglycemic therapies reduce MACE in an HbA1c-dependent manner. These findings indicate that HbA1c can be a useful marker of MACE risk reduction across a wide range of antihyperglycemic therapies, including drugs with pleiotropic effects. In contrast, HF is reduced not in an HbA1c-dependent but in a bodyweight-dependent manner. Notably, SGLT2i have shown class-specific benefits for HF beyond HbA1c or bodyweight reductions.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 19 Mar 2023; 22:62</small></div>

<div><h4>Estimated glucose disposal rate is associated with retinopathy and kidney disease in young people with type 1 diabetes: a nationwide observational study.</h4><i>Linn W, Persson M, Rathsman B, Ludvigsson J, ... Andersson Franko M, Nyström T</i><br /><b>Aims</b><br />The aim of this study was to investigate the association between estimated glucose disposal rate (eGDR), a proxy for insulin resistance, and retinopathy or kidney disease, i.e. micro-, or macroalbuminuria, in young individuals with type 1 diabetes (T1D).<br /><b>Material and methods</b><br />Using data from the Swedish pediatric registry for diabetes (SweDiabKids) and the registry for adults (NDR), all individuals with T1D with a duration of diabetes of less than 10 years between 1998 and 2017 were included. We calculated the crude incidence rates with 95% confidence intervals (CIs) and used multivariable Cox regression to estimate crude and adjusted hazard ratios (HRs) for two cohorts: retinopathy cohort or kidney disease cohort, stratified by eGDR categories: < 4, 4 to 5.99, 6 to 7.99, and ≥ 8 mg/kg/min (reference).<br /><b>Results</b><br />A total of 22 146 (10 289 retinopathy cohort, and 11 857 kidney disease cohort with an overlapping of 9575) children and adults with T1D (median age 21 years, female 42% and diabetes duration of 6 and 7 years, respectively for the cohorts) were studied. During a median follow-up of 4.8 years (IQR 2.6-7.7) there were 5040 (24.7%), 1909 (48.1%), 504 (52.3%) and 179 (57.6%) events for retinopathy in individuals with an eGDR ≥ 8, 7.99 to 6, 5.99 to 4, and < 4 mg/kg/min, respectively. Corresponding numbers for kidney disease was 1321 (6.5%), 526 (13.3%), 255 (26.8%) and 145 (46.6%). After multiple adjustments for different covariates, individuals with an eGDR 7.99 to 6, 5.99 to 4 and < 4 mg/kg/min, had an increased risk of retinopathy compared to those with an eGDR ≥ 8 mg/kg/min (adjusted HRs, 95% CIs) 1.29 (1.20 to 1.40); 1.50 (1.31 to 1.71) and 1.74 (1.41 to 2.14). Corresponding numbers for kidney disease was (adjusted HRs, 95% CIs) 1.30 (1.11 to 1.52); 1.58 (1.25 to 1.99) and 1.33 (0.95 to 1.86), respectively.<br /><b>Conclusions</b><br />eGDR, a proxy for insulin resistance, is associated with retinopathy and kidney disease in young adults with T1D. The risk of retinopathy increased with lower eGDR. The risk of kidney disease also increased with lower eGDR; however results show no association between the lowest eGDR and kidney disease. eGDR can be helpful to identify young T1D individuals at risk.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 19 Mar 2023; 22:61</small></div>

<div><h4>The cardiovascular and renal effects of glucagon-like peptide 1 receptor agonists in patients with advanced diabetic kidney disease.</h4><i>Lin Y, Wang TH, Tsai ML, Wu VC, ... Hung MJ, Chen TH</i><br /><b>Background</b><br />To determine whether glucagon-like peptide 1 receptor agonists (GLP-1RAs) have cardiovascular and renal protective effects in patients with advanced diabetic kidney disease (DKD) with an estimated glomerular filtration rate (eGFR) < 30 mL/min per 1.73 m<sup>2</sup>.<br /><b>Methods</b><br />In this cohort study, patients with type 2 diabetes mellitus and eGFR < 30 mL/min per 1.73 m<sup>2</sup> with a first prescription for GLP-1RAs or dipeptidyl peptidase 4 inhibitors (DPP-4is) from 2012 to 2021 (n = 125,392) were enrolled. A Cox proportional hazard model was used to assess the cardiorenal protective effects between the GLP-1RA and DDP-4i groups.<br /><b>Results</b><br />A total of 8922 participants [mean (SD) age 68.4 (11.5) years; 4516 (50.6%) males; GLP-1RAs, n = 759; DPP-4is, n = 8163] were eligible for this study. During a mean follow-up of 2.1 years, 78 (13%) and 204 (13.8%) patients developed composite cardiovascular events in the GLP-1RA and DPP-4i groups, respectively [hazard ratio (HR) 0.88, 95% confidence interval CI 0.68-1.13]. Composite kidney events were reported in 134 (38.2%) and 393 (44.2%) patients in the GLP-1RA and DPP-4i groups, respectively (subdistribution HR 0.72, 95% CI 0.56-0.93).<br /><b>Conclusions</b><br />GLP-1RAs had a neutral effect on the composite cardiovascular outcomes but reduced composite kidney events in the patients with advanced DKD compared with DPP-4is.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 17 Mar 2023; 22:60</small></div>

<div><h4>Positive association of triglyceride-glucose index with new-onset hypertension among adults: a national cohort study in China.</h4><i>Gao Q, Lin Y, Xu R, Luo F, ... Su L, Nie S</i><br /><b>Background</b><br />Previous studies showed that the triglyceride-glucose (TyG) index was a better predictor of adverse cardiovascular events than triglycerides or fasting blood glucose alone. However, few studies have focused on new-onset hypertension. We aimed to explore the association of TyG index with new-onset hypertension in Chinese adults.<br /><b>Methods</b><br />A total of 4,600 participants who underwent at least 2 rounds of visits from 2009 to 2015 in the China Health and Nutrition Survey were enrolled in this study. Our outcome of interest was new-onset hypertension. Multivariate Cox hazard regression models and restricted cubic spline were performed to explore the relationship between TyG index and new-onset hypertension.<br /><b>Results</b><br />The mean (standard deviation, SD) age of the study population was 48.1 (13.6) years, and 2058 (44.7%) of the participants were men. The mean (SD) TyG index level was 8.6 (0.7). A total of 1,211 (26.3%) participants developed new-onset hypertension during a median (interquartile range) follow-up duration of 6.0 (2.0-6.1) years. The incidences of new-onset hypertension were 18.1%, 25.3%, 28.5%, and 33.4% by quartiles of TyG index [from quartile 1 (Q1) to Q4], respectively. The Cox model showed that high levels of TyG index were significantly associated with increased risk of new-onset hypertension (adjusted hazard ratio [aHR]: 1.29, 95% confidence interval [CI] 1.07-1.55, Q2; aHR, 1.24, 95% CI 1.03-1.49, Q3; aHR, 1.50, 95% CI 1.22-1.84, Q4) compared with Q1. Consistently, as a continuous variable, for every 1.0 increase in TyG index, there was a 17% increase in the risk of new-onset hypertension (aHR, 1.17; 95% CI 1.04-1.31). The associations were consistent in various subgroups and sensitivity analysis. The dose-response curve indicated a positive, linear association between TyG index and the risk of new-onset hypertension.<br /><b>Conclusions</b><br />High TyG index was significantly associated with an increased risk of new-onset hypertension among Chinese adults. Our findings suggest that maintaining a relatively low level of TyG index might be effective in the primary prevention of hypertension.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 16 Mar 2023; 22:58</small></div>

<div><h4>CVOT Summit 2022 Report: new cardiovascular, kidney, and glycemic outcomes.</h4><i>Schnell O, Battelino T, Bergenstal R, Birkenfeld AL, ... Wilding J, Standl E</i><br /><AbstractText>The 8th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Kidney, and Glycemic Outcomes was held virtually on November 10-12, 2022. Following the tradition of previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed outcomes trials as well as key trials important to the cardiovascular (CV) field. This year\'s focus was on the results of the DELIVER, EMPA-KIDNEY and SURMOUNT-1 trials and their implications for the treatment of heart failure (HF) and chronic kidney disease (CKD) with sodium-glucose cotransporter-2 (SGLT2) inhibitors and obesity with glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists. A broad audience of primary care physicians, diabetologists, endocrinologists, cardiologists, and nephrologists participated online in discussions on new consensus recommendations and guideline updates on type 2 diabetes (T2D) and CKD management, overcoming clinical inertia, glycemic markers, continuous glucose monitoring (CGM), novel insulin preparations, combination therapy, and reclassification of T2D. The impact of cardiovascular outcomes on the design of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) trials, as well as the impact of real-world evidence (RWE) studies on the confirmation of CVOT outcomes and clinical trial design, were also intensively discussed. The 9th Cardiovascular Outcome Trial Summit will be held virtually on November 23-24, 2023 ( http://www.cvot.org ).</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 16 Mar 2023; 22:59</small></div>

<div><h4>Neutral effects of SGLT2 inhibitors in acute coronary syndromes, peripheral arterial occlusive disease, or ischemic stroke: a meta-analysis of randomized controlled trials.</h4><i>Tsai PC, Chuang WJ, Ko AM, Chen JS, ... Chen CH, Yeh YH</i><br /><b>Background</b><br />Patients with type 2 diabetes are at increased risk for cardiovascular diseases. Sodium-glucose transport 2 inhibitors (SGLT2i) have been shown to enhance cardiovascular health since their debut as a second-line therapy for diabetes. Acute coronary syndrome (ACS), peripheral arterial occlusive disease (PAOD), and ischemic stroke (IS) are types of atherosclerotic cardiovascular disease (ASCVD), although the benefits of treating these disorders have not been shown consistently.<br /><b>Methods</b><br />We searched four databases (PubMed, Embase, the Cochrane library, and clinicaltrial.gov) for randomized clinical trials (RCTs) until November of 2022. Comparisons were made between SGLT2i-treated and control individuals with type 2 diabetes. Primary outcomes were ACS, PAOD, and IS; secondary outcomes included cardiovascular mortality and all-cause mortality. Risk ratio (RR) and 95% confidence intervals (CI) were determined using a fixed effects model. Cochrane\'s risk-of-bias (RoB2) instrument was used to assess the validity of each study that met the inclusion criteria.<br /><b>Results</b><br />We enrolled 79,504 patients with type 2 diabetes from 43 RCTs. There was no difference in the risk of ACS (RR = 0.97, 95% CI 0.89-1.05), PAOD (RR = 0.98, 95% CI 0.78-1.24), or IS (RR = 0.95, 95% CI 0.79-1.14) among patients who took an SGLT2i compared to those who took a placebo or oral hypoglycemic drugs. Subgroup analysis revealed that none of the SGLT2i treatments (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) significantly altered outcomes when analyzed separately. Consistent with prior findings, SGLT2i reduced the risk of cardiovascular mortality (RR = 0.85, 95% CI 0.77-0.93) and all-cause mortality (RR = 0.88, 95% CI 0.82-0.94).<br /><b>Conclusion</b><br />Our results appear to contradict the mainstream concepts regarding the cardiovascular effects of SGLT2i since we found no significant therapeutic benefits in SGLT2i to reduce the incidence of ACS, PAOD, or IS when compared to placebo or oral hypoglycemic drugs.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 13 Mar 2023; 22:57</small></div>

<div><h4>Association of the triglyceride-glucose index with coronary artery disease complexity in patients with acute coronary syndrome.</h4><i>Xiong S, Chen Q, Long Y, Su H, ... Zhang Z, Cai L</i><br /><b>Aim</b><br />The triglyceride-glucose (TyG) index has been shown to be an independent predictor for the progression and prognosis of coronary artery disease (CAD). Whether the TyG index predicts the severity of CAD in patients presenting with acute coronary syndrome (ACS) remains unknown.<br /><b>Methods</b><br />A total of 1,007 individuals presenting with ACS undergoing coronary angiography were stratified according to the tertiles of the TyG index and The Synergy Between Percutaneous Coronary Intervention (SYNTAX) score (SYNTAX score ≤ 22 versus SYNTAX score > 22). CAD complexity was determined by the SYNTAX score.<br /><b>Results</b><br />After adjusting for multiple confounding factors, the TyG index was still an independent risk factor for mid/high SYNTAX scores (SYNTAX score > 22, OR 2.6452, 95% CI 1.9020-3.6786, P < 0.0001). Compared with the lowest tertile of the TyG (T1) group, the risk for a mid/high SYNTAX score in the T2 and T3 groups was 2.574-fold higher (OR, 2.574; 95% CI 1.610-4.112; P < 0.001) and 3.732-fold higher (OR, 3.732; 95% CI 2.330-5.975; P < 0.001), respectively. Furthermore, there was a dose‒response relationship between the TyG index and the risk of complicated CAD (SYNTAX score > 22; nonlinear P = 0.200). The risk for a mid/high SYNTAX score in the T2 and T3 groups was significantly higher in normoglycemia, prediabetes mellitus, and diabetes mellitus subgroups.<br /><b>Conclusions</b><br />A higher TyG index was associated with the presence of a higher coronary anatomical complexity (SYNTAX score > 22) in ACS patients, irrespective of diabetes mellitus status. The TyG index might serve as a noninvasive predictor of CAD complexity in ACS patients and could potentially influence the management and therapeutic approach.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 12 Mar 2023; 22:56</small></div>

<div><h4>Association of diabetes mellitus and glycemic control with left ventricular function and deformation in patients after acute myocardial infarction: a 3 T cardiac magnetic resonance study.</h4><i>Gao Y, Shi R, Li Y, Guo YK, ... Shi K, Yang ZG</i><br /><b>Background</b><br />Diabetes mellitus (DM) is considered a major risk factor for myocardial infarction (MI), and MI patients with DM have a poor prognosis. Accordingly, we aimed to investigate the additive effects of DM on LV deformation in patients after acute MI.<br /><b>Materials and methods</b><br />One hundred thirteen MI patients without DM [MI (DM-)], 95 with DM [MI (DM+)] and 71 control subjects who underwent CMRscanning were included. LV function, infarct size and LV global peak strains in the radial, circumferential and longitudinal directions were measured. MI (DM+) patients were divided into two subgroups based on the HbA1c level (< 7.0% and ≥ 7.0%). The determinants of reduced LV global myocardial strain for all MI patients and MI (DM+) patients were assessed using multivariable linear regression analyses.<br /><b>Results</b><br />Compared with control subjects, both MI (DM-) and MI (DM+) patients presented higher LV end-diastolic and end-systolic volume index and lower LV ejection fraction. LV global peak strains progressively declined from the control group to the MI(DM-) group to the MI(DM+) group (all p < 0.05). Subgroup analysis showed that LV global radial PS and longitudinal PS were worse in MI(MD+) patients with poor glycemic control than in those with good glycemic control (all p < 0.05). DM was an independent determinant of impaired LV global peak strain in radial, circumferential and longitudinal directions in patients after acute MI (β = - 0.166, 0.164 and 0.262, both p < 0.05). The HbA1c level was independently associated with a decreased LV global radial PS (β =  - 0.209, p = 0.025) and longitudinal PS (β = 0.221, p = 0.010) in MI (DM+) patients.<br /><b>Conclusions</b><br />DM has an additive deleterious effect on LV function and deformation in patients after acute MI, and HbA1c was independently associated with impaired LV myocardial strain.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 11 Mar 2023; 22:55</small></div>

<div><h4>Adherence to antidiabetic drug therapy and reduction of fatal events in elderly frail patients.</h4><i>Rea F, Savaré L, Valsassina V, Ciardullo S, ... Corrao G, Mancia G</i><br /><b>Background</b><br />To evaluate the protective effect of oral antidiabetic drugs in a large cohort of elderly patients with type 2 diabetes differing for age, clinical status, and life expectancy, including patients with multiple comorbidities and short survival.<br /><b>Methods</b><br />A nested case-control study was carried out by including the cohort of 188,983 patients from Lombardy (Italy), aged ≥ 65 years, who received ≥ 3 consecutive prescriptions of antidiabetic agents (mostly metformin and other older conventional agents) during 2012. Cases were the 49,201 patients who died for any cause during follow-up (up to 2018). A control was randomly selected for each case. Adherence to drug therapy was measured by considering the proportion of days of the follow-up covered by the drug prescriptions. Conditional logistic regression was used to model the risk of outcome associated with adherence to antidiabetic drugs. The analysis was stratified according to four categories of the clinical status (good, intermediate, poor, and very poor) differing for life expectancy.<br /><b>Results</b><br />There was a steep increase in comorbidities and a marked reduction of the 6-year survival from the very good to the very poor (or frail) clinical category. Progressive increase in adherence to treatment was associated with a progressive decrease in the risk of all-cause mortality in all clinical categories and at all ages (65-74, 75-84 and ≥ 85 years) except for the frail patient subgroup aged ≥ 85 years. The mortality reduction from lowest to highest adherence level showed a tendency to be lower in frail patients compared to the other categories. Similar although less consistent results were obtained for cardiovascular mortality.<br /><b>Conclusions</b><br />In elderly diabetic patients, increased adherence to antidiabetic drugs is associated with a reduction in the risk of mortality regardless of the patients\' clinical status and age, with the exception of very old patients (age ≥ 85 years) in the very poor or frail clinical category. However, in the frail patient category the benefit of treatment appears to be less than in patients in good clinical conditions.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 10 Mar 2023; 22:53</small></div>

<div><h4>General versus central adiposity as risk factors for cardiovascular-related outcomes in a high-risk population with type 2 diabetes: a post hoc analysis of the REWIND trial.</h4><i>Franek E, Pais P, Basile J, Nicolay C, ... Kan H, Gerstein HC</i><br /><b>Background</b><br />In clinical practice, anthropometric measures other than BMI are rarely assessed yet may be more predictive of cardiovascular (CV) risk. We analyzed the placebo group of the REWIND CV Outcomes Trial to compare several anthropometric measures as baseline risk factors for cardiovascular disease (CVD)-related outcomes in participants with type 2 diabetes (T2D).<br /><b>Methods</b><br />Data from the REWIND trial placebo group (N = 4952) were analyzed. All participants had T2D, age ≥ 50 years, had either a previous CV event or CV risk factors, and a BMI of ≥ 23 kg/m<sup>2</sup>. Cox proportional hazard models were used to investigate if BMI, waist-to-hip ratio (WHR), and waist circumference (WC) were significant risk factors for major adverse CV events (MACE)-3, CVD-related mortality, all-cause mortality, and heart failure (HF) requiring hospitalization. Models were adjusted for age, sex, and additional baseline factors selected by LASSO method. Results are presented for one standard deviation increase of the respective anthropometric factor.<br /><b>Results</b><br />Participants in the placebo group experienced 663 MACE-3 events, 346 CVD-related deaths, 592 all-cause deaths, and 226 events of HF requiring hospitalization during the median follow-up of 5.4 years. WHR and WC, but not BMI, were identified as independent risk factors of MACE-3 (hazard ratio [HR] for WHR: 1.11 [95% CI 1.03 to 1.21]; p = 0.009; HR for WC: 1.12 [95% CI 1.02 to 1.22]; p = 0.012). WC adjusted for hip circumference (HC) showed the strongest association with MACE-3 compared to WHR, WC, or BMI unadjusted for each other (HR: 1.26 [95% CI 1.09 to 1.46]; p = 0.002). Results for CVD-related mortality and all-cause mortality were similar. WC and BMI were risk factors for HF requiring hospitalization, but not WHR or WC adjusted for HC (HR for WC: 1.34 [95% CI 1.16 to 1.54]; p < 0.001; HR for BMI: 1.33 [95% CI 1.17 to 1.50]; p < 0.001). No significant interaction with sex was observed.<br /><b>Conclusions</b><br />In this post hoc analysis of the REWIND placebo group, WHR, WC and/or WC adjusted for HC were risk factors for MACE-3, CVD-related mortality, and all-cause mortality; while BMI was only a risk factor for HF requiring hospitalization. These findings indicate the need for anthropometric measures that consider body fat distribution when assessing CV risk.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 10 Mar 2023; 22:52</small></div>

<div><h4>Cardiovascular outcomes with SGLT2 inhibitors versus DPP4 inhibitors and GLP-1 receptor agonists in patients with heart failure with reduced and preserved ejection fraction.</h4><i>Gonzalez J, Bates BA, Setoguchi S, Gerhard T, Dave CV</i><br /><b>Background</b><br />No study has compared the cardiovascular outcomes for sodium-glucose cotransporter-2 inhibitors (SGLT2i) head-to-head against other glucose-lowering therapies, including dipeptidyl peptidase 4 inhibitor (DDP4i) or glucagon-like peptide-1 receptor agonist (GLP-1RA)-which also have cardiovascular benefits-in patients with heart failure with reduced (HFrEF) or preserved (HFpEF) ejection fraction.<br /><b>Methods</b><br />Medicare fee-for-service data (2013-2019) were used to create four pair-wise comparison cohorts of type 2 diabetes patients with: (1a) HFrEF initiating SGLT2i versus DPP4i; (1b) HFrEF initiating SGLT2i versus GLP-1RA; (2a) HFpEF initiating SGLT2i versus DPP4i; and (2b) HFpEF initiating SGLT2i versus GLP-1RA. The primary outcomes were (1) hospitalization for heart failure (HHF) and (2) myocardial infarction (MI) or stroke hospitalizations. Adjusted hazards ratios (HR) and 95% CIs were estimated using inverse probability of treatment weighting.<br /><b>Results</b><br />Among HFrEF patients, initiation of SGLT2i versus DPP4i (cohort 1a; n = 13,882) was associated with a lower risk of HHF (adjusted Hazard Ratio [HR (95% confidence interval)], 0.67 (0.63, 0.72) and MI or stroke (HR: 0.86 [0.75, 0.99]), and initiation of SGLT2i versus GLP-1RA (cohort 1b; n = 6951) was associated with lower risk of HHF (HR: 0.86 [0.79, 0.93]), but not MI or stroke (HR: 1.02 [0.85, 1.22]). Among HFpEF patients, initiation of SGLT2i versus DPP4i (cohort 2a; n = 17,493) was associated with lower risk of HHF (HR: 0.65 [0.61, 0.69]) but not MI or stroke (HR: 0.90 [0.79, 1.02]), and initiation of SGLT2i versus GLP-1RA (cohort 2b; n = 9053) was associated with lower risk of HHF (0.89 [0.83, 0.96]), but not MI or stroke (HR: 0.97 [0.83, 1.14]). Results were robust across range of secondary outcomes (e.g., all-cause mortality) and sensitivity analyses.<br /><b>Conclusions</b><br />Bias from residual confounding cannot be ruled out. Use of SGLT2i was associated with reduced risk of HHF against DPP4i and GLP-1RA, reduced risk of MI or stroke against DPP4i within the HFrEF subgroup, and comparable risk of MI or stroke against GLP-1RA. Notably, the magnitude of cardiovascular benefit conferred by SGLT2i was similar among patients with HFrEF and HFpEF.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 10 Mar 2023; 22:54</small></div>

<div><h4>Associations of genetic markers of diabetes mellitus with carotid atherosclerosis: a community-based case-control study.</h4><i>Wu TW, Chou CL, Cheng CF, Lu SX, Wu YJ, Wang LY</i><br /><b>Background</b><br />Diabetes mellitus (DM) is a well-established determinant of atherosclerosis and cardiovascular diseases (CVD). Recently, genome-wide association studies (GWAS) identified several single nucleotide polymorphism (SNP) significantly correlated with DM. The study aimed to explore the relationships of the top significant DM SNPs with carotid atherosclerosis (CA).<br /><b>Methods</b><br />We used a case-control design and randomly selected 309 cases and 439 controls with and without, respectively, carotid plaque (CP) from a community-based cohort. Eight recent GWAS on DM in East Asians reported hundreds of SNPs with genome-wide significance. The study used the top significant DM SNPs, with a p-value < 10<sup>-16</sup>, as the candidate genetic markers of CA. The independent effects of these DM SNPs on CA were assessed by multivariable logistic regression analyses to control the effects of conventional cardio-metabolic risk factors.<br /><b>Results</b><br />Multivariable analyses showed that, 9 SNPs, including rs4712524, rs1150777, rs10842993, rs2858980, rs9583907, rs1077476, rs7180016, rs4383154, and rs9937354, showed promising associations with the presence of carotid plaque (CP). Among them, rs9937354, rs10842993, rs7180016, and rs4383154 showed significantly independent effects. The means (SD) of the 9-locus genetic risk score (9-GRS) of CP-positive and -negative subjects were 9.19 (1.53) and 8.62 (1.63), respectively (p < 0.001). The corresponding values of 4-locus GRS (4-GRS) were 4.02 (0.81) and. 3.78 (0.92), respectively (p < 0.001). The multivariable-adjusted odds ratio of having CP for per 1.0 increase in 9-GRS and 4-GRS were 1.30 (95% CI 1.18-1.44; p = 4.7 × 10<sup>-7</sup>) and 1.47 (95% CI 1.74-9.40; p = 6.1 × 10<sup>-5</sup>), respectively. The means of multi-locus GRSs of DM patients were similar to those of CP-positive subjects and higher than those of CP-negative or DM-negative subjects.<br /><b>Conclusions</b><br />We identified 9 DM SNPs showing promising associations with CP. The multi-locus GRSs may be used as biomarkers for the identification and prediction of high-risks subjects for atherosclerosis and atherosclerotic diseases. Future studies on these specific SNPs and their associated genes may provide valuable information for the preventions of DM and atherosclerosis.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 09 Mar 2023; 22:51</small></div>

<div><h4>The vascular function effects of adding exenatide or meal insulin to basal insulin therapy in early type 2 diabetes.</h4><i>Retnakaran R, Pu J, Ye C, Emery A, Kramer CK, Zinman B</i><br /><b>Objective</b><br />Basal insulin glargine has a neutral effect on cardiovascular risk in type 2 diabetes (T2DM). In practice, basal insulin is often paired with a glucagon-like peptide-1 receptor agonist (GLP1-RA) or meal insulin; however, the cardiovascular implications of these combinations have not been fully elucidated. In this context, we sought to evaluate the vascular function effects of adding the GLP1-RA exenatide or meal insulin lispro to basal glargine therapy in early T2DM.<br /><b>Methods</b><br />In this 20-week trial, adults with T2DM of < 7-years duration were randomized to 8-weeks treatment with (i) insulin glargine (Glar), (ii) glargine + thrice-daily lispro (Glar/Lispro), or (iii) glargine + twice-daily exenatide (Glar/Exenatide), followed by 12-weeks washout. At baseline, 8-weeks, and washout, fasting endothelial function was assessed with reactive hyperemia index (RHI) measurement by peripheral arterial tonometry.<br /><b>Results</b><br />At baseline, there were no differences in blood pressure (BP), heart rate (HR) or RHI between participants randomized to Glar (n = 24), Glar/Lispro (n = 24), and Glar/Exenatide (n = 25). At 8-weeks, Glar/Exenatide decreased systolic BP (mean - 8.1 mmHg [95%CI - 13.9 to - 2.4], p = 0.008) and diastolic BP (mean - 5.1 mmHg [- 9.0 to - 1.3], p = 0.012) compared to baseline, with no significant changes in HR or RHI. Notably, baseline-adjusted RHI (mean ± SE) did not differ between the groups at 8-weeks (Glar 2.07 ± 0.10; Glar/Lispro 2.00 ± 0.10; Glar/Exenatide 1.81 ± 0.10; p = 0.19), nor did baseline-adjusted BP or HR. There were no differences between the groups in baseline-adjusted RHI, BP or HR after 12-weeks washout.<br /><b>Conclusion</b><br />Adding either exenatide or lispro to basal insulin therapy does not appear to affect fasting endothelial function in early T2DM.<br /><b>Trial registration</b><br />ClinicalTrials.Gov NCT02194595.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 09 Mar 2023; 22:50</small></div>

<div><h4>Weight-dependent and weight-independent effects of dulaglutide on blood pressure in patients with type 2 diabetes.</h4><i>Ferdinand KC, Dunn J, Nicolay C, Sam F, Blue EK, Wang H</i><br /><b>Background</b><br />Patients with type 2 diabetes (T2D) treated with glucagon-like peptide-1 receptor agonists may experience reductions in weight and blood pressure. The primary objective of the current study was to determine the weight-dependent and weight-independent effects of ~ 6 months treatment with dulaglutide 1.5 mg treatment in participants with T2D.<br /><b>Methods</b><br />Mediation analysis was conducted for five randomized, placebo-controlled trials of dulaglutide 1.5 mg to estimate the weight-dependent (i.e., mediated by weight) and weight-independent effects from dulaglutide vs. placebo on change from baseline for systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure. A random-effects meta-analysis combined these results. To investigate a dose response between dulaglutide 4.5 mg and placebo, mediation analysis was first conducted in AWARD-11 to estimate the weight-dependent and weight-independent effects of dulaglutide 4.5 mg vs. 1.5 mg, followed by an indirect comparison with the mediation result for dulaglutide 1.5 mg vs. placebo.<br /><b>Results</b><br />Baseline characteristics were largely similar across the trials. In the mediation meta-analysis of placebo-controlled trials, the total treatment effect of dulaglutide 1.5 mg after placebo-adjustment on SBP was - 2.6 mmHg (95% CI - 3.8, - 1.5; p < 0.001) and was attributed to both a weight-dependent effect (- 0.9 mmHg; 95% CI: - 1.4, - 0.5; p < 0.001) and a weight-independent effect (- 1.5 mmHg; 95% CI: - 2.6, - 0.3; p = 0.01), accounting for 36% and 64% of the total effect, respectively. For pulse pressure, the total treatment effect of dulaglutide (- 2.5 mmHg; 95% CI: - 3.5, - 1.5; p < 0.001) was 14% weight-dependent and 86% weight-independent. For DBP there was limited impact of dulaglutide treatment, with only a small weight-mediated effect. Dulaglutide 4.5 mg demonstrated an effect on reduction in SBP and pulse pressure beyond that of dulaglutide 1.5 mg which was primarily weight mediated.<br /><b>Conclusions</b><br />Dulaglutide 1.5 mg reduced SBP and pulse pressure in people with T2D across the placebo-controlled trials in the AWARD program. While up to one third of the effect of dulaglutide 1.5 mg on SBP and pulse pressure was due to weight reduction, the majority was independent of weight. A greater understanding of the pleotropic effects of GLP-1 RA that contribute to reduction in blood pressure could support developing future approaches for treating hypertension. Trial registrations (clinicaltrials.gov) NCT01064687, NCT00734474, NCT01769378, NCT02597049, NCT01149421, NCT03495102.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 09 Mar 2023; 22:49</small></div>

<div><h4>Myocardial fat accumulation is associated with cardiac dysfunction in patients with type 2 diabetes, especially in elderly or female patients: a retrospective observational study.</h4><i>Kashiwagi-Takayama R, Kozawa J, Hosokawa Y, Kato S, ... Matsuzawa Y, Shimomura I</i><br /><b>Background</b><br />Ectopic fat is fat that accumulates in or around specific organs or compartments of the body including myocardium. The clinical features of type 2 diabetes patients with high fat accumulation in the myocardium remain unknown. Moreover, little is known about the influence of myocardial fat accumulation in type 2 diabetes on coronary artery disease and cardiac dysfunction. We aimed to clarify the clinical features, including cardiac functions, of type 2 diabetes patients with myocardial fat accumulation.<br /><b>Methods</b><br />We retrospectively enrolled type 2 diabetes patients who underwent ECG-gated coronary computed tomography angiography (CCTA) and abdominal computed tomography (CT) scan examinations within 1 year of CCTA from January 2000 to March 2021. High fat accumulation in the myocardium was defined as the low mean myocardial CT value of three regions of interest, and the associations between CT values and clinical characteristics or cardiac functions were assessed.<br /><b>Results</b><br />In total, 124 patients were enrolled (72 males and 52 females). The mean age was 66.6 years, the mean BMI was 26.2 kg/m<sup>2</sup>, the mean ejection fraction (EF) was 67.6%, and the mean myocardial CT value was 47.7 Hounsfield unit. A significant positive correlation was found between myocardial CT value and EF (r = 0.3644, p = 0.0004). The multiple regression analyses also showed that myocardial CT value was independently associated with EF (estimate, 0.304; 95% confidence interval (CI) 0.092 to 0.517; p = 0.0056). Myocardial CT value showed significant negative correlations with BMI, visceral fat area and subcutaneous fat area (r = - 0.1923, - 0.2654, and -0.3569, respectively, p < 0.05). In patients who were ≥ 65 years or female, myocardial CT value showed significant positive correlations with not only EF (r = 0.3542 and 0.4085, respectively, p < 0.01) but also early lateral annular tissue Doppler velocity (Lat e\') (r = 0.5148 and 0.5361, respectively, p < 0.05). The multiple regression analyses showed that myocardial CT value was independently associated with EF and Lat e\' in these subgroups (p < 0.05).<br /><b>Conclusions</b><br />Patients with type 2 diabetes, especially in elderly or female patients, who had more myocardial fat had more severe left ventricular systolic and diastolic dysfunctions. Reducing myocardial fat accumulation may be a therapeutic target for type 2 diabetes patients.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 07 Mar 2023; 22:48</small></div>

<div><h4>Maternal obesity and gestational diabetes reprogram the methylome of offspring beyond birth by inducing epigenetic signatures in metabolic and developmental pathways.</h4><i>Alba-Linares JJ, Pérez RF, Tejedor JR, Bastante-Rodríguez D, ... Fraga MF, Lurbe E</i><br /><b>Background</b><br />Obesity is a negative chronic metabolic health condition that represents an additional risk for the development of multiple pathologies. Epidemiological studies have shown how maternal obesity or gestational diabetes mellitus during pregnancy constitute serious risk factors in relation to the appearance of cardiometabolic diseases in the offspring. Furthermore, epigenetic remodelling may help explain the molecular mechanisms that underlie these epidemiological findings. Thus, in this study we explored the DNA methylation landscape of children born to mothers with obesity and gestational diabetes during their first year of life.<br /><b>Methods</b><br />We used Illumina Infinium MethylationEPIC BeadChip arrays to profile more than 770,000 genome-wide CpG sites in blood samples from a paediatric longitudinal cohort consisting of 26 children born to mothers who suffered from obesity or obesity with gestational diabetes mellitus during pregnancy and 13 healthy controls (measurements taken at 0, 6 and 12 month; total N = 90). We carried out cross-sectional and longitudinal analyses to derive DNA methylation alterations associated with developmental and pathology-related epigenomics.<br /><b>Results</b><br />We identified abundant DNA methylation changes during child development from birth to 6 months and, to a lesser extent, up to 12 months of age. Using cross-sectional analyses, we discovered DNA methylation biomarkers maintained across the first year of life that could discriminate children born to mothers who suffered from obesity or obesity with gestational diabetes. Importantly, enrichment analyses suggested that these alterations constitute epigenetic signatures that affect genes and pathways involved in the metabolism of fatty acids, postnatal developmental processes and mitochondrial bioenergetics, such as CPT1B, SLC38A4, SLC35F3 and FN3K. Finally, we observed evidence of an interaction between developmental DNA methylation changes and maternal metabolic condition alterations.<br /><b>Conclusions</b><br />Our observations highlight the first six months of development as being the most crucial for epigenetic remodelling. Furthermore, our results support the existence of systemic intrauterine foetal programming linked to obesity and gestational diabetes that affects the childhood methylome beyond birth, which involves alterations related to metabolic pathways, and which may interact with ordinary postnatal development programmes.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 04 Mar 2023; 22:44</small></div>

<div><h4>Epicardial adipose tissue density is a better predictor of cardiometabolic risk in HFpEF patients: a prospective cohort study.</h4><i>Liu J, Yu Q, Li Z, Zhou Y, ... Gao L, Zhang D</i><br /><b>Background</b><br />Epicardial adipose tissue (EAT) accumulation is associated with multiple cardiometabolic risk factors and prognosis of heart failure with preserved ejection fraction (HFpEF). The correlation between EAT density and cardiometabolic risk and the effect of EAT density on clinical outcome in HFpEF remain unclear. We evaluated the relationship between EAT density and cardiometabolic risk factors, also the prognostic value of EAT density in patients with HFpEF.<br /><b>Methods</b><br />We included 154 HFpEF patients who underwent noncontrast cardiac computed tomography (CT) and all patients received follow-up. EAT density and volume were quantified semi-automatically. The associations of EAT density and volume with cardiometabolic risk factors, metabolic syndrome and the prognostic impact of EAT density were analyzed.<br /><b>Results</b><br />Lower EAT density was associated with adverse changes in cardiometabolic risk factors. Each 1 HU increase in fat density, BMI was 0.14 kg/m<sup>2</sup> lower (95% CI 0.08-0.21), waist circumference was 0.34 cm lower (95% CI 0.12-0.55), non-HDL-cholesterol was 0.02 mmol/L lower (95% CI 0-0.04), triglyceride was 0.03 mmol/L lower (95% CI 0.01-0.04), fasting plasma glucose was 0.05 mmol/L lower (95% CI 0.02-0.08), TyG index was 0.03 lower (95% CI 0.02-0.04), Log<sub>2</sub>(TG/HDL-C) was 0.03 lower (95% CI 0.02-0.05), METS-IR was 0.36 lower (95% CI 0.23-0.49), MetS Z-score was 0.04 lower (95% CI 0.02-0.06), and Log<sub>2</sub>(CACS + 1) was 0.09 lower (95% CI 0.02-0.15). After adjusting for BMI and EAT volume, the associations of non-HDL-cholesterol, triglyceride, fasting plasma glucose, insulin resistance indexes, MetS Z-score, and CACS with fat density remained significant. The area under the curve (AUC) for the presence and severity of metabolic syndrome was greater in EAT density than volume (AUC: 0.731 vs 0.694, 0.735 vs 0.662, respectively). Over a median follow-up of 16 months, the cumulative incidence of heart failure readmission and composite endpoint increased with lower level of EAT density (both p < 0.05).<br /><b>Conclusions</b><br />EAT density was an independent impact factor of cardiometabolic risk in HFpEF. EAT density might have better predictive value than EAT volume for metabolic syndrome and it might have prognostic value in patients with HFpEF.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 04 Mar 2023; 22:45</small></div>

<div><h4>Higher HbA variability is associated with increased arterial stiffness in individuals with type 1 diabetes.</h4><i>Tynjälä A, Harjutsalo V, Jansson Sigfrids F, Groop PH, Gordin D, FinnDiane Study Group</i><br /><b>Background</b><br />Both long-term glycaemic variability and arterial stiffness have been recognized as cardiovascular risk factors. This study aims to investigate whether an association between these phenomena exists in individuals with type 1 diabetes.<br /><b>Methods</b><br />This cross-sectional study included 673 adults (305 men, 368 women) with type 1 diabetes and combined available retrospective laboratory data on HbA<sub>1c</sub> from the preceding 10 years with outcome data on arterial stiffness and clinical variables from a comprehensive study visit. HbA<sub>1c</sub> variability was calculated as adjusted standard deviation (adj-HbA<sub>1c</sub>-SD), coefficient of variation (HbA<sub>1c</sub>-CV) and average real variability (HbA<sub>1c</sub>-ARV). As measures of arterial stiffness, carotid-femoral pulse wave velocity (cfPWV; n = 335) and augmentation index (AIx; n = 653) were assessed using applanation tonometry.<br /><b>Results</b><br />The study population had a mean age of 47.1 (± 12.0) years and a median duration of diabetes of 31.2 (21.2-41.3) years. The median number of HbA<sub>1c</sub> assessments per individual was 17 (12-26). All three indices of HbA<sub>1c</sub> variability were significantly correlated with both cfPWV and AIx after adjustment for sex and age (p < 0.001). In separate multivariable linear regression models, adj-HbA<sub>1c</sub>-SD and HbA<sub>1c</sub>-CV were significantly associated with cfPWV (p = 0.032 and p = 0.046, respectively) and AIx (p = 0.028 and p = 0.049, respectively), even after adjustment for HbA<sub>1c</sub>-mean. HbA<sub>1c</sub>-ARV was not associated with cfPWV or AIx in the fully adjusted models.<br /><b>Conclusions</b><br />An association independent of HbA<sub>1c</sub>-mean was found between HbA<sub>1c</sub> variability and arterial stiffness, suggesting a need to consider multiple HbA<sub>1c</sub> metrics in studies assessing cardiovascular risk in type 1 diabetes. Longitudinal and interventional studies are needed to confirm any causal relationship and to find strategies for reducing long-term glycaemic variability.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 04 Mar 2023; 22:47</small></div>

<div><h4>The joint association of diabetes status and NT-ProBNP with adverse cardiac outcomes in patients with non-ST-segment elevation acute coronary syndrome: a prospective cohort study.</h4><i>Wang M, Su W, Chen H, Li H</i><br /><b>Aims</b><br />To examine the joint association of diabetes status and N-terminal pro-B-type natriuretic peptide (NT-proBNP) with subsequent risk of major adverse cardio-cerebral events (MACCEs) and all-cause mortality in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS).<br /><b>Methods</b><br />A total of 7956 NSTE-ACS patients recruited from the Cardiovascular Center Beijing Friendship Hospital Database Bank were included in this cohort study. Patients were divided into nine groups according to diabetes status (normoglycemia, prediabetes, diabetes) and NT-proBNP tertiles (< 92 pg/ml, 92-335 pg/ml, ≥ 336 pg/ml). Multivariable Cox proportional hazards models were used to estimate the individual and joint association of diabetes status and NT-proBNP with the risk of MACCEs and all-cause mortality.<br /><b>Results</b><br />During 20,257.9 person-years of follow-up, 1070 MACCEs were documented. In the fully adjusted model, diabetes and a higher level of NT-proBNP were independently associated with MACCEs risk (HR 1.42, 95% CI: 1.20-1.68; HR 1.72, 95% CI: 1.40-2.11) and all-cause mortality (HR 1.37, 95% CI: 1.05-1.78; HR 2.80, 95% CI: 1.89-4.17). Compared with patients with normoglycemia and NT-proBNP < 92 pg/ml, the strongest numerical adjusted hazards for MACCEs and all-cause mortality were observed in patients with diabetes and NT-proBNP ≥ 336 pg/ml (HR 2.67, 95% CI: 1.83-3.89; HR 2.98, 95% CI: 1.48-6.00). The association between MACCEs and all-cause mortality with various combinations of NT-proBNP level, HbA1c, and fasting plasma glucose was studied.<br /><b>Conclusions</b><br />Diabetes status and elevated NT-proBNP were independently and jointly associated with MACCEs and all-cause mortality in patients with NSTE-ACS.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 04 Mar 2023; 22:46</small></div>