Journal: Cardiovasc Diabetol

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Abstract

Association between healthy lifestyle and the occurrence of cardiometabolic multimorbidity in hypertensive patients: a prospective cohort study of UK Biobank.

Xie H, Li J, Zhu X, Li J, ... Cheng X, Li C
Background
Cardiometabolic multimorbidity (CMM) is becoming increasingly common in patients with hypertension, and it is well established that healthy lifestyle plays a key role in the prevention of hypertension. However, the association between combined lifestyle factors and CMM in patients with hypertension is uncertain.
Methods
This prospective analysis included the data (obtained from the UK biobank) of participants with hypertension who did not have coronary heart disease (CHD), stroke, or diabetes. The outcome was the occurrence of CMM, defined as ≥ 1 disease of CHD, stroke, and diabetes that occurred in participants with hypertension. Four lifestyle factors (smoking, alcohol consumption, diet, and physical activity) were assessed using a weighted healthy lifestyle score, and participants were divided into four groups: the very unhealthy, unhealthy, healthy, and very healthy groups. The flexible parameter Royston-Parmar proportional hazard model was used to estimate hazard ratios (HRs) between lifestyles and CMM, as well as the difference in CMM-free life expectancy.
Results
During a median follow-up of 12.2 years, 9812 (18.4%) of the 53,397 hypertensive patients occurred CMM. Compared with the very unhealthy group, the very healthy group had a 41% reduction in the risk for CMM in hypertensive patients and a 32-50% reduction in the risk for specific cardiometabolic diseases such as CHD, stroke, and diabetes. For each lifestyle factor, non-smoking had the greatest protective effect against CMM (HR: 0.64, 95% confidence interval (CI) 0.60-0.68). A lifestyle combining multiple healthy factors extended CMM-free life expectancy (e.g., six years longer at age 45 years for participants in the very healthy group).
Conclusions
Combined healthy lifestyle factors were associated with a lower risk for CMM in hypertensive patients. This suggests that combined healthy lifestyle should be supported to decrease disease burden.

© 2022. The Author(s).

Cardiovasc Diabetol: 01 Oct 2022; 21:199
Xie H, Li J, Zhu X, Li J, ... Cheng X, Li C
Cardiovasc Diabetol: 01 Oct 2022; 21:199 | PMID: 36183084
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Abstract

Sex-related disparities in the incidence and outcomes of infective endocarditis according to type 2 diabetes mellitus status in Spain, 2016-2020.

Lopez-de-Andres A, Jimenez-Garcia R, Hernández-Barrera V, de-Miguel-Díez J, ... Zamorano-Leon JJ, Noriega C
Background
We performed a study to assess sex-differences in incidence (2016-2020), clinical characteristics, use of therapeutic procedures, and in-hospital outcomes in patients with infective endocarditis (IE) according to T2DM status.
Methods
Ours was a retrospective cohort study using data from the Spanish National Hospital Discharge Database. We estimated the incidence of hospitalizations for IE in men and women aged ≥ 40 years with and without T2DM. Propensity score matching (PSM) and multivariable logistic regression were used to compare subgroups according to sex and the presence of T2DM.
Results
From 2016 to 2020, IE was coded in 9,958 patients (66.79% men). T2DM was diagnosed in 2,668 (26.79%). The incidence of IE increased significantly from 15.29 cases per 100,000 persons with T2DM in 2016 to 17.69 in 2020 (p < 0.001). However, this increment was significant only among men with T2DM (19.47 cases per 100,000 in 2016 vs. 22.84 in 2020; p = 0.003). The age-adjusted incidence of IE was significantly higher in people with T2DM (both sexes) than in those without T2DM (IRR, 2.86; 95% CI, 2.74-2.99). The incidence of IE was higher in men with T2DM than in women with T2DM (adjusted IRR, 1.85; 95% CI, 1.54-3.31). After PSM, in-hospital mortality (IHM) was higher among T2DM women than matched T2DM men (22.65% vs. 18.0%; p = 0.018). The presence of T2DM was not associated with IHM in men or women.
Conclusions
T2DM is associated with a higher incidence of hospitalization for IE. Findings for T2DM patients who had experienced IE differed by sex, with higher incidence rates and lower IHM in men than in women. T2DM was not associated to IHM in IE in men or in women.

© 2022. The Author(s).

Cardiovasc Diabetol: 30 Sep 2022; 21:198
Lopez-de-Andres A, Jimenez-Garcia R, Hernández-Barrera V, de-Miguel-Díez J, ... Zamorano-Leon JJ, Noriega C
Cardiovasc Diabetol: 30 Sep 2022; 21:198 | PMID: 36180922
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Abstract

Dapagliflozin reduces the vulnerability of rats with pulmonary arterial hypertension-induced right heart failure to ventricular arrhythmia by restoring calcium handling.

Wu J, Liu T, Shi S, Fan Z, ... Wu G, Huang C
Background
Malignant ventricular arrhythmia (VA) is a major contributor to sudden cardiac death (SCD) in patients with pulmonary arterial hypertension (PAH)-induced right heart failure (RHF). Recently, dapagliflozin (DAPA), a sodium/glucose cotransporter-2 inhibitor (SGLT2i), has been found to exhibit cardioprotective effects in patients with left ventricular systolic dysfunction. In this study, we examined the effects of DAPA on VA vulnerability in a rat model of PAH-induced RHF.
Methods
Rats randomly received monocrotaline (MCT, 60 mg/kg) or vehicle via a single intraperitoneal injection. A day later, MCT-injected rats were randomly treated with placebo, low-dose DAPA (1 mg/kg/day), or high-dose (3 mg/kg/day) DAPA orally for 35 days. Echocardiographic analysis, haemodynamic experiments, and histological assessments were subsequently performed to confirm the presence of PAH-induced RHF. Right ventricle (RV) expression of calcium (Ca2+) handling proteins were detected via Western blotting. RV expression of connexin 43 (Cx43) was determined via immunohistochemical staining. An optical mapping study was performed to assess the electrophysiological characteristics in isolated hearts. Cellular Ca2+ imaging from RV cardiomyocytes (RVCMs) was recorded using Fura-2 AM or Fluo-4 AM.
Results
High-dose DAPA treatment attenuated RV structural remodelling, improved RV function, alleviated Cx43 remodelling, increased the conduction velocity, restored the expression of key Ca2+ handling proteins, increased the threshold for Ca2+ and action potential duration (APD) alternans, decreased susceptibility to spatially discordant APD alternans and spontaneous Ca2+ events, promoted cellular Ca2+ handling, and reduced VA vulnerability in PAH-induced RHF rats. Low-dose DAPA treatment also showed antiarrhythmic effects in hearts with PAH-induced RHF, although with a lower level of efficacy.
Conclusion
DAPA administration reduced VA vulnerability in rats with PAH-induced RHF by improving RVCM Ca2+ handling.

© 2022. The Author(s).

Cardiovasc Diabetol: 28 Sep 2022; 21:197
Wu J, Liu T, Shi S, Fan Z, ... Wu G, Huang C
Cardiovasc Diabetol: 28 Sep 2022; 21:197 | PMID: 36171554
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Abstract

Results of a prospective observational study of autologous peripheral blood mononuclear cell therapy for no-option critical limb-threatening ischemia and severe diabetic foot ulcers.

Panunzi A, Madotto F, Sangalli E, Riccio F, ... Spinetti G, Caravaggi CMF
Background
Cell therapy with autologous peripheral blood mononuclear cells (PB-MNCs) may help restore limb perfusion in patients with diabetes mellitus and critical limb-threatening ischemia (CLTI) deemed not eligible for revascularization procedures and consequently at risk for major amputation (no-option). Fundamental is to establish its clinical value and to identify candidates with a greater benefit over time. Assessing the frequency of PB circulating angiogenic cells and extracellular vesicles (EVs) may help in guiding candidate selection.
Methods
We conducted a prospective, non-controlled, observational study on no-option CLTI diabetic patients that underwent intramuscular PB-MNCs therapy, which consisted of more cell treatments repeated a maximum of three times. The primary endpoint was amputation rate at 1 year following the first treatment with PB-MNCs. We evaluated ulcer healing, walking capability, and mortality during the follow-up period. We assessed angiogenic cells and EVs at baseline and after each cell treatment, according to primary outcome and tissue perfusion at the last treatment [measured as transcutaneous oxygen pressure (TcPO2)].
Results
50 patients were consecutively enrolled and the primary endpoint was 16%. TcPO2 increased after PB-MNCs therapy (17.2 ± 11.6 vs 39.1 ± 21.8 mmHg, p < .0001), and ulcers healed with back-to-walk were observed in 60% of the study population (88% of survivors) during follow-up (median 1.5 years). Patients with a high level of TcPO2 (≥ 40 mmHg) after the last treatment showed a high frequency of small EVs at enrollment.
Conclusions
In no-option CLTI diabetic patients, PB-MNCs therapy led to an improvement in tissue perfusion, a high rate of healing, and back-to-walk. Coupling circulating cellular markers of angiogenesis could help in the identification of patients with a better clinical benefit over time.

© 2022. The Author(s).

Cardiovasc Diabetol: 28 Sep 2022; 21:196
Panunzi A, Madotto F, Sangalli E, Riccio F, ... Spinetti G, Caravaggi CMF
Cardiovasc Diabetol: 28 Sep 2022; 21:196 | PMID: 36171587
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Abstract

Initiation of the SGLT2 inhibitor canagliflozin to prevent kidney and heart failure outcomes guided by HbA1c, albuminuria, and predicted risk of kidney failure.

Tye SC, Jongs N, Coca SG, Sundström J, ... Vart P, Heerspink HJL
Background
Sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of kidney and heart failure events independent of glycemic effects. We assessed whether initiation of the SGLT2 inhibitor canagliflozin guided by multivariable predicted risk based on clinical characteristics and novel biomarkers is more efficient to prevent clinical outcomes compared to a strategy guided by HbA1c or urinary-albumin-creatinine ratio (UACR) alone.
Methods
We performed a post-hoc analysis of the CANVAS trial including 3713 patients with available biomarker measurements. We compared the number of composite kidney (defined as a sustained 40% decline in eGFR, chronic dialysis, kidney transplantation, or kidney death) and composite heart failure outcomes (defined as heart failure hospitalization or cardiovascular (CV) death) prevented per 1000 patients treated for 5 years when canagliflozin was initiated in patients according to HbA1c ≥ 7.5%, UACR, or multivariable risk models consisting of: (1) clinical characteristics, or (2) clinical characteristics and novel biomarkers. Differences in the rates of events prevented between strategies were tested by Chi2-statistic.
Results
After a median follow-up of 6.1 years, 144 kidney events were recorded. The final clinical model included age, previous history of CV disease, systolic blood pressure, UACR, hemoglobin, body weight, albumin, estimated glomerular filtration rate, and randomized treatment assignment. The combined biomarkers model included all clinical characteristics, tumor necrosis factor receptor-1, kidney injury molecule-1, matrix metallopeptidase-7 and interleukin-6. Treating all patients with HbA1c ≥ 7.5% (n = 2809) would prevent 33.0 (95% CI 18.8 to 43.3 ) kidney events at a rate of 9.6 (95% CI 5.5 to 12.6) events prevented per 1000 patients treated for 5 years. The corresponding rates were 5.8 (95% CI 3.4 to 7.9), 16.6 (95% CI 9.5 to 22.0) (P < 0.001 versus HbA1c or UACR approach), and 17.5 (95% CI 10.0 to 23.0) (P < 0.001 versus HbA1c or UACR approach; P = 0.54 versus clinical model). Findings were similar for the heart failure outcome.
Conclusion
Initiation of canagliflozin based on an estimated risk-based approach prevented more kidney and heart failure outcomes compared to a strategy based on HbA1c or UACR alone. There was no apparent gain from adding novel biomarkers to the clinical risk model. These findings support the use of risk-based assessment using clinical markers to guide initiation of SGLT2 inhibitors in patients with type 2 diabetes.

© 2022. The Author(s).

Cardiovasc Diabetol: 23 Sep 2022; 21:194
Tye SC, Jongs N, Coca SG, Sundström J, ... Vart P, Heerspink HJL
Cardiovasc Diabetol: 23 Sep 2022; 21:194 | PMID: 36151557
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Abstract

Plasma mannose as a novel marker of myocardial infarction across different glycaemic states: a case control study.

Fortin E, Ferrannini G, Campi B, Mellbin L, ... Ferrannini E, Rydén L
Background
Plasma mannose, an emerging novel biomarker of insulin resistance, is associated with both diabetes mellitus and coronary atherosclerosis, but the relationship between mannose concentrations and myocardial infarction (MI) across different glycaemic states remains to be elucidated. The aim of this study was to investigate the independent association between mannose and a first MI in a group of subjects characterized according to their glycaemic state.
Methods
Fasting plasma mannose concentrations were analysed in 777 patients 6-10 weeks after a first myocardial infarction and in 770 matched controls by means of high-performance liquid chromatography coupled to tandem mass spectrometry. Participants without known diabetes mellitus were categorized by an oral glucose tolerance test (OGTT) as having normal glucose tolerance (NGT, n = 1045), impaired glucose tolerance (IGT, n = 246) or newly detected type 2 diabetes (T2DM, n = 112). The association between mannose and MI was investigated across these glycaemic states by logistic regression.
Results
Mannose levels increased across the glycaemic states (p < 0.0001) and were significantly associated with a first MI in the whole study population (odds ratio, OR: 2.2; 95% CI 1.4 to - 3.5). Considering the different subgroups separately, the association persisted only in subjects with NGT (adjusted OR: 2.0; 95% CI 1.2-3.6), but not in subgroups with glucose perturbations (adjusted OR: 1.8, 95% CI 0.8-3.7).
Conclusions
Mannose concentrations increased across worsening levels of glucose perturbations but were independently associated with a first MI only in NGT individuals. Thus, mannose might be a novel, independent risk marker for MI, possibly targeted for the early management of previously unidentified patients at high cardiovascular risk.

© 2022. The Author(s).

Cardiovasc Diabetol: 23 Sep 2022; 21:195
Fortin E, Ferrannini G, Campi B, Mellbin L, ... Ferrannini E, Rydén L
Cardiovasc Diabetol: 23 Sep 2022; 21:195 | PMID: 36151569
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Abstract

Incremental prognostic value of triglyceride glucose index additional to coronary artery calcium score in asymptomatic low-risk population.

Song S, Choi SY, Park HE, Han HW, ... Sung JM, Chang HJ
Background
The triglyceride glucose (TyG) index has been suggested as a reliable surrogate marker of insulin resistance which is a substantial risk factor for atherosclerotic cardiovascular disease (ASCVD). Several recent studies have shown the relationship between the TyG index and cardiovascular disease; however, the role of the TyG index in coronary artery calcification (CAC) progression has not been extensively assessed especially in low-risk population.
Methods
We enrolled 5775 Korean adults who had at least two CAC evaluations. We determined the TyG index using ln (fasting triglycerides [mg/dL] x fasting glucose [mg/dL]/2). The CAC progression was defined as either incident CAC in a CAC-free population at baseline or an increase of ≥ 2.5 units between the square roots of the baseline and follow-up coronary artery calcium scores (CACSs) of subjects with detectable CAC at baseline.
Results
CAC progression was seen in 1,382 subjects (23.9%) during mean 3.5 years follow-up. Based on the TyG index, subjects were stratified into four groups. Follow-up CACS and incidence of CAC progression were markedly elevated with rising TyG index quartiles (group I [lowest]:17.6% vs. group II:22.2% vs. group III:24.6% vs. group IV [highest]: 31.3%, p < 0.001). In multivariate logistic regression analysis, the TyG index was independent predictor of CAC progression (odds ratio: 1.57; 95% confidence interval: 1.33 to 1.81; p < 0.001) especially in baseline CACS ≤ 100 group.
Conclusion
The TyG index is an independent predictor of CAC progression in low-risk population. It adds incremental risk stratification over established factors including baseline CACS.

© 2022. The Author(s).

Cardiovasc Diabetol: 23 Sep 2022; 21:193
Song S, Choi SY, Park HE, Han HW, ... Sung JM, Chang HJ
Cardiovasc Diabetol: 23 Sep 2022; 21:193 | PMID: 36151571
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Impact:
Abstract

Evaluating the impact of glucokinase activation on risk of cardiovascular disease: a Mendelian randomisation analysis.

Wang K, Shi M, Huang C, Fan B, ... Chan JCN, Chow E
Background
Glucokinase activators (GKAs) are an emerging class of glucose lowering drugs that activate the glucose-sensing enzyme glucokinase (GK). Pending formal cardiovascular outcome trials, we applied two-sample Mendelian randomisation (MR) to investigate the impact of GK activation on risk of cardiovascular diseases.
Methods
We used independent genetic variants in or around the glucokinase gene meanwhile associated with HbA1c at genome-wide significance (P < 5 × 10-8) in the Meta-Analyses of Glucose and Insulin-related traits Consortium study (N = 146,806; European ancestry) as instrumental variables (IVs) to mimic the effects of GK activation. We assessed the association between genetically proxied GK activation and the risk of coronary artery disease (CAD; 122,733 cases and 424,528 controls), peripheral arterial disease (PAD; 7098 cases and 206,541 controls), stroke (40,585 cases and 406,111 controls) and heart failure (HF; 47,309 cases and 930,014 controls), using genome-wide association study summary statistics of these outcomes in Europeans. We compared the effect estimates of genetically proxied GK activation with estimates of genetically proxied lower HbA1c on the same outcomes. We repeated our MR analyses in East Asians as validation.
Results
Genetically proxied GK activation was associated with reduced risk of CAD (OR 0.38 per 1% lower HbA1c, 95% CI 0.29-0.51, P = 8.77 × 10-11) and HF (OR 0.54 per 1% lower HbA1c, 95% CI 0.41-0.73, P = 3.55 × 10-5). The genetically proxied protective effects of GKA on CAD and HF exceeded those due to non-targeted HbA1c lowering. There was no causal relationship between genetically proxied GK activation and risk of PAD or stroke. The estimates in sensitivity analyses and in East Asians were generally consistent.
Conclusions
GKAs may protect against CAD and HF which needs confirmation by long-term clinical trials.

© 2022. The Author(s).

Cardiovasc Diabetol: 23 Sep 2022; 21:192
Wang K, Shi M, Huang C, Fan B, ... Chan JCN, Chow E
Cardiovasc Diabetol: 23 Sep 2022; 21:192 | PMID: 36151532
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Abstract

Eliminating exogenous insulin therapy in patients with type 2 diabetes by duodenal ablation and GLP-1RA decreases risk scores for cardiovascular events.

Meiring S, Busch CBE, van Baar ACG, Hemke R, ... Nieuwdorp M, Bergman JJGHM
Introduction
Duodenal Mucosal Resurfacing (DMR) is an endoscopic ablation technique aimed at improving glycaemia and metabolic health in patients with type 2 diabetes mellitus (T2DM). DMR has an insulin sensitizing effect in patients with T2DM. Reducing hyperinsulinemia can improve cardiovascular health. In the INSPIRE trial, we combined a single DMR with a glucagon-like-peptide-1 receptor agonist (GLP-1RA) and demonstrated elimination of insulin treatment in 69% of patients at 6 months and 53% of patients at 18 months while improving glycaemic control and metabolic health. We hypothesized that this treatment approach is associated with improved cardiovascular health, by reducing hyperinsulinemia.
Methods
Before and 6 months after starting the combination treatment to replace insulin, the following assessments were performed to evaluate cardiovascular health: magnetic resonance imaging (MRI) to measure abdominal visceral adipose tissue volume, ambulatory 24 h blood pressure (ABPM) analysis, postprandial insulin and triglycerides, fasting lipid panel and urine microalbumin. The Atherosclerotic Cardiovascular Disease (ASCVD) score was calculated to estimate 10-year risk of cardiovascular disease or stroke and the diabetes lifetime-perspective prediction (DIAL) score was calculated to estimate years free of cardiovascular disease.
Results
Six months after replacing exogenous insulin by DMR and GLP-1RA, visceral adipose tissue decreased significantly by 24%. Postprandial triglyceride and insulin concentrations decreased significantly (p < 0.001), as did total cholesterol (from median 3.64 (IQR 3.34-4.89) to 3.48 (3.18-3.97) mmol/l, p = 0.008), LDL (from median 1.92 (IQR 1.49-2.30) to 1.79 (1.49-2.08 mmol/l, p = 0.044), and urine microalbumin (from median 7 (IQR 3-27) to 4 (3-8) mg/l, p = 0.018). All daytime blood pressure values decreased significantly. The ASCVD 10-year risk score decreased (from median 13.6 (IQR 5.7-26.0) to 11.5 (4.2-22.5) %, p = 0.030)) and the DIAL score increased (from median 82 (IQR 81-83) to 83 (81-84) years, (p = 0.039)).
Discussion
The combination of DMR and GLP-1RA to replace insulin therapy in patients with T2DM is associated with a positive effect on multiple parameters of cardiovascular health. Taken together, they show a pattern of overall improvement in cardiovascular health, as evidenced by decreased risk scores for cardiovascular complications. However, it is not yet clear whether these improvements will translate into a true reduction in cardiovascular events.

© 2022. The Author(s).

Cardiovasc Diabetol: 22 Sep 2022; 21:191
Meiring S, Busch CBE, van Baar ACG, Hemke R, ... Nieuwdorp M, Bergman JJGHM
Cardiovasc Diabetol: 22 Sep 2022; 21:191 | PMID: 36138441
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Abstract

Proteomics of fibrin amyloid microclots in long COVID/post-acute sequelae of COVID-19 (PASC) shows many entrapped pro-inflammatory molecules that may also contribute to a failed fibrinolytic system.

Kruger A, Vlok M, Turner S, Venter C, ... Kell DB, Pretorius E
Background
Post-acute sequelae of COVID-19 (PASC), also now known as long COVID, has become a major global health and economic burden. Previously, we provided evidence that there is a significant insoluble fibrin amyloid microclot load in the circulation of individuals with long COVID, and that these microclots entrap a substantial number of inflammatory molecules, including those that might prevent clot breakdown. Scientifically, the most challenging aspect of this debilitating condition is that traditional pathology tests such as a serum CRP (C-reactive protein) may not show any significant abnormal inflammatory markers, albeit these tests measure only the soluble inflammatory molecules. Elevated, or abnormal soluble biomarkers such as IL-6, D-Dimer or fibrinogen indicate an increased risk for thrombosis or a host immune response in COVID-19. The absence of biomarkers in standard pathology tests, result in a significant amount of confusion for patients and clinicians, as patients are extremely sick or even bed-ridden but with no regular identifiable reason for their disease. Biomarkers that are currently available cannot detect the molecules present in the microclots we identified and are therefore unable to confirm their presence or the mechanisms that drive their formation.
Methods
Here we analysed the protein content of double-digested microclots of 99 long COVID patients and 29 healthy controls. The patients suffering from long COVID reported their symptoms through a questionnaire completed by themselves or their attending physician.
Results
Our long COVID cohort\'s symptoms were found to be in line with global findings, where the most prevalent symptoms were constant fatigue (74%,) cognitive impairment (71%) and depression and anxiety (30%). Our most noteworthy findings were a reduced level of plasma Kallikrein compared to our controls, an increased level of platelet factor 4 (PF4) von Willebrand factor (VWF), and a marginally increased level of α-2 antiplasmin (α-2-AP). We also found a significant presence of antibodies entrapped inside these microclots.
Conclusion
Our results confirm the presence of pro-inflammatory molecules that may also contribute to a failed fibrinolysis phenomenon, which could possibly explain why individuals with long COVID suffer from chronic fatigue, dyspnoea, or cognitive impairment. In addition, significant platelet hyperactivation was noted. Hyperactivation will result in the granular content of platelets being shed into the circulation, including PF4. Overall, our results provide further evidence of both a failed fibrinolytic system in long COVID/PASC and the entrapment of many proteins whose presence might otherwise go unrecorded. These findings might have significant implications for individuals with pre-existing comorbidities, including cardiovascular disease and type 2 diabetes.

© 2022. The Author(s).

Cardiovasc Diabetol: 21 Sep 2022; 21:190
Kruger A, Vlok M, Turner S, Venter C, ... Kell DB, Pretorius E
Cardiovasc Diabetol: 21 Sep 2022; 21:190 | PMID: 36131342
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Abstract

Nut consumption is associated with a shift of the NMR lipoprotein subfraction profile to a less atherogenic pattern among older individuals at high CVD risk.

García-Gavilán JF, Connelly MA, Babio N, Matzoros CS, Ros E, Salas-Salvadó J
Background
Scientific evidence has accumulated on the beneficial effects of nut consumption on cardiovascular risk and cholesterol reduction, but few studies have examined the effects of nuts on advanced measures of lipoprotein atherogenicity determined by nuclear magnetic resonance (NMR) spectroscopy. We analyzed associations between the amount and type of of nuts consumed and advanced measures of lipoprotein atherogenity and insulin resistance in older individuals at high cardiovascular risk.
Methods
The present observational study was carried out within the framework of the Prevención con Dieta Mediterránea (PREDIMED) trial. Cross-sectional and longitudinal analyses after 1-year of follow-up were conducted in 196 men and women recruited in the PREDIMED-Reus (Spain) center. Dietary intake was assessed using a validated semi-quantitative food questionnaire. Baseline and 1-year fasting plasma lipoprotein and metabolite profiling were performed in plasma using NMR spectra Vantera® Clinical Analyzer. Associations by tertiles of nut consumption between baseline and 1-year changes and advanced measures of lipoprotein atherogenicity, branched chain amminoacids, and measures of insulin resistance were tested by multivariable-adjusted ANCOVA models.
Results
Compared to paticipants in the bottom tertile, those in the top tertile of total nut consumption showed higher levels of large HDL particles and HDL-cholesterol, lower levels of branched-chain amino acids (BCAA) and GlycA, and reduced lipoprotein insulin resistance and diabetes risk index. Participants in the top tertile of walnut consumption disclosed lower levels of very large VLDL, total LDL particles, LDL-cholesterol, and GlycA. Participants in the top tertile of non-walnut nut consumption displayed higher levels of total HDL particles, HDL-cholesterol and apoliporotein A1, lower BCAA and GlycA, and reduced lipoprotein insulin resistance. Participants in the top tertile of 1-year changes in walnut consumption showed increases in medium-sized HDL particles in comparison to the bottom tertile.
Conclusions
In older individuals at high cardiovascular risk, increasing nut consumption was associated with a shift of the NMR lipoprotein subfraction profile to a less atherogenic pattern, as well as lower circulating concentrations of BCAA and decreased insulin resistance. These results provide novel mechanistic insight into the cardiovascular benefit of nut consumption. Trial registration ISRCTN35739639; registration date: 05/10/2005; recruitment start date 01/10/2003.

© 2022. The Author(s).

Cardiovasc Diabetol: 20 Sep 2022; 21:189
García-Gavilán JF, Connelly MA, Babio N, Matzoros CS, Ros E, Salas-Salvadó J
Cardiovasc Diabetol: 20 Sep 2022; 21:189 | PMID: 36127725
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Abstract

Immune-inflammatory biomarkers and the risk of cardiac injury in COVID-19 patients with diabetes: a retrospective cohort study.

Bo Y, Yuli C, Ye W, Junfeng L, ... Yan B, Zhongyuan W
Background
To determine the risk-assessment role of the immune-inflammatory biomarkers on myocardial damage in COVID-19 patients with diabetes mellitus (DM).
Methods
This retrospective study was conducted on 822 COVID-19 inpatients from 1 January to 10 March 2020 at Renmin Hospital of Wuhan University. The demographic data, clinical data, and immune-inflammatory parameters of participants were collected. The predictors of cardiac injury were assessed by Logistics regression analysis.
Results
A total of 246 COVID-19 inpatients were diagnosed with DM (29.9%). The incidence of cardiac injury was higher in patients with DM than in non-DM cases (28.9% vs 9.0%, p < 0.001), even grouped by age, gender, and the level of fasting plasma glucose (FPG). The mortality in diabetic COVID-19 patients with cardiac injury and without cardiac injury was 42.9% and 3.4%, respectively (p < 0.001). COVID-19 patients with DM and cardiac injury presented a decreased number of immunocyte subsets, lower C3 concentration, and a higher level of interleukin-6 (IL-6) and immunoglobulin A (IgA). The independent risk factors for cardiac injury in COVID-19 patients with DM were CD3+CD4+ T cells counts ≤ 288 cells/μl (adjusted Odds ratio (OR), 2.501; 95% confidence interval (CI) 1.282-4.877; p = 0.007) and IL-6 > 25.68mpg/ml (adjusted OR, 4.345; 95% CI 2.192-10.374; p < 0.001) (all Pinteraction < 0.05).
Conclusions
For diabetic patients with COVID-19, cardiac injury not only induce severer immune-inflammatory responses, but also increase in-hospital mortality. The decreased number of CD3+CD4+ T cells and increased IL-6 are recommended to distinguish the people who refer to high risk of cardiac injury and mortality from those persons. However, it remains a testable theory whether decision-making strategies based on the risk status of cardiac injury in COVID-19 patients, especially with DM, would be expected to get better outcomes.

© 2022. The Author(s).

Cardiovasc Diabetol: 19 Sep 2022; 21:188
Bo Y, Yuli C, Ye W, Junfeng L, ... Yan B, Zhongyuan W
Cardiovasc Diabetol: 19 Sep 2022; 21:188 | PMID: 36123740
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Impact:
Abstract

Association between triglyceride glucose index, coronary artery calcification and multivessel coronary disease in Chinese patients with acute coronary syndrome.

Wang J, Huang X, Fu C, Sheng Q, Liu P
Background
Multivessel coronary disease (MVCD) is the common type of coronary artery disease in acute coronary syndrome (ACS). Coronary artery calcification (CAC) has been confirmed the strong predictor of major adverse cardiovascular events (MACEs). Several studies have validated that triglyceride glucose (TyG) index can reflect the degree of coronary calcification or predict MACEs. However, no evidence to date has elucidated and compared the predictive intensity of TyG index or/and coronary artery calcification score (CACS) on multi-vascular disease and MACEs in ACS patients.
Methods
A total of 935 patients, diagnosed with ACS and experienced coronary computed tomography angiography (CCTA) from August 2015 to March 2022 in the Second Hospital of Shandong University, were selected for retrospective analysis. The subjects were divided into TyG index quartile 1-4 groups (Q1-Q4 groups), non-multivessel coronary disease (non-MVCD) and multivessel coronary disease (MVCD) groups, respectively. The general data, past medical or medication history, laboratory indicators, cardiac color Doppler ultrasound, CACS, and TyG indexes were respectively compared among these groups. The ROC curve preliminarily calculated and analyzed the diagnostic value of TyG index, CACS, and the combination of the two indicators for MVCD. Univariate and multivariate logistic regression analysis discriminated the independent hazard factors for forecasting MVCD.
Results
Compared with the lower TyG index and non-MVCD groups, the higher TyG index and MVCD groups had higher values of age, smoking history, waist circumference, systolic blood pressure, low-density lipoprotein cholesterol(LDL-C), fasting blood glucose and glycosylated hemoglobin, and CACS, but lower values of high-density lipoprotein cholesterol(HDL-C) (all P < 0.01). Coronary artery calcification is more common in the left anterior descending artery. Compared with non-MVCD, each unit increase in TyG index was associated with a 1.213-fold increased risk of MVCD. Logistic regression analysis adjusted for potential confounders indicated that TyG index is an independent risk factor for MVCD. With the increase of TyG index, the incidence of MACEs, apart from all-cause death, cardiac death, unexpected re-hospitalization of heart failure, recurrent ACS or unplanned revascularization, and non-fatal stroke in coronary artery increased (P log-rank < 0.001).
Conclusion
TyG index could completely substitute for CACS as a reliable, practical, and independent indicator for predicting the severity and prognosis of MVCD in patients with ACS.

© 2022. The Author(s).

Cardiovasc Diabetol: 16 Sep 2022; 21:187
Wang J, Huang X, Fu C, Sheng Q, Liu P
Cardiovasc Diabetol: 16 Sep 2022; 21:187 | PMID: 36114495
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Impact:
Abstract

Effect of dapagliflozin on the prognosis of patients with acute myocardial infarction undergoing percutaneous coronary intervention.

Zhu Y, Zhang JL, Yan XJ, Sun L, Ji Y, Wang FF
Background:
and aims
The effect of dapagliflozin (DAPA) on the prognosis of patients with acute myocardial infarction (AMI) is unclear. The present study was conducted to evaluate the association between DAPA administration and adverse events in patients with AMI undergoing percutaneous coronary intervention (PCI).
Methods
This single-center retrospective analysis study included a total of 786 patients with AMI from January 2019 to August 2021 who were or were not administered DAPA at discharge. The primary endpoint was the composite of major adverse cardiovascular events (MACE), including overall deaths, heart failure, nonfatal MI, nonfatal stroke, and unplanned repeat revascularization (URR). Differences in the triglyceride glucose (TyG) index and the atherogenic index of plasma (AIP) both during hospitalization and 12 months after discharge (if achievable) were also compared.
Results
During a median follow-up of 23 months, 130 patients had MACE (118 in the DAPA-free group and 12 in the DAPA group). Kaplan-Meier survival analyses revealed that the cumulative incidence of MACE (log-rank test, p = 0.009), heart failure (p = 0.003), nonfatal MI (p = 0.005), and URR (p = 0.031) was higher in the DAPA-free group. In addition, the multivariate Cox analysis showed that DAPA was significantly associated with the reduced risk of MACE (hazard ratio = 0.170, 95% confidence interval = 0.078-0.373, p < 0.001). Considering each specific adverse event, the DAPA-free group was associated with heart failure, nonfatal MI, and URR in multivariate Cox regression analyses. Stratification analyses suggested that DAPA has a strong protective effect in patients with AMI of advanced age with concomitant diabetes or those who are not on angiotensin receptor enkephalinase inhibitors. Furthermore, the TyG index and AIP of the patients 12 months after DAPA administration at discharge were significantly lower than those during hospitalization.
Conclusions
DAPA is an independent protective factor against MACE and may provide incremental prognostic information in patients with AMI undergoing PCI.

© 2022. The Author(s).

Cardiovasc Diabetol: 16 Sep 2022; 21:186
Zhu Y, Zhang JL, Yan XJ, Sun L, Ji Y, Wang FF
Cardiovasc Diabetol: 16 Sep 2022; 21:186 | PMID: 36114538
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Impact:
Abstract

CCL7 as a novel inflammatory mediator in cardiovascular disease, diabetes mellitus, and kidney disease.

Chang TT, Chen C, Chen JW
Chemokines are key components in the pathology of chronic diseases. Chemokine CC motif ligand 7 (CCL7) is believed to be associated with cardiovascular disease, diabetes mellitus, and kidney disease. CCL7 may play a role in inflammatory events by attracting macrophages and monocytes to further amplify inflammatory processes and contribute to disease progression. However, CCL7-specific pathological signaling pathways need to be further confirmed in these chronic diseases. Given the multiple redundancy system among chemokines and their receptors, further experimental and clinical studies are needed to clarify whether direct CCL7 inhibition mechanisms could be a promising therapeutic approach to attenuating the development of cardiovascular disease, diabetes mellitus, and kidney disease.

© 2022. The Author(s).

Cardiovasc Diabetol: 15 Sep 2022; 21:185
Chang TT, Chen C, Chen JW
Cardiovasc Diabetol: 15 Sep 2022; 21:185 | PMID: 36109744
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Impact:
Abstract

Time course of the triglyceride glucose index accumulation with the risk of cardiovascular disease and all-cause mortality.

Tian X, Chen S, Zhang Y, Zhang X, ... Wang A, Luo Y
Background
Future risk of cardiovascular disease (CVD) and mortality is associated with cumulative amount TyG index (cumTyG) exposure, while whether time course of TyG accumulation modulates the risk remains unclear. This study sought to examine the associations of cumTyG index accumulation time course with the risk of CVD and all-cause mortality.
Methods
We enrolled 51,734 participants free of CVD and underwent three examinations at year 2006, 2008, and 2010. CumTyG from baseline to the third examination was calculated. Time course of cumTyG accumulation was calculated as the slope of TyG versus time from 2006 to 2010, or as splinting the overall TyG index accumulation into early (cumTyG06 - 08) and late accumulation (cumTyG08 - 10). Participants were categorized by the combination of cumTyG < or ≥ median (34.44 × years) and a negative or positive TyG slope.
Results
During a median follow-up of 9.04 years, we identified 3,602 incident CVD cases and 3,165 deaths. The risk of CVD and all-cause mortality increased with decreased TyG slope, the corresponding adjusted hazard ratio (aHR) with 95% confidence interval (CI) was 1.11 (1.04-1.19) and 1.18 (1.10-1.26) for patients with a negative TyG slope, respectively. Consistently, a later accumulation of TyG index was not associated with the risk of CVD and all-cause mortality after adjustment for an early accumulation. When considering the combination of cumTyG index and time course, participants with a cumTyG ≥ median and a negative TyG slope had elevated risk of CVD (aHR, 1.37; 95% CI, 1.24-1.51) and all-cause mortality (aHR, 1.28; 95% CI, 1.15-1.43). Additionally, the association was more prominent in young adults.
Conclusion
Early TyG index accumulation resulted in a greater risk of CVD and all-cause mortality than later TyG later accumulation with the same overall cumulative exposure, emphasizing the importance of optimal TyG index control earlier in life.

© 2022. The Author(s).

Cardiovasc Diabetol: 13 Sep 2022; 21:183
Tian X, Chen S, Zhang Y, Zhang X, ... Wang A, Luo Y
Cardiovasc Diabetol: 13 Sep 2022; 21:183 | PMID: 36100896
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Impact:
Abstract

Risk prediction models for incident type 2 diabetes in Chinese people with intermediate hyperglycemia: a systematic literature review and external validation study.

Xu S, Coleman RL, Wan Q, Gu Y, ... Niu K, Tong N
Background
People with intermediate hyperglycemia (IH), including impaired fasting glucose and/or impaired glucose tolerance, are at higher risk of developing type 2 diabetes (T2D) than those with normoglycemia. We aimed to evaluate the performance of published T2D risk prediction models in Chinese people with IH to inform them about the choice of primary diabetes prevention measures.
Methods
A systematic literature search was conducted to identify Asian-derived T2D risk prediction models, which were eligible if they were built on a prospective cohort of Asian adults without diabetes at baseline and utilized routinely-available variables to predict future risk of T2D. These Asian-derived and five prespecified non-Asian derived T2D risk prediction models were divided into BASIC (clinical variables only) and EXTENDED (plus laboratory variables) versions, with validation performed on them in three prospective Chinese IH cohorts: ACE (n = 3241), Luzhou (n = 1333), and TCLSIH (n = 1702). Model performance was assessed in terms of discrimination (C-statistic) and calibration (Hosmer-Lemeshow test).
Results
Forty-four Asian and five non-Asian studies comprising 21 BASIC and 46 EXTENDED T2D risk prediction models for validation were identified. The majority were at high (n = 43, 87.8%) or unclear (n = 3, 6.1%) risk of bias, while only three studies (6.1%) were scored at low risk of bias. BASIC models showed poor-to-moderate discrimination with C-statistics 0.52-0.60, 0.50-0.59, and 0.50-0.64 in the ACE, Luzhou, and TCLSIH cohorts respectively. EXTENDED models showed poor-to-acceptable discrimination with C-statistics 0.54-0.73, 0.52-0.67, and 0.59-0.78 respectively. Fifteen BASIC and 40 EXTENDED models showed poor calibration (P < 0.05), overpredicting or underestimating the observed diabetes risk. Most recalibrated models showed improved calibration but modestly-to-severely overestimated diabetes risk in the three cohorts. The NAVIGATOR model showed the best discrimination in the three cohorts but had poor calibration (P < 0.05).
Conclusions
In Chinese people with IH, previously published BASIC models to predict T2D did not exhibit good discrimination or calibration. Several EXTENDED models performed better, but a robust Chinese T2D risk prediction tool in people with IH remains a major unmet need.

© 2022. The Author(s).

Cardiovasc Diabetol: 13 Sep 2022; 21:182
Xu S, Coleman RL, Wan Q, Gu Y, ... Niu K, Tong N
Cardiovasc Diabetol: 13 Sep 2022; 21:182 | PMID: 36100925
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Impact:
Abstract

Effect of empagliflozin on left ventricular contractility and peak oxygen uptake in subjects with type 2 diabetes without heart disease: results of the EMPA-HEART trial.

Nesti L, Pugliese NR, Sciuto P, Trico D, ... Di Bello V, Natali A
Background
The mechanism through which sodium-glucose cotransporter 2 inhibitors (SGLT2i) prevent the incidence of heart failure and/or affect cardiac structure and function remains unclear.
Methods
The EMPA-HEART trial is aimed at verifying whether empagliflozin improves myocardial contractility (left ventricle global longitudinal strain, LV-GLS) and/or cardiopulmonary fitness (peak oxygen uptake, VO2peak) in subjects with type 2 diabetes (T2D) without heart disease. Patients with T2D, normal LV systolic function (2D-Echo EF > 50%), and no heart disease were randomized to either empagliflozin 10 mg or sitagliptin 100 mg for 6 months and underwent repeated cardiopulmonary exercise tests with echocardiography and determination of plasma biomarkers.
Results
Forty-four patients completed the study, 22 per arm. Despite comparable glycaemic control, modest reductions in body weight (- 1.6; [- 2.7/- 0.5] kg, p = 0.03) and plasma uric acid (- 1.5; [- 2.3/- 0.6], p = 0.002), as well as an increase in haemoglobin (+ 0.7; [+ 0.2/+ 1.1] g/dL, p = 0.0003) were evident with empagliflozin. No difference was detectable in either LV-GLS at 1 month (empagliflozin vs sitagliptin: + 0.44; [- 0.10/+ 0.98]%, p = 0.11) and 6 months of therapy (+ 0.53; [- 0.56/+ 1.62]%), or in VO2peak (+ 0.43; [- 1.4/+ 2.3] mL/min/kg, p = 0.65). With empagliflozin, the subgroup with baseline LV-GLS below the median experienced a greater increase (time*drug p < 0.05) in LV-GLS at 1 month (+ 1.22; [+ 0.31/+ 2.13]%) and 6 months (+ 2.05; [+ 1.14/+ 2.96]%), while sitagliptin induced a modest improvement in LV-GLS only at 6 months (+ 0.92; [+ 0.21/+ 0.62]%).
Conclusions
Empagliflozin has neutral impact on both LV-GLS and exercise tolerance in subjects with T2D and normal left ventricular function. However, in patients with subclinical dysfunction (LV-GLS < 16.5%) it produces a rapid and sustained amelioration of LV contractility. Trial registration EUDRACT Code 2016-002225-10.

© 2022. The Author(s).

Cardiovasc Diabetol: 12 Sep 2022; 21:181
Nesti L, Pugliese NR, Sciuto P, Trico D, ... Di Bello V, Natali A
Cardiovasc Diabetol: 12 Sep 2022; 21:181 | PMID: 36096863
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Impact:
Abstract

Prognostic value of soluble ST2, high-sensitivity cardiac troponin, and NT-proBNP in type 2 diabetes: a 15-year retrospective study.

Sabbatinelli J, Giuliani A, Bonfigli AR, Ramini D, ... Moretti M, Olivieri F
Background
Patients with type 2 diabetes (T2DM) present an increased risk of cardiovascular (CV) disease and excess CV-related mortality. Beyond the established role of brain natriuretic peptide (BNP) and cardiac troponins (cTn), other non-cardiac-specific biomarkers are emerging as predictors of CV outcomes in T2DM.
Methods
Serum levels of soluble suppression of tumorigenesis 2 (sST2), high-sensitivity (hs)-cTnI, and N-terminal (NT)-proBNP were assessed in 568 patients with T2DM and 115 healthy controls (CTR). Their association with all-cause mortality and the development of diabetic complications was tested in T2DM patients over a median follow-up of 16.8 years using Cox models and logistic regressions.
Results
sST2 followed an increasing trend from CTR to uncomplicated T2DM patients (T2DM-NC) to patients with at least one complication (T2DM-C), while hs-cTnI was significantly higher in T2DM-C compared to CTR but not to T2DM-NC. A graded association was found between sST2 (HR 2.76 [95% CI 1.20-6.33] for ≥ 32.0 ng/mL and 2.00 [1.02-3.94] for 16.5-32.0 ng/mL compared to < 16.5 ng/mL, C-statistic = 0.729), NT-proBNP (HR 2.04 [1.90-4.55] for ≥ 337 ng/L and 1.48 [1.05-2.10] for 89-337 ng/L compared to < 89 ng/L, C-statistic = 0.741), and 15-year mortality in T2DM, whereas increased mortality was observed in patients with hs-cTnI ≥ 7.8 ng/L (HR 1.63 [1.01-2.62]). A \'cardiac score\' based on the combination of sST2, hs-cTnI, and NT-proBNP was significantly associated with all-cause mortality (HR 1.35 [1.19-1.53], C-statistic = 0.739) and development of CV events.
Conclusions
sST2, hs-cTnI, and NT-proBNP are associated with 15-year mortality and onset of CV events in T2DM. The long-term prognostic value of sST2 and its ability to track variables related to insulin resistance and associated metabolic disorders support its implementation into routine clinical practice.

© 2022. The Author(s).

Cardiovasc Diabetol: 10 Sep 2022; 21:180
Sabbatinelli J, Giuliani A, Bonfigli AR, Ramini D, ... Moretti M, Olivieri F
Cardiovasc Diabetol: 10 Sep 2022; 21:180 | PMID: 36088327
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Impact:
Abstract

Cardiovascular and metabolic morbidity in women with previous gestational diabetes mellitus: a nationwide register-based cohort study.

Christensen MH, Rubin KH, Petersen TG, Nohr EA, ... Andersen MS, Jensen DM
Background
Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes and has maternal health implications reaching beyond the perinatal period. We aimed to investigate the incidence and severity of cardiovascular and metabolic morbidity in women with previous GDM in a Danish population and to study whether proxies of impaired beta cell function-insulin treatment during GDM pregnancy and development of subsequent manifest diabetes mellitus-influence incident risk of cardiovascular and metabolic morbidity.
Methods
A nationwide register-based cohort study was conducted on the complete cohort of 700,648 women delivering in Denmark during 1997-2018. The exposure variable was GDM and primary outcome was overall cardiovascular and metabolic morbidity. Secondary outcomes were major cardiovascular disease (ischemic heart disease, heart failure, and/or stroke/transient cerebral ischemia), hypertension, dyslipidemia, and venous thrombosis. Severity of morbidity was assessed using number of hospital contacts with diagnosis codes related to cardiovascular and metabolic morbidity and number of redemptions of prescribed medication related to cardiovascular and metabolic morbidity in women who developed cardiovascular and metabolic morbidity after pregnancy.
Results
The median follow-up period was 10.2-11.9 years with a total range of 0-21.9 years. GDM was associated with increased risk of any cardiovascular and metabolic morbidity (adjusted HR 2.13 [95% CI 2.07-2.20]), major cardiovascular disease (adjusted HR 1.69 [95% CI 1.55-1.84]), hypertension (adjusted HR 1.89 [95% CI 1.82-1.96], dyslipidemia (adjusted HR 4.48 [95% CI 4.28-4.69]), and venous thrombosis (adjusted HR 1.32 [95% CI 1.16-1.50]). Insulin treatment during pregnancy and subsequent development of manifest diabetes exacerbated the risk estimates. Previous GDM was associated with more hospital contacts and more redeemed prescriptions in women developing cardiovascular and metabolic morbidity (p < 0.001).
Conclusions
Previous GDM was associated with significantly higher risk of cardiovascular and metabolic morbidity, especially incident dyslipidemia. Risks were exacerbated by proxies of beta cell impairment. Severity of morbidity was significantly worse if GDM preceded cardiovascular and metabolic morbidity.

© 2022. The Author(s).

Cardiovasc Diabetol: 09 Sep 2022; 21:179
Christensen MH, Rubin KH, Petersen TG, Nohr EA, ... Andersen MS, Jensen DM
Cardiovasc Diabetol: 09 Sep 2022; 21:179 | PMID: 36085031
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Impact:
Abstract

Higher pulse wave velocity in young adult offspring of mothers with type 1 diabetes: a case-control study.

Korpijaakko CA, Eriksson MD, Wasenius NS, Klemetti MM, ... Eriksson JG, Laine MK
Background
Offspring of mothers with type 1 diabetes have an increased risk for acquiring early onset cardiovascular disease (CVD). Arterial stiffness, measured as pulse wave velocity (PWV), is a non-invasive biomarker for CVD risk assessment. Our aim is to determine whether PWV is increased in young adult offspring of mothers with type 1 diabetes.
Methods
This is a case-control study carried out in the hospital district of Helsinki and Uusimaa, Finland. 75 offspring of mothers with type 1 diabetes (cases) and 84 offspring of mothers without diabetes (controls), aged 18-23 years, were enrolled in this study. All participants attended clinical assessments, including questionnaires and laboratory tests. Carotid-femoral PWV (cfPWV), carotid-radial PWV (crPWV), and PWV ratio were measured from each participant using the Complior Analyse mechanotransducer (Alam Medical, France). Student\'s t-test and chi-squared test were used to assess differences between the groups. Stata 17.0, StataCorp LP (College Station, TX, USA) statistical package was used for the analysis.
Results
We did not observe any differences in conventional CVD risk factors: systolic blood pressure, LDL, HbA1c, and smoking between cases and controls. We detected higher cfPWV in cases 6.5 (SD ± 1.2) m/s than in controls 6.2 (SD ± 0.7) m/s, p = 0.049, after adjustments for BMI, smoking, mean arterial pressure, height, and pulse rate was made. We did not observe any difference between cases and controls regarding crPWV or PWV ratio. Additionally, we detected no sex differences.
Conclusions
We report a novel finding of signs of increased arterial stiffness already in young adult offspring of mothers with type 1 diabetes compared to matched offspring of mothers without diabetes. Our finding suggests that exposure to an adverse intrauterine environment of type 1 diabetes mothers may affect the vascular health of offspring already in young adulthood. Additional research within this topic is warranted.

© 2022. The Author(s).

Cardiovasc Diabetol: 06 Sep 2022; 21:178
Korpijaakko CA, Eriksson MD, Wasenius NS, Klemetti MM, ... Eriksson JG, Laine MK
Cardiovasc Diabetol: 06 Sep 2022; 21:178 | PMID: 36068528
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Impact:
Abstract

Anti-obesity therapy for cardiovascular disease prevention: potential expected roles of glucagon-like peptide-1 receptor agonists.

Sawami K, Tanaka A, Node K
Obesity is characterized by visceral fat accumulation and various metabolic disturbances that cause metabolic syndrome and obesity-related cardiovascular diseases (ORCVDs). Hence, treatments targeting obesity should also prevent ORCVDs. Nonetheless, lifestyle modification therapy alone is still insufficient to reduce the risk of ORCVDs, although most cardiovascular guidelines still list it as the only treatment for obesity. Additionally, conventional anti-obesity drugs, such as orlistat, phentermine-topiramate, and naltrexone-bupropion, can reduce body weight but have not demonstrated a clear reduction in the risk of ORCVDs. To overcome this unmet clinical need, newer anti-obesity drugs must exhibit not only sufficient and long-lasting weight loss but also obvious cardiovascular benefits. Given recent clinical findings and evidences, in this context glucagon-like peptide-1 receptor agonist is currently available as a candidate that is clinically positioned as a first-line anti-obesity agent for the effective prevention of ORCVDs in people with obesity.

© 2022. The Author(s).

Cardiovasc Diabetol: 06 Sep 2022; 21:176
Sawami K, Tanaka A, Node K
Cardiovasc Diabetol: 06 Sep 2022; 21:176 | PMID: 36068534
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Impact:
Abstract

Long-term cardiovascular prognosis of patients with type 1 diabetes after myocardial infarction.

Kerola AM, Semb AG, Juonala M, Palomäki A, Rautava P, Kytö V
Background
To explore long-term cardiovascular prognosis after myocardial infarction (MI) among patients with type 1 diabetes.
Methods
Patients with type 1 diabetes surviving 90 days after MI (n = 1508; 60% male, mean age = 62.1 years) or without any type of diabetes (n = 62,785) in Finland during 2005-2018 were retrospectively studied using multiple national registries. The primary outcome of interest was a combined major adverse cardiovascular event (MACE; cardiovascular death, recurrent MI, ischemic stroke, or heart failure hospitalization) studied with a competing risk Fine-Gray analyses. Median follow-up was 3.9 years (maximum 12 years). Differences between groups were balanced by multivariable adjustments and propensity score matching (n = 1401 patient pairs).
Results
Cumulative incidence of MACE after MI was higher in patients with type 1 diabetes (67.6%) compared to propensity score-matched patients without diabetes (46.0%) (sub-distribution hazard ratio [sHR]: 1.94; 95% confidence interval [CI]: 1.74-2.17; p < 0.0001). Probabilities of cardiovascular death (sHR 1.81; p < 0.0001), recurrent MI (sHR 1.91; p < 0.0001), ischemic stroke (sHR 1.50; p = 0.0003), and heart failure hospitalization (sHR 1.98; p < 0.0001) were higher in patients with type 1 diabetes. Incidence of MACE was higher in diabetes patients than in controls in subgroups of men and women, patients aged < 60 and ≥ 60 years, revascularized and non-revascularized patients, and patients with and without atrial fibrillation, heart failure, or malignancy.
Conclusions
Patients with type 1 diabetes have notably poorer long-term cardiovascular prognosis after an MI compared to patients without diabetes. These results underline the importance of effective secondary prevention after MI in patients with type 1 diabetes.

© 2022. The Author(s).

Cardiovasc Diabetol: 06 Sep 2022; 21:177
Kerola AM, Semb AG, Juonala M, Palomäki A, Rautava P, Kytö V
Cardiovasc Diabetol: 06 Sep 2022; 21:177 | PMID: 36068573
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Impact:
Abstract

Revascularization outcomes in diabetic patients presenting with acute coronary syndrome with non-ST elevation.

Ram E, Fisman EZ, Tenenbaum A, Iakobishvili Z, ... Raanani E, Sternik L
Background
To compare the outcomes of diabetic patients hospitalized with non-ST elevation myocardial infarction (NSTEMI) or unstable angina (UA) referred for revascularization by either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) in a real-life setting.
Methods
The study included 1987 patients with diabetes mellitus enrolled from the biennial Acute Coronary Syndrome Israeli Survey between 2000 and 2016, who were hospitalized for NSTEMI or UA, and underwent either PCI (N = 1652, 83%) or CABG (N = 335, 17%). Propensity score-matching analysis compared all-cause mortality in 200 pairs (1:1) who underwent revascularization by either PCI or CABG.
Results
Independent predictors for CABG referral included 3-vessel coronary artery disease (OR 4.9, 95% CI 3.6-6.8, p < 0.001), absence of on-site cardiac surgery (OR 1.4, 95% CI 1.1-1.9, p = 0.013), no previous PCI (OR 1.5, 95% CI 1.1-2.2, p = 0.024) or MI (OR 1.7, 95% CI 1.2-2.6, p = 0.002). While at 2 years of follow-up, survival analysis revealed no differences in mortality risk between the surgical and percutaneous revascularization groups (log-rank p = 0.996), after 2 years CABG was associated with a significant survival benefit (HR 1.53, 95% CI 1.07-2.21; p = 0.021). Comparison of the propensity score matching pairs also revealed a consistent long-term advantage toward CABG (log-rank p = 0.031).
Conclusions
In a real-life setting, revascularization by CABG of diabetic patients hospitalized with NSTEMI/UA is associated with better long-term outcomes. Prospective randomized studies are warranted in order to provide more effective recommendations in future guidelines.

© 2022. The Author(s).

Cardiovasc Diabetol: 05 Sep 2022; 21:175
Ram E, Fisman EZ, Tenenbaum A, Iakobishvili Z, ... Raanani E, Sternik L
Cardiovasc Diabetol: 05 Sep 2022; 21:175 | PMID: 36064537
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Impact:
Abstract

The link between gestational diabetes and cardiovascular diseases: potential role of extracellular vesicles.

Ormazabal V, Nair S, Carrión F, Mcintyre HD, Salomon C
Extracellular vesicles are critical mediators of cell communication. They encapsulate a variety of molecular cargo such as proteins, lipids, and nucleic acids including miRNAs, lncRNAs, circular RNAs, and mRNAs, and through transfer of these molecular signals can alter the metabolic phenotype in recipient cells. Emerging studies show the important role of extracellular vesicle signaling in the development and progression of cardiovascular diseases and associated risk factors such as type 2 diabetes and obesity. Gestational diabetes mellitus (GDM) is hyperglycemia that develops during pregnancy and increases the future risk of developing obesity, impaired glucose metabolism, and cardiovascular disease in both the mother and infant. Available evidence shows that changes in maternal metabolism and exposure to the hyperglycemic intrauterine environment can reprogram the fetal genome, leaving metabolic imprints that define life-long health and disease susceptibility. Understanding the factors that contribute to the increased susceptibility to metabolic disorders of children born to GDM mothers is critical for implementation of preventive strategies in GDM. In this review, we discuss the current literature on the fetal programming of cardiovascular diseases in GDM and the impact of extracellular vesicle (EV) signaling in epigenetic programming in cardiovascular disease, to determine the potential link between EV signaling in GDM and the development of cardiovascular disease in infants.

© 2022. The Author(s).

Cardiovasc Diabetol: 03 Sep 2022; 21:174
Ormazabal V, Nair S, Carrión F, Mcintyre HD, Salomon C
Cardiovasc Diabetol: 03 Sep 2022; 21:174 | PMID: 36057662
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Impact:
Abstract

Dapagliflozin improves myocardial flow reserve in patients with type 2 diabetes: the DAPAHEART Trial: a preliminary report.

Leccisotti L, Cinti F, Sorice GP, D\'Amario D, ... Giordano A, Giaccari A
Objective
Cardiovascular (CV) outcome trials have shown that in patients with type 2 diabetes (T2D), treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) reduces CV mortality and hospital admission rates for heart failure (HF). However, the mechanisms behind these benefits are not fully understood. This study was performed to investigate the effects of the SGLT-2i dapagliflozin on myocardial perfusion and glucose metabolism in patients with T2D and stable coronary artery disease (coronary stenosis ≥ 30% and < 80%), with or without previous percutaneous coronary intervention (> 6 months) but no HF.
Methods
This was a single-center, prospective, randomized, double-blind, controlled clinical trial including 16 patients with T2D randomized to SGLT-2i dapagliflozin (10 mg daily) or placebo. The primary outcome was to detect changes in myocardial glucose uptake (MGU) from baseline to 4 weeks after treatment initiation by [(18)F]2-deoxy-2-fluoro-D-glucose (FDG) PET/CT during hyperinsulinemic euglycemic clamp. The main secondary outcome was to assess whether the hypothetical changes in MGU were associated with changes in myocardial blood flow (MBF) and myocardial flow reserve (MFR) measured by 13N-ammonia PET/CT. The study was registered at eudract.ema.europa.eu (EudraCT No. 2016-003614-27) and ClinicalTrials.gov (NCT03313752).
Results
16 patients were randomized to dapagliflozin (n = 8) or placebo (n = 8). The groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, renal and heart function). There was no significant change in MGU during euglycemic hyperinsulinemic clamp in the dapagliflozin group (2.22 ± 0.59 vs 1.92 ± 0.42 μmol/100 g/min, p = 0.41) compared with the placebo group (2.00 ± 0.55 vs 1.60 ± 0.45 μmol/100 g/min, p = 0.5). Dapagliflozin significantly improved MFR (2.56 ± 0.26 vs 3.59 ± 0.35 p = 0.006 compared with the placebo group 2.34 ± 0.21 vs 2.38 ± 0.24 p = 0.81; pint = 0.001) associated with a reduction in resting MBF corrected for cardiac workload (p = 0.005; pint = 0.045). A trend toward an increase in stress MBF was also detected (p = 0.054).
Conclusions
SGLT-2 inhibition increases MFR in T2D patients. We provide new insight into SGLT-2i CV benefits, as our data show that patients on SGLT-2i are more resistant to the detrimental effects of obstructive coronary atherosclerosis due to increased MFR, probably caused by an improvement in coronary microvascular dysfunction. Trial registration EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752.

© 2022. The Author(s).

Cardiovasc Diabetol: 03 Sep 2022; 21:173
Leccisotti L, Cinti F, Sorice GP, D'Amario D, ... Giordano A, Giaccari A
Cardiovasc Diabetol: 03 Sep 2022; 21:173 | PMID: 36057768
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Impact:
Abstract

Impact of semaglutide on high-sensitivity C-reactive protein: exploratory patient-level analyses of SUSTAIN and PIONEER randomized clinical trials.

Mosenzon O, Capehorn MS, De Remigis A, Rasmussen S, Weimers P, Rosenstock J
Background
Exploratory analysis to determine the effect of semaglutide versus comparators on high-sensitivity C-reactive protein (hsCRP) in subjects with type 2 diabetes.
Methods
Trials of once-weekly subcutaneous (SUSTAIN 3) and once-daily oral (PIONEER 1, 2, 5) semaglutide with hsCRP data were analyzed. Subjects with type 2 diabetes (N = 2482) received semaglutide (n = 1328) or comparators (placebo, n = 339; exenatide extended-release, n = 405; empagliflozin, n = 410). hsCRP ratio to baseline at end-of-treatment was analyzed overall, by clinical cutoff (< 1.0, ≥ 1.0 to ≤ 3.0, or > 3.0 mg/L), by tertile, and by estimated glomerular filtration rate in PIONEER 5 (a trial which was conducted in a population with type 2 diabetes and chronic kidney disease [CKD]). Mediation analyses assessed the effect of change in glycated hemoglobin (HbA1c) and/or change in body weight (BW) on hsCRP reductions.
Results
Geometric mean baseline hsCRP was similar across trials (range 2.7-3.0 mg/L). Semaglutide reduced hsCRP levels by clinical cutoffs and tertiles from baseline to end-of-treatment in all trials versus comparators (estimated treatment ratios [ETRs] versus comparators: 0.70-0.76; p < 0.01) except versus placebo in PIONEER 5 (ETR [95% CI]: 0.83 [0.67-1.03]; p > 0.05). The effect of semaglutide on hsCRP was partially mediated (20.6-61.8%) by change in HbA1c and BW.
Conclusions
Semaglutide reduced hsCRP ratios-to-baseline versus comparators in subjects with type 2 diabetes (not significant with CKD). This effect was partially mediated via reductions in HbA1c and BW and potentially by a direct effect of semaglutide. Semaglutide appears to have an anti-inflammatory effect, which is being further investigated in ongoing trials.
Trial registrations
ClinicalTrials.gov identifiers: NCT01885208 (first registered June 2013), NCT02906930 (first registered September 2016), NCT02863328 (first registered August 2016), NCT02827708 (first registered July 2016).

© 2022. The Author(s).

Cardiovasc Diabetol: 02 Sep 2022; 21:172
Mosenzon O, Capehorn MS, De Remigis A, Rasmussen S, Weimers P, Rosenstock J
Cardiovasc Diabetol: 02 Sep 2022; 21:172 | PMID: 36056351
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Impact:
Abstract

Association between the triglyceride-glucose index and severity of coronary artery disease.

Wang X, Xu W, Song Q, Zhao Z, ... Jin P, Wang F
Background
The triglyceride-glucose (TyG) index, which is a reliable surrogate marker of insulin resistance (IR), has been associated with cardiovascular diseases. However, evidence of the impact of the TyG index on the severity of coronary artery disease (CAD) is limited. This study investigated the relationship between the TyG index and CAD severity of individuals with different glucose metabolic statuses.
Methods
This study enrolled 2792 participants with CAD in China between January 1, 2018 and December 31, 2021. All participants were divided into groups according to the tertiles of the TyG index as follows: T1 group, TyG index < 6.87; T2 group, TyG index ≥ 6.87 to < 7.38; and T3 group, TyG index ≥ 7.38. The glucose metabolic status was classified as normal glucose regulation, pre-diabetes mellitus (pre-DM), and diabetes mellitus according to the standards of the American Diabetes Association. CAD severity was determined by the number of stenotic vessels (single-vessel CAD versus multi-vessel CAD).
Results
We observed a significant relationship between the TyG index and incidence of multi-vessel CAD. After adjusting for sex, age, body mass index, smoking habits, alcohol consumption, hypertension, estimated glomerular filtration rate, antiplatelet drug use, antilipidemic drug use, and antihypertensive drug use in the logistic regression model, the TyG index was still an independent risk factor for multi-vessel CAD. Additionally, the highest tertile of the TyG group (T3 group) was correlated with a 1.496-fold risk of multi-vessel CAD compared with the lowest tertile of the TyG group (T1 group) (odds ratio [OR], 1.496; 95% confidence interval [CI], 1.183-1.893; P < 0.001) in the multivariable logistic regression model. Furthermore, a dose-response relationship was observed between the TyG index and CAD severity (non-linear P = 0.314). In the subgroup analysis of different glucose metabolic statuses, the T3 group (OR, 1.541; 95% CI 1.013-2.344; P = 0.043) were associated with a significantly higher risk of multi-vessel CAD in individuals with pre-DM.
Conclusions
An increased TyG index was associated with a higher risk of multi-vessel CAD. Our study indicated that TyG as an estimation index for evaluating IR could be a valuable predictor of CAD severity, especially for individuals with pre-DM.

© 2022. The Author(s).

Cardiovasc Diabetol: 01 Sep 2022; 21:168
Wang X, Xu W, Song Q, Zhao Z, ... Jin P, Wang F
Cardiovasc Diabetol: 01 Sep 2022; 21:168 | PMID: 36050734
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Impact:
Abstract

Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction.

Nauck MA, D\'Alessio DA
Tirzepatide is the first dual GIP/GLP-1 receptor co-agonist approved for the treatment of type 2 diabetes in the USA, Europe, and the UAE. Tirzepatide is an acylated peptide engineered to activate the GIP and GLP-1 receptors, key mediators of insulin secretion that are also expressed in regions of the brain that regulate food intake. Five clinical trials in type 2-diabetic subjects (SURPASS 1-5) have shown that tirzepatide at 5-15 mg per week reduces both HbA1c (1.24 to 2.58%) and body weight (5.4-11.7 kg) by amounts unprecedented for a single agent. A sizable proportion of patients (23.0 to 62.4%) reached an HbA1c of < 5.7% (which is the upper limit of the normal range indicating normoglycaemia), and 20.7 to 68.4% lost more than 10% of their baseline body weight. Tirzepatide was significantly more effective in reducing HbA1c and body weight than the selective GLP-1 RA semaglutide (1.0 mg per week), and titrated basal insulin. Adverse events related to tirzepatide were similar to what has been reported for selective GLP-1RA, mainly nausea, vomiting, diarrhoea, and constipation, that were more common at higher doses. Cardiovascular events have been adjudicated across the whole study program, and MACE-4 (nonfatal myocardial infarction, non-fatal stroke, cardiovascular death and hospital admission for angina) events tended to be reduced over up to a 2 year-period, albeit with low numbers of events. For none of the cardiovascular events analysed (MACE-4, or its components) was a hazard ratio > 1.0 vs. pooled comparators found in a meta-analysis covering the whole clinical trial program, and the upper bounds of the confidence intervals for MACE were < 1.3, fulfilling conventional definitions of cardiovascular safety. Tirzepatide was found to improve insulin sensitivity and insulin secretory responses to a greater extent than semaglutide, and this was associated with lower prandial insulin and glucagon concentrations. Both drugs caused similar reductions in appetite, although tirzepatide caused greater weight loss. While the clinical effects of tirzepatide have been very encouraging, important questions remain as to the mechanism of action. While GIP reduces food intake and body weight in rodents, these effects have not been demonstrated in humans. Moreover, it remains to be shown that GIPR agonism can improve insulin secretion in type 2 diabetic patients who have been noted in previous studies to be unresponsive to GIP. Certainly, the apparent advantage of tirzepatide, a dual incretin agonist, over GLP-1RA will spark renewed interest in the therapeutic potential of GIP in type 2 diabetes, obesity and related co-morbidities.

© 2022. The Author(s).

Cardiovasc Diabetol: 01 Sep 2022; 21:169
Nauck MA, D'Alessio DA
Cardiovasc Diabetol: 01 Sep 2022; 21:169 | PMID: 36050763
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Impact:
Abstract

Cardiovascular risk of gabapentin and pregabalin in patients with diabetic neuropathy.

Pan Y, Davis PB, Kaebler DC, Blankfield RP, Xu R
Background
Gabapentin and pregabalin are commonly prescribed medications to treat pain in patients with diabetic neuropathy. Gabapentin and pregabalin can cause fluid retention, which is hypothesized to be associated with cardiovascular diseases. However, whether long-term use of gabapentin and pregabalin is associated with adverse cardiovascular diseases remains unknown. This study aims to examine the association between gabapentin use, pregabalin use and several adverse cardiovascular events.
Methods
This retrospective cohort study used propensity score matching within patient electronic health records (EHRs) from a multicenter database with 106 million patients from 69 health care organizations in the US. The study population comprised 210,064 patients who had a diagnosis of diabetic neuropathy and were prescribed diabetic neuropathy medications in their EHRs. The exposure cohort comprised patients who were prescribed gabapentin or pregabalin to treat diabetic neuropathy. The comparison cohort comprised patients who were not prescribed either gabapentin or pregabalin but were prescribed other drugs to treat diabetic neuropathy. The outcomes of interest were myocardial infarcts, strokes, heart failure, peripheral vascular disease, and venous thromboembolic events. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for 3-month and 5-year risk for adverse cardiovascular events between the propensity score-matched cohorts.
Results
Both gabapentin and pregabalin were associated with increased risk of 5-year adverse cardiovascular events compared with the comparison group. In patients prescribed gabapentin, the highest risk was observed for deep venous thrombosis (HR: 1.58, 95% CI 1.37-1.82), followed by pulmonary embolism (HR: 1.5, 95% CI 1.27-1.76), peripheral vascular disease (HR: 1.37, 95% CI 1.27-1.47), stroke (HR: 1.31, 95% CI 1.2-1.43), myocardial infarction (HR: 1.25, 95% CI 1.14-1.38) and heart failure (HR: 1.14, 95% CI 1.07-1.21). In patients prescribed pregabalin, the highest risk was observed for deep venous thrombosis (HR: 1.57, 95% CI 1.31-1.88), followed by peripheral vascular disease (HR: 1.35, 95% CI 1.22-1.49), myocardial infarction (HR: 1.29, 95% CI 1.13-1.47), pulmonary embolism (HR: 1.28, 95% CI 1.04-1.59), stroke (HR: 1.26, 95% CI 1.12-1.42), and heart failure (HR: 1.2, 95% CI 1.11-1.3). There were significant associations between short-term (3 month) gabapentin use and heart failure, myocardial infarction, peripheral vascular disease, deep venous thrombosis, and pulmonary embolism. Short-term (3 month) pregabalin use was associated with deep venous thrombosis, peripheral vascular disease.
Conclusion
In patients with diabetic neuropathy who were prescribed gabapentin and pregabalin, there is an increased risk for heart failure, myocardial infarction, peripheral vascular disease, stroke, deep venous thrombosis, and pulmonary embolism with long-term use. Our findings suggest that increased risk for adverse cardiovascular events, along with other side effects, the efficacy of pain control and the degree of tolerance of the patient, should be considered when prescribing gabapentin and pregabalin long-term in patients with diabetic neuropathy.

© 2022. The Author(s).

Cardiovasc Diabetol: 01 Sep 2022; 21:170
Pan Y, Davis PB, Kaebler DC, Blankfield RP, Xu R
Cardiovasc Diabetol: 01 Sep 2022; 21:170 | PMID: 36050764
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Impact:
Abstract

Association of serum levels of osteopontin and osteoprotegerin with adverse outcomes after endovascular revascularisation in peripheral artery disease.

Kadoglou NPE, Kapetanios D, Korakas E, Valsami G, ... Lambadiari V, Karkos C
Background
Osteoprotegerin (OPG) and osteopontin (OPN) are vascular calcification inhibitors with a known role in the atherosclerotic and inflammatory process. We investigated their relationship with adverse outcomes (restenosis/adverse cardiovascular events) after endovascular revascularisation of patients with peripheral arterial disease (PAD).
Methods
203 consecutive patients were enrolled in the PAD group (PADG) and 78 age and sex-matched subjects with less than two cardiovascular risk factors served as control group (COG). PADG underwent standard medical assessment at baseline and 12 months after the procedure. During follow up major adverse cardiovascular events (MACEs) including arterial restenosis with need for reintervention were documented and the PADG was divided accordingly into two subgroups.
Results
During 12-month follow-up, 82 MACE were recorded (MACE subgroup). The rest of 124 PAD patients remained free of MACE (non-MACE subgroup). At baseline, OPG (9.89 ± 2.85 ng/ml vs 3.47 ± 1.95 ng/ml, p < 0.001) and OPN (79.99 ± 38.29 ng/ml vs 35.21 ± 14.84 ng/ml, p < 0.001) levels were significantly higher in PADG compared to COG, as well as in MACE subgroup compared to non-MACE subgroup (13.29 ± 3.23 ng/ml vs 10.86 ± 3 ng/ml and 96.45 ± 40.12 ng/ml vs 78.1 ± 38.29 ng/ml, respectively). An independent association of PAD with OPG and OPN was found in the whole patient cohort. Although OPG and OPN were significantly related to MACE incidence in the univariate analysis, multiple logistic regression analysis failed to detect any independent predictor of MACE within the PADG.
Conclusion
Baseline high OPG and OPN levels were independently associated with PAD presence. Even higher levels of those biomarkers were detected among PAD patients with MACE, however, their prognostic role should be further clarified.

© 2022. The Author(s).

Cardiovasc Diabetol: 01 Sep 2022; 21:171
Kadoglou NPE, Kapetanios D, Korakas E, Valsami G, ... Lambadiari V, Karkos C
Cardiovasc Diabetol: 01 Sep 2022; 21:171 | PMID: 36050687
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Impact:
Abstract

Circulating ceramides and sphingomyelins and the risk of incident cardiovascular disease among people with diabetes: the strong heart study.

Jensen PN, Fretts AM, Hoofnagle AN, McKnight B, ... Sotoodehnia N, Lemaitre RN
Background
Plasma ceramides and sphingomyelins have been independently linked to diabetes risk, glucose and insulin levels, and the risk of several cardiovascular (CVD) outcomes. However, whether individual ceramide and sphingomyelin species contribute to CVD risk among people with type 2 diabetes is uncertain. Our goal was to evaluate associations of 4 ceramide and 4 sphingomyelin species with incident CVD in a longitudinal population-based study among American Indians with diabetes.
Methods
This analysis included participants with prevalent type 2 diabetes from two cohorts: a prospective cohort of 597 participants in the Strong Heart Family Study (116 incident CVD cases; mean age: 49 years; average length of follow-up: 14 years), and a nested case-control sample of 267 participants in the Strong Heart Study (78 cases of CVD and 189 controls; mean age: 61 years; average time until incident CVD in cases: 3.8 years). The average onset of diabetes was 7 years prior to sphingolipid measurement. Sphingolipid species were measured using liquid chromatography and mass spectrometry. Cox regression and logistic regression were used to assess associations of sphingolipid species with incident CVD; results were combined across cohorts using inverse-variance weighted meta-analysis.
Results
There were 194 cases of incident CVD in the two cohorts. In meta-analysis of the 2 cohort results, higher plasma levels of Cer-16 (ceramide with acylated palmitic acid) were associated with higher CVD risk (HR per two-fold higher Cer-16: 1.85; 95% CI 1.05-3.25), and higher plasma levels of sphingomyelin species with a very long chain saturated fatty acid were associated with lower CVD risk (HR per two-fold higher SM-22: 0.48; 95% CI 0.26-0.87), although none of the associations met our pre-specified threshold for statistical significance of p = 0.006.
Conclusions
While replication of the findings from the SHS in other populations is warranted, our findings add to a growing body of research suggesting that ceramides, in particular Cer-16, not only are associated with higher diabetes risk, but may also be associated with higher CVD risk after diabetes onset. We also find support for the hypothesis that sphingomyelins with a very long chain saturated fatty acid are associated with lower CVD risk among adults with type 2 diabetes.

© 2022. The Author(s).

Cardiovasc Diabetol: 30 Aug 2022; 21:167
Jensen PN, Fretts AM, Hoofnagle AN, McKnight B, ... Sotoodehnia N, Lemaitre RN
Cardiovasc Diabetol: 30 Aug 2022; 21:167 | PMID: 36042511
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Impact:
Abstract

Role of continuous glucose monitoring in diabetic patients at high cardiovascular risk: an expert-based multidisciplinary Delphi consensus.

Di Mario C, Genovese S, Lanza GA, Mannucci E, ... Pitocco D, Expert Panel Group
Background
Continuous glucose monitoring (CGM) shows in more detail the glycaemic pattern of diabetic subjects and provides several new parameters (\"glucometrics\") to assess patients\' glycaemia and consensually guide treatment. A better control of glucose levels might result in improvement of clinical outcome and reduce disease complications. This study aimed to gather an expert consensus on the clinical and prognostic use of CGM in diabetic patients at high cardiovascular risk or with heart disease.
Methods
A list of 22 statements concerning type of patients who can benefit from CGM, prognostic impact of CGM in diabetic patients with heart disease, CGM use during acute cardiovascular events and educational issues of CGM were developed. Using a two-round Delphi methodology, the survey was distributed online to 42 Italian experts (21 diabetologists and 21 cardiologists) who rated their level of agreement with each statement on a 5-point Likert scale. Consensus was predefined as more than 66% of the panel agreeing/disagreeing with any given statement.
Results
Forty experts (95%) answered the survey. Every statement achieved a positive consensus. In particular, the panel expressed the feeling that CGM can be prognostically relevant for every diabetic patient (70%) and that is clinically useful also in the management of those with type 2 diabetes not treated with insulin (87.5%). The assessment of time in range (TIR), glycaemic variability (GV) and hypoglycaemic/hyperglycaemic episodes were considered relevant in the management of diabetic patients with heart disease (92.5% for TIR, 95% for GV, 97.5% for time spent in hypoglycaemia) and can improve the prognosis of those with ischaemic heart disease (100% for hypoglycaemia, 90% for hyperglycaemia) or with heart failure (87.5% for hypoglycaemia, 85% for TIR, 87.5% for GV). The experts retained that CGM can be used and can impact the short- and long-term prognosis during an acute cardiovascular event. Lastly, CGM has a recognized educational role for diabetic subjects.
Conclusions
According to this Delphi consensus, the clinical and prognostic use of CGM in diabetic patients at high cardiovascular risk is promising and deserves dedicated studies to confirm the experts\' feelings.

© 2022. The Author(s).

Cardiovasc Diabetol: 27 Aug 2022; 21:164
Di Mario C, Genovese S, Lanza GA, Mannucci E, ... Pitocco D, Expert Panel Group
Cardiovasc Diabetol: 27 Aug 2022; 21:164 | PMID: 36030229
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Impact:
Abstract

Development and validation of a model to predict cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease.

Stevens SR, Segar MW, Pandey A, Lokhnygina Y, ... Peterson ED, Holman RR
Background
Among individuals with atherosclerotic cardiovascular disease (ASCVD), type 2 diabetes mellitus (T2DM) is common and confers increased risk for morbidity and mortality. Differentiating risk is key to optimize efficiency of treatment selection. Our objective was to develop and validate a model to predict risk of major adverse cardiovascular events (MACE) comprising the first event of cardiovascular death, myocardial infarction (MI), or stroke for individuals with both T2DM and ASCVD.
Methods
Using data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), we used Cox proportional hazards models to predict MACE among participants with T2DM and ASCVD. All baseline covariates collected in the trial were considered for inclusion, although some were excluded immediately because of large missingness or collinearity. A full model was developed using stepwise selection in each of 25 imputed datasets, and comprised candidate variables selected in 20 of the 25 datasets. A parsimonious model with a maximum of 10 degrees of freedom was created using Cox models with least absolute shrinkage and selection operator (LASSO), where the adjusted R-square was used as criterion for selection. The model was then externally validated among a cohort of participants with similar criteria in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial. Discrimination of both models was assessed using Harrell\'s C-index and model calibration by the Greenwood-Nam-D\'Agostino statistic based on 4-year event rates.
Results
Overall, 1491 (10.2%) of 14,671 participants in TECOS and 130 (9.3%) in the ACCORD validation cohort (n = 1404) had MACE over 3 years\' median follow-up. The final model included 9 characteristics (prior stroke, age, chronic kidney disease, prior MI, sex, heart failure, insulin use, atrial fibrillation, and microvascular complications). The model had moderate discrimination in both the internal and external validation samples (C-index = 0.65 and 0.61, respectively). The model was well calibrated across the risk spectrum-from a cumulative MACE rate of 6% at 4 years in the lowest risk quintile to 26% in the highest risk quintile.
Conclusion
Among patients with T2DM and prevalent ASCVD, this 9-factor risk model can quantify the risk of future ASCVD complications and inform decision making for treatments and intensity.

© 2022. The Author(s).

Cardiovasc Diabetol: 27 Aug 2022; 21:166
Stevens SR, Segar MW, Pandey A, Lokhnygina Y, ... Peterson ED, Holman RR
Cardiovasc Diabetol: 27 Aug 2022; 21:166 | PMID: 36030198
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Impact:
Abstract

MLKL-mediated necroptosis is a target for cardiac protection in mouse models of type-1 diabetes.

Cao T, Ni R, Ding W, Ji X, ... Zhang Z, Peng T
Background
Cardiomyocyte death contributes to cardiac pathology of diabetes. Studies have shown that the RIPK3/MLKL necroptosis signaling is activated in diabetic hearts. Deletion of RIPK3 was reported to attenuate myocardial injury and heart dysfunction in streptozocin (STZ)-induced diabetic mice, suggesting a potential role of necroptosis in diabetic cardiomyopathy. This study characterized cardiomyocyte necroptosis in diabetic hearts and investigated whether MLKL-mediated necroptosis is a target for cardiac protection in diabetes.
Methods
Type 1 diabetes was induced in RIPK3 knockout, MLKL knockout and wild-type mice. Akita Type-1 diabetic mice were injected with shRNA for MLKL. Myocardial function was assessed by echocardiography. Immuno-histological analyses determined cardiomyocyte death and fibrosis in the heart. Cultured adult mouse cardiomyocytes were incubated with high glucose in the presence of various drugs. Cell death and phosphorylation of RIPK3 and MLKL were analysed.
Results
We showed that the levels of phosphorylated RIPK3 and MLKL were higher in high glucose-stimulated cardiomyocytes and hearts of STZ-induced type-1 diabetic mice, akita mice and type-1 diabetic monkeys when compared to non-diabetic controls. Inhibition of RIPK3 by its pharmacological inhibitor or gene deletion, or MLKL deletion prevented high glucose-induced MLKL phosphorylation and attenuated necroptosis in cardiomyocytes. In STZ-induced type-1 diabetic mice, cardiomyocyte necroptosis was present along with elevated cardiac troponin I in serum and MLKL oligomerization, and co-localized with phosphorylated MLKL. Deletion of RIPK3 or MLKL prevented MLKL phosphorylation and cardiac necroptosis, attenuated serum cardiac troponin I levels, reduced myocardial collagen deposition and improved myocardial function in STZ-injected mice. Additionally, shRNA-mediated down-regulation of MLKL reduced cardiomyocyte necroptosis in akita mice. Interestingly, incubation with anti-diabetic drugs (empagliflozin and metformin) prevented phosphorylation of RIPK3 and MLKL, and reduced cell death in high glucose-induced cardiomyocytes.
Conclusions
We have provided evidence that cardiomyocyte necroptosis is present in diabetic hearts and that MLKL-mediated cardiomyocyte necroptosis contributes to diabetic cardiomyopathy. These findings highlight MLKL-mediated necroptosis as a target for cardiac protection in diabetes.

© 2022. The Author(s).

Cardiovasc Diabetol: 27 Aug 2022; 21:165
Cao T, Ni R, Ding W, Ji X, ... Zhang Z, Peng T
Cardiovasc Diabetol: 27 Aug 2022; 21:165 | PMID: 36030201
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Impact:
Abstract

Transitioning to active-controlled trials to evaluate cardiovascular safety and efficacy of medications for type 2 diabetes.

McGuire DK, D\'Alessio D, Nicholls SJ, Nissen SE, ... Kaiser JJ, Weerakkody GJ
Cardiovascular (CV) outcome trials (CVOTs) of type 2 diabetes mellitus (T2DM) therapies have mostly used randomized comparison with placebo to demonstrate non-inferiority to establish that the investigational drug does not increase CV risk. Recently, several glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter 2 inhibitors (SGLT-2i) demonstrated reduced CV risk. Consequently, future T2DM therapy trials could face new ethical and clinical challenges if CVOTs continue with the traditional, placebo-controlled design. To address this challenge, here we review the methodologic considerations in transitioning to active-controlled CVOTs and describe the statistical design of a CVOT to assess non-inferiority versus an active comparator and if non-inferiority is proven, using novel methods to assess for superiority versus an imputed placebo. Specifically, as an example of such methodology, we introduce the statistical considerations used for the design of the \"Effect of Tirzepatide versus Dulaglutide on Major Adverse Cardiovascular Events (MACE) in Patients with Type 2 Diabetes\" trial (SURPASS CVOT). It is the first active-controlled CVOT assessing antihyperglycemic therapy in patients with T2DM designed to demonstrate CV efficacy of the investigational drug, tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 RA, by establishing non-inferiority to an active comparator with proven CV efficacy, dulaglutide. To determine the efficacy margin for the hazard ratio, tirzepatide versus dulaglutide, for the composite CV outcome of death, myocardial infarction, or stroke (MACE-3), which is required to claim superiority versus an imputed placebo, the lower bound of efficacy of dulaglutide compared with placebo was estimated using a hierarchical Bayesian meta-analysis of placebo-controlled CVOTs of GLP-1 RAs. SURPASS CVOT was designed so that when the observed upper bound of the 95% confidence interval of the hazard ratio is less than the lower bound of efficacy of dulaglutide, it demonstrates non-inferiority to dulaglutide by preserving at least 50% of the CV benefit of dulaglutide as well as statistical superiority of tirzepatide to a theoretical placebo (imputed placebo analysis). The presented methods adding imputed placebo comparison for efficacy assessment may serve as a model for the statistical design of future active-controlled CVOTs.

© 2022. The Author(s).

Cardiovasc Diabetol: 24 Aug 2022; 21:163
McGuire DK, D'Alessio D, Nicholls SJ, Nissen SE, ... Kaiser JJ, Weerakkody GJ
Cardiovasc Diabetol: 24 Aug 2022; 21:163 | PMID: 36002856
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Impact:
Abstract

Effectiveness and safety of GLP-1 receptor agonists versus SGLT-2 inhibitors in type 2 diabetes: an Italian cohort study.

Baviera M, Foresta A, Colacioppo P, Macaluso G, ... Caruso I, Giorgino F
Background
GLP-1 receptor agonists (GLP-1 RA) and SGLT-2 inhibitors (SGLT-2i) have shown to reduce the risk of major adverse cardiovascular events (MACE), death and worsening nephropathy when added to standard of care. However, these two dug classes differ in efficacy and safety. We compared the effectiveness and safety profile of GLP-1 RA and SGLT-2i in a large and unselected cohort of patients with type 2 diabetes resident in Lombardy from 2015 to 2020.
Methods
Using linkable administrative health databases, we included patients aged 50 years and older initiating GLP-1 RA or SGLT-2i. Clinical events were: death, hospital admission for myocardial infarction (MI), stroke, heart failure (HF), and renal disease as individual and composite outcomes (MACE-3: all cause-death, non-fatal MI, non-fatal stroke; MACE-4: MACE-3 plus unstable angina). Outcomes were evaluated separately in subjects with and without previous cardiovascular (CV) diseases. Treatments were compared using Cox proportional hazards regression model after Propensity Score Matching (PSM) in both intention-to-treat (ITT) and per protocol (PP) analyses. Serious adverse events were also evaluated.
Results
The analysis comprised 20,762 patients per cohort. The ITT analysis showed a significant risk reduction for non-fatal MI (HR 0.77; CI 95% 0.66-0.90), MACE-3 (HR 0.91; CI 95% 0.84-0.98), and MACE-4 (HR 0.92; CI 95% 0.86-0.99) in GLP-1RA compared with SGLT-2i users, while no difference was reported in the incidence of HF hospitalization and stroke between the two cohorts. Similar benefits were found in the subgroup of patients without previous CV diseases only. PP analysis largely confirmed the main results. The incidence of serious adverse events was low in both cohorts (< 1%).
Conclusions
GLP-1RA showed to be equally safe and more effective than SGLT-2i in reducing the risk of MACE-3, MACE-4 and MI. This study adds to the growing body of real-world evidence addressing the specific clinical properties of GLP-1RA and SGLT-2i in everyday practice to tailor treatment to the individual patient.

© 2022. The Author(s).

Cardiovasc Diabetol: 24 Aug 2022; 21:162
Baviera M, Foresta A, Colacioppo P, Macaluso G, ... Caruso I, Giorgino F
Cardiovasc Diabetol: 24 Aug 2022; 21:162 | PMID: 35999556
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Impact:
Abstract

Association of the cumulative triglyceride-glucose index with major adverse cardiovascular events in patients with type 2 diabetes.

Tai S, Fu L, Zhang N, Yang R, ... Wang Y, Zhou S
Background
The triglyceride-glucose (TyG) index is a reliable surrogate marker of insulin resistance and is associated with major adverse cardiovascular events (MACEs) in patients with type 2 diabetes mellitus (T2DM). However, the long-term effect of the TyG index on the incidence of MACEs remains unclear. We aimed to investigate the association between the cumulative TyG index and the risk of MACEs in patients with T2DM.
Methods
This post-hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial assessed patients\' (T2DM > 3 months) cumulative TyG index and MACE data from the study database. Five fasting blood glucose and triglyceride measurements, at baseline and the first four visits, were taken from 5695 participants who had not experienced MACEs. Cumulative exposure to the TyG index was calculated as the weighted sum of the mean TyG index value for each time interval (value × time). Multivariable-adjusted Cox proportional hazard models and restricted cubic spline analysis were used to determine the association between the cumulative TyG index and MACEs. The incremental predictive value of the cumulative TyG index was further assessed.
Results
Over a median follow-up of 5.09 years, 673 (11.82%) MACEs occurred, including 256 (4.50%) cardiovascular disease (CVD) deaths, 288 (5.06%) non-fatal myocardial infarctions (MIs), and 197 (3.46%) strokes. The risk of developing MACEs increased with the cumulative TyG index quartile. After adjusting for multiple potential confounders, the hazard ratios for the very high cumulative TyG index group versus the low group were 1.59 (95% confidence interval [CI], 1.17-2.16), 1.97 (95% CI 1.19-3.26), and 1.66 (95% CI 1.02-2.70) for overall MACEs, CVD death, and non-fatal MI, respectively. Restricted cubic spline analysis also showed a cumulative increase in the risk of MACEs with an increase in the magnitude of the cumulative TyG index. The addition of the cumulative TyG index to a conventional risk model for MACEs improved the C-statistics, net reclassification improvement value, and integrated discrimination improvement value.
Conclusions
In patients with T2DM, the cumulative TyG index independently predicts the incidence of MACEs, and monitoring the long-term TyG index may assist with optimized-for-risk stratification and outcome prediction for MACEs. Trial registration URL: http://www.
Clinicaltrials
gov . Unique identifier: NCT00000620.

© 2022. The Author(s).

Cardiovasc Diabetol: 23 Aug 2022; 21:161
Tai S, Fu L, Zhang N, Yang R, ... Wang Y, Zhou S
Cardiovasc Diabetol: 23 Aug 2022; 21:161 | PMID: 35999546
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Impact:
Abstract

Time-resolved trajectory of glucose lowering medications and cardiovascular outcomes in type 2 diabetes: a recurrent neural network analysis.

Longato E, Di Camillo B, Sparacino G, Avogaro A, Fadini GP
Aim
Treatment algorithms define lines of glucose lowering medications (GLM) for the management of type 2 diabetes (T2D), but whether therapeutic trajectories are associated with major adverse cardiovascular events (MACE) is unclear. We explored whether the temporal resolution of GLM usage discriminates patients who experienced a 4P-MACE (heart failure, myocardial infarction, stroke, death for all causes).
Methods
We used an administrative database (Veneto region, North-East Italy, 2011-2018) and implemented recurrent neural networks (RNN) with outcome-specific attention maps. The model input included age, sex, diabetes duration, and a matrix of GLM pattern before the 4P-MACE or censoring. Model output was discrimination, reported as area under receiver characteristic curve (AUROC). Attention maps were produced to show medications whose time-resolved trajectories were the most important for discrimination.
Results
The analysis was conducted on 147,135 patients for training and model selection and on 10,000 patients for validation. Collected data spanned a period of ~ 6 years. The RNN model efficiently discriminated temporal patterns of GLM ending in a 4P-MACE vs. those ending in an event-free censoring with an AUROC of 0.911 (95% C.I. 0.904-0.919). This excellent performance was significantly better than that of other models not incorporating time-resolved GLM trajectories: (i) a logistic regression on the bag-of-words encoding all GLM ever taken by the patient (AUROC 0.754; 95% C.I. 0.743-0.765); (ii) a model including the sequence of GLM without temporal relationships (AUROC 0.749; 95% C.I. 0.737-0.761); (iii) a RNN model with the same construction rules but including a time-inverted or randomised order of GLM. Attention maps identified the time-resolved pattern of most common first-line (metformin), second-line (sulphonylureas) GLM, and insulin (glargine) as those determining discrimination capacity.
Conclusions
The time-resolved pattern of GLM use identified patients with subsequent cardiovascular events better than the mere list or sequence of prescribed GLM. Thus, a patient\'s therapeutic trajectory could determine disease outcomes.

© 2022. The Author(s).

Cardiovasc Diabetol: 22 Aug 2022; 21:159
Longato E, Di Camillo B, Sparacino G, Avogaro A, Fadini GP
Cardiovasc Diabetol: 22 Aug 2022; 21:159 | PMID: 35996111
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Impact:
Abstract

A novel kidney disease index reflecting both the albumin-to-creatinine ratio and estimated glomerular filtration rate, predicted cardiovascular and kidney outcomes in type 2 diabetes.

Gerstein HC, Ramasundarahettige C, Avezum A, Basile J, ... Turfanda I, Xavier D
Background
The estimated glomerular filtration rate (eGFR) and the albumin-to-creatinine ratio (ACR) are risk factors for diabetes-related outcomes. A composite that captures information from both may provide a simpler way of assessing risk.
Methods
9115 of 9901 Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) participants with both an ACR and eGFR at baseline were included in this post hoc epidemiologic analysis. The hazard of higher baseline levels of 1/eGFR and natural log transformed ACR (calculated as ln [ACR × 100] to eliminate negative values) and their interaction for incident major adverse cardiovascular events (MACE), kidney outcomes, and deaths was estimated. The hazard of the geometric mean of these two baseline measures (the kidney disease index or KDI) was also assessed.
Results
A non-linear relationship was observed between 1/eGFR and all three outcomes, and between ln [ACR × 100] and the kidney outcome. There was also a negative interaction between these two risk factors with respect to MACE and death. Conversely, a linear relationship was noted between the KDI and all three outcomes. People in the highest KDI fifth experienced the highest incidence of MACE, death, and the kidney outcome (4.43, 4.56, and 5.55/100 person-years respectively). C statistics for the KDI were similar to those for eGFR and albuminuria.
Conclusions
The KDI combines the baseline eGFR and ACR into a novel composite risk factor that has a simple linear relationship with incident serious outcomes in people with diabetes and additional CV risk factors.
Trial registration:
clinicaltrials.gov NCT01394952.

© 2022. The Author(s).

Cardiovasc Diabetol: 22 Aug 2022; 21:158
Gerstein HC, Ramasundarahettige C, Avezum A, Basile J, ... Turfanda I, Xavier D
Cardiovasc Diabetol: 22 Aug 2022; 21:158 | PMID: 35996147
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Impact:
Abstract

Managing thrombotic risk in patients with diabetes.

Camm AJ, Sabbour H, Schnell O, Summaria F, Verma A
It is well known that diabetes is a prominent risk factor for cardiovascular (CV) events. The level of CV risk depends on the type and duration of diabetes, age and additional co-morbidities. Diabetes is an independent risk factor for atrial fibrillation (AF) and is frequently observed in patients with AF, which further increases their risk of stroke associated with this cardiac arrhythmia. Nearly one third of patients with diabetes globally have CV disease (CVD). Additionally, co-morbid AF and coronary artery disease are more frequently observed in patients with diabetes than the general population, further increasing the already high CV risk of these patients. To protect against thromboembolic events in patients with diabetes and AF or established CVD, guidelines recommend optimal CV risk factor control, including oral anticoagulation treatment. However, patients with diabetes exist in a prothrombotic and inflammatory state. Greater clinical benefit may therefore be seen with the use of stronger antithrombotic agents or innovative drug combinations in high-risk patients with diabetes, such as those who have concomitant AF or established CVD. In this review, we discuss CV risk management strategies in patients with diabetes and concomitant vascular disease, stroke prevention regimens in patients with diabetes and AF and how worsening renal function in these patients may complicate these approaches. Accumulating evidence from clinical trials and real-world evidence show a benefit to the administration of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with diabetes and AF.

© 2022. The Author(s).

Cardiovasc Diabetol: 22 Aug 2022; 21:160
Camm AJ, Sabbour H, Schnell O, Summaria F, Verma A
Cardiovasc Diabetol: 22 Aug 2022; 21:160 | PMID: 35996159
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Impact:
Abstract

Contemporary use of SGLT2 inhibitors in heart failure patients with diabetes mellitus: a comparison of DPP4 inhibitors in a nationwide electric health database of the superaged society.

Nakai M, Iwanaga Y, Kanaoka K, Sumita Y, ... Yasuda S, Miyamoto Y
Background
There is a lack of recent data reflecting the actual use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for heart failure (HF) and type 2 diabetes (DM) in the superaged society. The present study investigated the association between the use of SGLT2 inhibitors and one-year prognosis in patients hospitalized across a broad spectrum of HF patients with DM in the superaged society using the Nationwide Electric Health Database in Japan.
Methods
The patients hospitalized with the first episode of acute HF were identified from the National Database of Health Insurance Claims and Specific Health Checkups of Japan between April 2014 and March 2019. A cohort of 2,277 users of SGLT2 inhibitors and 41,410 users of the active comparator, dipeptidyl peptidase-4 (DPP4) inhibitors were compared. A propensity score-matched cohort study of 2,101 users of each inhibitor was also conducted. A multivariable multilevel mixed-effects survival model was conducted with adjustments, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated.
Results
Among 300,398 patients discharged with HF in 4,176 hospitals, 216,016 (71.9%) were 75 years or older, and 60,999 (20.3%) took antidiabetic medications. Among them, the patients treated with SGLT2 inhibitors were younger and had a more severe status than those treated with DPP4 inhibitors. Kaplan-Meier analysis showed that patients treated with SGLT2 inhibitors had a lower mortality risk and HF readmission. In propensity-matched cohorts, SGLT2 inhibitor use was associated with a lower risk of mortality and HF readmission than DPP-4 inhibitor use (HR [95% CI]; 0.70 [0.56, 0.89] and 0.52 [0.45, 0.61], respectively). Very elderly (≥ 75 years) patients showed similar results. Favorable effects were also observed across all age groups, including ≥ 75 years, in patients with coronary artery disease or atrial fibrillation and with concomitant β-blocker, diuretics, or insulin.
Conclusion
The use of SGLT2 inhibitors at discharge was associated with a lower risk of one-year mortality and HF readmission in patients across a broad spectrum of HF with DM in the superaged society. The findings further support the benefits of using SGLT2 inhibitors in very elderly HF care and complement the current evidence.

© 2022. The Author(s).

Cardiovasc Diabetol: 13 Aug 2022; 21:157
Nakai M, Iwanaga Y, Kanaoka K, Sumita Y, ... Yasuda S, Miyamoto Y
Cardiovasc Diabetol: 13 Aug 2022; 21:157 | PMID: 35964039
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Impact:
Abstract

High neutrophil to lymphocyte ratio with type 2 diabetes mellitus predicts poor prognosis in patients undergoing percutaneous coronary intervention: a large-scale cohort study.

He J, Bian X, Song C, Zhang R, ... Yin D, Dou K
Background
Inflammation plays a crucial role in the pathogenesis and progression of coronary artery disease (CAD). The neutrophil to lymphocyte ratio (NLR) is a novel inflammatory biomarker and its association with clinical outcomes in CAD patients with different glycemic metabolism after percutaneous coronary intervention (PCI) remains undetermined. Therefore, this study aimed to investigate the effect of NLR on the prognosis of patients undergoing PCI with or without type 2 diabetes mellitus (T2DM).
Methods
We consecutively enrolled 8,835 patients with CAD hospitalized for PCI at Fuwai hospital. NLR was calculated using the following formula: neutrophil (*109/L)/lymphocyte (*109/L). According to optimal cut-off value, study patients were categorized as higher level of NLR (NLR-H) and lower level of NLR (NLR-L) and were further stratified as NLR-H with T2DM and non-T2DM, and NLR-L with T2DM and non-T2DM. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCEs), defined as all-cause mortality, myocardial infarction (MI), stroke and target vessel revascularization.
Results
A total of 674 (7.6%) MACCEs were recorded during a median follow-up of 2.4 years. The optimal cut-off value of NLR was 2.85 determined by the surv_cutpoint function. Compared to those in the NLR-H/T2DM groups, patients in the NLR-L/non-T2DM, NLR-H/non-T2DM and NLR-L/T2DM groups were at significantly lower risk of 2-year MACCEs [adjusted hazard ratio (HR): 0.67, 95% confidence interval (CI): 0.52 to 0.87, P = 0.003; adjusted HR: 0.62, 95%CI: 0.45 to 0.85, P = 0.003; adjusted HR: 0.77, 95%CI: 0.61 to 0.97, P = 0.025; respectively]. Remarkably, patients in the NLR-L/non-T2DM group also had significantly lower risk of a composite of all-cause mortality and MI than those in the NLR-H/T2DM group (adjusted HR: 0.57, 95%CI: 0.35 to 0.93, P = 0.024). Multivariable Cox proportional hazards model also indicated the highest risk of MACCEs in diabetic patients with higher level of NLR than others (P for trend = 0.009). Additionally, subgroup analysis indicated consistent impact of NLR on MACCEs across different subgroups.
Conclusions
Presence of T2DM with elevated NLR is associated with worse clinical outcomes in CAD patients undergoing PCI. Categorization of patients with elevated NLR and T2DM could provide valuable information for risk stratification of CAD patients.

© 2022. The Author(s).

Cardiovasc Diabetol: 13 Aug 2022; 21:156
He J, Bian X, Song C, Zhang R, ... Yin D, Dou K
Cardiovasc Diabetol: 13 Aug 2022; 21:156 | PMID: 35964050
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Impact:
Abstract

High triglyceride-glucose index in young adulthood is associated with incident cardiovascular disease and mortality in later life: insight from the CARDIA study.

Xu X, Huang R, Lin Y, Guo Y, ... Zhuang X, Liao X
Background
This study aimed to investigate the associations between the triglyceride-glucose (TyG) index in young adulthood with incident cardiovascular disease (CVD) and mortality.
Methods
We included 4,754 participants from the Coronary Artery Risk Development in Young Adults study at baseline. The TyG index was calculated as ln (fasting TG [mg/dl] × fasting glucose [mg/dl]/2), and the TyG index trajectories were identified by using the latent class growth mixture model. We evaluated the association between the baseline and trajectories of the TyG index with incident CVD events and all-cause mortality using Cox proportional hazards regression analysis. The added value of the TyG index included in pooled cohort equations for CVD prediction was also analyzed.
Results
Among 4754 participants (mean age 24.72 years, 45.8% male, 51.2% black), there were 158 incident CVD events and 246 all-cause mortality during a median 25 years follow-up. After adjusting for multiple confounding variables, each one-unit increase in the TyG index was associated with a 96% higher CVD risk (hazard ratio [HR] 1.96, 95% confidence interval [CI] 1.44-2.66) and a 85% higher all-cause mortality risk (HR 1.85, 95% CI 1.45-2.36). Three distinct trajectories of the TyG index along the follow-up duration were identified: low (44.0%), moderate (45.5%), and high (10.5%). Compared with those participants in the low TyG index trajectory group, those in the high TyG index trajectory group had a greater risk of CVD events (HR 2.35, 95% CI 1.34-4.12) and all-cause mortality (HR 3.04, 95% CI 1.83-5.07). The addition of baseline TyG index to pooled cohort equations for CVD improved the C-statistics (P < 0.001), integrated discrimination improvement value (P < 0.001), and category-free net reclassification improvement value (P = 0.003).
Conclusions
Higher baseline TyG index levels and higher long-term trajectory of TyG index during young adulthood were significantly associated with an increased risk of incident CVD events and all-cause mortality in later life.

© 2022. The Author(s).

Cardiovasc Diabetol: 12 Aug 2022; 21:155
Xu X, Huang R, Lin Y, Guo Y, ... Zhuang X, Liao X
Cardiovasc Diabetol: 12 Aug 2022; 21:155 | PMID: 35962377
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Impact:
Abstract

HDL functionality in type 1 diabetes: enhancement of cholesterol efflux capacity in relationship with decreased HDL carbamylation after improvement of glycemic control.

Denimal D, Monier S, Simoneau I, Duvillard L, Vergès B, Bouillet B
Background
Reduced cholesterol efflux capacity (CEC) of HDLs is likely to increase cardiovascular risk in type 1 diabetes (T1D). We aimed to assess whether improvement of glycemic control in T1D patients is associated with changes in CEC in relation with changes in carbamylation of HDLs.
Methods
In this open-label trial, 27 uncontrolled T1D patients were given a three-month standard medical intervention to improve glycemic control. HDL fraction was isolated from plasma, and CEC was measured on THP-1 macrophages. Carbamylation of HDLs was evaluated by an immunoassay. Control HDLs from healthy subjects were carbamylated in vitro with potassium cyanate.
Results
HbA1c decreased from 11.4% [10.2-12.9] (median [1st-3rd quartiles]) at baseline to 8.1% [6.6-9.0] after the three-month intervention (P < 0.00001). The CEC of HDLs increased after intervention in 19 (70%) patients (P = 0.038). At the same time, the carbamylation of HDLs decreased in 22 (82%) patients after intervention (P = 0.014). The increase in CEC significantly correlated with the decrease in carbamylated HDLs (r = -0.411, P = 0.034), even after adjustment for the change in HbA1c (β = -0.527, P = 0.003). In vitro carbamylation of control HDLs decreased CEC by 13% (P = 0.041) and 23% (P = 0.021) using 1 and 10 mmol/L of potassium cyanate, respectively.
Conclusions
The improvement of CEC in relation to a decrease in the carbamylation of HDLs may likely contribute to the beneficial cardiovascular effect of glycemic control in T1D patients.
Trial registration
NCT02816099 ClinicalTrials.gov.

© 2022. The Author(s).

Cardiovasc Diabetol: 12 Aug 2022; 21:154
Denimal D, Monier S, Simoneau I, Duvillard L, Vergès B, Bouillet B
Cardiovasc Diabetol: 12 Aug 2022; 21:154 | PMID: 35962339
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Impact:
Abstract

Age-specific difference in the association between prediabetes and subclinical atherosclerosis: an analysis of a chinese prospective cohort study.

Cao Q, Xin Z, He R, Wang T, ... Xu Y, Li M
Background
Prediabetes is an important risk factor of cardiovascular disease (CVD) and is associated with subclinical atherosclerosis. However, the evidence of prediabetes as a cardiovascular risk factor is mainly derived from middle-aged adults. Recently, multiple studies supported that prediabetes in older adults would not lead to higher risk of CVD or mortality. We aimed to investigate the age-specific difference in the association between prediabetes and subclinical atherosclerosis in a Chinese prospective cohort study.
Methods
We included 4739 individuals aged ≥ 40 years and without diagnosed diabetes or CVD history, and divided them into middle-aged adults (age < 60) and older adults (age ≥ 60). Fasting plasma glucose (FPG), 2-h post-load plasma glucose (2 h-PPG) and glycated hemoglobin (HbA1c) were measured at baseline to identify prediabetes status. At follow-up visits, subclinical atherosclerosis status was assessed by branchial-ankle pulse wave velocity (baPWV) and carotid intima-media thickness (CIMT). Logistic regression analysis, restricted cubic splines and cross-lagged path analysis were used in statistical analysis.
Results
1634 participants aged over 60 years, and 64.3% of them had prediabetes. 3105 participants aged 40-59 years, and 49.3% of them had prediabetes. We found that prediabetes was associated with increased risk of subclinical atherosclerosis in middle-aged adults, but the association attenuated substantially in older adults. Impaired glucose tolerance (IGT), compared to normal glucose tolerance, was associated with 39% lower risk of increased baPWV only in older adults. In accordance, the association between 2 h-PPG and risk of increased baPWV was \"U-shaped\" in older adults, while risk of elevated baPWV increased linearly with 2 h-PPG in middle-aged adults. In the cross-lagged analysis, increase in FPG and 2 h-PPG tended not to precede increase in baPWV in older adults, but appeared to increase simultaneously with baPWV in middle-aged ones.
Conclusion
Our results indicated that prediabetes might be less related to subclinical atherosclerosis in older adults than in middle-aged adults and suggested that age was important to consider in the care of adults with prediabetes.

© 2022. The Author(s).

Cardiovasc Diabetol: 10 Aug 2022; 21:153
Cao Q, Xin Z, He R, Wang T, ... Xu Y, Li M
Cardiovasc Diabetol: 10 Aug 2022; 21:153 | PMID: 35948892
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Impact:
Abstract

Ethnicity should be included as a risk factor for coronary artery calcium score.

Al-Sawalha I, Alzoubi D
Coronary artery calcium score (CACs) is a measurement of calcification in coronary arteries using a computed tomography scan. It has a predictive role for future myocardial infarction thus it aids in cardiovascular risk assessment and physician decision making. Multiple risk factors have been attributed to coronary artery calcification including age, male gender and ethnicity. Herein, we report our concerns regarding neglecting ethnicity within participants demographics and data analysis, which may affect the findings of the study.

© 2022. The Author(s).

Cardiovasc Diabetol: 08 Aug 2022; 21:150
Al-Sawalha I, Alzoubi D
Cardiovasc Diabetol: 08 Aug 2022; 21:150 | PMID: 35941652
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Impact:
Abstract

Association between serum insulin levels and heart failure-related parameters in patients with type 2 diabetes and heart failure treated with canagliflozin: a post-hoc analysis of the randomized CANDLE trial.

Tanaka A, Imai T, Shimabukuro M, Taguchi I, ... Node K, CANDLE trial investigators
Background
Insulin resistance and hyperinsulinemia in patients with type 2 diabetes (T2D) are adversely associated with the development and worsening of heart failure (HF). Herein, we sought to investigate the effect of canagliflozin on insulin concentrations and the associations of changes in insulin concentrations with HF-related clinical parameters in patients with T2D and HF.
Methods
This was a post-hoc analysis of the investigator-initiated, multicenter, open-label, randomized, controlled CANDLE trial for patients with T2D and chronic HF (UMIN000017669). The endpoints were the effects of 24 weeks of canagliflozin treatment, relative to glimepiride treatment, on insulin concentrations and the relationship between changes in insulin concentrations and clinical parameters of interest, including New York Heart Association (NYHA) classification. The effects of canagliflozin on those parameters were also analyzed by baseline insulin level.
Results
Among the participants in the CANDLE trial, a total of 129 patients (canagliflozin, n = 64; glimepiride, n = 65) who were non-insulin users with available serum insulin data both at baseline and week 24 were included in this analysis. Overall, the mean age was 69.0 ± 9.4 years; 75% were male; the mean HbA1c was 6.8 ± 0.7%; and the mean left ventricular ejection fraction was 59.0 ± 14.1%, with parameters roughly balanced between treatment groups. Canagliflozin treatment significantly reduced insulin concentrations at week 24 (p < 0.001), and the between-group difference (canagliflozin minus glimepiride) in those changes was - 3.52 mU/L (95% confidence interval, - 4.85 to - 2.19; p < 0.001). Decreases in insulin concentrations, irrespective of baseline insulin level, were significantly associated with improvement in NYHA class in patients treated with canagliflozin.
Conclusion
Our findings suggest that canagliflozin treatment in patients with T2D and HF ameliorated excess insulin overload, contributing to the improvement of clinical HF status.
Trial registration
University Medical Information Network Clinical Trial Registry, number 000017669, Registered on May 25, 2015.

© 2022. The Author(s).

Cardiovasc Diabetol: 08 Aug 2022; 21:151
Tanaka A, Imai T, Shimabukuro M, Taguchi I, ... Node K, CANDLE trial investigators
Cardiovasc Diabetol: 08 Aug 2022; 21:151 | PMID: 35941584
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Impact:
Abstract

The predictive value of the triglyceride-glucose index for cardiovascular events in patients with coronary chronic total occlusion.

Li Y, He S, Wu Z, Li W, ... Shi Y, Liu J
Background
Chronic total occlusion (CTO) of the coronary artery is a difficult problem in clinical practice. The triglyceride-glucose (TyG) index is an effective risk predictor of cardiovascular risk. However, the relationship between the TyG index and the prognosis of CTO patients remains unstudied. Thus, the present study aimed to investigate the relationship between the TyG index and cardiovascular risk in CTO patients.
Methods
This was a single-centre, retrospective cohort study. We retrospectively enrolled 652 patients with CTO lesions diagnosed by angiography and who underwent revascularization through PCI. Patients were routinely followed up for 24 months unless meeting the endpoint. The primary endpoint was the composite of all-cause death, nonfatal myocardial infarction, unplanned revascularization, and nonfatal ischaemic stroke. To test the association of the TyG index with cardiovascular risk, the categorized TyG index and Cox proportional hazards regression models were utilized.
Results
A total of 652 patients were enrolled in the final analysis (male: 83.7%, age: 58.2 ± 10.49 years). The average TyG index was 8.8 ± 0.57. CTO PCIs were procedurally successfully completed in 503 (77.15%) patients. During the follow-up period of 22.8 ± 3.84 months, 73 (11.19%) major adverse cardiovascular and cerebral events (MACCEs) occurred. When fully adjusted, there was a 2.09-fold risk for MACCEs among patients with the highest TyG index compared with those with the lowest TyG index [T2 vs. T1: hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.65-2.38, P = 0.057; T3 vs. T1: HR 2.09, 95% CI 1.14-3.86, P = 0.018; P for trend = 0.036]. The restricted cubic spline (RCS) analysis showed that the HR for MACCEs increased as the TyG index increased over 8.71 [HR per standard deviation (SD) 1.740, 95% CI 1.23-2.46, P = 0.002]. The risk of MACCEs increased with increasing tertiles of TyG index in successful CTO PCI patients and nondiabetes mellitus (DM) patients (P < 0.05) but not in patients with failed CTO PCI and DM patients.
Conclusion
The study revealed that the TyG index had significant relevance to cardiovascular risk in CTO patients and suggests that the TyG index is feasible for predicting cardiovascular risk in CTO patients.

© 2022. The Author(s).

Cardiovasc Diabetol: 08 Aug 2022; 21:149
Li Y, He S, Wu Z, Li W, ... Shi Y, Liu J
Cardiovasc Diabetol: 08 Aug 2022; 21:149 | PMID: 35941586
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Impact:
Abstract

Glucose tolerance and markers of myocardial injury after an acute coronary syndrome: predictive role of the 1-h plus 2-h plasma glucose at the oral glucose tolerance test.

Zywicki V, Capozza P, Caravelli P, Del Prato S, De Caterina R
Objective
Impaired glucose tolerance (IGT) has been related to adverse cardiovascular outcomes. We investigated the added value of 1-h plasma glucose (PG) at the oral glucose tolerance test (OGTT) in predicting admission and peak cardiac high-sensitivity troponin T (hs-TnT) and NT-proBNP values in IGT patients admitted for an acute coronary syndrome (ACS).
Research design and methods
Among 192 consecutive ACS patients, 109 had Hb1Ac and fasting plasma glucose negative for newly diagnosed diabetes. Upon OGTT performed > 96 h after admission, 88, conventionally diagnosed as IGT, were divided into: \"full glucose tolerance\" (1-h PG-OGTT < 155 mg/dL and 2-h PG-OGTT < 140 mg/dL, N = 12);\"early IGT\" (1 h-PG-OGTT ≥ 155 mg/dL and 2-h PG-OGTT < 140 mg/dL, N = 33);\"late IGT\" (1-h PG-OGTT < 155 mg/dL and 2-h PG-OGTT ≥ 140 mg/dL, N = 8); and \"full IGT\" (1-h PG-OGTT ≥ 155 mg/dL and 2-h PG-OGTT ≥ 140 mg/dL, N = 35). The 4 groups were compared for cardiac markers.
Results
The first three groups had similar cardiac marker values, but only full IGT patients had significantly higher admission hs-TnT compared with the 3 other groups [median (interquartile range): 911 (245-2976) vs 292 (46-1131), P < 0.001]. Full IGT patients also had higher hs-TnT peak compared with fully glucose tolerant and early IGT patients. Only full IGT patients had longer hospitalization and higher NT-proBNP vs fully glucose tolerant patients (P = 0.005).
Conclusions
Among non-diabetic ACS patients, only those with both 1-h PG ≥ 155 mg/dL and 2-h PG ≥ 140 mg/dL had more severe myocardial injury and longer hospitalization. One-h PG-OGTT importantly contributes to assessing post-ACS cardiac risk.

© 2022. The Author(s).

Cardiovasc Diabetol: 08 Aug 2022; 21:152
Zywicki V, Capozza P, Caravelli P, Del Prato S, De Caterina R
Cardiovasc Diabetol: 08 Aug 2022; 21:152 | PMID: 35941590
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Impact:
Abstract

Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/Post-Acute Sequelae of COVID-19 (PASC).

Pretorius E, Venter C, Laubscher GJ, Kotze MJ, ... Watson BW, Kell DB
Background
Fibrin(ogen) amyloid microclots and platelet hyperactivation previously reported as a novel finding in South African patients with the coronavirus 2019 disease (COVID-19) and Long COVID/Post-Acute Sequelae of COVID-19 (PASC), might form a suitable set of foci for the clinical treatment of the symptoms of Long COVID/PASC. A Long COVID/PASC Registry was subsequently established as an online platform where patients can report Long COVID/PASC symptoms and previous comorbidities.
Methods
In this study, we report on the comorbidities and persistent symptoms, using data obtained from 845 South African Long COVID/PASC patients. By using a previously published scoring system for fibrin amyloid microclots and platelet pathology, we also analysed blood samples from 80 patients, and report the presence of significant fibrin amyloid microclots and platelet pathology in all cases.
Results
Hypertension, high cholesterol levels (dyslipidaemia), cardiovascular disease and type 2 diabetes mellitus (T2DM) were found to be the most important comorbidities. The gender balance (70% female) and the most commonly reported Long COVID/PASC symptoms (fatigue, brain fog, loss of concentration and forgetfulness, shortness of breath, as well as joint and muscle pains) were comparable to those reported elsewhere. These findings confirmed that our sample was not atypical. Microclot and platelet pathologies were associated with Long COVID/PASC symptoms that persisted after the recovery from acute COVID-19.
Conclusions
Fibrin amyloid microclots that block capillaries and inhibit the transport of O2 to tissues, accompanied by platelet hyperactivation, provide a ready explanation for the symptoms of Long COVID/PASC. Removal and reversal of these underlying endotheliopathies provide an important treatment option that urgently warrants controlled clinical studies to determine efficacy in patients with a diversity of comorbidities impacting on SARS-CoV-2 infection and COVID-19 severity. We suggest that our platelet and clotting grading system provides a simple and cost-effective diagnostic method for early detection of Long COVID/PASC as a major determinant of effective treatment, including those focusing on reducing clot burden and platelet hyperactivation.

© 2022. The Author(s).

Cardiovasc Diabetol: 06 Aug 2022; 21:148
Pretorius E, Venter C, Laubscher GJ, Kotze MJ, ... Watson BW, Kell DB
Cardiovasc Diabetol: 06 Aug 2022; 21:148 | PMID: 35933347
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Impact:
Abstract

Evolocumab on top of empagliflozin improves endothelial function of individuals with diabetes: randomized active-controlled trial.

Sposito AC, Breder I, Barreto J, Breder J, ... Kimura-Medorima ST, EXCEED-BHS3 Group
Background
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve endothelial dysfunction and reduce cardiovascular events in individuals with type 2 diabetes (T2D). Proprotein convertase subtilisin/kexin 9 (PCSK9i) inhibitors reduce cardiovascular events in high-risk patients. Whether the addition of PCSK9i to SGLT2i treatment adds benefits is not known.
Objectives
To assess the PCSK9-i effect on the endothelial function of T2D individuals under treatment with SGLT2-i.
Methods
Individuals with T2D were randomized in a 1:1 ratio to a 16-week treatment with either empagliflozin (E) or empagliflozin plus evolocumab (EE). The primary endpoint was post-treatment change from baseline in flow-mediated dilation (FMD) at 1-min. Secondary outcomes included changes in plasma levels of nitric oxide metabolites and isoprostane.
Results
A total of 110 patients were enrolled, the mean age was 58 years, and 71% were men. The median post-treatment change in FMD at 1-min was 2.7% (interquartile range [IQR]: 0.9%) and 0.4% (IQR: 0.9%) in the EE and E groups, respectively (p < 0.001). There was a greater increase in plasma levels of nitrate [5.9 (16.5) vs. 2.6 (11.8); p = 0.001] and nitrite [0.14 (0.72) vs. 0.02 (0.74); p = 0.025] in the EE group than in the E group, respectively. Isoprostane reduction was more pronounced in the EE group when compared to the E group [-1.7 (5.9) vs. -1.1 (5.3); p < 0.001).
Conclusions
In individuals with T2D, the addition of evolocumab on top of empagliflozin improves endothelial function.

© 2022. The Author(s).

Cardiovasc Diabetol: 06 Aug 2022; 21:147
Sposito AC, Breder I, Barreto J, Breder J, ... Kimura-Medorima ST, EXCEED-BHS3 Group
Cardiovasc Diabetol: 06 Aug 2022; 21:147 | PMID: 35933413
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Impact:
Abstract

Adjustment of the GRACE score by the triglyceride glucose index improves the prediction of clinical outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention.

Xiong S, Chen Q, Chen X, Hou J, ... Zhang Z, Cai L
Background
The Global Registry of Acute Coronary Events (GRACE) score derived from clinical parameters at the time of hospital discharge is a powerful predictor of long-term mortality and reinfarction after acute coronary syndrome (ACS). The triglyceride glucose (TyG) index, which is a simple and reliable surrogate marker of insulin resistance, has been demonstrated to be an independent predictor of long-term adverse major adverse cardiac events, irrespective of diabetes mellitus. We investigate whether the addition of the TyG index improves the predictive ability of the GRACE score after percutaneous coronary intervention (PCI) in ACS patients regardless of diabetes mellitus.
Method
A retrospective cohort of 986 ACS patients undergoing PCI was enrolled in the present analyses. The GRACE score for discharge to 6 months and the TyG index were calculated. The primary endpoint was the composite of MACEs, including all-cause death and nonfatal myocardial infarction. Patients were stratified according to the primary endpoint and the tertiles of the TyG index. Cumulative curves were calculated using the Kaplan-Meier method. Multivariate Cox regression was adopted to identify predictors of MACEs. The predictive value of the GRACE score alone and combined with the TyG index or fasting blood glucose (FBG) was estimated by the area under the receiver‑operating characteristic curve, likelihood ratio test, Akaike\'s information criteria, continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Internal validation was assessed using the means of bootstrap method with 1000 bootstrapped samples.
Results
During a median follow-up of 30.72 months ((interquartile range, 26.13 to 35.07 months), 90 patients developed MACEs, more frequently in the patients with a higher TyG index. Multivariate Cox hazards regression analysis found that the TyG index, but not FBG was an independent predictor of MACEs (hazard ratio 1.6542; 95% CI 1.1555-2.3681; P = 0.006) in all types of ACS regardless of diabetes mellitus when included in the same model as GRACE score. Furthermore, Kaplan-Meier analysis revealed that the incidence of the primary endpoint rose with increasing TyG index tertiles (log-rank, P < 0.01). Adjustment the GRACE score by the TyG index improved the predictive ability for MACEs (increase in C-statistic value from 0.735 to 0.744; NRI, 0.282, 95% CI 0.028-0.426, P = 0.02; IDI, 0.019, 95% CI 0.004-0.046, P = 0.01). Likelihood ratio test showed that the TyG index significantly improved the prognostic ability of the GRACE score (χ2 = 12.37, 1 df; P < 0.001). The results remained consistent when the models were confirmed by internal bootstrap validation method.
Conclusion
The TyG index, but not FBG is an independent predictor of long-term MACEs after PCI in all types of ACS patients regardless of diabetes mellitus after adjusting for the GRACE score, and improves the ability of the GRACE score to stratify risk and predict prognosis of ACS patients undergoing PCI.

© 2022. The Author(s).

Cardiovasc Diabetol: 05 Aug 2022; 21:145
Xiong S, Chen Q, Chen X, Hou J, ... Zhang Z, Cai L
Cardiovasc Diabetol: 05 Aug 2022; 21:145 | PMID: 35932019
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Impact:
Abstract

Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts.

Marfella R, D\'Onofrio N, Mansueto G, Grimaldi V, ... Napoli C, Paolisso G
Background
High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control.
Objectives
We investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1-9, Ang 1-7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts.
Methods
We evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1-9, Ang 1-7, MasR, NAFT, and fibrosis.
Results
GlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1-9, Ang 1-7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression.
Conclusion
Poor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition.
Trial registration
https://clinicaltrials.gov/ NCT03546062.

© 2022. The Author(s).

Cardiovasc Diabetol: 05 Aug 2022; 21:146
Marfella R, D'Onofrio N, Mansueto G, Grimaldi V, ... Napoli C, Paolisso G
Cardiovasc Diabetol: 05 Aug 2022; 21:146 | PMID: 35932065
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Impact:
Abstract

Cardiovascular outcomes trials: a paradigm shift in the current management of type 2 diabetes.

Davies MJ, Drexel H, Jornayvaz FR, Pataky Z, Seferović PM, Wanner C
Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in patients with type 2 diabetes (T2D). Historical concerns about cardiovascular (CV) risks associated with certain glucose-lowering medications gave rise to the introduction of cardiovascular outcomes trials (CVOTs). Initially implemented to help monitor the CV safety of glucose-lowering drugs in patients with T2D, who either had established CVD or were at high risk of CVD, data that emerged from some of these trials started to show benefits. Alongside the anticipated CV safety of many of these agents, evidence for certain sodium-glucose transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have revealed potential cardioprotective effects in patients with T2D who are at high risk of CVD events. Reductions in 3-point major adverse CV events (3P-MACE) and CV death have been noted in some of these CVOTs, with additional benefits including reduced risks of hospitalisation for heart failure, progression of renal disease, and all-cause mortality. These new data are leading to a paradigm shift in the current management of T2D, with international guidelines now prioritising SGLT2 inhibitors and/or GLP-1 RAs in certain patient populations. However, clinicians are faced with a large volume of CVOT data when seeking to use this evidence base to bring opportunities to improve CV, heart failure and renal outcomes, and even reduce mortality, in their patients with T2D. The aim of this review is to provide an in-depth summary of CVOT data-crystallising the key findings, from safety to efficacy-and to offer a practical perspective for physicians. Finally, we discuss the next steps for the post-CVOT era, with ongoing studies that may further transform clinical practice and improve outcomes for people with T2D, heart failure or renal disease.

© 2022. The Author(s).

Cardiovasc Diabetol: 04 Aug 2022; 21:144
Davies MJ, Drexel H, Jornayvaz FR, Pataky Z, Seferović PM, Wanner C
Cardiovasc Diabetol: 04 Aug 2022; 21:144 | PMID: 35927730
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Impact:
Abstract

Triglyceride-glucose index in the prediction of adverse cardiovascular events in patients with premature coronary artery disease: a retrospective cohort study.

Wu Z, Liu L, Wang W, Cui H, ... Zheng T, Yang J
Background
Premature coronary artery disease (PCAD) has become more common in recent years and is often associated with poor outcomes. Triglyceride-glucose (TyG) index is a simple and reliable surrogate for insulin resistance (IR) and is an independent predictor of cardiovascular prognosis. However, the prognostic value of the TyG index in patients with PCAD remains uncertain. Thus, this study aimed to investigate the prognostic value and predictive performance of the TyG index in patients with PCAD.
Methods
A total of 526 young subjects (male < 45 years, female < 55 years) with angiographically proven CAD from January 2013 to December 2018 were included consecutively in this study. Their clinical and laboratory parameters were collected, and the TyG index was calculated as [Formula: see text]. The follow-up time after discharge was 40-112 months (median, 68 months; interquartile range, 49‒83 months). The primary endpoint was the occurrence of the major adverse cardiovascular events (MACE), defined as the composite of all-cause death, non-fatal myocardial infarction (MI), coronary artery revascularization, and non-fatal stroke.
Results
The TyG index was significantly associated with traditional cardiovascular risk factors and the Gensini score (GS). Kaplan-Meier survival (MACE-free) curves by tertiles of the TyG index showed statistically significant differences (log-rank test, p = 0.001). In the fully adjusted Cox regression model, the Hazard ratio (95% CI) of MACE was 2.17 (1.15-4.06) in tertile 3 and 1.45 (1.11-1.91) for per SD increase in the TyG index. Time-dependent ROC analyses of the TyG for prediction of MACE showed the area under the curves (AUC) reached 0.631 at 3 years, 0.643 at 6 years, and 0.710 at 9 years. Furthermore, adding TyG index to existing risk prediction model could improve outcome prediction [C-statistic increased from 0.715 to 0.719, p = 0.007; continuous net reclassification improvement (NRI) = 0.101, p = 0.362; integrated discrimination improvement (IDI) = 0.011, p = 0.017].
Conclusion
The TyG index is an independent predictor of MACE in patients with PCAD, suggesting that the TyG index has important clinical implications for risk stratification and early intervention of PCAD.

© 2022. The Author(s).

Cardiovasc Diabetol: 29 Jul 2022; 21:142
Wu Z, Liu L, Wang W, Cui H, ... Zheng T, Yang J
Cardiovasc Diabetol: 29 Jul 2022; 21:142 | PMID: 35906587
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Impact:
Abstract

Influence of diabetes on mortality and ICD therapies in ICD recipients: a systematic review and meta-analysis of 162,780 patients.

Liu H, Hu J, Zhuo W, Wan R, Hong K
Background
The influence of diabetes on the mortality and risk of implantable cardioverter defibrillator (ICD) therapies is still controversial, and a comprehensive assessment is lacking. We performed this systematic review and meta-analysis to address this controversy.
Methods
We systematically searched the PubMed, Embase, Web of Science and Cochrane Library databases to collect relevant literature. Fixed and random effects models were used to estimate the hazard ratio (HR) with 95% CIs.
Results
Thirty-six articles reporting on 162,780 ICD recipients were included in this analysis. Compared with nondiabetic ICD recipients, diabetic ICD recipients had higher all-cause mortality (HR = 1.45, 95% CI 1.36-1.55). The subgroup analysis showed that secondary prevention patients with diabetes may suffer a higher risk of all-cause mortality (HR = 1.89, 95% CI 1.56-2.28) (for subgroup analysis, P = 0.03). Cardiac mortality was also higher in ICD recipients with diabetes (HR = 1.68, 95% CI 1.35-2.08). However, diabetes had no significant effect on the risks of ICD therapies, including appropriate or inappropriate therapy, appropriate or inappropriate shock and appropriate anti-tachycardia pacing (ATP). Diabetes was associated with a decreased risk of inappropriate ATP (HR = 0.56, 95% CI 0.39-0.79).
Conclusion
Diabetes is associated with an increased risk of mortality in ICD recipients, especially in the secondary prevention patients, but does not significantly influence the risks of ICD therapies, indicating that the increased mortality of ICD recipients with diabetes may not be caused by arrhythmias. The survival benefits of ICD treatment in diabetes patients are limited.

© 2022. The Author(s).

Cardiovasc Diabetol: 29 Jul 2022; 21:143
Liu H, Hu J, Zhuo W, Wan R, Hong K
Cardiovasc Diabetol: 29 Jul 2022; 21:143 | PMID: 35906611
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Impact:
Abstract

Triglyceride-glucose index trajectory and stroke incidence in patients with hypertension: a prospective cohort study.

Huang Z, Ding X, Yue Q, Wang X, ... Wu S, Chen Y
Background
It has been suggested that the baseline triglyceride-glucose (TyG) index, a simple surrogate measure for insulin resistance, is significantly associated with the occurrence of stroke. Nevertheless, the impact of longitudinal patterns of TyG on the stroke risk in hypertensive patients is still unknown. Hence, this study aimed to investigate the association between TyG index trajectory and stroke risk among hypertensive patients.
Methods
This prospective study included 19,924 hypertensive patients from the Kailuan Study who underwent three waves survey and were free of myocardial infarction, cancer and stroke before or during 2010. The TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting plasma glucose (mg/dL)/2], and latent mixed modelling was used to identify the trajectory of TyG during the exposure period (2006-2010). Furthermore, the Cox proportional hazard models were applied to estimate the hazard ratio (HR) and 95% confidence interval (CI) for incident stroke of different trajectory groups.
Results
Five distinct TyG trajectory were identified during 2006-2010: low-stable (n = 2483; range, 8.03-8.06), moderate low-stable (n = 9666; range, 8.58-8.57), moderate high-stable (n = 5759; range, 9.16-9.09), elevated-stable (n = 1741; range, 9.79-9.75), and elevated-increasing (n = 275; range, 10.38-10.81). During the median follow-up of 9.97 years, 1,519 cases of incident stroke were identified, including 1,351 with ischemic stroke and 215 with hemorrhage stroke. After adjusting for confounding variables, the HR and 95% CI of stroke were 2.21 (1.49,3.28) for the elevated-increasing group, 1.43 (1.13,1.83) for the elevated-stable group, 1.35 (1.10,1.64) for the moderate high-stable group, 1.26 (1.06,1.52) for the moderate low-stable group, respectively, when compare with the low-stable group. Similar results were observed in ischemic stroke, but a significant association was not found between TyG trajectory and risk of hemorrhage stroke.
Conclusion
A long-term elevated TyG index in hypertensive patients is associated with an increased risk of stroke, especially ischemic stroke. This finding implies that regular monitoring of TyG index may assist in identifying individuals at a higher risk of stroke among patients with hypertension.

© 2022. The Author(s).

Cardiovasc Diabetol: 27 Jul 2022; 21:141
Huang Z, Ding X, Yue Q, Wang X, ... Wu S, Chen Y
Cardiovasc Diabetol: 27 Jul 2022; 21:141 | PMID: 35897017
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Impact:
Abstract

Association of stress induced hyperglycemia with angiographic findings and clinical outcomes in patients with ST-elevation myocardial infarction.

Stalikas N, Papazoglou AS, Karagiannidis E, Panteris E, ... Sianos G, Giannakoulas G
Background
Stress induced hyperglycemia (SIH) is common among patients with ST-elevation myocardial infarction (STEMI), even in patients without diabetes mellitus. However, evidence regarding its role on the angiographic outcomes and the prognosis of patients presenting with STEMI is scarce.
Methods
This study included 309 consecutively enrolled STEMI patients undergoing primary percutaneous coronary intervention (pPCI). Patients were diagnosed with SIH if blood glucose on admission was > 140 mg/dl. Also, patients had to fast for at least 8 hours before blood sampling. The objective was to assess whether SIH was associated with major adverse cardiovascular and cerebrovascular (MACCE) events and explore its relationship with angiographic predictors of worse prognosis such as poor initial TIMI flow, intracoronary thrombus burden, distal embolization, and presence of residual thrombus after pPCI.
Results
SIH in diabetic and non-diabetic patients was associated with a higher incidence of LTB (aOR = 2.171, 95% CI 1.27-3.71), distal embolization (aOR = 2.71, 95% CI 1.51-4.86), and pre-procedural TIMI flow grade = 0 (aOR = 2.69, 95% CI 1.43-5.04) after adjusting for relevant clinical variables. Importantly, during a median follow-up of 1.7 years STEMI patients with SIH with or without diabetes experienced increased occurrence of MACCE both in univariate (HR = 1.92, 95% CI 1.19-3.01) and multivariate analysis (aHR = 1.802, 95% CI 1.01-3.21).
Conclusions
SIH in STEMI patients with or without diabetes was independently associated with increased MACCE. This could be attributed to the fact that SIH was strongly correlated with poor pre-procedural TIMI flow, LTB, and distal embolization. Large clinical trials need to validate SIH as an independent predictor of adverse angiographic and clinical outcomes to provide optimal individualized care for patients with STEMI.

© 2022. The Author(s).

Cardiovasc Diabetol: 26 Jul 2022; 21:140
Stalikas N, Papazoglou AS, Karagiannidis E, Panteris E, ... Sianos G, Giannakoulas G
Cardiovasc Diabetol: 26 Jul 2022; 21:140 | PMID: 35883091
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Impact:
Abstract

Effect of sodium-glucose cotransporter-2 inhibitors on blood pressure in patients with heart failure: a systematic review and meta-analysis.

Li M, Yi T, Fan F, Qiu L, ... Zhang Y, Huo Y
Background
Recent studies have shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) can achieve significant improvement in blood pressure in people with diabetes. Furthermore, randomized controlled trials (RCTs) have established that SGLT2i have a cardioprotective effect in adults with heart failure (HF). Therefore, we performed this systematic review an meta-analysis to determine the effect of SGLT2i on blood pressure in patients with HF.
Methods
We used the Medline, Cochrane Library, Embase, and PubMed databases to identify RCTs (published through to April 29, 2022) that evaluated the effect of SGLT2i on HF. The primary endpoint was defined as change in blood pressure. Secondary composite outcomes were heart rate, hematocrit, body weight, and glycated hemoglobin. The N-terminal pro-brain natriuretic peptide level, Kansas City Cardiomyopathy Questionnaire scores, and estimated glomerular filtration rate were also evaluated.
Results
After a literature search and detailed evaluation, 16 RCTs were included in the quantitative analysis. Pooled analyses showed that SGLT2i were associated with a statistically significant reduction in systolic blood pressure of 1.68 mmHg (95% confidence interval [CI] - 2.7, - 0.66; P = 0.001; I2 = 45%) but not diastolic blood pressure (mean difference [MD] -1.06 mmHg; 95% CI -3.20, 1.08; P = 0.33; I2 = 43%) in comparison with controls. Furthermore, SGLT2i decreased body weight (MD - 1.36 kg, 95% CI - 1.68, - 1.03; P < 0.001; I2 = 61%) and the glycated hemoglobin level (MD - 0.16%, 95% CI - 0.28, -0.04, P = 0.007; I2 = 91%) but increased hematocrit (MD 1.63%, 95% CI 0.63, 2.62, P = 0.001; I2 = 100%). There was no significant between-group difference in heart rate (MD - 0.35; 95% CI - 2.05, 1.35, P = 0.69; I2 = 0).
Conclusions
SGLT2i decreased systolic blood pressure in patients with HF but had no effect on diastolic blood pressure. These inhibitors may have numerous potentially beneficial clinical effects in patients with HF.

© 2022. The Author(s).

Cardiovasc Diabetol: 25 Jul 2022; 21:139
Li M, Yi T, Fan F, Qiu L, ... Zhang Y, Huo Y
Cardiovasc Diabetol: 25 Jul 2022; 21:139 | PMID: 35879763
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Impact:
Abstract

Effect of acute ketosis on lipid profile in prediabetes: findings from a cross-over randomized controlled trial.

Liu Y, Bharmal SH, Kimita W, Petrov MS
Background
Ketone monoester β-hydroxybutyrate (KEβHB) ingestion has emerged as an effective method of inducing acute ketosis. Although evidence suggests that KEβHB can offer several therapeutic benefits, whether KEβHB affects lipid profile is still unknown.
Aims
The primary aim was to study the effect of KEβHB on plasma lipid profile in individuals with prediabetes. The secondary aim was to investigate the role of saturated fat intake in that effect.
Methods
This study was a randomized controlled trial with cross-over design. Following an overnight fast, 18 adults (six women and 12 men) with prediabetes (diagnosed based on the American Diabetes Association criteria) ingested a single dose of KEβHB drink or placebo drink. Blood samples were collected every 30 min, from baseline to 150 min. Outcome variables included changes in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, remnant cholesterol, triglycerides, and the triglycerides to HDL cholesterol ratio. The area under the curve (AUC) over 150 min was calculated for each outcome following ingestion of the drinks. Habitual saturated fat intake was ascertained using the EPIC-Norfolk food frequency questionnaire.
Results
Significant elevation of blood β-hydroxybutyrate from 0.2 mmol/L to 3.5 mmol/L (p < 0.001) was achieved within 30 min. Acute ketosis resulted in significantly lower AUCs for remnant cholesterol (p = 0.022) and triglycerides (p = 0.022). No statistically significant differences in the AUCs for total cholesterol, HDL cholesterol, LDL cholesterol, and the triglycerides to HDL cholesterol ratio were found. The changes in remnant cholesterol and triglycerides were statistically significant in individuals with high, but not low, habitual saturated fat intake.
Conclusion
Acute ketosis had no untoward effect on plasma lipid profile. Moreover, it led to significantly reduced circulating levels of remnant cholesterol and triglycerides. This paves the way for investigating whether exogenous ketone supplementation reduces cardiovascular disease risk (via its actions on triglyceride-rich lipoproteins) in at-risk populations.  Trial registration: ClinicalTrials.gov, NCT03889210.

© 2022. The Author(s).

Cardiovasc Diabetol: 23 Jul 2022; 21:138
Liu Y, Bharmal SH, Kimita W, Petrov MS
Cardiovasc Diabetol: 23 Jul 2022; 21:138 | PMID: 35871064
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Impact:
Abstract

Association between triglyceride-glucose index and carotid atherosclerosis detected by ultrasonography.

Li W, Chen D, Tao Y, Lu Z, Wang D
Background
Several previous studies have indicated that the triglyceride-glucose index (TyG) index is associated with carotid atherosclerosis (CA); however, the evidence of the association is limited and inconsistent, which may result from small sample sizes or differences in study populations. Therefore, we examined the relation between the TyG index and CA in a large general population of Chinese middle-aged and elderly population.
Methods
A total of 59,123 middle-aged and elderly participants were enrolled. The TyG index was calculated as ln[fasting triglycerides (mg/dL)×fasting glucose (mg/dL)/2]. Logistic regression models were used to analyze the relationship between the TyG index as continuous variables and quartiles and CA. The relationships between the TyG index and CA according to sex, age groups, blood pressure groups and body mass index groups were also assessed.
Results
The multivariate logistic regression analysis showed that the TyG index was significantly associated with the prevalence of CA (OR: 1.48; 95% CI 1.39-1.56), carotid intima-media thickness (CMT) (1.55; 1.45-1.67), plaques (1.38; 1.30-1.47) and stenosis severity (> 50%) (1.33; 1.14-1.56). Compared with the quartile 1, quartile 4 was significantly associated with a higher prevalence of CA (1.59; 1.45-1.75), CMT (1.93; 1.82-2.18), plaques (1.36; 1.22-1.51) and stenosis severity (> 50%) (1.56; 1.20-2.04). Subgroup analyses showed significant associations between the continuous TyG index and the prevalence of CA, CMT, plaques and stenosis severity (> 50%) according to sex, with a higher prevalence of CA, CMT, and plaques among males, while a higher prevalence of stenosis severity in females (> 50%). For participants aged < 60 years old and with hypertension, the relationship between the TyG index and stenosis severity (> 50%) was not observed (1.47; 0.97-2.22 and 1.13; 0.91-1.41). For body mass index (BMI), the association was just observed among overweight participants (1.48; 1.17-1.86). In addition, similar results were also observed when the TyG index was used as a categorical variable.
Conclusions
There is a positive association between the TyG index and CA. The association is higher in males and middle-aged individuals than those in females and elderly individuals. Besides, the relationship is stronger among individuals with normal blood pressure and underweight subjects.

© 2022. The Author(s).

Cardiovasc Diabetol: 21 Jul 2022; 21:137
Li W, Chen D, Tao Y, Lu Z, Wang D
Cardiovasc Diabetol: 21 Jul 2022; 21:137 | PMID: 35864527
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Abstract

Proteomic analysis of cardiometabolic biomarkers and predictive modeling of severe outcomes in patients hospitalized with COVID-19.

Schroeder PH, Brenner LN, Kaur V, Cromer SJ, ... Mercader JM, Leong A
Background
The high heterogeneity in the symptoms and severity of COVID-19 makes it challenging to identify high-risk patients early in the disease. Cardiometabolic comorbidities have shown strong associations with COVID-19 severity in epidemiologic studies. Cardiometabolic protein biomarkers, therefore, may provide predictive insight regarding which patients are most susceptible to severe illness from COVID-19.
Methods
In plasma samples collected from 343 patients hospitalized with COVID-19 during the first wave of the pandemic, we measured 92 circulating protein biomarkers previously implicated in cardiometabolic disease. We performed proteomic analysis and developed predictive models for severe outcomes. We then used these models to predict the outcomes of out-of-sample patients hospitalized with COVID-19 later in the surge (N = 194).
Results
We identified a set of seven protein biomarkers predictive of admission to the intensive care unit and/or death (ICU/death) within 28 days of presentation to care. Two of the biomarkers, ADAMTS13 and VEGFD, were associated with a lower risk of ICU/death. The remaining biomarkers, ACE2, IL-1RA, IL6, KIM1, and CTSL1, were associated with higher risk. When used to predict the outcomes of the future, out-of-sample patients, the predictive models built with these protein biomarkers outperformed all models built from standard clinical data, including known COVID-19 risk factors.
Conclusions
These findings suggest that proteomic profiling can inform the early clinical impression of a patient\'s likelihood of developing severe COVID-19 outcomes and, ultimately, accelerate the recognition and treatment of high-risk patients.

© 2022. The Author(s).

Cardiovasc Diabetol: 21 Jul 2022; 21:136
Schroeder PH, Brenner LN, Kaur V, Cromer SJ, ... Mercader JM, Leong A
Cardiovasc Diabetol: 21 Jul 2022; 21:136 | PMID: 35864532
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Impact:
Abstract

Multi-dimensional characterization of prediabetes in the Project Baseline Health Study.

Chatterjee R, Kwee LC, Pagidipati N, Koweek LH, ... Shah SH, Project Baseline Health Study
Background
We examined multi-dimensional clinical and laboratory data in participants with normoglycemia, prediabetes, and diabetes to identify characteristics of prediabetes and predictors of progression from prediabetes to diabetes or reversion to no diabetes.
Methods
The Project Baseline Health Study (PBHS) is a multi-site prospective cohort study of 2502 adults that conducted deep clinical phenotyping through imaging, laboratory tests, clinical assessments, medical history, personal devices, and surveys. Participants were classified by diabetes status (diabetes [DM], prediabetes [preDM], or no diabetes [noDM]) at each visit based on glucose, HbA1c, medications, and self-report. Principal component analysis (PCA) was performed to create factors that were compared across groups cross-sectionally using linear models. Logistic regression was used to identify factors associated with progression from preDM to DM and for reversion from preDM to noDM.
Results
At enrollment, 1605 participants had noDM; 544 had preDM; and 352 had DM. Over 4 years of follow-up, 52 participants with preDM developed DM and 153 participants reverted to noDM. PCA identified 33 factors composed of clusters of clinical variables; these were tested along with eight individual variables identified a priori as being of interest. Six PCA factors and six a priori variables significantly differed between noDM and both preDM and DM after false discovery rate adjustment for multiple comparisons (q < 0.05). Of these, two factors (one comprising glucose measures and one of anthropometry and physical function) demonstrated monotonic/graded relationships across the groups, as did three a priori variables: ASCVD risk, coronary artery calcium, and triglycerides (q < 10-21 for all). Four factors were significantly different between preDM and noDM, but concordant or similar between DM and preDM: red blood cell indices (q = 8 × 10-10), lung function (q = 2 × 10-6), risks of chronic diseases (q = 7 × 10-4), and cardiac function (q = 0.001), along with a priori variables of diastolic function (q = 1 × 10-10), sleep efficiency (q = 9 × 10-6) and sleep time (q = 6 × 10-5). Two factors were associated with progression from prediabetes to DM: anthropometry and physical function (OR [95% CI]: 0.6 [0.5, 0.9], q = 0.04), and heart failure and c-reactive protein (OR [95% CI]: 1.4 [1.1, 1.7], q = 0.02). The anthropometry and physical function factor was also associated with reversion from prediabetes to noDM: (OR [95% CI]: 1.9 [1.4, 2.7], q = 0.02) along with a factor of white blood cell indices (OR [95% CI]: 0.6 [0.4, 0.8], q = 0.02), and the a priori variables ASCVD risk score (OR [95% CI]: 0.7 [0.6, 0.9] for each 0.1 increase in ASCVD score, q = 0.02) and triglycerides (OR [95% CI]: 0.9 [0.8, 1.0] for each 25 mg/dl increase, q = 0.05).
Conclusions
PBHS participants with preDM demonstrated pathophysiologic changes in cardiac, pulmonary, and hematology measures and declines in physical function and sleep measures that precede DM; some changes predicted an increased risk of progression to DM. A factor with measures of anthropometry and physical function was the most important factor associated with progression to DM and reversion to noDM. Future studies may determine whether these changes elucidate pathways of progression to DM and related complications and whether they can be used to identify individuals at higher risk of progression to DM for targeted preventive interventions. Trial registration ClinicalTrials.gov NCT03154346.

© 2022. The Author(s).

Cardiovasc Diabetol: 18 Jul 2022; 21:134
Chatterjee R, Kwee LC, Pagidipati N, Koweek LH, ... Shah SH, Project Baseline Health Study
Cardiovasc Diabetol: 18 Jul 2022; 21:134 | PMID: 35850765
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Abstract

Circulating metabolites and molecular lipid species are associated with future cardiovascular morbidity and mortality in type 1 diabetes.

Ferreira-Divino LF, Suvitaival T, Rotbain Curovic V, Tofte N, ... Legido-Quigley C, Rossing P
Background
Cardiovascular disease remains the leading cause of mortality in individuals with diabetes and improved understanding of its pathophysiology is needed. We investigated the association of a large panel of metabolites and molecular lipid species with future cardiovascular events in type 1 diabetes.
Methods
The study included 669 individuals with type 1 diabetes. Non-targeted serum metabolomics and lipidomics analyses were performed using mass spectrometry. Data on cardiovascular events (cardiovascular mortality, coronary artery disease, stroke, and peripheral arterial interventions) were obtained from Danish Health registries and analyzed by Cox hazards models. Metabolites and molecular lipid species were analyzed in univariate models adjusted for false discovery rate (FDR). Metabolites and molecular lipid species fulfilling a pFDR < 0.05 were subsequently analyzed in adjusted models including age, sex, hemoglobin A1c, mean arterial pressure, smoking, body mass index, low-density lipoprotein cholesterol, estimated glomerular filtration rate, urinary albumin excretion rate and previous cardiovascular disease. Analyses of molecular lipid species were further adjusted for triglycerides and statin use.
Results
Of the included participants, 55% were male and mean age was 55 ± 13 years. Higher 4-hydroxyphenylacetic acid (HR 1.35, CI [1.01-1.80], p = 0.04) and lower threonine (HR 0.81, CI [0.67-0.98] p = 0.03) were associated with development of cardiovascular events (n = 95). In lipidomics analysis, higher levels of three different species, diacyl-phosphatidylcholines (PC)(36:2) (HR 0.82, CI [0.70-0.98], p = 0.02), alkyl-acyl-phosphatidylcholines (PC-O)(34:2) (HR 0.76, CI [0.59-0.98], p = 0.03) and (PC-O)(34:3) (HR 0.75, CI [0.58-0.97], p = 0.03), correlated with lower risk of cardiovascular events, whereas higher sphingomyelin (SM)(34:1) (HR 1.32, CI [1.04-1.68], p = 0.02), was associated with an increased risk.
Conclusions
Circulating metabolites and molecular lipid species were associated with future cardiovascular events in type 1 diabetes. While the causal effect of these biomolecules on the cardiovascular system remains unknown, our findings support that omics-based technologies, although still in an early phase, may have the potential to unravel new pathways and biomarkers in the field of cardiovascular disease in type 1 diabetes.

© 2022. The Author(s).

Cardiovasc Diabetol: 18 Jul 2022; 21:135
Ferreira-Divino LF, Suvitaival T, Rotbain Curovic V, Tofte N, ... Legido-Quigley C, Rossing P
Cardiovasc Diabetol: 18 Jul 2022; 21:135 | PMID: 35850688
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Abstract

Associations between glycated hemoglobin and the risks of incident cardiovascular diseases in patients with gout.

Li L, Lip GYH, Li S, Adachi JD, Thabane L, Li G
Background
Evidence for the relationship between glycated hemoglobin (HbA1c) levels and risk of cardiovascular diseases (CVD) in patients with gout remained sparse and limited. This study aims to explore the associations between HbA1c levels and risks of incident CVD in patients with gout.
Methods
We included patients with gout who had an HbA1c measurement at baseline from the UK Biobank. CVD events were identified from through medical and death records. We used multivariable Cox proportional hazards model with a restricted cubic spline to assess the potential non-linear effect of HbA1c on CVD risk.
Results
We included a total of 6,685 patients (mean age 59.7; 8.1% females) with gout for analyses. During a mean follow-up of 7.3 years, there were 1,095 CVD events documented with an incidence of 2.26 events per 100 person-years (95% confidence interval [CI]: 2.13-2.40). A quasi J-shaped association between HbA1c and risk of CVD was observed, with the potentially lowest risk found at the HbA1c of approximately 5.0% (hazard ratio [HR] = 0.65, 95% CI: 0.53-0.81). When compared with the HbAlc level of 7%, a significantly decreased risk of CVD was found from 5.0 to 6.5%, while an increased risk was observed at 7.5% (HR = 1.05) and 8.0% (HR = 1.09). Subgroup analyses yielded similar results to the main findings in general.
Conclusions
Based on data from a nationwide, prospective, population-based cohort, we found a quasi J-shaped relationship between HbA1c and risk of CVD in patients with gout. More high-quality evidence is needed to further clarify the relationship between HbA1c and CVD risk in patients with gout.

© 2022. The Author(s).

Cardiovasc Diabetol: 15 Jul 2022; 21:133
Li L, Lip GYH, Li S, Adachi JD, Thabane L, Li G
Cardiovasc Diabetol: 15 Jul 2022; 21:133 | PMID: 35841094
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Abstract

Modest effect of statins on fasting glucose in a longitudinal electronic health record based cohort.

Haldar T, Oni-Orisan A, Hoffmann TJ, Schaefer C, ... Medina MW, Risch N
Background
Prior studies of the glycemic effect of statins have been inconsistent. Also, most studies have only considered a short duration of statin use; the effect of long-term statin use on fasting glucose (FG) has not been well examined. The aim of this work is to investigate the effect of long-term statin exposure on FG levels.
Methods
Using electronic health record (EHR) data from a large and diverse longitudinal cohort, we defined long-term statin exposure in two ways: the cumulative years of statin use (cumulative supply) and the years\' supply-weighted sum of doses (cumulative dose). Simvastatin, lovastatin, atorvastatin and pravastatin were included in the analysis. The relationship between statin exposure and FG was examined using linear regression with mixed effects modeling, comparing statin users before and after initiating statins and statin never-users.
Results
We examined 593,130 FG measurements from 87,151 individuals over a median follow up of 20 years. Of these, 42,678 were never-users and 44,473 were statin users with a total of 730,031 statin prescriptions. FG was positively associated with cumulative supply of statin but not comulative dose when both measures were in the same model. While statistically significant, the annual increase in FG attributable to statin exposure was modest at only 0.14 mg/dl, with only slight and non-significant differences among statin types.
Conclusions
Elevation in FG level is associated with statin exposure, but the effect is modest. The results suggest that the risk of a clinically significant increase in FG attributable to long-term statin use is small for most individuals.

© 2022. The Author(s).

Cardiovasc Diabetol: 14 Jul 2022; 21:132
Haldar T, Oni-Orisan A, Hoffmann TJ, Schaefer C, ... Medina MW, Risch N
Cardiovasc Diabetol: 14 Jul 2022; 21:132 | PMID: 35836181
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Abstract

Polygenic risk for type 2 diabetes, lifestyle, metabolic health, and cardiovascular disease: a prospective UK Biobank study.

Yun JS, Jung SH, Shivakumar M, Xiao B, ... Won HH, Kim D
Background
Few studies have examined associations between genetic risk for type 2 diabetes (T2D), lifestyle, clinical risk factors, and cardiovascular disease (CVD). We aimed to investigate the association of and potential interactions among genetic risk for T2D, lifestyle behavior, and metabolic risk factors with CVD.
Methods
A total of 345,217 unrelated participants of white British descent were included in analyses. Genetic risk for T2D was estimated as a genome-wide polygenic risk score constructed from > 6 million genetic variants. A favorable lifestyle was defined in terms of four modifiable lifestyle components, and metabolic health status was determined according to the presence of metabolic syndrome components.
Results
During a median follow-up of 8.9 years, 21,865 CVD cases (6.3%) were identified. Compared with the low genetic risk group, participants at high genetic risk for T2D had higher rates of overall CVD events, CVD subtypes (coronary artery disease, peripheral artery disease, heart failure, and atrial fibrillation/flutter), and CVD mortality. Individuals at very high genetic risk for T2D had a 35% higher risk of CVD than those with low genetic risk (HR 1.35 [95% CI 1.19 to 1.53]). A significant gradient of increased CVD risk was observed across genetic risk, lifestyle, and metabolic health status (P for trend > 0.001). Those with favorable lifestyle and metabolically healthy status had significantly reduced risk of CVD events regardless of T2D genetic risk. This risk reduction was more apparent in young participants (≤ 50 years).
Conclusions
Genetic risk for T2D was associated with increased risks of overall CVD, various CVD subtypes, and fatal CVD. Engaging in a healthy lifestyle and maintaining metabolic health may reduce subsequent risk of CVD regardless of genetic risk for T2D.

© 2022. The Author(s).

Cardiovasc Diabetol: 14 Jul 2022; 21:131
Yun JS, Jung SH, Shivakumar M, Xiao B, ... Won HH, Kim D
Cardiovasc Diabetol: 14 Jul 2022; 21:131 | PMID: 35836215
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Abstract

Improvement in insulin sensitivity and prevention of high fat diet-induced liver pathology using a CXCR2 antagonist.

Phillips BE, Lantier L, Engman C, Garciafigueroa Y, ... Wasserman D, Giannoukakis N
Background
Liver pathology (LP) characteristic of non-alcoholic fatty acid disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is a prevalent co-morbidity of type 2 diabetes (T2D). Accumulating evidence indicates that neutrophils driving insulin resistance (IR), including hepatic IR, precipitate T2D-associated NAFLD/NASH. We hypothesized that targeting neutrophil accumulation into insulin-sensitive tissues in mice using a CXCR2 antagonist under T2D-precipitating high fat diet (HFD) could improve insulin sensitivity and prevent the progression towards liver pathology reminiscent of NAFLD/NASH.
Methods
Mice were age-matched and on standard rodent chow prior to 1:1 randomization into control and HFD formulated with the CXCR2 antagonist AZD5069 or with biologically inactive substitute. They were monitored for metabolic changes including insulin sensitivity using the hyperinsulinemic-euglycemic clamp and hepatic histopathologic evaluation in H&E-stained sections as well as via immunofluorescence microscopy of liver sections for leukocyte markers, collagen 1A1 formation, α-smooth muscle actin (SMA), and galectin-3 expression, for 16 weeks. Statistical tests used to determine significant differences among study groups and outcomes include Student\'s t-test, one-way ANOVA, repeated measures two-way ANOVA, and Fisher\'s exact test, depending on the analytical question.
Results
Compared to mice on HFD, mice in the AZD5069-formulated HFD exhibited improved insulin sensitivity, a modest reduction in weight gain, and a significant improvement in LP and markers related to NAFLD/NASH. Mice in the AZD5069-formulated HFD also exhibited reduced neutrophil accumulation into the liver at the end of the 16 week study period.
Conclusions
These results show, for the first time, the effectiveness of a selective CXCR2 antagonist to improve insulin sensitivity, concomitantly preventing the progression towards LP characteristic of NAFLD/NASH. This represents a novel approach to target IR and developing LP under T2D-susceptible conditions using a single agent. Furthermore, our data extend the growing evidence in support of neutrophils as a leukocyte population that imprints and maintains a chronic inflammatory state in the progression of dysregulated metabolism in liver-specific co-morbid conditions.

© 2022. The Author(s).

Cardiovasc Diabetol: 12 Jul 2022; 21:130
Phillips BE, Lantier L, Engman C, Garciafigueroa Y, ... Wasserman D, Giannoukakis N
Cardiovasc Diabetol: 12 Jul 2022; 21:130 | PMID: 35831885
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Abstract

Mannose-binding lectin does not explain the dismal prognosis after an acute coronary event in dysglycaemic patients. A report from the GAMI cohort.

Meziani S, Ferrannini G, Bjerre M, Hansen TK, ... Rydén L, Mellbin LG
Background
Mannose binding lectin (MBL) has been suggested to be associated with an impaired cardiovascular prognosis in dysglycaemic conditions, but results are still contrasting. Our aims are (i) to examine whether MBL levels differ between patients with an acute myocardial infarction (MI) and healthy controls and between subgroups with different glucose tolerance status, and (ii) to investigate the relation between MBL and future cardiovascular events.
Methods
MBL levels were assessed at discharge and after 3 months in 161 AMI patients without any previously known glucose perturbations and in 183 age- and gender-matched controls from the Glucose metabolism in patients with Acute Myocardial Infarction (GAMI) study. Participants were classified as having dysglycaemia, i.e. type 2 diabetes or impaired glucose tolerance, or not by an oral glucose tolerance test. The primary outcome was a composite of cardiovascular events comprising cardiovascular death, AMI, stroke or severe heart failure during 11 years of follow-up. Total and cardiovascular mortality served as secondary outcomes.
Results
At hospital discharge patients had higher MBL levels (median 1246 μg/L) than three months later (median 575 μg/L; p < 0.01), the latter did not significantly differ from those in the controls (801 μg/L; p = 0.47). MBL levels were not affected by dysglycaemia either in patients or controls. Independent of glycaemic state, increasing MBL levels did not predict any of the studied outcomes in patients. In unadjusted analyses increasing MBL levels predicted cardiovascular events (hazard ratio HR: 1.67, 95% confidence interval CI 1.06-2.64) and total mortality (HR 1.53, 95% CI 1.12-2.10) in the control group. However, this did not remain in adjusted analyses.
Conclusions
Patients had higher MBL levels than controls during the hospital phase of AMI, supporting the assumption that elevated MBL reflects acute stress. MBL was not found to be independently associated with cardiovascular prognosis in patients with AMI regardless of glucose state.

© 2022. The Author(s).

Cardiovasc Diabetol: 08 Jul 2022; 21:129
Meziani S, Ferrannini G, Bjerre M, Hansen TK, ... Rydén L, Mellbin LG
Cardiovasc Diabetol: 08 Jul 2022; 21:129 | PMID: 35804351
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Impact:
Abstract

Triglyceride-glucose index linked to all-cause mortality in critically ill patients: a cohort of 3026 patients.

Liao Y, Zhang R, Shi S, Zhao Y, ... Chen K, Fang Y
Background
Triglyceride-glucose (TyG) index as a reliable surrogate of insulin resistance (IR) has been shown to be related to adverse clinical outcomes in patients with acute coronary syndrome, heart failure, ischemic stroke and so on. However, the relationship between TyG index and all-cause mortality in intensive care unit (ICU) patients remains unknown. The purpose of this study was to investigate the correlation between TyG index and all-cause mortality to evaluate the impact of IR on the prognosis of this population.
Methods
This was a retrospective observational study that included 3026 patients who had an initial triglyceride and glucose data on the first day of ICU admission, and all data were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. These patients were grouped into quartiles (Q1-Q4) according to TyG index. The Kaplan-Meier analysis was used to compare all-cause mortality among the above four groups. Cox proportional hazards analyses were performed to examine the association between TyG index and all-cause mortality.
Results
During 10.46 years of follow-up, 1148 (37.9%) patients died, of which 350 (11.6%) occurred during the hospital stay and 258 (8.5%) occurred during the ICU stay. Kaplan-Meier analysis showed that the risk of all-cause mortality was significantly higher in patients with higher TyG index (log-rank P = 0.021). Multivariable Cox proportional hazards analyses showed that the TyG index was an independent risk predictor of ICU death (HR: 1.72, 95% CI 1.18-2.52, P = 0.005) and hospital death (HR: 2.19, 95% CI 1.59-3.03, P < 0.001), and each 1-unit increased in the TyG index, a 1.19-fold increase in the risk of death during the hospital stay.
Conclusions
TyG index is strongly related to the all-cause mortality increasing in critically ill patients. This finding indicates that the TyG index might be useful in identifying people at high risk of ICU death and hospital death.

© 2022. The Author(s).

Cardiovasc Diabetol: 08 Jul 2022; 21:128
Liao Y, Zhang R, Shi S, Zhao Y, ... Chen K, Fang Y
Cardiovasc Diabetol: 08 Jul 2022; 21:128 | PMID: 35804386
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Impact:
Abstract

Liver function markers predict cardiovascular and renal outcomes in the CANVAS Program.

Ferrannini G, Rosenthal N, Hansen MK, Ferrannini E
Background
Raised liver function tests (LFTs) have been correlated with multiple metabolic abnormalities and variably associated with cardiorenal outcomes. We sought to systematically test the relationship between LFT levels within the accepted range and major cardiorenal outcomes in a large clinical trial in type 2 diabetes, and the possible impact of placebo-controlled canagliflozin treatment.
Methods
We measured serum alanine aminotransferase (ALT), aspartic aminotransferase (AST), gamma-glutamyl transferase (γGT), alkaline phosphatase (ALP), and bilirubin concentrations in 10,142 patients, at baseline and repeatedly over follow-up. The relation of LFTs to first hospitalized heart failure (HHF), cardiovascular (CV) and all-cause mortality, and progression of renal impairment was investigated using multivariate proportional-hazards models.
Results
In univariate association, ALT was reciprocally predictive, and ALP was positively predictive, of all adjudicated outcomes; γGT also was directly associated with CV-but not renal-outcomes. In multivariate models including all 5 LFTs and 19 potential clinical confounders, ALT was independently associated with lower, and γGT with higher, CV outcomes risk. Canagliflozin treatment significantly reduced ALT, AST, and γGT over time. In a fully adjusted model including updated LFT levels and treatment, γGT was independently associated with CV and all-cause mortality, ALP with renal dysfunction progression, and canagliflozin treatment with significant reduction in HHF and renal risk.
Conclusions
Higher γGT levels are top LFT markers of risk of HHF and death in patients with diabetes and high CV risk, while ALT are protective. Canagliflozin lowers the risk of HHF and renal damage independently of LFTs and potential confounders.

© 2022. The Author(s).

Cardiovasc Diabetol: 04 Jul 2022; 21:127
Ferrannini G, Rosenthal N, Hansen MK, Ferrannini E
Cardiovasc Diabetol: 04 Jul 2022; 21:127 | PMID: 35787704
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Abstract

A novel 6-metabolite signature for prediction of clinical outcomes in type 2 diabetic patients undergoing percutaneous coronary intervention.

Wang XB, Cui NH, Liu X
Background
Outcome prediction tools for patients with type 2 diabetes mellitus (T2DM) undergoing percutaneous coronary intervention (PCI) are lacking. Here, we developed a machine learning-based metabolite classifier for predicting 1-year major adverse cardiovascular events (MACEs) after PCI among patients with T2DM.
Methods
Serum metabolomic profiling was performed in a nested case-control study of 108 matched pairs of patients with T2DM occurring and not occurring MACEs at 1 year after PCI, then the matched pairs were 1:1 assigned into the discovery and internal validation sets. External validation was conducted using targeted metabolite analyses in an independent prospective cohort of 301 patients with T2DM receiving PCI. The function of candidate metabolites was explored in high glucose-cultured human aortic smooth muscle cells (HASMCs).
Results
Overall, serum metabolome profiles differed between diabetic patients with and without 1-year MACEs after PCI. Through VSURF, a machine learning approach for feature selection, we identified the 6 most important metabolic predictors, which mainly targeted the nicotinamide adenine dinucleotide (NAD+) metabolism. The 6-metabolite model based on random forest and XGBoost algorithms yielded an area under the curve (AUC) of ≥ 0.90 for predicting MACEs in both discovery and internal validation sets. External validation of the 6-metabolite classifier also showed good accuracy in predicting MACEs (AUC 0.94, 95% CI 0.91-0.97) and target lesion failure (AUC 0.89, 95% CI 0.83-0.95). In vitro, there were significant impacts of altering NAD+ biosynthesis on bioenergetic profiles, inflammation and proliferation of HASMCs.
Conclusion
The 6-metabolite model may help for noninvasive prediction of 1-year MACEs following PCI among patients with T2DM.

© 2022. The Author(s).

Cardiovasc Diabetol: 04 Jul 2022; 21:126
Wang XB, Cui NH, Liu X
Cardiovasc Diabetol: 04 Jul 2022; 21:126 | PMID: 35788230
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Impact:

This program is still in alpha version.